Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
Doc. No.: FDISM/FDIC/GDL/002  Revision Date: 03/10/2022  Review Due Date: 20/10/2025  
Revision No.: 1  Approval Date: 19/10/2022  Effective Date: 21/10/2022  
  
 
 
 
 
 
 
 
 
 
 
 
GUIDELINES ON GOOD MANUFACTURING PRACTICE S 
FOR MEDICAL PRODUCTS_ANNEXES  
 
 
 
 
 
 
 
 
 
 
OCTOBER , 2022
Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
Doc. No.: FDISM/FDIC/GDL/002  Revision  Date: 03/10/2022  Review Due Date: 20/10/2025  
Revision No.: 1  Approval Date: 19/10/2022  Effective Date: 21/10/2022  
Page 2 of 234  FOREWORD  
 
 
 
 
 
  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
Doc. No.: FDISM/FDIC/GDL/002  Revision  Date: 03/10/2022  Review Due Date: 20/10/2025  
Revision No.: 1  Approval Date: 19/10/2022  Effective Date: 21/10/2022  
Page 3 of 234  GUIDELINES  DEVELOPMENT  HISTORY   
 
DRAFT ZERO   18/08/ 2020  
ADOPTION BY RWANDA FDA  18/08/2020  
STAKEHOLDERS CONSULTATION  25/08/ 2020  
ADOPTION OF STAKEHOLDERS’ COMMENTS  28/08/2020  
DATE FOR COMING INTO EFFECT  21/10/2022  
 
DOCUMENT REVISION HISTORY  
 
Date of revision  Revision 
number  Changes made and/or reasons  for revision  
18/08/2020  0 First Issue  
03/10/2022  1 1. Changed the title of the Guideline; 
replaced the word Pharmaceutical with 
medical product  
2. Removed Annex 18: GMP Guide for 
Active Pharmaceutical Ingredients / This 
is because it was a blank page and there 
is already a Guideline on GMP for API 
manufacturers  
3. Changed the names of Signers  of this 
document/ This is because the authorized 
individuals responsible for signing this 
document have changed since the last 
revision.  
4. Annex16: “Qualified Person and Batch 
release” Added information under this 
annex that was missing in the last 
revision. / this is as per recommendation 
of WHO  
5. Annex 21: “ Model Guidance for the 
storage and transport of time and 
temperature sensitive pharma ceutical 
products / this annex was added to 
incorporate recommendations of WHO  
 
 
 
  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
Doc. No.: FDISM/FDIC/GDL/002  Revision  Date: 03/10/2022  Review Due Date: 20/10/2025  
Revision No.: 1  Approval Date: 19/10/2022  Effective Date: 21/10/2022  
Page 4 of 234  TABLE OF CONTENTS  
 
FOREWORD  ................................ ................................ ................................ ................................ ....... 2 
GUIDELINES  DEVELOPMENT  HISTORY  ................................ ................................ .....................  3 
DOCUMENT REVISION HISTORY  ................................ ................................ ................................ . 3 
TABLE OF CONTENTS  ................................ ................................ ................................ ....................  4 
ACRONYMS AND ABBREVIATIONS  ................................ ................................ ..........................  16 
GLOSSARY / Definitions  ................................ ................................ ................................ .................  17 
ANNEX 1: MANUFACTURE OF STERILE MEDICINAL PRODUCTS PRINCIPLE  ................  22 
1.1 GENERAL  ................................ ................................ ................................ .............................  22 
1.2 CLEAN ROOM AND CLEAN AIR DEVICE CLASSIFICATION  ................................ .... 23 
1.3 CLEAN ROOM AND CLEAN AIR DEVICE MONITORING  ................................ ...........  24 
1.4 ISOLATOR TECHNOLOGY  ................................ ................................ ...............................  26 
1.5 BLOW/FILL/SEAL TECHNOLOGY  ................................ ................................ ...................  27 
1.6 TERMINALLY STERILISED PRODUCTS  ................................ ................................ ........  27 
1.7 ASEPTIC PREPARATION  ................................ ................................ ................................ ... 27 
1.8 PERSONNEL  ................................ ................................ ................................ ........................  28 
1.9 PREMISES  ................................ ................................ ................................ ............................  29 
1.10  EQUIPMENT  ................................ ................................ ................................ ........................  30 
1.11  SANITATION  ................................ ................................ ................................ .......................  31 
1.12  PROCESSING  ................................ ................................ ................................ .......................  31 
1.13  STERILISATION  ................................ ................................ ................................ ..................  33 
1.14  STERILISATION BY HEAT  ................................ ................................ ................................  33 
1.15  MOIST HEAT  ................................ ................................ ................................ .......................  34 
1.16  DRY HEAT  ................................ ................................ ................................ ...........................  34 
1.17  STERILISATION BY RADIATION  ................................ ................................ ....................  34 
1.18  STERILISATION WITH ETHYLENE OXIDE  ................................ ................................ ... 35 
1.19  FILTRATION OF MEDICINAL PRODUCTS WHICH CANNOT BE STERILISED IN 
THEIR FINAL CONTAINER  ................................ ................................ ...............................  35 
1.20  FINISHING OF STERILE PRODUCTS ................................ ................................ ...............  36 
1.21  QUALITY CONTROL  ................................ ................................ ................................ ..........  37 
ANNEX 2: MA NUFACTURE OF BIOLOGICAL MEDICINAL SUBSTANCES AND 
PRODUCTS FOR HUMAN USE  ................................ ................................ .........................  38 
SCOPE  ................................ ................................ ................................ ................................ ...............  38 
PRINCIPLE  ................................ ................................ ................................ ................................ ....... 42 
PART A. GENERAL GUIDANCE PERSONNEL ................................ ................................ ...........  43 
2.1 PREMISE AND EQUIPMENT  ................................ ................................ .............................  43 
2.2 ANIMALS  ................................ ................................ ................................ .............................  45 
2.3 DOCUMENTATION  ................................ ................................ ................................ ............  46 
2.4 PRODUCTION  ................................ ................................ ................................ ......................  47 
2.5 STARTING MATERIALS  ................................ ................................ ................................ .... 47 
2.6 SEED LOT AND CELL BANK SYSTEM  ................................ ................................ ...........  49 Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
Doc. No.: FDISM/FDIC/GDL/002  Revision  Date: 03/10/2022  Review Due Date: 20/10/2025  
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Page 5 of 234  2.7 OPERATING PRINCIPLES  ................................ ................................ ................................ . 51 
2.8 QUALITY CONTROL  ................................ ................................ ................................ ..........  52 
PART B. SPECIFIC GUIDANCE ON SELECTED PRODUCT TYPES  ................................ ........  53 
2.9 ANIMAL SOURCED PRODUCTS  ................................ ................................ ......................  53 
2.10  B2. ALLERGEN PRODUCTS  ................................ ................................ ..............................  55 
2.11  B.3. ANIMAL IMMUNOSERA PRODUCTS  ................................ ................................ ...... 55 
2.12  B.4. VACCINES  ................................ ................................ ................................ ....................  55 
2.13  B.5. RECOMBINANT PRODUCTS  ................................ ................................ .....................  56 
2.14  B.6. MONOCLONAL ANTIBODY PRODUCTS  ................................ ................................  56 
2.15  B.7. TRANSGENIC ANIMAL PRODUCTS  ................................ ................................ ........  56 
2.16  B8. TRANSGENIC PLANT PRODUCTS  ................................ ................................ ............  57 
2.17  B9. GENE THERAPY PRODUCTS  ................................ ................................ .....................  57 
2.18  B.10. SOMATIC AND XENOGENEIC CELL THERAPY PRODUCTS AND TISSUE 
ENGINEERED PRODUCTS  ................................ ................................ ................................  59 
GLOSSARY TO ANNEX 2  ................................ ................................ ................................ ..............  60 
ANN EX 3: MANUFACTURE OF RADIOPHARMACEUTICALS PRINCIPLE  ..........................  64 
INTRODUCTION  ................................ ................................ ................................ .............................  64 
Clinical Trials  ................................ ................................ ................................ ................................ .... 65 
3.1 QUALITY ASSURANCE  ................................ ................................ ................................ ..... 65 
3.2 PERSONNEL  ................................ ................................ ................................ ........................  66 
3.3 PREMISES AND EQUIPMENT  ................................ ................................ ...........................  66 
Sterile production  ................................ ................................ ................................ ...............................  67 
3.4 DOCUMENTATION  ................................ ................................ ................................ ............  67 
3.5 PRODUCTION  ................................ ................................ ................................ ......................  68 
3.6 QUALITY CONTROL  ................................ ................................ ................................ ..........  68 
3.7 REFERENCE AND RETENTION SAMPLES ................................ ................................ ..... 69 
3.8 DISTRIBUTION ................................ ................................ ................................ ....................  69 
GLOSSARY  ................................ ................................ ................................ ................................ ...... 69 
ANNEX 4: MANUFACTURE OF VETERINARY MEDICINAL PRODUCTS OTHER THAN 
IMMUNOLOGICALS  ................................ ................................ ................................ ...........  71 
4.1 MANUFACTURE OF PREMIXES FOR MEDICATED FEEDING STUFFS  ...................  71 
4.2 THE MANUFACTURE OF ECTOPARASITICIDES  ................................ .........................  71 
4.3 THE MANUFACTURE OF VETERINARY MEDICINAL PRODUCTS CONTAINING 
PENICILLINS  ................................ ................................ ................................ .......................  72 
RETENTION OF SAMPLES (POINT 1.4. VIII AND POINT 6.14.)  ................................ ..............  72 
STERILE VETERINARY MEDICINAL PRODUCTS  ................................ ................................ ... 72 
ANNEX 5: MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL PRODUCTS 
PRINCIPLE  ................................ ................................ ................................ ...........................  73 
1.1 PERSONNEL  ................................ ................................ ................................ ........................  73 
1.2 PREMISES  ................................ ................................ ................................ ............................  74 
1.3 EQUIPMENT  ................................ ................................ ................................ ........................  76 
1.4 ANIMALS AND ANIMAL HOUSES  ................................ ................................ ..................  77 Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
Doc. No.: FDISM/FDIC/GDL/002  Revision  Date: 03/10/2022  Review Due Date: 20/10/2025  
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Page 6 of 234  1.5 DISINFECTION - WASTE DISPOSAL  ................................ ................................ ...............  77 
1.6 PRODUCTION  ................................ ................................ ................................ ......................  78 
STARTING MATERIALS  ................................ ................................ ................................ ................  78 
MEDIA  ................................ ................................ ................................ ................................ ..............  78 
SEED LOT AND CELL BANK SYSTEM  ................................ ................................ .......................  78 
OPERATING PRINCIPLES  ................................ ................................ ................................ .............  79 
1.7 QUALITY CONTROL  ................................ ................................ ................................ ..........  81 
ANNEX 6: MANUFACTURE OF MEDICINAL GASES PRINCIPLE  ................................ .........  82 
MANUFACTURE OF ACTIVE SUBSTANCE GASES  ................................ ................................ . 82 
MANUFACTURE OF MEDICINAL GASES  ................................ ................................ ..................  83 
6.1 PERSONNEL  ................................ ................................ ................................ ........................  83 
6.2 PREMISES AND EQUIPMENT  ................................ ................................ ...........................  83 
Premises  ................................ ................................ ................................ ................................ .............  83 
Equipment  ................................ ................................ ................................ ................................ ..........  84 
6.3 DOCUMENTATION  ................................ ................................ ................................ ............  85 
6.4 PRODUCTION  ................................ ................................ ................................ ......................  86 
Transfers  and deliveries of cryogenic and liquefied gas  ................................ ................................ ... 86 
Filling and labeling of cylinders and mobile cryogenic vessels  ................................ ........................  86 
6.5 QUALITY CONTROL  ................................ ................................ ................................ ..........  88 
6.6 TRANSPORTATION OF PACKAGED GASES  ................................ ................................ . 89 
GLOSSARY  ................................ ................................ ................................ ................................ ...... 89 
ANNEX 7: MANUFACTURE OF HERBAL MEDICINAL PRODUCTS PRINCIPLE  ................  92 
1.1 PREMISES  ................................ ................................ ................................ ............................  93 
Storage areas  ................................ ................................ ................................ ................................ ...... 93 
Production area  ................................ ................................ ................................ ................................ .. 94 
1.2 EQUIPMENT  ................................ ................................ ................................ ........................  94 
1.3 DOCUMENTATION  ................................ ................................ ................................ ............  94 
Specifications for starting materials  ................................ ................................ ................................ .. 94 
Processing instructions  ................................ ................................ ................................ ......................  95 
1.4 QUALITY CONTROL  ................................ ................................ ................................ ..........  95 
Sampling  ................................ ................................ ................................ ................................ ............  95 
ANNEX 8: SAMPLING OF STARTING AND PACKAGING MATERIALS PRINCIPLE ..........  97 
8.1 PERSONNEL  ................................ ................................ ................................ ........................  97 
8.2 STARTING MATERIALS  ................................ ................................ ................................ .... 97 
8.3 PACKAGING MATERIAL  ................................ ................................ ................................ .. 98 
ANNEX 9: MANUFACTURE OF LIQUIDS, CREAMS AND OINTMENTS PRINCIPLE  .........  99 
1.1 PREMISES AND EQUIPMENT  ................................ ................................ ...........................  99 
1.2 PRODUCTION  ................................ ................................ ................................ ......................  99 
ANNEX 10: MANUFACTURE OF PRESSURISED METERED DOSE AEROSOL 
PREPARATIONS FOR INHALATION  ................................ ................................ .............  100 
PRINCIPLE  ................................ ................................ ................................ ................................ ..... 100 
GENERAL  ................................ ................................ ................................ ................................ ....... 100 Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
Doc. No.: FDISM/FDIC/GDL/002  Revision  Date: 03/10/2022  Review Due Date: 20/10/2025  
Revision No.: 1  Approval Date: 19/10/2022  Effective Date: 21/10/2022  
Page 7 of 234  10.1  PREMISES AND EQUIPMENT  ................................ ................................ .........................  100 
10.2  PRODUCTION AND QUALITY CONTROL  ................................ ................................ ... 100 
ANNEX 11: COMPUTERIZED SYSTEMS  ................................ ................................ ..................  102 
PRINCIPLE  ................................ ................................ ................................ ................................ ..... 102 
GENERAL  ................................ ................................ ................................ ................................ ....... 102 
1.1 Risk Management  ................................ ................................ ................................ ................  102 
1.2 Personnel  ................................ ................................ ................................ ..............................  102 
1.3 Suppliers and Service Providers  ................................ ................................ ..........................  102 
PROJECT PHASE  ................................ ................................ ................................ ...........................  103 
OPERATIONAL PHASE  ................................ ................................ ................................ ................  103 
1. Data  ................................ ................................ ................................ ................................ ...... 103 
2. Accuracy Checks  ................................ ................................ ................................ .................  103 
3. Data Storage  ................................ ................................ ................................ .........................  103 
4. Printouts  ................................ ................................ ................................ ...............................  104 
5. Audit Trails  ................................ ................................ ................................ ..........................  104 
6. Change and Configuration Management  ................................ ................................ .............  104 
7. Periodic Evaluation  ................................ ................................ ................................ ..............  104 
8. Security  ................................ ................................ ................................ ................................  104 
9. Incident Management ................................ ................................ ................................ ...........  104 
10. Electronic Signature  ................................ ................................ ................................ .............  105 
11. Batch release  ................................ ................................ ................................ ........................  105 
12. Business Continuity  ................................ ................................ ................................ .............  105 
13. Archiving  ................................ ................................ ................................ .............................  105 
GLOSSARY  ................................ ................................ ................................ ................................ .... 105 
ANNEX 12: USE OF IONISING RADIATION IN THE MANUFACTURE OF MEDICINAL 
PRODUCTS  ................................ ................................ ................................ .........................  107 
INTRODUCTION  ................................ ................................ ................................ ...........................  107 
12.1  RESPONSIBILITIES  ................................ ................................ ................................ ..........  107 
12.2  DOSIMETRY  ................................ ................................ ................................ ......................  107 
12.3  VALIDATION OF THE PROCESS  ................................ ................................ ...................  108 
12.4  COMMISSIONING OF THE PLANT  ................................ ................................ ................  108 
12.5  PREMISES  ................................ ................................ ................................ ..........................  110 
12.6  PROCESSING  ................................ ................................ ................................ .....................  111 
12.7  DOCUMENTATION  ................................ ................................ ................................ ..........  111 
12.8  MICROBIOLOGICAL MONITORING  ................................ ................................ .............  112 
ANNEX 13: MANUFACTURE OF INVESTIGATIONAL MEDICINAL PRODUCTS  .............  113 
PRINCIPLE  ................................ ................................ ................................ ................................ ..... 113 
1. NON -INVESTIGATIONAL MEDICINAL PRODUCT  ................................ ....................  113 
2. MANUFACTURING AUTHORIZATION AND RECONSTI TUTION  ...........................  114 
GLOSSARY  ................................ ................................ ................................ ................................ .... 114 
13.1  QUALITY MANAGEMENT  ................................ ................................ ..............................  115 
13.2  PERSONNEL  ................................ ................................ ................................ ......................  116 Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
Doc. No.: FDISM/FDIC/GDL/002  Revision  Date: 03/10/2022  Review Due Date: 20/10/2025  
Revision No.: 1  Approval Date: 19/10/2022  Effective Date: 21/10/2022  
Page 8 of 234  13.3  PREMISES AND EQUIPMENT  ................................ ................................ .........................  116 
13.4  DOCUMENTATION  ................................ ................................ ................................ ..........  116 
Specifications and instructions  ................................ ................................ ................................ ........  116 
Order  ……………………………………………………………………………………………..116 
Product specification file  ................................ ................................ ................................ .................  117 
Manufacturing formulae and processing instructions  ................................ ................................ ...... 117 
Packaging instructions  ................................ ................................ ................................ .....................  117 
Processing, testing and packaging batch records  ................................ ................................ .............  117 
13.5  PRODUCTION  ................................ ................................ ................................ ....................  118 
Packaging materials  ................................ ................................ ................................ .........................  118 
Manufacturing operations  ................................ ................................ ................................ ................  118 
Principles applicable to comparator product  ................................ ................................ ...................  118 
Blinding operations  ................................ ................................ ................................ ..........................  119 
Randomization code  ................................ ................................ ................................ ........................  119 
Packaging  ................................ ................................ ................................ ................................ .........  119 
Labelling  ................................ ................................ ................................ ................................ ..........  119 
13.6  QUALITY CONTROL  ................................ ................................ ................................ ........  121 
13.7  RELEASE OF BATCHES  ................................ ................................ ................................ ... 122 
13.8  SHIPPING ................................ ................................ ................................ ............................  123 
13.9  COMPLAINTS  ................................ ................................ ................................ ....................  124 
13.10  RECALLS AND RETURNS  ................................ ................................ ...............................  124 
Recalls  ……………………………………………………………………………………………. 124 
Returns  ................................ ................................ ................................ ................................ .............  124 
13.11  DESTRUCTION  ................................ ................................ ................................ ..................  124 
13.12  SUMMARY OF LABELING DETAILS  ................................ ................................ ............  125 
GENERAL CASE  ................................ ................................ ................................ ...........................  126 
PRIMARY PACKAGE  ................................ ................................ ................................ ...................  126 
ANNEX 14: MANUFACTURE OF MEDICINAL PRODUCTS DERIVED FROM HUMAN 
BLOOD OR PLASMA  ................................ ................................ ................................ ........  127 
GLOSSARY  ................................ ................................ ................................ ................................ .... 127 
Fractionation, fractionation plant  ................................ ................................ ................................ ..... 127 
SCOPE  ................................ ................................ ................................ ................................ .............  128 
PRINCIPLES  ................................ ................................ ................................ ................................ ... 129 
14.1  QUALITY MANAGEMENT  ................................ ................................ ..............................  130 
14.2  TRACEABILITY AND POST COLLECTION MEASURES ................................ ............  131 
14.3  PREMISES AND EQUIPMENT  ................................ ................................ .........................  133 
14.4  MANUFACTURING  ................................ ................................ ................................ ..........  133 
Starting material  ................................ ................................ ................................ ...............................  133 
Certification/release of plasma for fractionation as starting material  ................................ ..............  134 
Processing of plasma for fractionation  ................................ ................................ ............................  134 
14.5  QUALITY CONTROL  ................................ ................................ ................................ ........  135 
14.6  RELEASE OF INTERMEDIAT E AND FINISHED PRODUCTS  ................................ .... 135 Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
Doc. No.: FDISM/FDIC/GDL/002  Revision  Date: 03/10/2022  Review Due Date: 20/10/2025  
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Page 9 of 234  14.7  RETENTION OF PLASMA POOL SAMPLES  ................................ ................................ . 136 
14.8  DISPOSAL OF WASTE ................................ ................................ ................................ ...... 136 
ADDENDUM  ................................ ................................ ................................ ................................ .. 136 
Addendum  ................................ ................................ ................................ ................................ ........  136 
ANNEX 15: QUALIFICATION AND VALIDATION  ................................ ................................ .. 141 
PRINCIPLE  ................................ ................................ ................................ ................................ ..... 141 
GENERAL  ................................ ................................ ................................ ................................ ....... 141 
15.1  ORGANISING AND PLANNING FOR QUALIFICATION AND VALIDATION.  ........  141 
15.2  DOCUMENTATION INCLUDING VMP ................................ ................................ ..........  142 
15.3  QUALIFICATION STAGES FOR EQUIPMENT, FACILITIES, UTILITIES AND 
SYSTEMS. ................................ ................................ ................................ ...........................  143 
User requirements  specification (URS)  ................................ ................................ ...........................  143 
Design qualification (DQ)  ................................ ................................ ................................ ...............  143 
Factory accep tance testing (FAT) /Site acceptance testing (SAT)  ................................ ..................  143 
Installation qualification (IQ)  ................................ ................................ ................................ ..........  143 
Operational qualification (OQ)  ................................ ................................ ................................ ........  144 
Performance qualification (PQ)  ................................ ................................ ................................ ....... 144 
15.4  RE-QUALIFICATION  ................................ ................................ ................................ ........  144 
15.5  PROCESS VALIDATION  ................................ ................................ ................................ .. 144 
General  ................................ ................................ ................................ ................................ .............  144 
Validation.  ................................ ................................ ................................ ................................ ....... 145 
Concurrent validation  ................................ ................................ ................................ ......................  146 
Traditional process validation  ................................ ................................ ................................ ..........  146 
Continuous process verification  ................................ ................................ ................................ ...... 147 
Hybrid approach  ................................ ................................ ................................ ..............................  147 
Ongoing Process Verification during Lifecycle  ................................ ................................ ..............  148 
15.6  VERIFICATION OF TRANSPORTATION  ................................ ................................ ....... 148 
15.7  VALIDATION OF PACKAGING  ................................ ................................ ......................  149 
15.8  QUALIFICATION OF UTILITIES  ................................ ................................ ....................  149 
15.9  VALIDATION OF TEST METHODS  ................................ ................................ ................  149 
15.10  CLEANING VALIDATION  ................................ ................................ ...............................  149 
15.11  CHANGE CONTROL  ................................ ................................ ................................ .........  151 
GLOSSARY  ................................ ................................ ................................ ................................ .... 151 
ANNEX 16: QUALIFIED PERSON AND BATCH RELEASE  ................................ ....................  155 
SCOPE  ................................ ................................ ................................ ................................ .............  155 
1.1 THE PROCESS OF CERTIFICATION  ................................ ................................ ..............  155 
GMP Guide, Part I.  ................................ ................................ ................................ ..........................  158 
1.2 RELYING ON GMP ASSESSMENTS BY THIRD PARTIES, E.G. AUDITS  .................  161 
1.3 HANDLING OF UNEXPECTED DEVIATIONS  ................................ ..............................  161 
GLOSSARY  ................................ ................................ ................................ ................................ .... 162 
APPENDIX I  ................................ ................................ ................................ ................................ ... 163 
APPENDIX II  ................................ ................................ ................................ ................................ .. 164 Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
Doc. No.: FDISM/FDIC/GDL/002  Revision  Date: 03/10/2022  Review Due Date: 20/10/2025  
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Page 10 of 234  ANNEX 17: PARAMETRIC RELEASE  ................................ ................................ ........................  164 
PRINCIPLE  ................................ ................................ ................................ ................................ ..... 164 
17.1  PARAMETRIC RELEASE  ................................ ................................ ................................ . 164 
17.2  PARAMETRIC RELEASE FOR STERILE PRODUCTS  ................................ .................  165 
ANNEX 18: REFERENCE AND RETENTION SAMPLES  ................................ .........................  167 
SCOPE  ................................ ................................ ................................ ................................ .............  167 
PRINCIPLE  ................................ ................................ ................................ ................................ ..... 167 
1.1 DURATION OF STORAGE  ................................ ................................ ...............................  168 
1.2 SIZE OF REFERENCE AND RETENTION SAMPLES  ................................ ...................  168 
1.3 STORAGE CONDITIONS  ................................ ................................ ................................ .. 168 
1.4 WRITTEN AGREEMENTS  ................................ ................................ ................................  169 
1.5 REFERENCE SAMPLES – GENERAL POINTS  ................................ ..............................  169 
1.6 RETENTION SAMPLES – GENERAL POINTS  ................................ ..............................  169 
1.7 REFERENCE AND RETENTION SAMPLES FOR PARALLEL IMPORTED / 
PARALLEL DISTRIBUTED PRODUCTS  ................................ ................................ ........  169 
1.8 REFERENCE AND RETENTION SAMPLES IN THE CASE OF CLOSEDOWN OF A 
MANUFACTURER  ................................ ................................ ................................ ............  170 
ANNEX 19: QUALITY RISK MANAGEMENT  ................................ ................................ ..........  171 
FOREWORD AND SCOPE OF APPLICATIONS  ................................ ................................ ........  171 
INTRODUCTION  ................................ ................................ ................................ ...........................  171 
SCOPE  ................................ ................................ ................................ ................................ .............  172 
PRINCIPLES OF QUALITY RISK MANAGEMENT  ................................ ................................ .. 172 
19.1  GENERAL QUALITY RISK MANAGEMENT PROCESS  ................................ ..............  173 
Responsibilities  ................................ ................................ ................................ ................................  173 
Decision makers should:  ................................ ................................ ................................ ..................  173 
Initiating a Quality Risk Management Process  ................................ ................................ ...............  173 
Risk Assessment  ................................ ................................ ................................ ..............................  174 
Risk Control  ................................ ................................ ................................ ................................ ..... 175 
Risk control might focus on the following questions:  ................................ ................................ ..... 175 
Risk Communication  ................................ ................................ ................................ .......................  175 
Risk Review  ................................ ................................ ................................ ................................ ..... 176 
19.2  RISK MANAGEMENT METHODOLOGY  ................................ ................................ ...... 176 
19.3  INTEGRATION OF QUALITY RISK MANAGEMENT INTO INDUSTRY AND 
REGULATORY OPERATIONS ................................ ................................ .........................  177 
Examples for industry and regulatory operations (see Annex II):  ................................ ...................  177 
Examples for industry operati ons and activities (see Annex II):  ................................ .....................  177 
Examples for regulatory operations (see Annex II):  ................................ ................................ ........  177 
GLOSSARY  ................................ ................................ ................................ ................................ .... 178 
REFERENCES  ................................ ................................ ................................ ................................  180 
APPENDIX I: RISK MANAGEMENT METHODS AND TOOLS  ................................ ..............  180 
1. Basic Risk Management Facilitation Methods  ................................ ................................ .... 180 
2. Failure Mode Effects Analysis (FMEA)  ................................ ................................ ..............  181 Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 11 of 234  Potential Areas of Us e(s) ................................ ................................ ................................ .................  181 
3. Failure Mode, Effects and Criticality Analysis (FMECA)  ................................ ..................  181 
Potential Areas of Use(s)  ................................ ................................ ................................ .................  181 
4. Fault Tree Analysis (FTA)  ................................ ................................ ................................ ... 181 
Potential Areas of Use(s)  ................................ ................................ ................................ .................  182 
5. Hazard Analysis and Critical Control Points (HACCP)  ................................ ......................  182 
HACCP consists of the following seven steps:  ................................ ................................ ...............  182 
Potential Areas of Use(s)  ................................ ................................ ................................ .................  182 
6. Hazard Operability Analysis (HAZOP)  ................................ ................................ ...............  182 
Potential Areas of Use( s) ................................ ................................ ................................ .................  183 
7. Preliminary Hazard Analysis (PHA)  ................................ ................................ ...................  183 
Potential Areas of Us e(s) ................................ ................................ ................................ .................  183 
8. Risk Ranking and Filtering  ................................ ................................ ................................ .. 183 
Potential Areas of Use(s)  ................................ ................................ ................................ .................  183 
9. Supporting Statistical Tools  ................................ ................................ ................................ . 184 
APPENDIX II: POTENTIAL APPLICATIONS FOR QUALITY RISK MANAGEMENT  .........  184 
1. Quality Risk Management as P art of Integrated Quality Management  ...............................  184 
Documentation  ................................ ................................ ................................ ................................ . 184 
Training and education  ................................ ................................ ................................ ....................  184 
Quality defects  ................................ ................................ ................................ ................................ . 185 
Auditing/Inspection  ................................ ................................ ................................ .........................  185 
Periodic review  ................................ ................................ ................................ ................................  185 
Continual improvement  ................................ ................................ ................................ ...................  185 
2. Quality Risk Management as Part of Regulatory Operations Inspection and assessment 
activitie s ................................ ................................ ................................ ...............................  185 
To evaluate impact of proposed variations or changes  ................................ ................................ .... 186 
3. Quality Risk Management as Part of Development  ................................ .............................  186 
To decrease variability of quality attribut es: ................................ ................................ ...................  186 
4. Quality Risk Management for Facilities, Equipment and Utilities  ................................ ...... 186 
Design of facility / equipment  ................................ ................................ ................................ .........  186 
Hygiene aspects in facilities  ................................ ................................ ................................ ............  187 
Qualification of facility/equipment/utilities  ................................ ................................ ....................  187 
Cleaning of equipment and environmental control  ................................ ................................ .........  187 
5. Quality Risk Management as Part of Materials Management  ................................ .............  187 
Starting material  ................................ ................................ ................................ ...............................  188 
Use of materials  ................................ ................................ ................................ ...............................  188 
Storage, logistics and distribution conditions  ................................ ................................ ..................  188 
6. Quality Risk Management as Part of Production  ................................ ................................ . 188 
Validation  ................................ ................................ ................................ ................................ ........  188 
In-process sampling & testing  ................................ ................................ ................................ .........  188 
Productio n planning  ................................ ................................ ................................ .........................  188 
7. Quality Risk Management as Part of Laboratory Control and Stability Studies  .................  189 Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 12 of 234  Out of specification results  ................................ ................................ ................................ ..............  189 
8. Quality Risk Management as Part of Packaging and Labelling Des ign of packages  ..........  189 
GLOSSARY  ................................ ................................ ................................ ................................ .... 189 
ANNEX 21: MODEL GUIDANCE FOR THE STOR AGE AND TRANSPORT OF TIME AND 
TEMPERATURE -SENSITIVE PHARMACEUTICAL PRODUCTS.  ..............................  196 
Background  ................................ ................................ ................................ ................................ ...... 196 
Key to conventions used  ................................ ................................ ................................ ..................  196 
GLOSSARY  ................................ ................................ ................................ ................................ .... 197 
1. Importation  ................................ ................................ ................................ ...........................  199 
a. Port handling and customs clearance  ................................ ................................ ...................  199 
i. Port of entry  ................................ ................................ ................................ .........................  199 
ii. Ofﬂoading  ................................ ................................ ................................ ............................  200 
iii. Temporary storage at port of entry  ................................ ................................ ......................  200 
iv. Customs clearance  ................................ ................................ ................................ ...............  200 
2. WAREHOUSING SITES  ................................ ................................ ................................ .... 200 
a. Site layout  ................................ ................................ ................................ ............................  200 
i. Natural hazards  ................................ ................................ ................................ ....................  200 
b. Site access  ................................ ................................ ................................ ............................  201 
c. Site security  ................................ ................................ ................................ ..........................  201 
d. Site cleanliness  ................................ ................................ ................................ .....................  201 
3. STORAGE BUILDINGS ................................ ................................ ................................ ..... 201 
a. Construction standards  ................................ ................................ ................................ .........  201 
b. Accommodation and layout  ................................ ................................ ................................ . 202 
4. LOADING AND RECEIVING BAYS  ................................ ................................ ...............  202 
a. Loading bays  ................................ ................................ ................................ ........................  202 
b. Receiving bays  ................................ ................................ ................................ .....................  202 
5. GOODS ASSEMBLY AND QUARANTINE AREAS  ................................ ......................  202 
a. Goods assembly areas  ................................ ................................ ................................ ..........  202 
b. Holding area for incoming goods  ................................ ................................ ........................  202 
c. Quarantine area  ................................ ................................ ................................ ....................  203 
6. ENVIRONMENTAL CONTROL OF ANCILLARY AREAS  ................................ ...........  203 
7. BUILDING SECURITY  ................................ ................................ ................................ ...... 203 
a. General building security  ................................ ................................ ................................ ..... 203 
b. Controlled and hazardous substances areas  ................................ ................................ .........  204 
8. FIRE PROTECTION  ................................ ................................ ................................ ...........  204 
a. Fire protection equipment  ................................ ................................ ................................ .... 204 
b. Fire prevention, detection and control procedures  ................................ ...............................  204 
9. BUILDING HYGIENE  ................................ ................................ ................................ ....... 204 
a. Building cleanliness  ................................ ................................ ................................ .............  204 
b. Pest control ................................ ................................ ................................ ...........................  205 
10. POWER SUPPLY  ................................ ................................ ................................ ................  205 
a. Uninterrupted power supply  ................................ ................................ ................................  205 Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 13 of 234  b. Power failure contingency plan  ................................ ................................ ...........................  206 
c. Building Maintenance  ................................ ................................ ................................ ..........  206 
11. TEMPERATURE -CONTROLLED STORAGE  ................................ ................................ . 206 
a. Normative references  ................................ ................................ ................................ ...........  206 
b. Storage capacity of temperature -controlled stores  ................................ ...............................  206 
c. Temperature -controlled storage  ................................ ................................ ...........................  207 
d. Temperature -controlled storage for controlled and hazard ous products  .............................  208 
12. TEMPERATURE AND HUMIDITY CONTROL AND MONITORING IN STORAGE . 208 
a. Temperature control  ................................ ................................ ................................ .............  208 
b. Temperature monitoring  ................................ ................................ ................................ ...... 208 
c. Humidity control  ................................ ................................ ................................ ..................  209 
d. Humidity monitoring  ................................ ................................ ................................ ...........  210 
13. ALARM SYSTEMS  ................................ ................................ ................................ ............  210 
a. Temperature alarms  ................................ ................................ ................................ .............  210 
b. Temperature -controlled rooms, cold rooms and freezer rooms  ................................ ...........  210 
c. Refrigerators and freezers  ................................ ................................ ................................ .... 211 
d. Humidity alarms ................................ ................................ ................................ ...................  211 
14. QUALICATION OF TEMPERATURE -CONTROLLED STORES  ................................ .. 211 
15. CLEANLINESS OF TEMPERATURE -CONTROLLED STORES ................................ ... 212 
a. Refrigeration equipment maintenance  ................................ ................................ .................  212 
16. CALIBRATION AND VERIFICATION OF CONTROL AND MONITORING 
DEVICES  ................................ ................................ ................................ .............................  212 
a. Calibration of temperature control and monitoring devices  ................................ ................  212 
b. Calibration of humidity control and monitoring devices  ................................ .....................  213 
c. Alarm equipment veriﬁcation  ................................ ................................ ..............................  213 
17. MATERIALS HANDLING ................................ ................................ ................................ . 213 
a. Materials handling equipment ................................ ................................ ..............................  213 
18. TRANSPORT AND DELIVERY ................................ ................................ ........................  213 
a. Normative references  ................................ ................................ ................................ ...........  213 
b. Product stability proﬁles  ................................ ................................ ................................ ...... 214 
c. Transport route proﬁling and qualiﬁcation  ................................ ................................ ..........  214 
19. TEMPERATURE -CONTROLLED TRANSPORT  ................................ ............................  214 
a. Air and sea transport  ................................ ................................ ................................ ............  214 
b. Temperature -controlled road vehicles operated by common carriers  ................................ .. 215 
c. Temperature -controlled  road vehicles generally  ................................ ................................ . 215 
d. Transport of controlled TTSPPs and TTSPPs with high illicit value  ................................ .. 215 
20. TEMPERATURE AND HUMIDITY CONTROL AND MONITORING DURING 
TRANSIT  ................................ ................................ ................................ .............................  216 
a. Temperature control in t emperature -controlled road vehicles  ................................ .............  216 
b. Temperature monitoring in temperature -controlled road vehicles  ................................ ...... 216 
c. Humidity monitoring in temperature -controlled road vehicles  ................................ ...........  217 
d. Temperature monitoring in passive and active shipping containers  ................................ .... 217 Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 14 of 234  e. Qualiﬁcation of temperature -controlled road vehicles  ................................ ........................  217 
21. CALIBRATION OF TRANSPORT TEMPERATURE CONTROL DEVICES  ................  218 
a. Calibration of transport temperature monitoring devices  ................................ ....................  218 
b. Calibration of transport humidity monitoring devices  ................................ .........................  218 
c. Veriﬁcation of transport alarm  equipment  ................................ ................................ ...........  218 
22. SHIPPING CONTAINERS  ................................ ................................ ................................ . 218 
a. Container selection ge nerally  ................................ ................................ ...............................  218 
b. Uninsulated containers  ................................ ................................ ................................ .........  219 
c. Qualiﬁcation of insulate d passive containers  ................................ ................................ ....... 219 
d. Qualiﬁcation of active containers  ................................ ................................ ........................  220 
e. Product handling during packing and transport  ................................ ................................ ... 220 
f. Cleaning road vehicles and transport conta iners  ................................ ................................ . 221 
23. TRANSPORT OF RETURNED AND RECALLED TTSPPS  ................................ ...........  221 
a. Transp ort of returned TTSPPs  ................................ ................................ .............................  221 
b. Transport of recalled TTSPPs  ................................ ................................ ..............................  221 
24. LABELLING  ................................ ................................ ................................ .......................  222 
Normative references: IATA Perishable Cargo Regulations Chapter 179th Edition, July 2009. 
Clauses 17.10.5 and 17.10.6.  ................................ ................................ ...............................  222 
a. Labelling generally  ................................ ................................ ................................ ..............  222 
b. Labelling air -freighted shipments  ................................ ................................ ........................  222 
25. STOCK MANAGEMENT ................................ ................................ ................................ ... 222 
STOCK CONTROL SYSTEMS  ................................ ................................ ................................ ..... 222 
a. General stock control systems and procedures  ................................ ................................ .... 222 
b. Stock control procedures for controlled and hazardous TTSPPs ................................ .........  223 
INCOMING GOODS  ................................ ................................ ................................ ......................  223 
c. Product arrival checks  ................................ ................................ ................................ ..........  223 
d. Actions following arrival checks  ................................ ................................ .........................  223 
OUTGOING GOODS (EXTERNAL DELIVERIES) ................................ ................................ ..... 224 
e. Management of outgoing goods ................................ ................................ ...........................  224 
f. Actions following dispatch  ................................ ................................ ................................ .. 224 
g. Product complaint procedures ................................ ................................ ..............................  225 
SUSPECT PRODUCT PROCEDURES ................................ ................................ ..........................  225 
h. Suspect products  ................................ ................................ ................................ ..................  225 
26. PRODUCT RETURN, RECALL, WITHDRAWAL AND DISPOSAL PROCEDURES  . 225 
a. Return procedures  ................................ ................................ ................................ ................  225 
b. Recall procedures  ................................ ................................ ................................ .................  226 
c. Disposal procedures  ................................ ................................ ................................ .............  226 
d. Traceability or stock tracking  ................................ ................................ ..............................  226 
27. GENERAL PROCEDURES AND RECORD -KEEPING  ................................ ...................  227 
a. Emergencies and contingency planning ................................ ................................ ...............  227 
28. GENERAL RECORD -KEEPING  ................................ ................................ .......................  227 
a. Record -keeping  ................................ ................................ ................................ ....................  227 Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 15 of 234  b. Content of records  ................................ ................................ ................................ ................  228 
c. Record review and retention  ................................ ................................ ................................  228 
d. Temperature records  ................................ ................................ ................................ ............  228 
e. Humidity records  ................................ ................................ ................................ .................  229 
29. ENVIRONMENTAL MANAGEMENT  ................................ ................................ .............  229 
a. Normative references  ................................ ................................ ................................ ...........  229 
b. Environmental management of refrigeration equipment  ................................ .....................  229 
30. QUALITY MANAGEMENT  ................................ ................................ ..............................  230 
a. Normative references  ................................ ................................ ................................ ...........  230 
b. Organizational structure  ................................ ................................ ................................ ....... 230 
c. Quality system  ................................ ................................ ................................ .....................  230 
d. Self-inspections  ................................ ................................ ................................ ....................  231 
e. Contractors subject to service level agreements  ................................ ................................ .. 231 
31. MANAGEMENT OF DOCUMENTS AND STANDARD OPERATING 
PROCEDURES ................................ ................................ ................................ ....................  231 
a. Standard operating procedures  ................................ ................................ .............................  231 
b. Document control ................................ ................................ ................................ .................  232 
32. PERSONNEL/TRAINING  ................................ ................................ ................................ .. 232 
a. General training  ................................ ................................ ................................ ...................  232 
b. Specialist training ................................ ................................ ................................ .................  233 
ENDORSEMENT  OF THE  GUIDELINES ................................ ................................ .....................  234 
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Page 16 of 234  ACRONYMS AND ABBREVIATIONS  
 
ATMP   Advanced Therapy Medicinal Products   
CTA   Clinical Trial Authorization  
GMO   Genetically modified organism  
GMP   Good Manufacturing Practices  
HVAC   Heating, Ventilation and Air Conditioning  
HEPA   High -Efficiency Particulate Air  
ISO  International  Organization for Standardization  
MA  Marketing Authorization  
MCB   Master Cell Bank  
PET   Positron Emitting  
PIC  Pharmaceutical Inspection Cooperation  
PQ  Performance Qualification  
QC  Quality Control  
QRM   Quality Risk Management  
RP  Responsible Person  
SPF  Specified Pathogen Free  
WCB   Working Cell Bank  
WVS   Working Virus Seed  
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Page 17 of 234  GLOSSARY / Definitions  
 
Definitions given below apply to the words as used in these Annexes. They may have different 
meanings in other contexts.  
 
1. “Action limit” established criteria, requiring immediate follow -up and corrective action if 
exceeded.  
 
2. “Air lock” is an enclosed  space with two or more doors, and which is interposed between 
two or more rooms, e.g.  of differing class of cleanliness, for the purpose of controlling t he 
air-flow between those rooms when they need to be entered. An air -lock is designed for and 
used by either people or goods.  
 
3. “Alert limit" established criteria giving early warning of potential drift from normal 
conditions which are not necessarily groun ds for definitive corrective action but which 
require follow -up investigation.  
 
4. “Authorized person" is a person  recognized by the authority as having the necessary basic 
scientific and technical background and experience.  
 
5. “Batch (or lot)" is a defined  quantity of starting material, packaging material or product 
processed in one process or series of processes so that it could be expected to be 
homogeneous.  
 
6. “Batch number (or lot number)” a distinctive combination of numbers and/or letters which 
specifically  identifies a batch.  
 
7. “Bio generator" A contained system, such as a fermenter, into which biological agents are 
introduced along with other materials so as to affect their multiplication or their production 
of other substances by reaction with the other materials. Bio generators are generally fitted 
with devices for regulation, control, connection, material addition and material withdrawal.  
 
8. “Biological agents" microorganisms, including genetically engineered microorganisms, cell 
cultures and endoparasite s, whether pathogenic or not.  
 
9. “Bulk product” any product which has completed all processing stages up to, but not 
including, final packaging.  
 
10. “Calibration” is the set of operations which establish, under specified conditions, the 
relationship between values indicated by a measuring instrument or measuring system, or 
values represented by a material measure, and the corresponding known values of a reference 
standard.  
 
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Page 18 of 234  11. “Cell bank system ” a cell bank system is a system whereby successive batches of a product 
are manufactured by culture in cells derived from the same master cell bank (fully 
characterized for identity and absence of contamination). A number of containers from the 
master cell bank are used to prepare a working cell bank. The cell bank sys tem is validated 
for a passage level or number of population doublings beyond that achieved during routine 
production.  
 
12. “Master cell bank”  is a culture of (fully characterized) cells distributed into containers in a 
single operation, processed together in such a manner as to ensure uniformity and stored in 
such a manner as to ensure stability. A master cell bank is usually stored at -70°C or lower.  
 
13. “Working cell bank ” is a culture  of cells derived from the master cell bank and intended for 
use in the prepa ration of production cell cultures. The working cell bank is usually stored at 
-70°C or lower.  
 
14. “Cell culture” results  from the in -vitro growth of cells isolated from multicellular organisms.  
 
15. “Clean area” an area with defined environmental control of part iculate and microbial 
contamination, constructed and used in such a way as to reduce the introduction, generation 
and retention of contaminants within the area. The different degrees of environmental control 
are defined in the Supplementary Guidelines for the Manufacture of sterile medicinal 
products.  
 
16. “Clean/contained area" An area constructed and operated in such a manner that will achieve 
the aims of both a clean area and a contained area at the same time.  
 
17. “Containment” The action of confining a biologi cal agent or other entity within a defined 
space.  
 
18. “Primary containment ” is a system of containment which prevents the escape of a biological 
agent into the immediate working environment. It involves the use of closed containers or 
safety biological cabinets along with secure operating procedures.  
 
19. “Secondary containment” is a system of containment which prevents the escape of a 
biological agent into the external environment or into other working areas. It involves the use 
of rooms with specially desi gned air handling, the existence of airlocks and/or sterilizes for 
the exit of materials and secure operating procedures. In many cases it may add to the 
effectiveness of primary containment.  
 
20. Contained area  is an area constructed and operated in such a ma nner (and equipped with 
appropriate air handling and filtration) so as to prevent contamination of the external 
environment by biological agents from within the area.  
 
21. “Controlled area" an area constructed and operated in such a manner that some attempt is  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 19 of 234  made to control the introduction of potential contamination (an air supply approximating to 
grade D may be appropriate), and the consequences of accidental release of living organisms. 
The level of control exercised should reflect the nature of the organi sm employed in the 
process. At a minimum, the area should be maintained at a pressure negative to the immediate 
external environment and allow for the efficient removal of small quantities of airborne 
contaminants.  
 
22. “Computerized system" A system including  the input of data, electronic processing and the 
output of information to be used either for reporting or automatic control.  
 
23. “Cross contamination" contamination of a starting material or of a product with another 
material or product.  
 
24. “Crude plant (veget able drug)” fesh or dried medicinal plant or parts thereof.  
 
25. “Cryogenic vessel" a container designed to contain liquefied gas at extremely low 
temperature.  
 
26. “Cylinder" a container designed to contain gas at a high pressure.  
 
27. “Exotic organism” a biological agent where either the corresponding disease does not exist 
in a given country or geographical area, or where the disease is the subject of prophylactic 
measures or an eradication program undertaken in the given country or geographical area.  
28. “Finished prod uct” A medicinal product which has undergone all stages of production, 
including packaging in its final container.  
 
29. "Herbal medicinal products" medicinal products containing, as active ingredients, 
exclusively plant material and/or vegetable drug preparati ons. 
 
30. “Infected" Contaminated with extraneous biological agents and therefore capable of 
spreading infection.  
 
31. "In-process control” checks performed during production in order to monitor and if 
necessary to adjust the process to ensure that the product conforms to its specification. The 
control of the environment or equipment may also be regarded as a part of in - process control.  
 
32. “Intermediate product" partly processed material which must undergo further 
manufacturing steps before it becomes a bulk product.  
 
33. “Liquefiable gases” those which, at the normal filling temperature and pressure, remain as a 
liquid in the cylinder.  
 
34. “Manifold" Equipment or apparatus designed to enable one or more gas containers to be 
filled simultaneously from the same source . Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 20 of 234   
35. “Manufacture" All operations of purchase of materials and products, Production, Quality 
Control, release, storage, distribution of medicinal products and the related controls.  
 
36. “Manufacturer” Holder of a manufacturing authorization.  
 
37. “Media fill ” Method  of evaluating an aseptic process using a microbial growth medium. 
(Media fills are synonymous to simulated product fills, broth trials, broth fills etc.).  
 
38. “Medicinal plant ” Plant the whole or part of which is used for pharmaceutical purpose.  
 
39. “Medicinal products”  Any medicine or similar product intended for human use, which is 
subject to control under health legislation in the manufacturing or importing State.  
40. “Packaging ” All operations, including filling and labelling, which a bulk product has to 
undergo  in order to become a finished product.  
41. Note: Sterile filling would not normally be regarded as part of packaging, the bulk product 
being the filled, but not finally packaged, primary containers.  
 
42. Packaging material  is any material employed in the packagin g of a medicinal product , 
excluding any outer packaging used for transportation or shipment. Packaging materials are 
referred to as primary or secondary according   to whether or not they are intended to be in 
direct contact with the product.  
 
43. Procedures  are a d escription of the operations to be carried out, the precautions to be taken 
and measures to be applied directly or indirectly related to the manufacture of medicinal 
products.  
 
44. Production  is all operations involved in the preparation of medicinal pro ducts, from receipt 
of materials, through processing and packaging, to its completion as a finished product.  
 
45. Qualification  is an a ction of proving that any equipment works correctly and actually leads 
to the expected results. The word validation is someti mes widened to incorporate the concept 
of qualification.  
 
46. Quarantine  is the status of starting or packaging materials, intermediate, bulk or finished 
products isolated physically or by other effective means whilst awaiting a decision on their 
release or re fusal.  
 
47. Radiopharmaceutical  means any medicinal product  which, when ready for use, contains one 
or more radionuclides (radioactive isotopes) included for a pharmaceutical purpose.  
 
48. Reconciliation  means a  comparison, making due allowance for normal variation, between 
the amount of product or materials theoretically and actually produced or used.  
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Page 21 of 234  49. Recovery  means t he introduction of all or part of previous batches of the required quality into 
another batch a t a defined stage of manufacture.  
 
50. Reprocessing  means t he reworking of all or part of a batch of product of an unacceptable 
quality from a defined stage of production so that its quality may be rendered acceptable by 
one or more additional operations.  
 
51. Return means s ending back to the manufacturer or distributor of a medicinal product which 
may or may not present a quality defect.  
 
52. Seed lot  Seed lot system  means a seed lot system is a system according to which successive 
batches of a product are derived from the same master seed lot at a given passage level. For 
routine production, a working seed lot is prepared from the master seed lot. The final product 
is derive d from the working seed lot and has not undergone more passages from the master 
seed lot than the vaccine shown in clinical studies to be satisfactory with respect to safety and 
efficacy. The origin and the passage history of the master seed lot and the wo rking seed lot 
are recorded.  
 
53. Master seed lot  means a  culture of a micro -organism distributed from a single bulk into 
containers in a single operation in such a manner as to ensure uniformity, to prevent 
contamination and to ensure stability. A master seed  lot in liquid form is usually stored at or 
below -70°C. A freeze -dried master seed lot is stored at a temperature known to ensure 
stability.  
 
54. Working seed lo t means a  culture of a micro -organism derived from the master seed lot and 
intended for use in pro duction. Working seed lots are distributed into containers and stored 
as described above for master seed lots.  
 
55. “Starting material"  Any substance used in the production of medicinal products, but 
excluding packaging materials.  
 
56. “Sterility"  Sterility is the absence of living organisms. The conditions of the sterility tests 
are given in the European (or other relevant) Pharmacopoeia. (Note: The procedures and 
precautions employed should be such as to give a theoretical level of not more than one living 
micro -organism in 106 units in the final product.)  
 
57. “Validation”  Action of proving, in accordance with the principles of Good Manufacturing 
Practice, that any procedure, process, equipment, material, activity or system actually leads 
to the expe cted results (see also qualification).  
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Page 22 of 234  ANNEX  1: MANUFACTURE  OF STERILE  MEDICINAL  PRODUCTS  PRINCIPLE  
 
The manufacture of sterile products is subject to special requirements in order to minimize risks of 
microbiological contamination, and of particulate a nd pyrogenic contamination. Much depends on 
the skill, training and attitudes of the personnel involved. Quality Assurance is particularly important, 
and this type of manufacture must strictly follow carefully established and validated methods of 
preparati on and procedure. Sole reliance for sterility or other quality aspects must not be placed on 
any terminal process or finished product test.  
 
Note: This guidance does not lay down detailed methods for determining the microbiological and 
particulate cleanlin ess of air, surfaces, etc. Reference should be made to other documents such as the 
EN/ISO Standards.  
 
1.1 GENERAL  
 
The manufacture of sterile products should be carried out in clean areas entry to which should be 
through airlocks for personnel and/or for equipment and materials. Clean areas should be maintained 
to an appropriate cleanliness standard and supplied with air which has passed through filters of an 
appropriate efficiency.  
The various operations of component preparation, product preparation and f illing should be carried 
out in separate areas within the clean area. Manufacturing operations are divided into two categories; 
firstly, those where the product is terminally sterilized, and secondly those which are conducted 
aseptically at some or all sta ges. 
Clean areas for the manufacture of sterile products are classified according to the required 
characteristics of the environment. Each manufacturing operation requires an appropriate 
environmental cleanliness level in the operational state in order to minimize the risks of particulate 
or microbial contamination of the product or materials being handled.  
 
In order to meet “in operation” conditions, these areas should be designed to reach certain specified 
air-cleanliness levels in the “at rest” occupancy  state. The “at rest” state is the condition where the 
installation is installed and operating, complete with production equipment but with no operating 
personnel present. The “in operation” state is the condition where the installation is functioning in 
the defined operating mode with the specified number of personnel working.  
 
The “in operation” and “at rest” states should be defined for each clean room or suite of clean rooms. 
For the manufacture of sterile medicinal products, 4 grades can be distinguish ed: 
 
i. Grade A : The local zone for high risk operations, e.g. filling zone, stopper bowls, open 
ampoules and vials, making aseptic connections. Normally such conditions are provided by 
a laminar airflow  workstation . Laminar air flow systems should provide a homogeneous air 
speed in a range of 0.36 – 0.54 m/s (guidance value) at the working position in open clean 
room applications. The maintenance of laminarity should be demonstrated and validated.  
 
A uni -directional air flow and lower velocities may be used in closed isolators and glove Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 23 of 234  boxes.  
ii. Grade B : For aseptic preparation and filling, this is the background environment for 
the grade A zone.  
iii. Grade C and D:  Clean areas for carrying out less critical stages in the manufacture of 
sterile products.  
 
1.2 CLEAN ROOM AND CLEAN AIR DEVICE CLASSIFICATION  
 
Clean rooms and clean air devices should be classified in accordance with EN ISO 14644 -1. 
Classification should be clearly differentiated from operational process environmental monitoring. 
The maximum permitted airborne particle concentration for each grade is given in the following 
table:  
 
Grade  Maximum permitted number of particles/m³ equal to or 
greater than the tabulated size  
 At rest  In operation  
 0.5µ
m 5
.
0
µ
m 0.5µm  5.0µm  
A 3,520  2
0 3,520  20 
B 3,520  2
9 352,00
0 2,900  
C 352,0
00 2
,
9
0
0 3,520,0
00 29,000  
D 3,520,
000 2
9
,
0
0
0 not 
define
d not 
defined  
 
For classification purposes in Grade A zones, a minimum sample volume of 1m³ should be taken per 
sample location. For Grade The airborne particle classification is ISO 4.8 dictated by the limit for 
particles ≥5.0 μm. For Grade B (at rest) the airborne part icle classification is ISO 5 for both 
considered particle sizes. For Grade C (at rest & in operation) the airborne particle classification is 
ISO 7 and ISO 8 respectively. For Grade D (at rest) the airborne particle classification is ISO 8. For 
classificat ion purposes EN/ISO 14644 -1 methodology defines both the minimum number of sample Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 24 of 234  locations and the sample size based on the class limit of the largest considered particle size and the 
method of evaluation of the data collected.  
 
Portable particle counters with a short length of sample tubing should be used for classification 
purposes because of the relatively higher rate of precipitation of particles ≥5.0μm in remote sampling 
systems with long lengths of tubing. Isokinetic sample heads should be us ed in unidirectional airflow 
systems.  
“In operation” classification may be demonstrated during normal operations, simulated operations or 
during media fills as worst -case simulation is required for this. EN ISO 14644 -2 provides information 
on testing to demonstrate continued compliance with the assigned cleanliness classifications.  
 
1.3 CLEAN ROOM AND CLEAN AIR DEVICE MONITORING  
 
Clean rooms and clean air devices should be routinely monitored in operation and the monitoring 
locations based on a formal risk analysis study and the results obtained during the classification of 
rooms and/or clean air devices.  
 
For Grade A zones, particle monitoring should be undertaken for the full duration of critical 
processing, including equipment assembly, except where justi fied by contaminants in the process 
that would damage the particle counter or present a hazard, e.g. live organisms and radiological 
hazards. In such cases monitoring during routine equipment set up operations should be undertaken 
prior to exposure to the risk. Monitoring during simulated operations should also be performed. The 
Grade A zone should be monitored at such a frequency and with suitable sample size that all 
interventions, transient events and any system deterioration would be captured and alarms  triggered 
if alert limits are exceeded. It is accepted that it may not always be possible to demonstrate low levels 
of ≥5.0 μm particles at the point of fill when filling is in progress, due to the generation of particles 
or droplets from the product itse lf. 
 
It is recommended that a similar system be used for Grade B zones although the sample frequency 
may be decreased. The importance of the particle monitoring system should be determined by the 
effectiveness of the segregation between the adjacent Grade A and B zones. The Grade B zone should 
be monitored at such a frequency and with suitable sample size that changes in levels of 
contamination and any system deterioration would be captured and alarms triggered if alert limits are 
exceeded.  
 
Airborne particle monitoring systems may consist of independent particle counters; a network of 
sequentially accessed sampling points connected by manifold to a single particle counter; or a 
combination of the two. The system selected must be appropriate for the pa rticle size considered. 
Where remote sampling systems are used, the length of tubing and the radii of any bends in the tubing 
must be considered in the context of particle losses in the tubing. The selection of the monitoring 
system should take account of any risk presented by the materials used in the manufacturing 
operation, for example, those involving live organisms or radiopharmaceuticals.  
 
The sample sizes taken for monitoring purposes using automated systems will usually be a function Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 25 of 234  of the sampling  rate of the system used. It is not necessary for the sample volume to be the same as 
that used for formal classification of clean rooms and clean air devices.  
 
In Grade A and B zones, the monitoring of the ≥5.0 μm particle concentration count takes on a 
particular significance as it is an important diagnostic tool for early detection of failure. The 
occasional indication of ≥5.0 μm particle counts may be false counts due to electronic noise, stray 
light, coincidence, etc. However, consecutive or regular co unting of low levels is an indicator of a 
possible contamination event and should be investigated. Such events may indicate early failure of 
the HVAC system, filling equipment failure or may also be diagnostic of poor practices during 
machine set -up and ro utine operation.  
 
The particle limits given in the table for the “at rest” state should be achieved after a short “clean up” 
period of 15 -20 minutes (guidance value) in an unmanned state after completion of operations.  
The monitoring of Grade C and D are as in operation should be performed in accordance with the 
principles of quality risk management. The requirements and alert/action limits will depend on the 
nature of the operations carried out, but the recommended “clean up period” should be attained.  
 
Other characteristics such as temperature and relative humidity depend on the product and nature of 
the operations carried out. These parameters should not interfere with the defined cleanliness 
standard.  
 
Examples of operations to be carried out in the var ious grades are given in the table below (see also 
paragraphs 28 to 35):  
 
 
Grade  Examples of operations for terminally sterilized products  
(see para. 28 -30) 
A Filling of products, when unusually at risk  
C Preparation of solutions, when unusually at risk.  Filling of products  
D Preparation of solutions and components for subsequent filling  
 
 
Grade  Examples of operations for aseptic preparations  
(see para. 31 -35) 
A Aseptic preparation and filling  
C Preparation of solutions to be filtered  
D Handling of components after washing  
 
Where aseptic operations are performed monitoring should be frequent using methods such as settle 
plates, volumetric air and surface sampling (e.g. swabs and contact plates). Sampling methods used 
in operation should not interfere with zone protection. Results from monitoring should be considered 
when reviewing batch documentation for finished product release. Surfaces and personnel should be 
monitored after critical operations. Additional microbiological monitoring is als o required outside 
production operations, e.g. after validation of systems, cleaning and sanitization.  Recommended Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 26 of 234  limits for microbiological monitoring of clean areas during operation:  
 
 Recommended limits for microbial contamination (a) 
Grad
e Air 
sam
ple 
cfu/
m³ Settle 
plates 
(diam. 90 
mm), 
cfu/4 
hours (b) Contact 
plates (diam. 
55 mm), 
cfu/plate  Glove print 5 fingers 
cfu/glove  
 
A < 1 < 1 < 1 < 1 
 
B 10 5 5 5 
 
C 100 50 25 - 
 
D 200 100 50 - 
 
Notes:  
a) These are average values.  
b) Individual settle plates may be exposed for less than 4 hours.  
 
1. Appropriate alert and action limits should be set for the results of particulate and 
microbiological monitoring. If these limits are exceeded, operating  procedures should prescribe 
corrective action.  
 
1.4 ISOLATOR TECHNOLOGY  
 
The utilization of isolator technology to minimize human interventions in processing areas may result 
in a significant decrease in the risk of microbiological contamination of aseptically manufactured 
products from the environment. There are many possible  designs of isolators and transfer devices. 
The isolator and the background environment should be designed so that the required air quality for 
the respective zones can be realized. Isolators are constructed of various materials more or less prone 
to punct ure and leakage. Transfer devices may vary from a single door to double door designs to 
fully sealed systems incorporating sterilization mechanisms.  
 
The transfer of materials into and out of the unit is one of the greatest potential sources of 
contamination. In general, the area inside the isolator is the local zone for high risk manipulations, 
although it is recognized that laminar airflow may not exist in the working zone of all such devices.  
 
The air classification required for the background  environment depends on the design of the isolator 
and its application. It should be controlled and for aseptic processing it should be at least grade D.  
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Page 27 of 234  Isolators should be introduced only after appropriate validation. Validation should take into account  
all critical factors of isolator technology, for example the quality of the air inside and outside 
(background) the isolator, sanitization of the isolator, the transfer process and isolator integrity.  
 
Monitoring should be carried out routinely and should  include frequent leak testing of the isolator 
and glove/sleeve system.  
 
1.5 BLOW/FILL/SEAL TECHNOLOGY  
 
Blow/fill/seal units are purpose built machines in which, one continuous operation, containers are 
formed from a thermoplastic granulate, filled and then sealed, all by the one automatic machine. 
Blow/fill/seal equipment used for aseptic production which is fitted with an effective grade A air 
shower may be installed in at least a grade C environment, provided that grade A/B clothing is used. 
The environmen t should comply with the viable and non -viable limits at rest and the viable limit only 
when in operation. Blow/fill/seal equipment used for the production of products which are terminally 
sterilized should be installed in at least a grade D environment.  
 
Because of this special technology particular attention should be paid to, at least the following:  
a. equipment design and qualification  
b. validation and reproducibility of cleaning -in-place and sterilization -in- place  
c. background clean room environment in which  the equipment is located  
d. operator training and clothing  
e. interventions in the critical zone of the equipment including any aseptic assembly prior to 
the commencement of filling.  
 
1.6 TERMINALLY STERILISED PRODUCTS  
 
Preparation of components and most products should be done in at least a grade D environment in 
order to give low risk of microbial and particulate contamination, suitable for filtration and 
sterilization. Where the product is at a high or unusual risk of microbial contamination, (for example, 
becau se the product actively supports microbial growth or must be held for a long period before 
sterilization or is necessarily processed not mainly in closed vessels), then preparation should be 
carried out in a grade C environment.  
 
Filling of products for terminal sterilization should be carried out in at least a grade C environment.  
Where the product is at unusual risk of contamination from the environment, for example because 
the filling operation is slow or the containers are wide -necked or are necessari ly exposed for more 
than a few seconds before sealing, the filling should be done in a grade A zone with at least a grade 
C background. Preparation and filling of ointments, creams, suspensions and emulsions should 
generally be carried out in a grade C env ironment before terminal sterilization.  
 
1.7 ASEPTIC PREPARATION  
 
Components after washing should be handled in at least a grade D environment. Handling of sterile Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 28 of 234  starting materials and components, unless subjected to sterilization or filtration through a mic ro-
organism -retaining filter later in the process, should be done in a grade A environment with grade B 
background.  
 
Preparation of solutions which are to be sterile filtered during the process should be done in a grade 
C environment; if not filtered, the preparation of materials and products should be done in a grade A 
environment with a grade B background.  
 
Handling and filling of aseptically prepared products should be done in a grade A environment with 
a grade B background.  Prior to the completion of st oppering, transfer of partially closed containers, 
as used in freeze drying, should be done either in a grade A environment with grade B background 
or in sealed transfer trays in a grade B environment.  
 
Preparation and filling of sterile ointments, creams,  suspensions and emulsions should be done in a 
grade A environment, with a grade B background, when the product is exposed and is not 
subsequently filtered.  
 
1.8 PERSONNEL  
 
Only the minimum number of personnel required should be present in clean areas; this is  particularly 
important during aseptic processing. Inspections and controls should be conducted outside the clean 
areas as far as possible.  
 
All personnel (including those concerned with cleaning and maintenance) employed in such areas 
should receive regul ar training in disciplines relevant to the correct manufacture of sterile products. 
This training should include reference to hygiene and to the basic elements of microbiology. When 
outside staff who have not received such training (e.g. building or mainte nance contractors) need to 
be brought in, particular care should be taken over their instruction and supervision.  
 
Staff who have been engaged in the processing of animal tissue materials or of cultures of micro - 
organisms other than those used in the current manufacturing process should not enter sterile - product 
areas unless rigorous and clearly defined entry procedures have been followed.  
 
High standards of personal hygiene and cleanliness are essential. Personnel involved in the 
manufacture of steri le preparations should be instructed to report any condition which may cause the 
shedding of abnormal numbers or types of contaminants; periodic health checks for such conditions 
are desirable. Actions to be taken about personnel who could be introducing  
 undue microbiological hazard should be decided by a designated competent person. Wristwatches, 
make -up and jewelry should not be worn in clean areas.  
 
Changing and washing should follow a written procedure designed to minimize contamination of 
clean area c lothing or carry -through of contaminants to the clean areas.  The clothing and its quality 
should be appropriate for the process and the grade of the working area. It should be worn in such a 
way as to protect the product from contamination.  The description  of clothing required for each grade Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 29 of 234  is given below:  
 
a. Grade D:  Hair and, where relevant, beard should be covered. A general protective suit and 
appropriate shoes or overshoes should be worn. Appropriate measures should be taken to avoid 
any contamination coming from outside the clean area.  
b. Grade C:  Hair and where rel evant beard and moustache should be covered. A single or two - 
piece trouser suit, gathered at the wrists and with high neck and appropriate shoes or overshoes 
should be worn. They should shed virtually no fibers or particulate matter.  
c. Grade A/B:  Headgear should totally enclose hair and, where relevant, beard and moustache; 
it should be tucked into the neck of the suit; a face mask should be worn to prevent the shedding 
of droplets. Appropriate sterilized, non -powdered rubber or plastic gloves and  sterilized or 
disinfected footwear should be worn. Trouser -legs should be tucked inside the footwear and 
garment sleeves into the gloves. The protective clothing should shed virtually no fibers or 
particulate matter and retain particles shed by the body.  
 
Outdoor clothing should not be brought into changing rooms leading to grade B and C rooms. For 
every worker in a grade A/B area, clean sterile (sterilized or adequately sanitized) protective garments 
should be provided at each work session. Gloves should be regularly disinfected during operations. 
Masks and gloves should be changed at least for every working session.  
 
Clean area clothing should be cleaned and handled in such a way that it does not gather additional 
contaminants which can later be shed. These operations should follow written procedures. Separate 
laundry facilities for such clothing are desirable. Inappropriate treatment of clothing will damage 
fibers and may increase the risk of shedding of particles.  
 
1.9 PREMISES  
 
In clean areas, all expose d surfaces should be smooth, impervious and unbroken in order to minimize 
the shedding or accumulation of particles or micro -organisms and to permit the repeated application 
of cleaning agents, and disinfectants where used.  
 
To reduce accumulation of dust and to facilitate cleaning there should be no uncleanable recesses 
and a minimum of projecting ledges, shelves, cupboards and equipment. Doors should be designed 
to avoid those uncleanable recesses; sliding doors may be undesirable for this reason.  False c eilings 
should be sealed to prevent contamination from the space above them.  
 
Pipes and ducts and other utilities should be installed so that they do not create recesses, unsealed 
openings and surfaces which are difficult to clean.  Sinks and drains should be prohibited in grade 
A/B areas used for aseptic manufacture. In other areas air breaks should be fitted between the machine 
or sink and the drains.  Floor drains in lower grade clean rooms should be fitted with traps or water 
seals to prevent backflow.  
 
Changing rooms should be designed as airlocks and used to provide physical separation of the 
different stages of changing and so minimize microbial and particulate contamination of protective Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 30 of 234  clothing. They should be flushed effectively with filtered air. The final stage of the changing room 
should, in the at -rest state, be the same grade as the area into which it leads. The use of separate 
changing rooms for entering and leaving clean areas is sometimes desirable. In general, hand washing 
facilities should  be provided only in the first stage of the changing rooms.  
 
Both airlock doors should not be opened simultaneously. An interlocking system or a visual and/or 
audible warning system should be operated to prevent the opening of more than one door at a time.  
 
A filtered air supply should maintain a positive pressure and an air flow relative to surrounding areas 
of a lower grade under all operational conditions and should flush the area effectively. Adjacent 
rooms of different grades should have a pressure differential of 10 -15 Pascal’s (guidance values). 
Particular attention should be paid to the protection of the zone of greatest risk, that is, the immediate 
environment to which a product and cleaned components which contact the product are exposed. The 
various recommendations regarding air supplies and pressure differentials may need to be modified 
where it becomes necessary to contain some materials, e.g. pathogenic, highly toxic, radioactive or 
live viral or bacterial materials or products. Decontaminati on of facilities and treatment of air leaving 
a clean area may be necessary for some operations.  
 
It should be demonstrated that air -flow patterns do not present a contamination risk, e.g. care should 
be taken to ensure that air flows do not distribute par ticles from a particle generating person, 
operation or machine to a zone of higher product risk.  A warning system should be provided to 
indicate failure in the air supply. Indicators of pressure differences should be fitted between areas 
where these differ ences are important. These pressure differences should be recorded regularly or 
otherwise documented.  
 
1.10 EQUIPMENT  
 
A conveyor belt should not pass through a partition between a grade A or B area and a processing 
area of lower air cleanliness, unless the bel t itself is continually sterilized (e.g. in a sterilizing tunnel).  
As far as practicable equipment, fittings and services should be designed and installed so that 
operations, maintenance and repairs can be carried out outside the clean area. If sterilizati on is 
required, it should be carried out, wherever possible, after complete reassembly.  
 
When equipment maintenance has been carried out within the clean area, the area should be cleaned, 
disinfected and/or sterilized where appropriate, before processing r ecommences if the required 
standards of cleanliness and/or asepsis have not been maintained during the work.  Water treatment 
plants and distribution systems should be designed, constructed and maintained so as to ensure a 
reliable source of water of an app ropriate quality. They should not be operating beyond their designed 
capacity. Water for injections should be produced, stored and distributed in a manner which prevents 
microbial growth, for example by constant circulation at a temperature above 70°C.  
 
All equipment such as sterilizers, air handling and filtration systems, air vent and gas filters, water 
treatment, generation, storage and distribution systems should be subject to validation and planned 
maintenance; their return to use should be approved.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 31 of 234   
1.11 SANITATION  
 
The sanitation of clean areas is particularly important. They should be cleaned thoroughly in 
accordance with a written program. Where disinfectants are used, more than one type should be 
employed. Monitoring should be undertaken regularly in o rder to detect the development of resistant 
strains.  
 
Disinfectants and detergents should be monitored for microbial contamination; dilutions should be 
kept in previously cleaned containers and should only be stored for defined periods unless sterilized. 
Disinfectants and detergents used in Grades A and B areas should be sterile prior to use.  
 
Fumigation of clean areas may be useful for reducing microbiological contamination in inaccessible 
places.  
 
1.12 PROCESSING  
 
Precautions to minimize contamination should be taken during all processing stages including the 
stages before sterilization.  
 
Preparations of microbiological origin should not be made or filled in areas used for the processing 
of other medicinal products; however, vaccines of dead organisms or of bacterial extracts may be 
filled, after inactivation, in the same premises as other sterile medicinal products.  
 
Validation of aseptic processing should include a process simulation test using a nutrient medium 
(media fill). Selection of the nutrient mediu m should be made based on dosage form of the product 
and selectivity, clarity, concentration and suitability for sterilization of the nutrient medium.  
 
The process simulation test should imitate as closely as possible the routine aseptic manufacturing 
process and include all the critical subsequent manufacturing steps. It should also take into account 
various interventions known to occur during normal production as well as worst -case situations.  
 
Process simulation tests should be performed as initial valid ation with three consecutive satisfactory 
simulation tests per shift and repeated at defined intervals and after any significant modification to 
the HVAC -system, equipment, process and number of shifts. Normally process simulation tests 
should be repeated twice a year per shift and process.  
 
The number of containers used for media fills should be sufficient to enable a valid evaluation. For 
small batches, the number of containers for media fills should at least equal the size of the product 
batch. The targe t should be zero growth and the following should apply:  
 
a. When filling fewer than 5000 units, no contaminated units should be detected.  
b. When filling 5,000 to 10,000 units:  
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Page 32 of 234  i. One (1) contaminated unit should result in an investigation, including consideration  
of a repeat media fill;  
ii. Two (2) contaminated units are considered cause for revalidation, following 
investigation1.When filling more than 10,000 units:  
iii. One (1) contaminated unit should result in an investigation;  
iv. Two (2) contaminated units are considered cause for revalidation, following 
investigation1.  
 
For any run size, intermittent incidents of microbial contamination may be indicative of low -level 
contamination that should be investigated. Investigation of gross failures should include the potential 
impact on the sterility assurance of batches manufactured since the last successful media fill.  
 
Care should be taken that any validation does not compromise the processes.  Water sources, water 
treatment equipment and treated water should be monitored regularly for chemical and biological 
contamination and, as appropriate, for endotoxins. Records should be maintained of the results of the 
monitoring and of any action taken.  
 
Activities in clean areas and especially when aseptic operations are in progres s should be kept to a 
minimum and movement of personnel should be controlled and methodical, to avoid excessive 
shedding of particles and organisms due to over -vigorous activity. The ambient temperature and 
humidity should not be uncomfortably high because  of the nature of the garments worn.  
 
Microbiological contamination of starting materials should be minimal. Specifications should include 
requirements for microbiological quality when the need for this has been indicated by monitoring.  
Containers and mate rials liable to generate fibers should be minimized in clean areas.  
 
Where appropriate, measures should be taken to minimize the particulate contamination of the end 
product.  Components, containers and equipment should be handled after the final cleaning p rocess 
in such a way that they are not contaminated.  
 
The interval between the washing and drying and the sterilization of components, containers and 
equipment as well as between their sterilization and use should be minimized and subject to a time - 
limit appropriate to the storage conditions.  The time between the start of the preparation of a solution 
and its sterilization or filtration through a micro -organism -retaining filter should be minimized. There 
should be a set maximum permissible time for each pr oduct that takes into account its composition 
and the prescribed method of storage.  
 
The bioburden should be monitored before sterilization. There should be working limits on 
contamination immediately before sterilization, which are related to the efficiency of the method to 
be used. Bioburden assay should be performed on each batch for bo th aseptically filled product and 
terminally sterilized products. Where overkill sterilization parameters are set for terminally sterilized 
products, bioburden might be monitored only at suitable scheduled intervals. For parametric release 
systems, bioburd en assay should be performed on each batch and considered as an in -process test. 
Where appropriate, the level of endotoxins should be monitored. All solutions, in particular large Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 33 of 234  volume infusion fluids, should be passed through a micro - organism -retaining  filter, if possible sited 
immediately before filling.  
 
Components, containers, equipment and any other article required in a clean area where aseptic work 
takes place should be sterilized and passed into the area through double -ended sterilizers sealed in to 
the wall, or by a procedure which achieves the same objective of not introducing contamination. Non -
combustible gases should be passed through micro -organism retentive filters.  
 
The efficacy of any new procedure should be validated, and the validation v erified at scheduled 
intervals based on performance history or when any significant change is made in the process or 
equipment.  
 
1.13 STERILISATION  
 
All sterilization processes should be validated. Particular attention should be given when the adopted 
sterilization method is not described in the current edition of the European (or other relevant) 
Pharmacopoeia or when it is used for a product which is not a simple aqueous or oily solution. Where 
possible, heat sterilization is the method of choice. In a ny case, the sterilization process must be in 
accordance with the marketing and manufacturing authorizations.  
Before any sterilization process is adopted, its  suitability for the product and its efficacy in achieving 
the desired sterilizing conditions in a ll parts of each type of load to be processed should be 
demonstrated by physical measurements and by biological indicators where appropriate. The validity 
of the process should be verified at scheduled intervals, at least annually, and whenever significant  
modifications have been made to the equipment. Records should be kept of the results.  
 
For effective sterilization, the whole of the material must be subjected to the required treatment and 
the process should be designed to ensure that this is achieved.  Validated loading patterns should be 
established for all sterilization processes.  
 
Biological indicators should be considered as an additional method for monitoring sterilization . They 
should be stored and used according to the manufacturer’s instructions, and their quality checked by 
positive controls. If biological indicators are used, strict precautions should be taken to avoid 
transferring microbial contamination from them.  
 
There should be a clear means of differentiating products which have not been st erilized from those 
which have. Each basket, tray or other carrier of products or components should be clearly labelled 
with the material name, its batch number and an indication of whether or not it has been sterilized. 
Indicators such as autoclave tape m ay be used, where appropriate, to indicate whether or not a batch 
(or sub -batch) has passed through a sterilization process, but they do not give a reliable indication 
that the lot is, in fact, sterile. Sterilization records should be available for each st erilization run. They 
should be approved as part of the batch release procedure.  
 
1.14 STERILISATION BY HEAT  
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Page 34 of 234  Each heat sterilization cycle should be recorded on a time/temperature chart with a sufficiently large 
scale or by other appropriate equipment with suitable accuracy and precision. The position of the 
temperature probes used for controlling and/or recording should have been determined during the 
validation, and where applicable also checked against a second independent temperature probe 
located at the  same position.  Chemical or biological indicators may also be used, but should not take 
the place of physical measurements.  
 
Sufficient time must be allowed for the whole of the load to reach the required temperature before 
measurement of the sterilizing t ime-period is commenced. This time must be determined for each 
type of load to be processed.  After the high temperature phase of a heat sterilization cycle, precautions 
should be taken against contamination of a sterilized load during cooling. Any cooling fluid or gas 
in contact with the product should be sterilized unless it can be shown that any leaking container 
would not be approved for use.  
 
1.15 MOIST HEAT  
 
Both temperature and pressure should be used to monitor the process. Control instrumentation should 
normally be independent of monitoring instrumentation and recording charts. Where automated 
control and monitoring systems are used for these applications they should be validated to ensure 
that critical process requirements are met. System and cycle fault s should be registered by the system 
and observed by the operator. The reading of the independent temperature indicator should be 
routinely checked against the chart recorder during the sterilization period. For sterilizers fitted with 
a drain at the botto m of the chamber, it may also be necessary to record the temperature at this 
position, throughout the sterilization period. There should be frequent leak tests on the chamber when 
a vacuum phase is part of the cycle.  
 
The items to be sterilized, other than  products in sealed containers, should be wrapped in a material 
which allows removal of air and penetration of steam but which prevents recontamination after 
sterilization. All parts of the load should be in contact with the sterilizing agent at the requir ed 
temperature for the required time.  Care should be taken to ensure that steam used for sterilization is 
of suitable quality and does not contain additives at a level which could cause contamination of 
product or equipment.  
 
1.16 DRY HEAT  
 
The process used should include air circulation within the chamber and the maintenance of a positive 
pressure to prevent the entry of non -sterile air. Any air admitted should be passed through a HEPA 
filter. Where this process is also intended to remove pyrogens, challenge  tests using endotoxins 
should be used as part of the validation.  
 
1.17 STERILISATION BY RADIATION  
 
Radiation sterilization is used mainly for the sterilization of heat sensitive materials and products. 
Many medicinal products and some packaging materials are radiation -sensitive, so this method is Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 35 of 234  permissible only when the absence of deleterious effects on the product has been confirmed 
experimentally. Ultraviolet irradiation is not normally an acceptable method of sterilization.  
 
During the sterilization procedure the radiation dose should be measured. For this purpose, dosimetry 
indicators which are ind ependent of dose rate should be used, giving a quantitative measurement of 
the dose received by the product itself. Dosimeters should be inserted in the load in sufficient 
numbers  and close enough together to ensure that there is always a dosimeter in the irradiator. Where 
plastic dosimeters are used, they should be used within the time -limit of their calibration. Dosimeter 
absorbance should  be read within a short period after exposure to radiation.  
 
Biological indicators may be used as an additional contro l. Validation procedures should ensure that 
the effects of variations in density of the packages are considered.  Materials handling procedures 
should prevent mix -up between irradiated and non -irradiated materials. Radiation sensitive color 
disks should als o be used on each package to differentiate between packages which have been 
subjected to irradiation and those which have not.  The total radiation dose should be administered 
within a predetermined time span.  
 
1.18 STERILISATION WITH ETHYLENE OXIDE  
 
This method  should only be used when no other method is practicable. During process validation it 
should be shown that there is no damaging effect on the product and that the conditions and time 
allowed for degassing are such as to reduce any residual gas and reactio n products to defined 
acceptable limits for the type of product or material.  Direct contact between gas and microbial cells 
is essential; precautions should be taken to avoid the presence of organisms likely to be enclosed in 
material such as crystals or d ried protein. The nature and quantity of packaging materials can 
significantly affect the process.  
 
Before exposure to the gas, materials should be brought into equilibrium with the humidity and 
temperature required by the process. The time required for th is should be balanced against the 
opposing need to minimize the time before sterilization.  
Each sterilization cycle should be monitored with suitable biological indicators, using the appropriate 
number of test pieces distributed throughout the load. The in formation so obtained should form part 
of the batch record.  
 
For each sterilization cycle, records should be made of the time taken to complete the cycle, of the 
pressure, temperature and humidity within the chamber during the process and of the gas 
concen tration and of the total amount of gas used. The pressure and temperature should be recorded 
throughout the cycle on a chart. The record(s) should form part of the batch record.  After sterilization, 
the load should be stored in a controlled manner under ve ntilated conditions to allow residual gas and 
reaction products to reduce to the defined level. This process should be validated.  
 
1.19 FILTRATION OF MEDICINAL PRODUCTS WHICH CANNOT BE STERILISED IN 
THEIR FINAL CONTAINER  
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Page 36 of 234  Filtration alone is not considered sufficient when sterilization in the final container is possible. With 
regard to methods currently available, steam sterilization is to be preferred. If the product cannot be 
sterilized in the final container, solutions or liquids can be filtered through a  sterile filter of nominal 
pore size of 0.22 micron (or less), or with at least equivalent micro -organism retaining properties, 
into a previously sterilized container. Such filters can remove most bacteria and molds, but not all 
viruses or mycoplasmas. Con sideration should be given to complementing the filtration process with 
some degree of heat treatment.  Due to the potential additional risks of the filtration method as 
compared with other sterilization processes, a second filtration via a further steriliz ed micro -organism 
retaining filter, immediately prior to filling, may be advisable. The final sterile filtration should be 
carried out as close as possible to the filling point.  Fiber -shedding characteristics of filters should be 
minimal.  
 
The integrity of  the sterilized filter should be verified before use and should be confirmed 
immediately after use by an appropriate method such as a bubble point, diffusive flow or pressure 
hold test. The time taken to filter a known volume of bulk solution and the press ure difference to be 
used across the filter should be determined during validation and any significant differences from 
this during routine manufacturing should be noted and investigated.  
 
Results of these checks should be included in the batch record. The integrity of critical gas and air 
vent filters should be confirmed after use. The integrity of other filters should be confirmed at 
appropriate intervals.  The same filter should not be used for more than one working day unless such 
use has been validat ed. The filter should not affect the product by removal of ingredients from it or 
by release of substances into it.  
 
1.20 FINISHING OF STERILE PRODUCTS  
 
Partially stoppered freeze drying vials should be maintained under Grade A conditions at all times 
until the  stopper is fully inserted.  
 
Containers should be closed by appropriately validated methods. Containers closed by fusion, e.g. 
glass or plastic ampoules should be subject to 100% integrity testing. Samples of other containers 
should be checked for integrit y according to appropriate procedures.  
 
The container closure system for aseptically filled vials is not fully integral until the aluminum cap 
has been crimped into place on the stoppered vial. Crimping of the cap should therefore be performed 
as soon as p ossible after stopper insertion.  As the equipment used to crimp vial caps can generate 
large quantities of non -viable particulates, the equipment should be located at a separate station 
equipped with adequate air extraction.  
 
Vial capping can be undertaken  as an aseptic process using sterilized caps or as a clean process 
outside the aseptic core. Where this latter approach is adopted, vials should be protected by Grade.  
A condition up to the point of leaving the aseptic processing area, and thereafter stoppered vials 
should be protected with a Grade A air supply until the cap has been crimped.  
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Page 37 of 234  Vials with missing or displaced stoppers should be rejected prior to capping.  Where human 
intervention is required at the capping station, appropriate technology  should be used to prevent direct 
contact with the vials and to minimize microbial contamination.  
 
Restricted access barriers and isolators may be beneficial in assuring the required conditions and 
minimizing direct human interventions into the capping ope ration.  Containers sealed under vacuum 
should be tested for maintenance of that vacuum after an appropriate, pre -determined period.  
 
Filled containers of parenteral products should be inspected individually for extraneous 
contamination or other defects. Wh en inspection is done visually, it should be done under suitable 
and controlled conditions of illumination and background. Operators doing the inspection should 
pass regular eye -sight checks, with spectacles if worn, and be allowed frequent breaks from 
inspection. Where other methods of inspection are used, the process should be validated and the 
performance of the equipment checked at intervals. Results should be recorded.  
 
1.21 QUALITY CONTROL  
 
The sterility test applied to the finished product should only be regarded as the last in a series of 
control measures by which sterility is assured. The test should be validated for the product(s) 
concerned.  
 
In those cases, where parametric release has been authorized, special attention should be paid to the 
validation and the monitoring of the entire manufacturing process.  Samples taken for sterility testing 
should be representative of the whole of the batch, but should in particular include samples taken 
from parts of the batch consider ed to be most at risk of contamination, e.g.for products which have 
been filled aseptically, samples should include containers filled at the beginning and end of the batch 
and after any significant intervention.  for products which have been heat sterilized  in their final 
containers, consideration should be given to taking samples from the potentially coolest part of the 
load.Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 38 of 234  ANNEX 2: MANUFACTURE OF BIOLOGICAL MEDICINAL SUBSTANCES AND 
PRODUCTS FOR HUMAN USE  
 
SCOPE  
 
The methods employed in the manufacture of  biological medicinal substances and products for 
human use are a critical factor in shaping the appropriate regulatory control. Biological medicinal 
substances and products for human use can be defined therefore largely by reference to their method 
of man ufacture. This annex provides guidance on the full range of medicinal substances and products 
defined as biological.  
 
This annex is divided into two main parts:  
 
Part A contains supplementary guidance on the manufacture of biological medicinal substances and 
products, from control over seed lots and cell banks or starting material through to finishing activities 
and testing.  
 
Part B contains further guidance on selected types of biological medicinal substances and products.  
 
This annex, along with several other annexes of the Guide to GMP, provides guidance which 
supplements that in Part I and in Part II of the Guide. There are two aspects to the scope of this annex:  
 
1. Stage of manufacture for biological active substances to the point immediately prior to their 
being rendered sterile, the primary guidance source is Part II. Guidance for the subsequent 
manufacturing steps of biological products are covered in Part I. For some types of product 
(e.g. Advanced Therapy Medicinal Products (ATMP) cell -based produc ts) all manufacturing 
steps need to be conducted aseptically.  
 
2. Type of product - this annex provides guidance on the full range of medicinal substances and 
products defined as biological.  
 
These two aspects are shown in Table 1; it should be noted that this table is illustrative only and is 
not meant to describe the precise scope. It should also be understood that in line with the 
corresponding table in Part II of the Guide, the level of GMP increases in detail from early to later 
steps in the manufactur e of biological substances but GMP principles should always be adhered to. 
The inclusion of some early steps of manufacture within the scope of the annex does not imply that 
those steps will be routinely subject to inspection by the authorities. Antibiotic s are not defined or 
included as biological products, however where biological stages of manufacture occur, guidance in 
this Annex may be used. Guidance for medicinal products derived from fractionated human blood or 
plasma is covered in Annex 14 and for n on-transgenic plant products in Annex 7  
 
In certain cases, other legislation may be applicable to the starting materials for biologicals:  
 
1. For tissue and cells used for industrially manufactured products (such as pharmaceuticals), the 
donation, procurement  and testing of tissue and cells may be covered by national legislation.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 39 of 234   
2. Where blood or blood components are used as starting materials for ATMPs, national 
legislation may provide the technical requirements for the selection of donors and the collection 
and testing of blood and blood components1. 
 
3. The manufacture and control of genetically modified organisms needs to comply with local and 
national requirements. Appropriate containment should be established and maintained in 
facilities where any genetically  modified micro -organism is handled2. Advice should be 
obtained according to national legislation in order to establish and maintain the appropriate 
Biological Safety Level including measures to prevent cross contamination. There should be 
no conflicts wit h GMP requirements.  
 
Table 1. Illustrative guide to manufacturing activities within the scope of Annex 2  
 
Type 
and 
source  o
f 
materi
al Exampl
e 
produc
t Application of this guide to manufacturing 
steps shown in grey  
1) Animal or 
plant sources: 
non-
transgenic  Heparins, 
insulin, 
enzymes, 
proteins,  
allergen 
extract, 
ATMPs 
immunosera  Collection 
of plant, 
organ, 
tissue or 
fluid3 Cutting, 
mixing, 
and/ or 
initial 
processing  Isolatio
n and 
purifica
tion Formu
lation, 
filling  
2) Virus or 
bacteria/ 
fermentation/ 
cell culture  Viral or 
bacterial 
vaccines; 
enzymes, 
proteins  Establish
ment & 
maintenan
ce 
of 
MCB4, 
WCB,   
MVS, 
WVS  Cell 
culture 
and/or 
fermentati
on Inactiv
ation 
when 
applica
ble, 
isolatio
n
 
and 
purific
ation  For
mula
tion, 
fillin
g 
                                                 
1 See section B1 for the extent to which GMP principles apply.  
2 See section on ‘Seed lot and cell bank system’ for the extent to which GMP applies.  
3 In the EEA: HMPC guideline on Good Agricultural and Collection Practice - EMEA/HMPC/246816/2005 may be 
applied to growing, harvesting and initial processing in open fields.  
4 For principles of GMP apply, see explanatory text in ‘Scope’  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 40 of 234  3 
Biotechnolog
y 
fermentation/ 
cell culture  Recombinant 
products, 
MAb, 
allergens, 
vaccines Gene 
Therapy(viral 
and non -viral 
vectors, 
plasmids)  Establishm
ent & 
maintenanc
e of MCB 
and WCB,  
MSL, WSL  Cell culture 
and 
/or 
fermentatio
n Isolatio
n, 
purificat
ion, 
modific
ation  Form
ulatio
n, 
filling  
4) Animal  
sources: 
transgenic  Recombinant 
proteins, 
ATMPs  Master and 
working 
transgenic 
bank  Collection, 
cutting, 
mixing, 
and/or 
initial 
processing  Isolation
, 
purificat
ion and 
modifica
tion Form
ulatio
n, 
filling  
5) Plant 
sources: 
transgenic  Recombinant 
proteins, 
vaccines, 
allergen  Master and 
working 
transgenic 
bank  Growing, 
harvesting  Initial 
extractio
n, 
isolation
, 
purificat
ion, 
modifica
tion Form
ulatio
n, 
filling  
6) Human  
sources  Urine derived 
enzymes, 
hormones  Collection  
of fluid  Mixing, 
and/or 
initial 
processing  Isolation 
and 
purificat
ion Form
ulatio
n, 
filling  
7) Human 
and/or 
animal 
sources  Gene therapy: 
genetically 
modified cells  Donation, 
procureme
nt and 
testing of 
starting 
tissue / 
cells Manufactur
e vector 
and cell 
purification 
and 
processing,  Ex-vivo 
genetic 
modifica
tion of 
cells, 
Establis
h MCB, 
WCB or 
primary 
cell lot  Form
ulatio
n, 
filling  
Somatic
 cell 
therapy  Donation, 
procureme
nt and 
testing of 
starting 
tissue / Establish 
MCB, 
WCB or 
primary 
cell lot or 
cell pool  Cell
 is
olation, 
culture 
purificat
ion, Form
ulatio
n, 
combi
nation
, fill Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 41 of 234  cells5 combina
tion with 
non- 
cellular 
compon
ents 
Tissue 
engineered 
products  Donation, 
procureme
nt and 
testing of 
starting 
tissue / 
cells Initial 
processing, 
isolation 
and 
purification
, establish 
MCB, 
WCB,
 pri
mary cell 
lot or cell 
pool Cell 
isolation
, culture, 
purificat
ion, 
combina
tion 
with 
 n
on- 
cellular 
compon
ents Form
ulatio
n, 
combi
nation
, fill 
 
 
See Glossary for explanation of acronyms.
                                                 
5 In the EEA, these  are Directive 2004/23/EC and Directive 2006/17/EC.  
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Page 42 of 234  PRINCIPLE  
 
The manufacture of biological medicinal products involves certain specific considerations arising 
from the nature of the products and the processes. The ways in which biological medicinal products 
are manufactured, controlled and administered make some particular precautions necessary.  
 
Unlike conventional medicinal products, which are manufactured using chemical and physical 
techniques capable of a high degree of consistency, the manufacture of biological medicinal 
substances and products involves biological processes and materials, su ch as cultivation of cells or 
extraction of material from living organisms. These biological processes may display inherent 
variability, so that the range and nature of by -products may be variable. As a result, quality risk 
management (QRM) principles are particularly important for this class of materials and should be 
used to develop their control strategy across all stages of manufacture so as to minimize variability 
and to reduce the opportunity for contamination and cross -contamination.  
 
Since materials  and processing conditions used in cultivation processes are designed to provide 
conditions for the growth of specific cells and microorganisms, this provides extraneous microbial 
contaminants the opportunity to grow. In addition, many products are limited  in their ability to 
withstand a wide range of purification techniques particularly those designed to inactivate or remove 
adventitious viral contaminants. The design of the processes, equipment, facilities, utilities, the 
conditions of preparation and add ition of buffers and reagents, sampling and training of the operators 
are key considerations to minimize such contamination events.  
 
Specifications related to products (such as those in Pharmacopoeia monographs, Marketing 
Authorization (MA), and Clinical T rial Authorization (CTA)) will dictate whether and to what stage 
substances and materials can have a defined level of bioburden or need to be sterile. For biological 
materials that cannot be sterilized (e.g. by filtration), processing must be conducted ase ptically to 
minimize the introduction of contaminants. The application of appropriate environmental controls 
and monitoring and, wherever feasible, in -situ cleaning and sterilization systems together with the 
use of closed systems can significantly reduce the risk of accidental contamination and cross -
contamination.  
 
Control usually involves biological analytical techniques, which typically have a greater variability 
than physicochemical determinations. A robust manufacturing process is therefore crucial and in -
process controls take on a particular importance in the manufacture of biological medicinal 
substances and products.  
 
Biological medicinal products which incorporate human tissues or cells, such as certain ATMPs must 
comply with national requirements for the donation, procurement and testing stages6. Collection and 
testing of this material must be done in accordance with an appropriate quality system and in 
accordance with applicable national requirements7. Furthermore, national requiremen ts on 
traceability apply from the donor (while maintaining donor confidentiality) through stages applicable 
                                                 
6 In the EEA, this is Directive 2006/86/EC.  
 
7 Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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Page 43 of 234  at the Tissue Establishment and then continued under medicines legislation through to the institution 
where the product is used. Biological medicina l substances and products must comply with the 
applicable national guidance on minimizing the risk of transmitting animal spongiform 
encephalopathy agents via human and veterinary medicinal products.  
 
PART A. GENERAL GUIDANCE PERSONNEL  
 
Personnel (includin g those concerned with cleaning, maintenance or quality control) employed in 
areas where biological medicinal products are manufactured and tested should receive training, and 
periodic retraining, specific to the products manufactured and to their work, in cluding any specific 
measures to protect product, personnel and the environment.  
 
The health status of personnel should be taken into consideration for product safety. Where necessary, 
personnel engaged in production, maintenance, testing and animal care (and inspections) should be 
vaccinated with appropriate specific vaccines and have regular health checks.  
 
Any changes in the health status of personnel, which could adversely affect the quality of the product, 
should preclude work in the production area a nd appropriate records kept. Production of BCG 
vaccine and tuberculin products should be restricted to staff who are carefully monitored by regular 
checks of immunological status or chest X -ray. Health monitoring of staff should be commensurate 
with the ri sk; medical advice should be sought for personnel involved with hazardous organisms.  
 
Where required to minimize the opportunity for cross -contamination, restrictions on the movement 
of all personnel (including QC, maintenance and cleaning staff) should be  controlled on the basis of 
QRM principles. In general, personnel should not pass from areas where exposure to live micro -
organisms, genetically modified organisms, toxins or animals to areas where other products, 
inactivated products or different organism s are handled. If such passage is unavoidable, the 
contamination control measures should be based on QRM principles.  
 
2.1 PREMISE AND EQUIPMENT  
 
As part of the control strategy, the degree of environmental control of particulate and microbial 
contamination of the production premises should be adapted to the product and the production step, 
bearing in mind the level of contamination of the starting materials and the risks to the product.  
 
The environmental monitoring program in addition to Annex 1 should be supp lemented by the 
inclusion of methods to detect the presence of specific microorganisms (e.g.  host organism, 
anaerobes, etc) where indicated by the QRM process.  
 
Manufacturing and storage facilities, processes and environmental classifications should be designed 
to prevent the extraneous contamination of products. Although contamination is likely to become 
evident during processes such as fermentation and cell cult ure, prevention of contamination is more 
appropriate than detection and removal. In fact, the environmental monitoring and material bioburden 
testing programs are intended to verify a state of control. Where processes are not closed and there 
is therefore exposure of the product to the immediate room environment (e.g. during additions of Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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Page 44 of 234  supplements, media, buffers, gasses, manipulations during the manufacture of ATMPs) measures 
should be put in place, including engineering and environmental controls on the  basis of QRM 
principles. These QRM principles should take into account the principles and requirements from the 
appropriate sections of Annex 112 when selecting environmental classification cascades and 
associated controls.  
 
Dedicated production areas sho uld be used for the handling of live cells, capable of persistence in the 
manufacturing environment, until inactivation. Dedicated production area should be used for the 
manufacture of pathogenic organisms capable of causing severe human disease13. 
 
Manufa cture in a multi -product facility may be acceptable where the following, or equivalent (as 
appropriate to the product types involved) considerations and measures are part of an effective control 
strategy to prevent cross -contamination using QRM principles:  
 
a. Knowledge of key characteristics of all cells, organisms and any adventitious agents (e.g. 
pathogenicity, detectability, persistence, susceptibility to inactivation) within the same facility.  
 
b. Where production is characterized by multiple small batches from different starting materials 
(e.g. cell -based products), factors such as the health status of donors and the risk of total loss 
of product from and/or for specific patients should be taken into account when considering the 
acceptance of concurrent wor king during development of the control strategy.  
 
c. Live organisms and spores (where relevant) are prevented from entering non -related areas or 
equipment. Control measures to remove the organisms and spores before the subsequent 
manufacture of other products, these control measures should also take the HVAC system into 
account. Cleaning and decontamination for the removal of the organisms and spores should be 
validated.  
 
d. Environmental monitoring, specific for the micro -organism being manufactured, is also 
conducted in adjacent areas during manufacture and after completion of cleaning and 
decontamination. Attention should also be given to risks arising with use of certain monitoring 
equipment.  
 
e. Products, equipment, ancillary equipment (e.g. for calibrat ion and validation) and disposable 
items are only moved within and removed from such areas in a manner that prevents 
contamination of other areas, other products and different product stages (e.g. prevent 
contamination of inactivated or toxoid products wit h non -inactivated products).  
 
f. Campaign -based manufacturing followed by validated cleaning and decontamination 
procedures.  
 
1. For finishing operations, the need for dedicated facilities will depend on consideration of the 
above together with additional considerations such as the specific needs of the biological 
product and on the characteristics of other products, including any n on-biological products, in 
the same facility. Other control measures for finishing operations may include the need for Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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Page 45 of 234  specific addition sequences, mixing speeds, time and temperature controls, limits on exposure 
to light and containment and cleaning proce dures in the event of spillages.  
 
The measures and procedures necessary for containment (i.e. for environment and operator safety) 
should not conflict with those for product safety.  Air handling units should be designed, constructed  
and maintained to minim ize the risk of cross -contamination between different manufacturing areas 
and may need to be specific for an area. Consideration, based on QRM principles, should be given 
to the use of single pass air systems.  
 
Positive pressure areas should be used to pro cess sterile products but negative pressure in specific 
areas at the point of exposure of pathogens is acceptable for containment reasons. Where negative 
pressure areas or safety cabinets are used for aseptic.  
 
Processing of materials with particular risks  (e.g. pathogens), they should be surrounded by a positive 
pressure clean zone of appropriate grade. These pressure cascades should be clearly defined and 
continuously monitored with appropriate alarm settings.  Equipment used during handling of live 
organi sms and cells, including those for sampling, should be designed to prevent any contamination 
of the live organism or cell during processing.  
 
Primary containment15 should be designed and periodically tested to ensure the prevention of escape 
of biological agents into the immediate working environment.  
 
The use of clean in place and steam in place (‘sterilization in place’) systems should be used where 
possible. Valves on fermentation vessels should be completely steam serializable.  Air vent filters 
should be hydrophobic and validated for their scheduled life span with integrity testing at appropriate 
intervals based on appropriate QRM principles.  
 
Drainage systems must be designed so that effluents can be effectively neutralized or decontaminated 
to minimiz e the risk of cross -contamination. Compliance with local regulations is required to 
minimize the risk of contamination of the external environment according to the risk associated with 
the biohazardous nature of waste materials.  
 
Due to the variability of biological products or processes, relevant/critical additives or ingredients 
may have to be measured or weighed during the production process. In these cases, stocks of these 
substances may be kept in the production area for a specified duration based on d efined criteria such 
as for the duration of manufacture of the batch or of the campaign. Materials must be stored 
appropriately.  
 
2.2 ANIMALS  
 
A wide range of animal species are used in the manufacture of a number of biological medicinal 
products or starting materials. These can be divided into 2 broad types of sources:  
 
a. Live groups, herds, flocks: examples include polio vaccine (monkeys), immunosera 
to snake venoms and tetanus (horses, sheep and goats), allergens (cats), rabies vaccine Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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Page 46 of 234  (rabbits, mice and hams ters), transgenic products (goats, cattle).  
b. Animal tissues and cells derived post -mortem and from establishments such as 
abattoirs: examples include xenogeneic cells from animal tissues and cells, feeder 
cells to support the growth of some ATMPs, abattoir sources for enzymes, 
anticoagulants and hormones (sheep and pigs).  
c. In addition, animals may also be used in quality control either in generic assays, e.g. 
pyrogenicity, or specific potency assays, e.g. pertussis vaccine (mice), pyrogenicity 
(rabbits), BCG vaccine (guinea pigs).  
 
In addition to compliance with TSE regulations, other adventitious agents that are of concern 
(zoonotic diseases, diseases of source animals) should be monitored by an ongoing health program 
and recorded. Specialist advice should be  obtained in establishing such programmes. Instances of ill -
health occurring in the source animals should be investigated with respect to their suitability and the 
suitability of in -contact animals for continued use (in manufacture, as sources of starting materials, 
in quality control and safety testing), the decisions must be documented. A look -back procedure 
should be in place which informs the decision making process on the continued suitability of the 
medicinal substance(s) or product(s) in which the ma terials have been used or incorporated. This 
decision -making process may include the re -testing of retained samples from previous collections 
from the same donor (where applicable) to establish the last negative donation. The withdrawal 
period of therapeut ic agents used to treat source animals must be documented and used to determine 
the removal of those animals from the program for defined periods.  
 
Particular care should be taken to prevent and monitor infections in the source / donor animals. 
Measures should include the sourcing, facilities, husbandry, biosecurity procedures, testing regimes, 
control of bedding and feed materials. This is of special  relevance to specific  pathogen free animals 
where pharmacopoeia monograph requirements must be met. Housing and health monitoring should 
be defined for other categories of animals (e.g. healthy flocks or herds).  
 
For products manufactured from transgenic animals, traceability should be maintained in the creation 
of such animals from the source animals.  Note should be taken of national requirements for animal 
quarters, care and quarantine8. Housing for animals used in production and control of biological 
products should be separated from production and control areas.  
 
For different animal species, key criteria should be defined, monitored, and recorded. These may 
include age, weight and health status of the animals.  Animals, biological agents, and tests carr ied out 
should be appropriately identified to prevent any risk of mix up and to control all identified hazards.  
 
2.3 DOCUMENTATION  
 
Specifications for biological starting materials may need additional documentation on the source, 
origin, distribution chain, method of manufacture, and controls applied, to assure an appropriate level 
of control including their microbiological quality.  
                                                 
8 In the EEA, Directive 201/63/EC took effect on 1st January 2013. In the EEA see Article 15 of 
Regulation 1394/ 2007.  
 Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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Page 47 of 234   
Some product types may require specific definition of what materials constitutes a batch, particularly 
somatic cells in the con text of ATMPs. For autologous and donor -matched situations, the 
manufactured product should be viewed as a batch.  
 
Where human cell or tissue donors are used, full traceability is required from starting and raw 
materials, including all substances coming into contact with the cells or tissues through to 
confirmation of the receipt of the products at the point of use whilst maintaining the privacy of 
individuals and confidentiality of health related information9. Traceability records10 must be retained 
for 3 0 years after the expiry date of the product. Particular care should be taken to maintain the 
traceability of products for special use cases, such as donor -matched cells. National requirements 
apply to blood components when they are used as supportive or r aw material in the manufacturing 
process of medicinal products19. For ATMPs, traceability requirement regarding human cells 
including hematopoietic cells must comply with the principles laid down in national legislation. The 
arrangements necessary to achie ve the traceability and retention period should be incorporated into 
technical agreements between the responsible parties.  
 
2.4 PRODUCTION  
 
Given the variability inherent in many biological substances and products, steps to increase process 
robustness thereby reducing process variability and enhancing reproducibility at the different stages 
of the product life cycle  such as process design should be reassessed during Product Quality Reviews.  
 
Since cultivation conditions, media and reagents are designed to promote the growth of cells or 
microbial organisms, typically in an axenic state, particular attention should be paid in the control 
strategy to ensure there are robust steps that prevent or minimize the occurrence of unwanted 
bioburden and associated meta bolites and endotoxins. For cell based ATMPs where production 
batches are frequently small the risk of cross -contamination between cell preparations from different 
donors with various health status should be controlled under defined procedures and requirem ents. 
 
2.5 STARTING MATERIALS  
 
The source, origin and suitability of biological starting and raw materials (e.g. cryoprotectants, feeder 
cells, reagents, culture media, buffers, serum, enzymes, cytokines, growth factors) should be clearly 
defined. Where the ne cessary tests take a long time, it may be permissible to process starting materials 
before the results of the tests are available, the risk of using a potentially failed material and its 
potential impact on other batches should be clearly understood and as sessed under the principles of 
QRM. In such cases, release of a finished product is conditional on satisfactory results of these tests. 
The identification of all starting materials should be in compliance with the requirements appropriate 
to its stage of m anufacture. For biological medicinal products further guidance can be found in Part 
                                                 
9 In the EEA, see ENTR/F/2/SF/dn D(2009) 35810, ‘Detailed guidelines on good clinical 
practice specific to advanced therapy medicinal Products’ for further information on 
traceability.  
10 In the EEA, these are Directives 2002/98/EC and 2005/61/EC.  
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Page 48 of 234  I and Annex 8 and for biological substances in Part II.  
 
The risk of contamination of starting materials during their passage along the supply chain must be 
assessed, with particular emphasis on TSE. Materials that come into direct contact with 
manufacturing equipment or the product (such as media used in media fill experiments and lubricants 
that may contact the product) must also be taken into account.  
 
Given that the risk s from the introduction of contamination and the consequences to the product is 
the same irrespective of the stage of manufacture, establishment of a control strategy to protect the 
product and the preparation of solutions, buffers and other additions shou ld be based on the principles 
and guidance contained in the appropriate sections of Annex 1. The controls required for the quality 
of starting materials and on the aseptic manufacturing process, particularly for cell -based products, 
where final sterilisati on is generally not possible and the ability to remove microbial by -products is 
limited, assume greater importance. Where an MA or CTA provides for an allowable type and level 
of bioburden, for example at active substance stage, the control strategy should  address the means by 
which this is maintained within the specified limits.  
 
Where sterilization of starting materials is required, it should be carried out where possible by heat. 
Where necessary, other appropriate methods may also be used for inactivatio n of biological materials 
(e.g. irradiation and filtration).  
 
Reduction in bioburden associated with procurement of living tissues and cells may require the use 
of other measures such as antibiotics at early manufacturing stages. This should be avoided, bu t 
where it is necessary their use should be justified and carefully controlled, they should be removed 
from the manufacturing process at the stage specified in the MA or CTA.11 For human tissues and 
cells used as starting materials for biological medicinal products:  
 
a. Their procurement, donation and testing is regulated in some countries12. 
b. Such supply sites must hold appropriate approvals from the national competent authority(ies) 
which should be verified as part of starting  
c. material supplier management.  
d. Where such human cells or tissues are imported they must meet equivalent national standards 
of quality and safety13. The traceability and serious adverse reaction and serious adverse event 
notification requirements may be set out in national legislation.  
e. There may be some instances where processing of cells and tissues used as starting materials 
for biological medicinal products will be conducted at tissue establishments, e.g. to derive early 
cell lines or banks prior to establishing a Master Cell Bank, MCB1425. 
                                                 
11 Some si tuations in which antibiotic use may be justified include maintenance of plasmids in expression systems and 
in fermentation. Generally, antibiotics used in humans should be avoided because of the potential development of 
antibiotic resistant strains. Addit ionally, the use of antibiotics is not an effective mechanism to control microbial 
contamination.  
 
12 In the EEA, this is Directive 2004/23/EC and its Commission directives.  
13 In the EEA, they must be equivalent to those laid down in Directive 2004/23/EC. 2 4 In the EEA, this is Directive 
2006/86/EC.  
14 In the EEA, such processing steps, are under the scope of 2004/23/EC and the Responsible Person (RP)  Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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Page 49 of 234  f. Tissue and cells are released by the Responsible Person in the tissue establishment before 
shipment to the medicinal product manufacturer, after which normal medicinal product starting 
material controls apply. The test results of all tissues / cells su pplied by the tissue establishment 
should be available to the manufacturer of the medicinal product. Such information must be 
used to make appropriate material segregation and storage decisions. In cases where 
manufacturing must be initiated prior to recei ving test results from the tissue establishment, 
tissue and cells may be shipped to the medicinal product manufacturer provided controls are in 
place to prevent cross -contamination with tissue and cells that have been released by the RP in 
the tissue estab lishment.  
 
g. The transport of human tissues and cells to the manufacturing site must be controlled by a 
written agreement between the responsible parties. The manufacturing sites should have 
documentary evidence of adherence to the specified storage and tran sport conditions. 
Continuation of traceability requirements started at tissue establishments through to the 
recipient(s), and vice versa, including materials in contact with the cells or tissues, should be 
maintained.  
 
h. A technical agreement should be in place between the responsible parties (e.g. manufacturers, 
tissue establishment, Sponsors, MA Holder) which defines responsibilities of each party, 
including the RP.  
 
With regard to gene therapy15: 
a) For products consisting of viral vectors, the starting materials are the components from which 
the viral vector is obtained, i.e. the master virus seed or the plasmids to transfect the packaging 
cells and the MCB of the packaging cell line.  
b) For products consisting of plasmids, non -viral vectors and genetically  modified micro - 
organisms other than viruses or viral vectors, the starting materials are the components used to 
generate the producing cell, i.e. the plasmid, the host bacteria and the MCB of the recombinant 
microbial cells.  
c) For genetically modified cells, the starting materials are the components used to obtain the 
genetically modified cells, i.e. the starting materials to manufacture the vector and the human 
or animal cell preparations.  
d) The principles of GMP apply from the bank system used to manufa cture the vector or plasmid 
used for gene transfer.  
e) Where human or animal cells are used in the manufacturing process as feeder cells, appropriate 
controls over the sourcing, testing, transport and storage should be in place16, including 
compliance with nat ional requirements for human cells.  
 
2.6 SEED LOT AND CELL BANK SYSTEM  
 
In order to prevent the unwanted drift of properties which might ensue from repeated subcultures or 
multiple generations, the production of biological medicinal substances and products obtained by 
                                                 
15 In the EEA, see details in section 3.2 of Directive 2009/120/EC.  
16 In the EEA, this includes compliance with Directive 2004/23 EC for human cells.  
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Page 50 of 234  microbial culture, cell culture or propagation in embryos a nd animals should be based on a system 
of master and working virus seed lots and/or cell banks. Such a system may not be applicable to all 
types of ATMPs.  
 
The number of generations (doublings, passages) between the seed lot or cell bank, the drug 
substanc e and finished product should be consistent with specifications in the MA or CTA.  
 
As part of product lifecycle management, establishment of seed lots and cell banks, including master 
and working generations, should be performed under circumstances which are demonstrably 
appropriate. This should include an appropriately controlled environment to protect the seed lot, the 
cell bank and the personnel handling it. During the establishment of the seed lot and cell bank, no 
other living or infectious material ( e.g. virus, cell lines or cell strains) should be handled 
simultaneously in the same area or by the same persons. For stages prior to the master seed or cell 
bank generation, where only the principles of GMP may be applied, documentation should be 
availabl e to support traceability including issues related to components used during development 
with potential impact on product safety (e.g. reagents of biological origin) from initial sourcing and 
genetic development if applicable. For vaccines, the requirement s of pharmacopoeia monographs 
will apply.  
 
Following the establishment of master and working cell banks, master and working seed lots, 
quarantine and release procedures should be followed. This should include adequate characterization 
and testing for conta minants. Their on -going suitability for use should be further demonstrated by 
the consistency of the characteristics and quality of the successive batches of product. Evidence of 
the stability and recovery of the seeds and banks should be documented and re cords should be kept 
in a manner permitting trend evaluation.  
 
Seed lots and cell banks should be stored and used in such a way as to minimize the risks of 
contamination or alteration (e.g. stored in the vapor phase of liquid nitrogen in sealed containers) . 
Control measures for the storage of different seeds and/or cells in the same area or equipment should 
prevent mix -up and take into account the infectious nature of the materials to prevent cross 
contamination.  
 
Cell based medicinal products are often gen erated from a cell stock obtained from limited number of 
passages. In contrast with the two tiered system of Master and Working cell banks, the number of 
production runs from a cell stock is limited by the number of aliquots obtained after expansion and 
does not cover the entire life cycle of the product. Cell stock changes should be covered by a 
validation protocol.  
 
Storage containers should be sealed, clearly labelled and kept at an appropriate temperature. A stock 
inventory must be kept. The storage tem perature should be recorded continuously and, where used, 
the liquid nitrogen level monitored. Deviation from set limits, corrective and preventive action taken 
should be recorded.  
 
It is desirable to split stocks and to store the split stocks at different  locations so as to minimize the 
risks of total loss. The controls at such locations should provide the assurances outlined in the Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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Page 51 of 234  preceding paragraphs.  
 
The storage and handling conditions for stocks should be managed according to the same procedures 
and parameters. Once containers are removed from the seed lot / cell bank management system, the 
containers should not be returned to stock.  
 
2.7 OPERATING PRINCIPLES  
 
Change management should, on a periodic basis, take into account the effects, including cumulative 
effects of changes (e.g. to the process) on the quality of the final product.  Critical operational 
(process) parameters, or other input parameters which affect product quality, need to be identified, 
validated, documented and be shown to be main tained within requirements.  
 
A control strategy for the entry of articles and materials into production areas should be based on 
QRM principles to minimize the risk of contamination. For aseptic processes, heat stable articles and 
materials entering a clean area or clean/contained area should preferably do so through a double -
ended autoclave or oven. Heat labile articles and materials should enter through an air lock with 
interlocked doors where they are subject to effective surface sanitization procedu res. Sterilization of 
articles and materials elsewhere is acceptable provided that they are multiple wrappings, as 
appropriate to the number of stages of entry to the clean area, and enter through an airlock with the 
appropriate surface sanitization precau tions.  
 
The growth promoting properties of culture media should be demonstrated to be suitable for its 
intended use. If possible, media should be sterilized in situ. In - line sterilizing filters for routine 
addition of gases, media, acids or alkalis, anti -foaming agents etc. fermenters should be used where 
possible.  
 
Addition of materials or cultures to fermenters and other vessels and sampling should be carried out 
under carefully controlled conditions to prevent contamination. Care should be taken to ensu re that 
vessels are correctly connected when addition or sampling takes place.  
 
Continuous monitoring of some production processes (e.g. fermentation) may be necessary; such 
data should form part of the batch record. Where continuous culture is used, speci al consideration 
should be given to the quality control requirements arising from this type of production method.  
 
Centrifugation and blending of products can lead to aerosol formation and containment of such 
activities to minimize cross -contamination is necessary.  
 
Accidental spillages, especially of live organisms, must be dealt with quickly and safely. Validated 
decontamination measures should be available for each organism or groups of related organisms. 
Where different strains of single bacteria speci es or very similar viruses are involved, the 
decontamination process may be validated with one representative strain, unless there is reason to 
believe that they may vary significantly in their resistance to the agent(s) involved.  
 
If obviously contaminate d, such as by spills or aerosols, or if a potentially hazardous organism is Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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Page 52 of 234  involved, production and control materials, including paperwork, must be adequately disinfected, or 
the information transferred out by other means. The methods used for sterilizati on, disinfection, virus 
removal or inactivation should be validated17. 
 
In cases where a virus inactivation or removal process is performed during manufacture, measures 
should be taken to avoid the risk of recontamination of treated products by non - treated  products.  For 
products that are inactivated by the addition of a reagent (e.g. micro -organisms in the course of 
vaccine manufacture) the process should ensure the complete inactivation of live organisms . In 
addition to the thorough mixing of culture and inactivation , consideration should be given to contact 
of all product -contact surfaces exposed to live culture and, where required, the transfer to a second 
vessel.  
 
A wide variety of equipment is used for chromatography. QRM principles should be used to de vise 
the control strategy on matrices, the housings and associated equipment when used in campaign 
manufacture and in multi -product environments. The re -use of the same matrix at different stages of 
processing is discouraged. Acceptance criteria, operating  conditions, regeneration methods, life span 
and sanitization or sterilization methods of columns should be defined. Where ionizing radiation is 
used in the manufacture of medicinal products, Annex 12 should be consulted for further guidance.  
 
There should  be a system to assure the integrity and closure of containers after filling where the final 
products or intermediates represent a special risk and procedures to deal with any leaks or spillages. 
Filling and packaging operations need to have procedures in place to maintain the product within any 
specified limits, e.g. time and/or temperature.  
 
Activities in handling containers, which have live biological agents, must be performed in such a 
way to prevent the contamination of other products or egress of the live agents into the work 
environment or the external environment. This risk assessment should take into consideration the 
viability of such organisms and their biological classification.  
 
Care should be taken in the preparation, printing, storage and appl ication of labels, including any 
specific text for patient -specific products or signifying the use of genetic engineering of the contents 
on the primary container and secondary packaging. In the case of products used for autologous use, 
the unique patient identifier and the statement “for autologous use only” should be indicated on the 
immediate label.  
 
The compatibility of labels with ultra -low storage temperatures, where such temperatures are used, 
should be verified.  Where donor and/or animal health info rmation becomes available after 
procurement, which affects product quality, it should be taken into account in recall procedures.  
 
2.8 QUALITY CONTROL  
 
In-process controls have a greater importance in ensuring the consistency of the quality of biological 
medicinal products than for conventional products. In -process control testing should be performed at 
                                                 
17 In the EEA, see CHMP guidance.  Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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Page 53 of 234  appropriate stages of production to control those co nditions that are important for the quality of the 
finished product.  
 
Where intermediates can be stored for extended periods of time (days, weeks or longer), 
consideration should be given to the inclusion of final product batches made from materials held f or 
their maximum in -process periods in the on -going stability program.  
 
Certain types of cells (e.g. autologous cells used in ATMPs) may be available in limited quantities 
and, where allowed in the MA or CTA, a modified testing and sample retention strategy may be 
developed and documented.  For cell -based ATMPs, sterility tests should be conducted on antibiotic -
free cultures of cells or cell banks to provide evidence for absence of bacterial and fungal 
contamination and to be able to detection fastidi ous organisms where appropriate.  
 
For products with a short shelf life, which need batch certification before completion of all end 
product quality control tests (e.g. sterility tests) a suitable control strategy must be in place. Such 
controls need to be built on enhanced understanding of product and process performance and take 
into account the controls and attributes of input materials. The exact and detailed description of the 
entire release procedure, including the responsibilities of the different per sonnel involved in 
assessment of production and analytical data is essential. A continuous assessment of the 
effectiveness of the quality assurance system must be in place including records kept in a manner 
which permit trend evaluation. Where end product tests are not possible due to their short shelf life, 
alternative methods of obtaining equivalent data to permit batch certification should be considered 
(e.g. rapid microbiological methods). The procedure for batch certification and release may be carried  
out in two or more stages before and after full end process analytical test results are available:  
 
a. Assessment by designated person(s) of batch processing records and results from 
environmental monitoring (where available) which should cover production co nditions, all 
deviations from normal procedures and the available analytical results for review and 
conditional certification by the Responsible Person.  
 
b. Assessment of the final analytical tests and other information available before end product 
dispatch for final product certification by the Responsible Person.  
 
c. A procedure should be in place to describe the measures to be taken (including liaison with 
clinical staff) where out of specification test results are obtained after product dispatch. Such 
events  should be fully investigated and the relevant corrective and preventative actions taken 
to prevent recurrence documented.  
 
d. A procedure should describe those measures which will be taken by the Responsible Person if 
unsatisfactory test results are obtained  after dispatch.  
 
PART B. SPECIFIC GUIDANCE ON SELECTED PRODUCT TYPES  
 
2.9 ANIMAL SOURCED PRODUCTS  
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Page 54 of 234  This guidance applies to animal materials, which includes materials from establishments such as 
abattoirs. Since the supply chains can be extensive and complex, controls based on QRM principles 
need to be applied, see also requirements of appropriate pharm acopeia  monographs, including the 
need for specific tests at defined stages. Documentation to demonstrate the supply chain 
traceability18 and clear roles of participants in the supply chain, typically including a sufficiently 
detailed and current process map, should be in place.  
 
Monitoring programs should be in place for animal disease that are of concern to human health. 
Organizations should take into account reports from trustworthy sources on national disease 
prevalence and control measures when compiling their assessment of risk and mitigation factors. 
Such organizations include the World Organization for Animal Health (OIE, Office International des 
Epizooties19). This should be supplemented by information on health monitoring and control 
program( s) at national and local levels, the latter to include the sources (e.g. farm or feedlot) from 
which the animals are drawn and the control measures in place during transport to the abattoirs.  
 
Where abattoirs are used to source animal tissues, they should be shown to operate to stringent 
standards. Account should be taken of reports from national regulatory organizations20 which verify 
compliance with the requirements of food, safety, quality and veterinary and plant health legislation.  
 
Control measures for  the pharmaceutical raw materials at establishments such as abattoirs should 
include appropriate elements of Quality Management System to assure a satisfactory level of operator 
training, materials traceability, control and consistency. These measures may be drawn from sources 
outside PIC/S GMP but should be shown to provide equivalent levels of control.  
 
Control measures for materials should be in place which prevent interventions which may affect the 
quality of materials, or which at least provides eviden ce of such activities, during their progression 
through the manufacturing and supply chain. This includes the movement of material between sites 
of initial collection, partial and final purification(s), storage sites, hubs, consolidators and brokers. 
Detai ls of such arrangements should be recorded within the traceability system and any breaches 
recorded, investigated and actions taken.  
 
Regular audits of the raw material supplier should be undertaken which verify compliance with 
controls for materials at th e different stages of manufacture. Issues must be investigated to a depth 
appropriate to their significance, for which full documentation should be available. Systems should 
also be in place to ensure that effective corrective and preventive actions are ta ken. 
 
Cells, tissues and organs intended for the manufacture of xenogeneic cell - based medicinal products 
should be obtained only from animals that have been bred in captivity (barrier facility) specifically 
for this purpose and under no circumstances should cel ls, tissues and organs from wild animals or 
from abattoirs be used. Tissues of founder animals similarly should not be used. The health status of 
                                                 
18 See PIC/S GMP Chapter 5  
19 http://www.oie.int/eng/en_index.htm  
20 the EEA,  this is the Food  and Veterinary  Office 
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Page 55 of 234  the animals should be monitored and documented.  For xenogeneic cell therapy products appropriate 
guidance in r elation to procurement and testing of animal cells should be followed21. 
 
2.10 B2. ALLERGEN PRODUCTS  
 
Materials may be manufactured by extraction from natural sources or manufactured by recombinant 
DNA technology.  Source materials should be described in sufficie nt detail to ensure consistency in 
their supply, e.g. common and scientific name, origin, nature, contaminant limits  collection. Those 
derived from animals should be from healthy sources. Appropriate biosecurity controls should be in 
place for colonies (e. g. mites, animals) used for the extraction of allergens. Allergen should be stored 
under defined conditions to minimize deterioration.  
 
The production process steps including pre -treatment, extraction, filtration, dialysis, concentration or 
freeze -drying steps should be described in detail and validated.  The modification processes to 
manufacture modified allergen extracts (e.g. allergoids, conjugates) should be described. 
Intermediates in the manufacturing process should be identified and controlled.  Aller gen extract 
mixtures should be prepared from individual extracts from single source materials. Each individual 
extract should be considered as one active substance.  
 
2.11 B.3. ANIMAL IMMUNOSERA PRODUCTS  
 
Particular care should be exercised on the control of ant igens of biological origin to assure their 
quality, consistency and freedom from adventitious agents. The preparation of materials used to 
immunize the source animals (e.g. antigens, hapten carriers, adjuvants, stabilizing agents), the storage 
of such mate rial immediately prior to immunization should be in accordance with documented 
procedures.  
 
The immunization, test bleed and harvest bleed schedules should conform to those approved in the 
CTA or MA.  The manufacturing conditions for the preparation of antibody sub -fragments (e.g. Fab 
or F(ab’) 2) and any further modifications must be in accordance with validated and approved 
parameters. Where such enzymes are made up of several components, their consistency should be 
assured.  
 
2.12 B.4. VACCINES  
 
Where eggs are used, the health status of all source flocks used in the production of eggs (whether 
specific  pathogen free or healthy flocks) should be assured.  The integrity of containers used to store 
intermediate products  and the hold times must be validated.  Vessels containing inactivated products  
should not be opened or sampled in areas containing live biological agents.  
 
The sequence of addition of active ingredients, adjuvants and excipients during the formulation of a n 
intermediate or final product must be in compliance with the manufacturing instructions or the batch 
record.  Where organisms with a higher biological safety level (e.g.  pandemic vaccine strains) are to 
                                                 
21 In the EEA, reference is made to the EMA Guideline document on xenogeneic cell -based medicinal products (EMEA/CHMP/CPWP/8 3508/2009)  
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Page 56 of 234  be used in manufacture or testing, appropriate cont ainment arrangements must be in place.  The 
approval of such arrangements should be obtained from the appropriate national Authority(ies) and 
the approval documents be available for verification.  
 
2.13 B.5. RECOMBINANT PRODUCTS  
 
Process conditions  during cell gr owth, protein expression and purification must be maintained within 
validated parameters to assure a consistent product with a defined range of impurities that is within 
the capability of the process to reduce to acceptable levels. The type of cell used in  production may 
require increased measures to be taken to assure freedom from viruses. For production involving 
multiple harvests, the period of continuous cultivation should be within specified limits.  
 
The purification processes to remove unwanted host cell proteins, nucleic acids, carbohydrates, 
viruses and other impurities should be within defined validated limits.  
 
2.14 B.6. MONOCLONAL ANTIBODY PRODUCTS  
 
Monoclonal antibodies may be manufactured from murine hybridisms, human hybridisms or by 
recombinant DN A technology. Control measures appropriate to the different source cells (including 
feeder cells if used) and materials used to establish the hybridoma / cell line should be in place to 
assure the safety and quality of the product. It should be verified th at these are within approved limits. 
Freedom from viruses should be given particular emphasis. It should be noted that data originating 
from products generated by the same manufacturing technology platform may be acceptable to 
demonstrate suitability.  
 
Criteria to be monitored at the end of a production cycle and for early termination of production cycle 
should be verified that these are within approved limits.  The manufacturing conditions for the 
preparation of antibody sub -fragments (e.g. Fab, F(ab’) 2, scFv) and any further modifications (e.g. 
radio labelling, conjugation, chemical linking) must be in accordance with validated parameters.  
 
2.15 B.7. TRANSGENIC ANIMAL PRODUCTS  
 
Consistency of starting material from a transgenic source is likely to be more problematic than is 
normally the case for non -transgenic biotechnology sources. Consequently, there is an increased 
requirement to demonstrate batch -to-batch consistency of product in all respects.  
 
A range of species may be used to produce biological medi cinal products, which may be expressed 
into body fluids (e.g. milk) for collection and purification.  Animals should be clearly and uniquely 
identified and backup arrangements should be put in place in the event of loss of the primary marker.  
 
The arrangements for housing and care of the animals should be defined such that they minimize the 
exposure of the animals to pathogenic and zoonotic agents. Appropriate measures to protect the 
external environment should be established. A health -monitorin g program should be established and 
all results documented, any incident should be investigated and its impact on the continuation of the 
animal and on previous batches of product should be determined. Care should be taken to ensure that Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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Page 57 of 234  any therapeutic pr oducts used to treat the animals do not contaminate the product.  
 
The genealogy of the founder animals through to production animals must be documented. Since a 
transgenic line will be derived from a single genetic founder animal, materials from different 
transgenic lines should not be mixed.  The conditions under which the product is harvested should be 
in accordance with MA or CTA conditions. The harvest schedule and conditions under which animals 
may be removed from production should be performed accordin g to approved procedures and 
acceptance limits.  
 
2.16 B8. TRANSGENIC PLANT PRODUCTS  
 
Consistency of starting material from a transgenic source is likely to be more problematic than is 
normally the case for non -transgenic biotechnology sources. Consequently, there is an increased 
requirement to demonstrate batch -to-batch consistency of product in all respects.  Additional 
measures, over and above those given in Part A, may be required to prevent contamination of master 
and working transgenic banks by extraneous  plant materials and relevant adventitious agents. The 
stability of the gene within defined generation numbers should be monitored.  
 
Plants should be clearly and uniquely identified, the presence of key plant features, including health 
status, across the c rop should be verified at defined intervals through the cultivation period to assure 
consistency of yield between crops.  Security arrangements for the protection of crops should be 
defined, wherever possible, such that they minimize the exposure to contami nation by 
microbiological agents and cross - contamination with non -related plants. Measures should be in place 
to prevent materials such as pesticides and fertilizers from contaminating the product. A monitoring 
program should be established and all result s documented, any incident should be investigated and 
its impact on the continuation of the crop in the production program should be determined.  
 
Conditions under which plants may be removed from production should be defined. Acceptance 
limits should be se t for materials (e.g. host proteins) that may interfere with the purification process. 
It should be verified that the results are within approved limits.  Environmental conditions 
(temperature, rain), which may affect the quality attributes and yield of the  recombinant protein from 
time of planting, through cultivation to harvest and interim storage of harvested materials should be 
documented. The principles in documents such as ‘Guideline on Good Agricultural and Collection 
Practice for Starting Materials o f Herbal origin22 should be taken into account when drawing up such 
criteria.  
 
2.17 B9. GENE THERAPY PRODUCTS23 
 
There are potentially 2 types of GT products (vectors and genetically modified cells) and both are 
within the scope of the guidance in this section.  For cell based GT products, some aspects of guidance 
in section B10 may be applicable.  
 
                                                 
22 EMA, WHO or equivalent  
23 In the EEA, Part IV (1) of Directive 2001/83/EC as revised in 2009 contains a definition of gene therapy (GT) medicinal produ cts. 
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Page 58 of 234  Since the cells used in the manufacture of gene therapy products are obtained either from humans 
(autologous or allogeneic) or animals (xenogeneic), there is a potentia l risk of contamination by 
adventitious agents. Special considerations must be applied to the segregation of autologous materials 
obtained from infected donors. The robustness of the control and test measures for such starting 
materials, cryoprotectants, c ulture media, cells and vectors should be based on QRM principles and 
in line with the MA or CTA. Established cell lines used for viral vector production and their control 
and test measures should similarly be based on QRM principles. Virus seed lots and c ell banking 
systems should be used where relevant.  
 
Factors such as the nature of the genetic material, type of (viral or non -viral) vector and type of cells 
have a bearing on the range of potential impurities, adventitious agents and cross -contaminations that 
should be taken into account as part of the development of an overall strategy to minimize risk. This 
strategy should be used as a basis for the design of the process, the manufacturing and storage 
facilities and equipment, cleaning and decontaminatio n procedures, packaging, labelling and 
distribution.  
 
The manufacture and testing of gene therapy medicinal products raises specific issues regarding the 
safety and quality of the final product and safety issues for recipients and staff. A risk based appro ach 
for operator, environment and patient safety and the implementation of controls based on the 
biological hazard class should be applied. Legislated local and, if applicable, international safety 
measures should be applied.  
 
Personnel (including QC and m aintenance staff) and material flows, including those for storage and 
testing (e.g. starting materials, in -process and final product samples and environmental monitoring 
samples), should be controlled on the basis of QRM principles, where possible utilizin g 
unidirectional flows. This should take into account movement between areas containing different 
genetically modified organisms and areas containing non -genetically -modified organisms.  
 
Any special cleaning and decontamination methods required for the ran ge of organisms being 
handled should be considered in the design of facilities and equipment. Where possible, the 
environmental monitoring program should be supplemented by the inclusion of methods to detect the 
presence of the specific organisms being cul tivated.  Where replication limited vectors are used, 
measures should be in place to prevent the introduction of wild -type viruses, which may lead to the 
formation of replication competent recombinant vectors.  
 
An emergency plan for dealing with accidental release of viable organisms should be in place. This 
should address methods and procedures for containment, protection of operators, cleaning, 
decontamination and safe return to use. An assessment of impact on the immediate products and any 
others in the a ffected area should also be made.  
 
Facilities for the manufacture of viral vectors should be separated from other areas by specific 
measures. The arrangements for separation should be demonstrated to be effective. Closed systems 
should be used wherever pos sible, sample collection additions and transfers should prevent the 
release of viral material.  
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Page 59 of 234  Concurrent manufacture of different viral gene therapy vectors in the same area is not acceptable. 
Concurrent production of non -viral vectors in the same area s hould be controlled on the basis of 
QRM principles. Changeover procedures between campaigns should be demonstrated to be effective.  
 
A description of the production of vectors and genetically modified cells should be available in 
sufficient detail to ensure the traceability of the products from the starting material (plasmids, gene 
of interest and regulatory sequences, cell banks, and viral or non -viral vector stock) to the finished 
product.  
 
Shipment of products containing and/or consisting of GMO sho uld conform to appropriate 
legislation.  The following considerations apply to the ex -vivo gene transfer to recipient cells:  
 
a. These should take place in facilities dedicated to such activities where appropriate containment 
arrangements exist.  
b. Measures (incl uding considerations outlined under paragraph 10 in Part A) to minimize the 
potential for cross -contamination and mix -up between cells from different patients are required. 
This should include the use of validated cleaning procedures. The concurrent use of  different 
viral vectors should be subject to controls based on QRM principles. Some viral vectors (e.g. 
Retro - or Lenti -viruses) cannot be used in the manufacturing process of genetically modified 
cells until they have been shown to be devoid of replicati on-competent contaminating vector.  
c. Traceability requirements must be maintained. There should be a clear definition of a batch, 
from cell source to final product container(s).  
d. Products that utilize non -biological means to deliver the gene, their physico - chemical 
properties should be documented and tested.  
 
2.18 B.10. SOMATIC AND XENOGENEIC CELL THERAPY PRODUCTS AND TISSUE 
ENGINEERED PRODUCTS24  
 
For genetically modified cell based products that are not classified as GT products, some aspects of 
guidance in section B9 may be applicable.  
 
Use should be made, where they are available, of authorized sources (i.e.  licensed medicinal products 
or medical devices which have gone through a conformity assessment procedure) of additional 
substances (such as cellular p roducts, bio -molecules, bio - materials, scaffolds, matrices). Where 
devices, including custom -made devices, are incorporated as part of the products:  
 
There should be written agreement between the manufacturer of the medicinal product and the 
manufacturer of the medical device, which should provide enough information on the medical device 
to avoid alteration of its properties during manufacturing of the ATMP. This should include the 
requirement to control changes proposed for the medical device.  The technic al agreement should also 
require the exchange of information on deviations in the manufacture of the medical device.  
 
                                                 
24 In the EEA, Annex I, Part IV (2) of Directive 2001/83/EC as amended in 2009 contains a definition of somatic cell therapy (SC T) medicinal products and the definition of a 
tissue engineered medicinal product is given in Article 2 of Regulation 1394/2007/EC . 
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Page 60 of 234  Since somatic cells are obtained either from humans (autologous or allogeneic) or animals 
(xenogeneic), there is a potential risk of conta mination by adventitious agents. Special considerations 
must be applied to the segregation of autologous materials obtained from infected donors or related 
to cell pooling. The robustness of the control and test measures put in place for these source mater ials 
should be ensured. Animals from which tissues and cells are collected should be reared and processed 
according to the principles defined in the relevant guidelines.  
 
Careful attention should be paid to specific requirements at any cryopreservation sta ges, e.g. the rate 
of temperature changes during freezing or thawing. The type of storage chamber, placement and 
retrieval process should minimize the risk of cross -contamination, maintain the quality of the 
products and facilitate their accurate retrieval . Documented procedures should be in place for the 
secure handling and storage of products with positive serological markers.  
 
Sterility tests should be conducted on antibiotic -free cultures of cells or cell banks to provide 
evidence for absence of bacteri al and fungal contamination and consider the detection of fastidious 
organisms . Where relevant, a stability -monitoring program should be in place together with reference 
and retain samples in sufficient quantity to permit further examination.  
 
GLOSSARY TO ANNEX 2  
 
Entries are only included where the terms are used in Annex 2 and require further explanation. 
Definitions which already exist in legislation are cross -referenced only.  
 
Adjuvant. A chemical or biological substance that enhances the immune response against an antigen.  
 
Advanced Therapeutic Medicinal Products (ATMP). ATMP means any of the following 
medicinal products for human use: gene therapy medicinal products, somatic cell therapy medicinal 
products and tissue engineered medicinal products25. 
 
Allergoids. Allergens which are chemically modified to reduce IgE reactivity.  
 
Antigens. Substances (e.g. toxins, foreign proteins, bacteria, tissue cells) capable of inducing specific 
immune responses.  
 
Antibody. Proteins produced by the B -lymphocytes that bind to specific antigens. Antibodies may 
divide into 2 main types based on key differences in their method of manufacture:  
- Monoclonal antibodies (MAb) – homogeneous  antibody population obtained from a single clone of 
lymphocytes or by recombinant technology and which bind to a single epitope.  
- Polyclonal antibodies – derived from a range of lymphocyte clones, produced in humans  and 
animals in response to the epitopes on most ‘non -self’ molecules.  
 
Area. A specific set of rooms within a building associated with the manufacturing of any one product 
or multiple products that has a common air handling unit.  
                                                 
25 In the EEA, see Article 2(1) of Regulation EC 1394/2007  Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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Page 61 of 234   
Bioburden. The level and type (i.e. objectionable or not) of micr o-organism present in raw materials, 
media, biological substances, intermediates or products. Regarded as contamination when the level 
and/or type exceed specifications.  
 
Biological medicinal product. A biological medicinal product is a product, of which t he active 
substance is a biological substance. A biological substance is a substance that is produced by or 
extracted from a biological source and that needs for its characterization and the determination of its 
quality a combination of physicochemical - biological testing, together with the production process 
and its control26. 
Biosafety level (BSL). The containment conditions required to safely handle organisms of different 
hazards ranging from BSL1 (lowest risk, unlikely to cause human disease) to BSL4 (hi ghest risk, 
cause severe disease, likely to spread and no effective prophylaxis or treatment available).  
 
Campaigned manufacture. The manufacture of a series of batches of the same product in sequence 
in a given period of time followed by strict adherence to accepted control measures before transfer 
to another product. The products are not run at the same time but may be run on the same  
equipment.  
  
Closed system . Where a drug substance or product is not exposed to the immediate room 
environment during man ufacture.  
 
Contained use. An operation, in which genetically modified organisms are cultured, stored, used, 
transported, destroyed or disposed of and for which barriers (physical / chemical / biological) are 
used to limit their contact with the general pop ulation and the environment.  
 
Deliberate release. The deliberate release into the environment of genetically modified organisms.  
 
Ex-vivo.  Where procedures are conducted on tissues or cells outside the living body and returned to 
the living body.  
 
Feeder cells. Cells used in co -culture to maintain pluripotent  stem cells. For human  embryonic   stem 
cell culture, typical feeder layers include mouse embryonic fibroblasts (MEFs) or human embryonic 
fibroblasts that have been treated to prevent them from dividing.  
 
Fermenter. In case of (mammalian) cell lines the term fermenter should be understood as a 
bioreactor . 
Gene. A sequence of DNA that codes for one (or more) protein(s).  
 
Gene transfer . A process to transfer a gene in cells, involving an expression system contained in a 
delivery system known as a vector, which can be of viral, as well as non - viral origin. After gene 
transfer, genetically modified cells are also termed transduced cells.  
 
                                                 
26 In the EEA, see Annex 1 to 2001/83/EC – 3.2.1.1(b).  
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Page 62 of 234  Genetically modified organism (GMO) – means an organism, with the exception of human bei ngs, 
in which the genetic material has been altered in a way that does not occur naturally by mating and/or 
natural recombination.  
 
Hapten. A low molecular weight molecule that is not in itself antigenic unless conjugated to a 
‘carrier’ molecule.  
 
Hybridoma. An immortalized cell line that secrete desired (monoclonal) antibodies and are typically 
derived by fusing B -lymphocytes with tumor cells.  
 
In-vivo. Procedures conducted in living organisms.  
Look -back: documented procedure to trace biological me dicinal substances or products which may 
be adversely affected by the use or incorporation of animal or human materials when either such 
materials fail release tests due to the presence of contaminating agent(s) or when conditions of 
concern become apparen t in the source animal or human.  
 
Master cell bank (MCB). An aliquot of a single pool of cells which generally has been prepared 
from the selected cell clone under defined conditions, dispensed into multiple containers and stored 
under defined conditions. The MCB is used to derive all working cell banks.  
 
Master virus seed (MVS) – as above, but in relation to viruses; master transgenic bank – as above 
but for transgenic plants or animals.  
 
Monosepsis (axenic). A single organism in culture which is not cont aminated with any other 
organism.  
 
Multi -product facility. A facility that manufactures, either concurrently or in campaign mode, a 
range of different biological medicinal substances and products and within which equipment train(s) 
may or may not be dedica ted to specific substances or products.  
 
Plasmid. A plasmid is a piece of DNA usually present in a bacterial cell as a circular entity separated 
from the cell chromosome; it can be modified by molecular biology techniques, purified out of the 
bacterial cel l and used to transfer its DNA to another cell.  
 
Primary cell lot – a pool of primary cells minimally expanded to attain a sufficient number for a 
limited number of applications . 
 
Responsible Person (RP). A person responsible for ensuring  that each batch of (biological) active 
substance or medicinal product has been manufactured and checked in compliance with the laws in 
force and in accordance with the specifications and/or requirements of the marketing authorization. 
The RP is equivalent  to the EU term “Qualified Person”27. 
 
Responsible Person (RP) for blood or tissue establishment. This term is equivalent to the EU term 
                                                 
27 In the EEA, see Article 48 of Directive 2001/83/EC and Article 52 of Directive 2001/82/EC.  
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Page 63 of 234  “Responsible Person”28. 
 
Scaffold – a support, delivery vehicle or matrix that may provide structure for or facilitate th e 
migration, binding or transport of cells and/or bioactive molecules.  
 
Somatic cells. Cells, other than reproductive (germ line) cells, which make up the body of a human 
or animal. These cells may be autologous (from the patient), allogeneic (from another  human being) 
or xenogeneic (from animals) somatic living cells, that have been manipulated or altered ex vivo, to 
be administered in humans to obtain therapeutic , diagnostic or preventive effects.  
 
Specified pathogen free (SPF) – animal materials (e.g. ch ickens, embryos or cell cultures) used for 
the production or quality control of biological medicinal products derived from groups (e.g. flocks 
or herds) of animals free from specific  pathogens (SPF). Such flocks or herds are defined as animals 
sharing a co mmon environment and having their own caretakers who have no contact with non -SPF 
groups.  
 
Transgenic. An organism that contains a foreign gene in its normal genetic component for the 
expression of biological pharmaceutical materials.  
 
Vector. An agent of transmission, which transmits genetic information from one cell or organism to 
another, e.g. plasmids, liposomes, viruses.  
 
Viral vector. A vector derived from a virus and modified by means of molecular biology techniques 
in a way as to retain some, but no t all, the parental virus genes; if the genes responsible for virus 
replication capacity are deleted, the vector is made replication -incompetent.  
 
Working cell bank (WCB) – a homogeneous pool of micro -organisms or cells, that are distributed 
uniformly into  a number of containers derived from a MCB that are stored in such a way to ensure 
stability and for use in production Working virus seed (WVS) – as above but in relation to viruses, 
working transgenic bank – as above but for transgenic plants or animals.  
 
Zoonosis. Animal diseases that can be transmitted to humans.  
  
                                                 
28 In the EEA, see Article 17 of Directive 2004 /23/EC.  
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Page 64 of 234  ANNEX 3: MANUFACTURE OF RADIOPHARMACEUTICALS PRINCIPLE  
 
The manufacture of radiopharmaceuticals should be undertaken in accordance with the principles of 
Good Manufacturing Practice for Medici nal Products Part I and II. This annex specifically addresses 
some of the practices, which may be specific for radiopharmaceuticals.  
 
Note i . Preparation of radiopharmaceuticals in radio -pharmacies (hospitals or certain pharmacies), 
using Generators and Ki ts with a marketing authorization or a national license, is not covered by this 
guideline, unless covered by national requirement.  
 
Note ii.  According to radiation protection regulations it should be ensured that any medical exposure 
is under the clinical responsibility of a practitioner. In diagnostic and therapeutic nuclear medicine 
practices a medical physics expert should be available.  
 
Note iii . This annex is also applicable to radiopharmaceuticals used in clinical trials.  
 
Note iv . Transport of radiopharmaceuticals is regulated by the International Atomic Energy 
Association (IAEA) and radiation protection requirements.  
 
Note v . It is recognized that there are acceptable methods, other than those described in this annex, 
which are capable of achie ving the principles of Quality Assurance. Other methods should be 
validated and provide a level of Quality Assurance at least equivalent to those set out in this annex.  
 
INTRODUCTION  
 
The manufacturing and handling of radiopharmaceuticals is potentially ha zardous. The level of risk 
depends in particular upon the types of radiation, the energy of radiation and the half -lives of 
radioactive isotopes. Particular attention must be paid to the prevention of cross - contamination, to 
the retention of radionuclide contaminants, and to waste disposal.  
 
Due to short shelf -life of their radionuclides, some radiopharmaceuticals may be released before 
completion of all quality control tests. In this case, the exact and detailed description of the whole 
release procedure including the responsibilities of the involved personnel and the continuous 
assessment of the effectiveness of the quality assurance system is essential.  
 
This guideline is applicable to manufacturing procedures employed by industrial manufacturers, 
Nuclear Centers/Institutes and PET Centers for the production and quality control of the following 
types of products:  
 
a. Radiopharmaceuticals  
b. Positron Emitting (PET) Radiopharmaceuticals  
c. Radioactive Precursors for radiopharmaceutical production  
d. Radionuclide Generators  
 
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Page 65 of 234  Type of 
manufac
ture Non - 
GMP 
* GMP part II & I (Increasing) including 
relevant annexes  
Radiopharm
aceuticals 
PET 
Radiopharm
aceuticals 
Radioactive 
Precursors  Reactor/Cy
clotron 
Production  Chemic
al 
synthes
is Purificati
on steps  Processi
ng, 
formulati
on and 
dispensin
g Aseptico
r final 
sterilizat
ion 
Radionuclide  
Generators  Reactor/
Cyclotro
n 
Producti
on Processing  
* Target and transfer system from cyclotron to synthesis rig may be considered as the first step of 
active substance manufacture.  
 
The manufacturer of the final radiopharmaceutical should describe and justify the steps for 
manufacture of the active substance and the final medicinal product and which GMP (part I or II) 
applies for the specific process/manufacturing steps.  
 
Preparation of radiopharmaceuticals involves adherence to regulations on radiation protection.  
Radiopharmaceuticals to be administered parenterally should comply with sterility requirements for 
parenteral and, where relevant, aseptic working conditions for the manufac ture of sterile medicinal 
products, which are covered in PIC/S GMP Guide, Annex 1.  Specifications and quality control testing 
procedures for the most commonly used radiopharmaceuticals are specified in the European (or other 
relevant) Pharmacopoeia or in t he marketing authorization.  
 
Clinical Trials  
 
Radiopharmaceuticals intended for use in clinical trials as investigational medicinal products should 
in addition be produced in accordance with the principles in PIC/S GMP Guide, Annex 13.  
 
3.1 QUALITY ASSURANCE  
 
Quality assurance is of even greater importance in the manufacture of radiopharmaceuticals because 
of their particular characteristics, low volumes and in some circumstances the need to administer the 
product before testing is complete.  
 
As with all pharmaceuticals, the products must be well protected against contamination and cross -
contamination. However, the environment and the operators must also be protected against radiation. 
This means that the role of an effective quality assurance system is of  the utmost importance.  
 
It is important that the data generated by the monitoring of premises and processes are rigorously Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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Page 66 of 234  recorded and evaluated as part of the release process.  The principles of qualification and validation 
should be applied to the manuf acturing of radiopharmaceuticals and a risk management approach 
should be used to determine the extent of qualification/validation, focusing on a combination of Good 
Manufacturing Practice and Radiation Protection.  
 
3.2 PERSONNEL  
 
All manufacturing operations should be carried out under the responsibility of personnel with 
additional competence in radiation protection. Personnel involved in production, analytical control 
and release of radiopharmaceuticals should be appropriately trained in radiopharmaceutical specific 
aspects of the quality management system. The Authorized Person should have the overall 
responsibility for release of the products.  
 
All personnel (including those concerned with cleaning and maintenance) employed in areas where 
radioactive produc ts are manufactured should receive additional training adapted to this class of 
products.  Where production facilities are shared with research institutions, the research personnel 
must be adequately trained in GMP regulations and the QA function must revie w and approve the 
research activities to ensure that they do not pose any hazard to the manufacturing of 
radiopharmaceuticals.  
 
3.3 PREMISES AND EQUIPMENT  
 
General  
 
Radioactive products should be manufactured in controlled (environmental and radioactive) areas. 
All manufacturing steps should take place in self -contained facilities dedicated to 
radiopharmaceuticals  
 
Measures should be established and implemented to prevent cross - contamination from personnel, 
materials, radionuclides etc. Closed or contained equipment should be used whenever appropriate. 
Where open equipment is used, or equipment is opened, precautions should be taken to minimize the 
risk of contamination. The risk assessment should demonstrate that the environmental cleanliness 
level proposed is suitable for the type of product being manufactured.  
 
Access to the manufacturing areas should be via a gowning area and should be restricted to authorized 
personnel.  Workstations and their environment should be monitored with respect to radi oactivity, 
particulate and microbiological quality as established during performance qualification (PQ).  
 
Preventive maintenance, calibration and qualification programs should be operated to ensure that all 
facilities and equipment used in the manufacture of radiopharmaceutical are suitable and qualified. 
These activities should be carried out by competent personnel and records and logs should be 
maintained.  
 
Precautions should be taken to avoid radioactive contamination within the facility. Appropriate 
controls should be in place to detect any radioactive contamination, either directly through the use of 
radiation detectors or indirectly through a swabbing routine.  Equipment should be constructed so that Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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Page 67 of 234  surfaces that come into contact with the product are not reactive, additive or absorptive so as to alter 
the quality of the radiopharmaceutical.  
 
Re-circulation of air extracted from area where radioactive products are handled should be avoided 
unless justified. Air outlets should be designed to minimize env ironmental contamination by 
radioactive particles and gases and appropriate measures should be taken to protect the controlled 
areas from particulate and microbial contamination.  In order to contain radioactive particles, it may 
be necessary for the air pr essure to be lower where products are exposed, compared with the 
surrounding areas. However, it is still necessary to protect the product from environmental 
contamination. This may be achieved by, for example, using barrier technology or airlocks, acting a s 
pressure sinks.  
 
Sterile production  
 
Sterile radiopharmaceuticals may be divided into those, which are manufactured aseptically, and 
those, which are terminally sterilized. The facility should maintain the appropriate level of 
environmental cleanliness for the type of operation being performed. For manufacture of sterile 
products, the working zone where products or containers may be exposed to the environment, the 
cleanliness requirements should comply with the requirements described in the PIC/S GMP Gui de, 
Annex 1.  For manufacture of radiopharmaceuticals a risk assessment may be applied to determine 
the appropriate pressure differences, air flow direction and air quality.  
 
In case of use of closed and automated systems (chemical synthesis, purification, on-line sterile 
filtration) a grade C environment (usually “Hot -cell”) will be suitable. Hot -cells should meet a high 
degree of air cleanliness, with filtered feed air, when closed. Aseptic activities must be carried out in 
a grade A area.  Prior to the sta rt of manufacturing assembly of sterilized equipment and consumables 
(tubing, sterilized filters and sterile closed and sealed vials to a sealed fluid path) must be performed 
under aseptic conditions.  
 
3.4 DOCUMENTATION  
 
All documents related to the manufactur e of radiopharmaceuticals should be prepared, reviewed, 
approved and distributed according to written procedures.  
 
Specifications should be established and documented for raw materials, labelling and packaging 
materials, critical intermediates and the finished radiopharmaceutical. Specifications should also be 
in place for any other critical items used in the manufacturing process, such as process aids, gaskets, 
sterile filtering kits, that could critically impact on quality.  
 
Acceptance criteria should  be established for the radiopharmaceutical including criteria for release 
and shelf life specifications (examples: chemical identity of the isotope, radioactive concentration, 
purity, and specific activity).  
 
Records of major equipment use, cleaning, sani tization or sterilization and maintenance should show 
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Page 68 of 234  for the persons involved in these activities.  Records should be retained for at least 3 years unless 
another time frame  is specified in national requirements.  
 
3.5 PRODUCTION  
 
Production of different radioactive products in the same working area (i.e. hot - cell, LAF unit), at the 
same time should be avoided in order to minimize the risk of cross -contamination  or mix - up. 
 
Special attention should be paid to validation including validation of computerized systems which 
should be carried out in accordance with compliance  PIC/S GMP Guide, Annex 11. New 
manufacturing processes should be validated prospectively.  
 
The critical parameters should normally be identified before or during validation and the ranges 
necessary for reproducible operation should be defined.  Integrity testing of the membrane filter 
should be performed for aseptically filled products, taking int o account the need for radiation 
protection and maintenance of filter sterility.  
 
Due to radiation exposure it is accepted that most of the labelling of the direct container is  done prior 
to manufacturing. Sterile empty closed vials may be labelled with pa rtial information prior to filling 
providing that this procedure does not compromise sterility or prevent visual control of the filled vial.  
 
3.6 QUALITY CONTROL  
 
Some radiopharmaceuticals may have to be distributed and used on the basis of an assessment of 
batch documentation and before all chemical and microbiology tests have been completed.  
 
Radiopharmaceutical product release may be carried out in two or more stages, before and after full 
analytical testing:  
a. Assessment by a designated person of batch processing records, which should cover production 
conditions and analytical testing performed thus far, before allowing transportation of the 
radiopharmaceutical under quarantine status to the clinical department.  
b. Assessment of the final analytical data, e nsuring all deviations from normal procedures are 
documented, justified and appropriately released prior to documented certification by the 
Authorized Person. Where certain test results are not available before use of the product, the 
Authorized Person sho uld conditionally certify the product before it is used and should finally 
certify the product after all the test results are obtained.  
 
Most radiopharmaceuticals are intended for use within a short time and the period of validity with 
regard to the radioactive shelf -life, must be clearly stated.  Radiopharmaceuticals having 
radionuclides with long half -lives should be tested to show that  they meet all relevant acceptance 
criteria before release and certification by the Authorized Person.  
 
Before testi ng is performed samples can be stored to allow sufficient radioactivity decay. All tests 
including the sterility test should be performed as soon as possible.  A written procedure detailing the 
assessment of production and analytical data, which should be c onsidered before the batch is Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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Products that fail to meet acceptance criteria should be rejected. If the material is reprocessed, pre -
established procedures should be followed and the finished product should meet acceptan ce criteria 
before release. Returned products may not be reprocessed and must be stored as radioactive waste.  
 
A procedure should also describe the measures to be taken by an Authorized  Person if unsatisfactory 
test results (Out -of-Specification) are obtai ned after dispatch and before expiry. Such events should 
be investigated to include the relevant corrective and preventative actions taken to prevent future 
events. This process must be documented.  
 
Information should be given to the clinical responsible p ersons, if necessary. To facilitate this, a 
traceability system should be implemented for radiopharmaceuticals.  A system to verify the quality 
of starting materials should be in place. Supplier approval should include an evaluation that provides 
adequate a ssurance that the material consistently meets specifications. The starting materials, 
packaging materials and critical process aids should be purchased from approved suppliers.  
 
3.7 REFERENCE AND RETENTION SAMPLES  
 
For radiopharmaceuticals sufficient samples o f each batch of bulk formulated product should be 
retained for at least six months after expiry of the finished medicinal product unless otherwise 
justified through risk management.  
 
Samples of starting materials, other than solvents, gases  or water used in the manufacturing process 
should be retained for at least two years after the release of the product. That period may be shortened 
if the period of stability of the material as indicated in the relevant specification is shorter.  
 
Other co nditions may be defined by agreement with the competent authority, for the sampling and 
retaining of starting materials and products manufactured individually or in small quantities or when 
their storage could raise special problems.  
 
3.8 DISTRIBUTION  
 
Distribution of the finished product under controlled conditions, before all appropriate test results 
are available, is acceptable for radiopharmaceuticals, providing the product is not administered by 
the receiving institute until satisfactory test result s have been received and assessed by a designated 
person.  
 
GLOSSARY  
 
Preparation : handling and radio -labelling of kits with radionuclide eluted from generators or 
radioactive precursors within a hospital. Kits, generators and precursors should have a marke ting 
authorization or a national license.  
 
Manufacturing : production, quality control and release and delivery of radiopharmaceuticals from Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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Hot–cells: shielded workstations for manufacture and handling of radioactive materials. Hot -cells 
are not necessarily designed as an isolator.  
 
Authorized person : Person recognized by the authority as having the necessary basic scientific and 
technical background and experience.  
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Page 71 of 234  ANNEX 4: MANUFACTURE OF VETERINARY MEDI CINAL PRODUCTS OTHER THAN 
IMMUNOLOGICALS  
 
4.1 MANUFACTURE OF PREMIXES FOR MEDICATED FEEDING STUFFS  
 
For the purposes of these paragraphs,  
1. A medicated feeding stuff is any mixture of a veterinary medicinal product or products and 
feed or feeds which is ready prepared for marketing and intended to be fed to animals without 
further processing because of its curative or preventative properties or other properties (e.g. 
medical diagnosis, restoration, correction or modification of physiological functions in 
animal s): 
 
2. A pre -mix for medicated feeding stuffs is any veterinary medicinal product prepared in advance 
with a view to the subsequent manufacture of medicated feeding stuffs.  
 
The manufacture of premixes for medicated feeding stuffs requires the use of large quantities of 
vegetable matter which is likely to attract insects and rodents. Premises should be designed, equipped 
and operated to minimize this risk (point 3.4.) and should also be subject to a regular pest control 
program.  Because of the large volume o f dust generated during the production of bulk material for 
premixes, specific attention should be given to the need to avoid cross contamination and facilitate 
cleaning (point 3.14), for example through the installation of sealed transport systems and dus t 
extraction, whenever possible. The installation of such systems does not, however, eliminate the need 
for regular cleaning of production areas.  
 
Parts of the process likely to have a significant adverse influence on the stability of the active 
ingredient s) (e.g. use of steam in pellet manufacture) should be carried out in a uniform manner from 
batch to batch.  Consideration should be given to undertake the manufacture of premixes in dedicated 
areas. Which, if at all possible, do not form part of a main man ufacturing plant. Alternatively, such 
dedicated areas should be surrounded by a buffer zone in order to minimize the risk of contamination 
of other manufacturing areas.  
 
4.2 THE MANUFACTURE OF ECTOPARASITICIDES  
 
In derogation from point 3.6, ectoparasiticides for external application to animals, which are 
veterinary medicinal products, and subject to marketing authorization, may be produced and filled 
on a campaign basis in pesticide specific areas. However, other categories of veterinary  medicinal 
products should not be produced in such areas.  Adequate validated cleaning procedures should be 
employed to prevent cross contamination, and steps should be taken to ensure the secure storage of 
the veterinary medicinal product in accordance wit h the guide.Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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 4.3 THE MANUFACTURE OF VETERINARY MEDICINAL PRODUCTS CONTAINING 
PENICILLINS  
 
The use of penicillins in veterinary medicine does not present the same risks of hypersensitivity in 
animals as in humans. Although incidents of hypersensitivity have bee n recorded in horses and dogs, 
there are other materials which are toxic to certain species, e.g. the ionophore antibiotics in horses. 
Although desirable, the requirements that such products be manufactured in dedicated, self -contained 
facilities (point 3. 6) may be dispensed with in the case of facilities dedicated to the manufacture of 
veterinary medicinal products only.  
However, all necessary measures should be taken to avoid cross contamination and any risk to 
operator safety in accordance with the guid e. In such circumstances, penicillin -containing products 
should be manufactured on a campaign basis and should be followed by appropriate, validated 
decontamination and cleaning procedures.  
 
RETENTION OF SAMPLES (POINT 1.4. VIII AND POINT 6.14.)  
 
It is recognized that because of the large volume of certain veterinary medicinal products in their 
final packaging, in particular premixes, it may not be feasible for manufacturers to retain samples 
from each batch in its final packaging. However, manufacturers  should ensure that sufficient 
representative samples of each batch are retained and stored in accordance with the guide.  
In all cases, the container used for storage should be composed of the same material as the market 
primary container in which the prod uct is marketed.  
 
STERILE VETERINARY MEDICINAL PRODUCTS  
 
Where this has been accepted by the competent authorities, terminally sterilized veterinary medicinal 
products may be manufactured in a clean area of a lower grade than the grade required in the annex 
on "Sterile preparations", but at least in a grade D environment.  
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 ANNEX 5: MANUFACTURE OF IMMUNOLOGICAL VETERINARY MEDICAL 
PRODUCTS PRINCIPLE  
 
The manufacture of immunological veterinary medicinal products has special characteristics which 
should be taken into consideration when implementing and assessing the quality assurance system.  
 
Due to the large number of animal species and related pathogenic agents, the variety of products 
manufactured is very wide and the volume of manufacture is often low ; hence, work on a campaign 
basis is common. Moreover, because of the very nature of this manufacture (cultivation steps, lack 
of terminal sterilization, etc.), the products must be particularly well protected against contamination 
and cross -contamination.  The environment also must be protected especially when the manufacture 
involves the use of pathogenic or exotic biological agents and the worker must be particularly well 
protected when the manufacture involves the use of biological agents pathogenic to m an. 
 
These factors, together with the inherent variability of immunological veterinary medicinal products 
and the relative inefficiency in particular of final product quality control tests in providing adequate 
information about products, means that the ro le of the quality assurance system is of the utmost 
importance. The need to maintain control over all of the following aspects of GMP, as well  as those 
outlined in this Guide, cannot be overemphasized. In particular, it is important that the data generate d 
by the monitoring of the various aspects of GMP (equipment, premises, product etc.) are rigorously 
assessed and informed decisions, leading to appropriate action, are made and recorded.  
 
1.1 PERSONNEL  
 
All personnel (including those concerned with cleaning and maintenance) employed in areas where 
immunological products are manufactured should be given training in and information on hygiene 
and microbiology. They should receive additional training specific to the products with which they 
work.  
 
Responsible pe rsonnel should be formally trained in some or all of the following fields: bacteriology, 
biology, biometry, chemistry, immunology, medicine, parasitology, pharmacy, pharmacology, 
virology and veterinary medicine and should also have an adequate knowledge o f environmental 
protection measures.  
 
Personnel should be protected against possible infection with the biological agents used in 
manufacture. In the case of biological agents known to cause disease in humans, adequate measures 
should be taken to prevent infection of personnel working with the agent or with experimental 
animals.  Where relevant, the personnel should be vaccinated and subject to medical examination.  
 
Adequate measures should be taken to prevent biological agents being taken outside the 
manuf acturing plant by personnel acting as a carrier. Dependent on the type of biological agent, such 
measures may include complete change of clothes and compulsory showering before leaving the 
production area.  
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 particularly important.  Prevention of contamination by personnel should be achieved by a set of 
measures and procedures to ensure that appropriate protective clothing is used during the different 
stages of the pro duction process.  
 
Prevention of cross -contamination by personnel involved in production should be achieved by a set 
of measures and procedures to ensure that they do not pass from one area to another unless they have 
taken appropriate measures to eliminate  the risk of contamination. In the course of a working day, 
personnel should not pass from areas where contamination with live microorganisms is likely or 
where animals are housed to premises where other products or organisms are handled. If such a 
passage  is unavoidable, clearly defined decontamination procedures, including change of clothing 
and shoes, and, where necessary, showering, should be followed by staff involved in any such 
production.  
 
Personnel entering a contained area where organisms had not been handled in open circuit operations 
in the previous twelve hours to check on cultures in sealed, surface decontaminated flasks would not 
be regarded as being at risk of contamination, unless the organism involved was an exotic.  
 
1.2 PREMISES  
 
Premises should be designed in such a way as to control both the risk to the product and to the 
environment. This can be achieved by the use of containment, clean, clean/contained or controlled 
areas.  Live biological agents should be handled in contained areas. The  level of containment should 
depend on the pathogenicity of the microorganism and whether it has been classified as exotic.  
 
Inactivated biological agents should be handled in clean areas. Clean areas should also be used when 
handling non -infected cells is olated from multicellular organisms and, in some cases, filtration -
sterilized media.  Open circuit operations involving products or components not subsequently 
sterilized should be carried out within a laminar air flow work station (grade A) in a grade B ar ea. 
 
Other operations where live biological agents are handled (quality control, research and diagnostic 
services, etc.) should be appropriately, contained and separated if production operations are carried 
out in the same building. The level of containmen t should depend on the pathogenicity of the 
biological agent and whether they have been classified as exotic. Whenever diagnostic activities are 
carried out, there is the risk of introducing highly pathogenic organisms. Therefore, the level of 
containment should be adequate to cope with all such risks. Containment may also be required if 
quality control or other activities are carried out in buildings in close proximity to those used for 
production.  Containment premises should be easily disinfected and shou ld have the following 
characteristics:  
a) The absence of direct venting to the outside;  
 
b) a ventilation with air at negative pressure. Air should be extracted through HEPA filters and 
not be recirculated except to the same area, and provided further HEPA filtration is used 
(normally this condition would be met by routing the recirculated air th rough the normal supply 
HEPAs for that area). However, recycling of air between areas may be permissible provided Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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 that it passes through two exhaust HEPAs, the first of which is continuously monitored for 
integrity, and there are adequate measures for safe  venting of exhaust air should this filter fail;  
 
c) Air from manufacturing areas used for the handling of exotic organisms should be vented 
through 2 sets of HEPA filters in series, and that from production areas not recirculated;  
 
d) A system for the collectio n and disinfect ion of liquid effluents including contaminated 
condensate from sterilizers, biogenerators, etc. Solid wastes, including animal carcasses, 
should be disinfected, sterilized or incinerated as appropriate. Contaminated filters should be 
remove d using a safe method;  
 
e) Changing rooms designed and used as air locks, and equipped with washing and showering 
facilities if appropriate. Air pressure differentials should be such that there is no flow of air 
between the work area and the external environm ent or risk of contamination of outer clothing 
worn outside the area;  
 
f) An air lock system for the passage of equipment, which is constructed so that there is no flow 
of contaminated air between the work area and the external environment or risk of 
contamin ation of equipment within the lock. The air lock should be of a size which enables the 
effective surface decontamination of materials being passed through it. Consideration should 
be given to having a timing device on the door interlock to allow sufficient  time for the 
decontamination process to be effective.  
 
g) In many instances, a barrier double -door autoclave for the secure removal of waste materials 
and introduction of sterile items.  
 
Equipment passes and changing rooms should have an interlock mechanism or other appropriate 
system to prevent the opening of more than one door at a time. Changing rooms should be supplied 
with air filtered to the same standard as that for the work area, and extracts to produce an adequate 
air circulation independent of that of the work area. Equipment passes should normally be ventilated 
in the same way, but unventilated passes, or those equipped with supply air only, may be acceptable.  
 
Production operations such as cell maintenance, media preparation, virus culture, etc. likely to cause 
contamination should be performed in separate areas. Animals and animal products should be 
handled with appropriate precautions.  
 
Production areas where biological agents particularly resistant to disinfect ion (e.g. spore - forming 
bacteria ) are handled should be separated and dedicated to that particular purpose until the biological 
agents have been inactivated.  
 
With the exception of blending and subsequent filling operations, one biological agent only should 
be handled at a time within an  area.  Production areas should be designed to permit disinfect ion 
between campaigns, using validated methods.  
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 Production of biological agents may take place in controlled areas provided it is carried out in totally 
enclosed and heat sterilized equipment,  all connections being also heat sterilized after making and 
before breaking. it may be acceptable for connections to be made under local laminar air flow 
provided these are few in number and proper aseptic techniques are used and there is no risk of 
leaka ge. The sterilization parameters used before breaking the connections must be validated for the 
organisms being used. Different products may be placed in different biogenerators, within the same 
area, provided that there is no risk of accidental cross - contamination. However, organisms generally 
subject to special requirements for containment should be in areas dedicated to such products.  
 
Animal houses where animals intended or used for production are accommodated, should be provided 
with the appropriate containment and/or clean area measures, and should be separate from other 
animal accommodation. Animal houses where animals used for quality control, involving the use of 
pathogenic biological agents, are accommodated, should be adequately contained.  Acces s to 
manufacturing areas should be restricted to authorized personnel. Clear and concise written 
procedures should be posted as appropriate.  Documentation relating to the premises should be readily 
available in a plant master file.  
 
The manufacturing site and buildings should be described in sufficient detail (by means of plans and 
written explanations) so that the designation and conditions. of use of all the rooms are correctly 
identified as well as the biological agents which are handled in them. The flo w of people and product 
should also be clearly marked.  
The animal species accommodated in the animal houses or otherwise on the site should be identified . 
The activities carried out in the vicinity of the site should also be indicated.  
Plans of contained a nd/or clean area premises, should describe the ventilation system indicating inlets 
and outlets, filters and their specifications, the number of air changes per hour, and pressure gradients. 
They should indicate which pressure gradients are monitored by a pressure  indicator.  
 
1.3 EQUIPMENT  
 
The equipment used should be designed and constructed so that it meets the particular requirements 
for the manufacture of each product.  Before being put into operation the equipment should be 
qualified and validated and subsequently be regularly maintained and validated.  Where appropriate, 
the equipment should ensure satisfactory primary containment of the biological agents . Where 
appropriate, the equipment should be designed and constructed to  allow easy and effective 
decontamination and/or sterilization.  
 
Closed equipment used for the primary containment of the biological agents should be designed and 
constructed as to prevent any leakage or the formation of droplets and aerosols.  Inlets and outlets for 
gases should be p rotected so as to achieve adequate containment e.g. by the use of sterilizing 
hydrophobic filters.  The introduction or removal of material should take place using a stabilizable 
closed system, or possibly in an appropriate laminar air flow.  
 
Equipment wher e necessary should be properly sterilized before use, preferably by pressurized dry 
steam. Other methods can be accepted if steam sterilization cannot be used because of the nature of Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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 the equipment. It is important not to overlook such individual items as bench centrifuges and water 
baths.  Equipment used for purification, separation or concentration should be sterilized or disinfected 
at least between use for different products. The effect of the sterilization methods on the effectiveness 
and validity of -the equipment should be studied in order to determine the life span of the equipment.  
All sterilization procedures should be validated.  
 
Equipment should be designed so as to prevent any mix -up between different organisms or products. 
Pipes, valves and filte rs should be identified as to their function.  Separate incubators should be used 
for infected and non -infected containers and also generally for different organisms or cells. 
Incubators containing more than one organism or cell type will only be acceptable  if adequate steps 
are taken to seal, surface decontaminate and segregate the containers. Culture vessels, etc. should be 
individually labelled. The cleaning and disinfection of the items can be particularly difficult and 
should receive special attention.  Equipment used for the storage of biological agents or products 
should be designed and used in such a manner as to prevent any possible mix -up. All stored items 
should be clearly and unambiguously labelled and in leak -proof containers. Items such as cells and 
organisms seed stock should be stored in dedicated equipment.  
 
Relevant equipment, such as that requiring temperature control, should be fitted with recording 
and/or alarm systems.  To avoid breakdowns, a system of preventive maintenance, together with trend 
analyses of recorded data, should be implemented.  The loading of freeze driers requires an 
appropriate clean/contained area:  
 
h) Unloading freeze dryers  contaminates the immediate environment. Therefore, for single -ended 
freeze dryers , the clean room should be decontaminated before a further manufacturing batch 
is introduced into the area, unless this contains the same organisms, and double door freeze 
dryers  should be sterilized after each cycle unless opened in a clean area.  
 
i) Sterili zation of freeze dryers  should be done in accordance with item 23. In case of campaign 
working, they should at least be sterilized after each campaign.  
 
1.4 ANIMALS AND ANIMAL HOUSES  
 
Animal houses should be separated from the other production premises and suitably designed.  The 
sanitary status of the animals used for production should be defined, monitored, and recorded. Some 
animals should be handled as defined in specific monographs (e.g. Specific Pathogens Free flocks).  
 
Animals, biological agents, and t ests carried out should be the subject of an identification system so 
as to prevent any risk of confusion and to control all possible hazards.  
 
1.5 DISINFECTION - WASTE DISPOSAL  
 
Disinfection  and/or wastes and effluents disposal may be particularly important i n the case of 
manufacture of immunological products. Careful consideration should therefore be given to 
procedures and equipment aiming at avoiding environmental contamination as well as to their Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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 validation and qualification.  
 
1.6 PRODUCTION  
 
Because of the wide variety of products, the frequently large number of stages involved in the 
manufacture of immunological veterinary medicinal products and the nature of the biological 
processes, careful attention must be paid to adherence to validated operating proced ures, to the 
constant monitoring of production at all stages and to in -process controls.  Additionally, special 
consideration should be given to starting materials, media and the use of a seed lot system.  
 
STARTING MATERIALS  
 
The suitability of starting materials should be clearly defined in written specifications. These should 
include details of the supplier, the method of manufacture, the geographical origin and the animal 
species from which the materials are derived. The controls to be applied to start ing materials must be 
included. Microbiological controls are particularly important.  
 
The results of tests on starting materials must comply with the specifications.  Where the tests take a 
long time (e.g. eggs from SPF flocks) it may be necessary to process starting materials before the 
results of analytical controls are available. In such cases, the release of a finished product is 
conditional upon satisfactory results of the tests on starting materials.  
 
Special attention should be paid to knowledge  of the supplier's quality assurance system in assessing 
the suitability of a source and the extent of quality control testing required.  Where possible, heat is 
the preferred method for sterilizing starting materials. If necessary, other validated methods,  such as 
irradiation, may be used.  
 
MEDIA  
 
The ability of media to support the desired growth should be properly validated in advance.  Media 
should preferably be sterilized in situ or in line. Heat is the preferred method. Gases, media, acids, 
alkalis, defoaming agents and other materials introduced into sterile biogenerators should themselves 
be sterile.  
 
SEED LOT AND CELL BANK SYSTEM  
 
In order to prevent the unwanted drift of properties which might ensue from repeated subcultures or 
multiple generation s, the production of immunological veterinary medicinal products obtained by 
microbial, cell or tissue culture, or propagation in embryos and animals, should be based on a system 
of seed lots and/or cell banks.  
 
The number of generations (doublings, passag es) between the seed lot or cell bank and the finished 
product should be consistent with the dossier of authorization for marketing.  Seed lots and cell banks 
should be adequately characterized and tested for contaminants. Acceptance criteria for new seed l ots Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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 should be established. Seed lots and cell banks should be established, stored and used in such a way 
as to minimize the risks of contamination, or any alteration. During the establishment of the seed lot 
and cell bank, no other living or infectious mat erial (e.g. virus or cell lines) should be handled 
simultaneously in the same area or by the same person.  
 
Establishment of the seed lot and cell bank should be performed in a suitable environment to protect 
the seed lot and the cell bank and, if applicabl e, the personnel handling it and the external 
environment.  The origin, form and storage conditions of seed material should be described in full. 
Evidence of the stability and recovery of the seeds and banks should be provided. Storage containers 
should be hermetically sealed, clearly labelled and stored at an appropriate temperature. Storage 
conditions should be properly monitored. An inventory should be kept and each container accounted 
for. 
 
Only authorized personnel should be allowed to handle the materi al and this handling should be done 
under the supervision of a responsible person. Different seed lots or cell banks should be stored in 
such a way to avoid confusion or cross -contamination errors. It is desirable to split the seed lots and 
cell banks and to store the parts at different locations so as to minimize the risk of total loss.  
 
OPERATING PRINCIPLES  
 
The formation of droplets and the production of foam should be avoided or minimized during 
manufacturing processes. centrifugation and blending procedures which can lead to droplet formation 
should be carried out in appropriate contained or clean/contained areas to prevent transfer of live 
organisms.  
 
Accidental spillages, especially of live organisms, must be dealt with quickly and safely. Validated 
decontamination measures should be available for each organism. Where different strains of single 
bacteria species or very similar viruses are involved, the process need be validated against only one 
of them, unless there is reason to believe tha t they may vary significantly in their resistance to the 
agent(s) involved.  
 
Operations involving the transfer of materials such as sterile media, cultures or product should be 
carried out in pre -sterilized closed systems wherever possible. Where this is n ot possible, transfer 
operations must be protected by laminar airflow work stations.  Addition of media or cultures to 
biogenerators and other vessels should be carried out under carefully controlled conditions to ensure 
that contamination is not introduced . Care must be taken to ensure that vessels are correctly connected 
when addition of cultures takes place.  
 
When necessary, for instance when two or more fermenters are within a single area, sampling and 
addition ports, and connectors (after connection, be fore the flow of product, and again before 
disconnection) should be sterilized with steam. In other circumstances, chemical disinfection of ports 
and laminar air flow protection of connections may be acceptable.  
 
Equipment, glassware, the external surfaces  of product containers and other such materials must be Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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 disinfected before transfer from a contained area using a validated method (see 47 above). Batch 
documentation can be a particular problem. only the absolute minimum required to allow operations 
to GM P standards should enter and leave the area. If obviously contaminated, such as by spills or 
aerosols, or if the organism involved is an exotic, the paperwork must be adequately disinfected 
through an equipment pass, or the information transferred out by s uch means as photocopy or fax.  
 
Liquid or solid wastes such as the debris after harvesting eggs, disposable culture bottles, unwanted 
cultures or biological agents, are best sterilized or disinfected before transfer from a contained area. 
However, alternat ives such as sealed containers or piping may be appropriate in some cases.  
 
Articles and materials, including documentation, entering a production room should be carefully 
controlled to ensure that only materials concerned with production are introduced. T here should be a 
system which ensures that materials entering a room are reconciled with those leaving so that 
accumulation of materials within the room does not occur.  
 
Heat stable articles and materials entering a clean area or clean/contained area shoul d do so through 
a double -ended autoclave or oven. Heat labile articles and materials should enter through an airlock 
with interlocked doors where they are disinfected. Sterilization of articles and materials elsewhere is 
acceptable provided that they are d ouble wrapped and enter through an airlock with the appropriate 
precautions.  Precautions must be taken to avoid contamination or confusion during incubation. There 
should be a cleaning and disinfection procedure for incubators. Containers in incubators sho uld be 
carefully and clearly labeled.  
 
With the exception of blending and subsequent filling operations (or when totally enclosed systems 
are used) only one live biological agent may be handled within a production room at any given time. 
Production rooms m ust be effectively disinfected between the handling of different live biological 
agents.  Products should be inactivated by the addition of inactivant accompanied by sufficient 
agitation. The mixture should then be transferred to a second sterile vessel, un less the container is of 
such a size and shape as to be easily inverted and shaken so as to wet all internal surfaces with the 
final culture/ inactivant mixture.  
 
Vessels containing inactivated product should not be opened or sampled in areas containing live 
biological agents. All subsequent processing of inactivated products should take place in clean areas 
grade A -B or enclosed equipment dedicated to inactivated products.  Careful consideration should be 
given to the validation of methods for sterilizati on, disinfection, virus removal and inactivation.  
 
Filling should be carried out as soon as possible following production.  Containers of bulk product 
prior to filling should be sealed, appropriately labelled and stored under specified conditions of 
temperature.  There should be a system to assure the integrity and closure of containers after filling.  
 
The capping of vials containing live biological agents must be performed in such a way that ensures 
that contamination of other products or escape of th e live agents into other areas or the external 
environment does not occur.  
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 For various reasons there may be a delay between the filling of final containers and their labelling 
and packaging. Procedures should be specified for the storage of unlabelled con tainers in order to 
prevent confusion and to ensure satisfactory storage conditions. Special attention should be paid to 
the storage of heat labile or photosensitive products. Storage temperatures should be specified.  For 
each stage of production, the yiel d of product should be reconciled with that expected from that 
process. Any significant discrepancies should be investigated.  
 
1.7 QUALITY CONTROL  
 
In-process controls play an especially  important role in ensuring the consistency of the quality of 
biological medicinal products. Those controls which are crucial for the quality (e.g. virus removal) 
but which cannot be carried out on the finished product, should be performed at an appropriat e stage 
of production.  It may be necessary to retain samples of intermediate products in sufficient amounts  
and under appropriate storage conditions to allow repetition or confirmation of a batch control.  
 
There may be a requirement for the continuous monitoring of data during a production process, for 
example monitoring of physical parameters during fermentation.  Continuous culture of biological 
products is a common practice and special consideration needs to be given to the quality control 
requirement s arising from this type of production method.  
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 ANNEX 6: MANUFACTURE OF MEDICINAL GASES PRINCIPLE  
 
This Annex deals with the manufacture of active substance gases and the manufacture of medicinal 
gases.  
 
The delineation between the manufacture of the acti ve substance and the manufacture of the 
medicinal product should be clearly defined in each Marketing Authorization dossier. Normally, the 
production and purification steps of the gas belong to the field of manufacture of active substances. 
Gases enter the  pharmaceutical field from the first storage of gas intended for such use.  
 
Manufacture of active substance gases should comply with the Basic Requirements of this Guide 
(Part II), with the relevant part of this Annex, and with the other Annexes of the Gui de if relevant.  
 
Manufacture of medicinal gases should comply with the basic requirements of this Guide (Part I), 
with the relevant part of this Annex and with the other Annexes of the Guide if relevant.  
 
In the exceptional cases of continuous processes wh ere no intermediate storage of gas between the 
manufacture of the active substance and the manufacture of the medicinal product is possible, the 
whole process (from starting materials of active substance to medicinal finished product) should be 
considered as belonging to the pharmaceutical field. This should be clearly stated in the Marketing 
Authorization dossier.  
 
The Annex does not cover the manufacture and handling of medicinal gases in hospitals unless this 
is considered industrial preparation or manufacturing. However, relevant parts of this Annex may be 
used as a basis for such activities.  
 
MANUFACTURE OF ACTIVE SUBSTANCE GASES  
 
Active substance gases can be prepared by chemical synthesis or be obtained from natural sources 
followed by purificati on steps, if necessary (as for example in an air separation plant).  The processes 
corresponding to these two methods of manufacturing active substance gases should comply with 
Part II of the Basic Requirements. However:  
 
(a) the requirements regarding starting  materials for active substances (Part II, Chapter 7) do not 
apply to the production of active substance gases by air separation (however, the manufacturer 
should ensure that the quality of ambient air is suitable for the established process and any 
change s in the quality of ambient air do not affect the quality of the active substance gas);  
(b) the requirements regarding on -going stability studies (Part II, Chapter 11.5), which are used to 
confirm storage conditions and expiry/retest dates (Part II, Chapter 11 .6), do not apply in case 
initial stability studies have been replaced by bibliographic data; and  
(c) the requirements regarding reserve/retention samples (Part II, Chapter 11.7) do not apply to 
active substance gases, unless otherwise specified.  
  
The production of active substance gases through a continuous process (e.g. air separation) should Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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 be continuously monitored for quality. The results of this monitoring should be kept in a manner 
permitting trend evaluation.  In addition:  
 
(c) transfers and del iveries of active substance gases in bulk should comply with the same 
requirements as those mentioned below for the medicinal gases (sections 19 to 21 of this 
Annex);  
(d) filling of active substance gases into cylinders or into mobile cryogenic vessels should comply 
with the same requirements as those mentioned below for the medicinal gases (sections 22 to 
37 of this Annex) as well as Part II Chapter 9.  
 
MANUFACTURE OF MEDICINAL GASES  
 
Manufacture of medicinal gases is generally carried out in closed equipment.  Consequently, 
environmental contamination of the product is minimal. However, risks of contamination (or cross 
contamination with other gases) may arise, in particular because of the reuse of containers.  
Requirements applying to cylinders should also appl y to cylinders’ bundles (except storage and 
transportation under cover).  
 
6.1 PERSONNEL  
 
All personnel involved in the manufacture and distribution of medicinal gases should receive an 
appropriate GMP training applying to this type of products. They should be aware of the critically 
important aspects and potential hazards for patients from these products.  Personnel of subcontractors 
that could influence the quality of medicinal gases (such as personnel in charge of maintenance of 
cylinders or valves) should be appropriately trained.  
 
6.2 PREMISES AND EQUIPMENT  
 
Premises  
 
Cylinders and mobile cryogenic vessels should be checked, prepared, filled and stored in a separate 
area from non -medicinal gases, and there should be no exchange of cylinders/mobile cryogenic 
vessels between these areas. However, it could be accepted to check, prepare, fill and store other 
gases in the same areas, provided they comply with the specifications of medicinal gases and that the 
manufacturing operations are performed according to GMP  standards.  
 
Premises should provide sufficient space for manufacturing, testing and storage operations to avoid 
the risk of mix -up. Premises should be designated to provide:  
a) separate marked areas for different gases;  
b) clear identification and segregation of cylinders/mobile cryogenic vessels at various stages of 
processing (e.g. “waiting checking”, "awaiting filling", "quarantine", "certified", “rejected”, 
“prepared deliveries”).  
 
The method used to achieve these various levels of segregation will depend o n the nature, extent and Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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 complexity of the overall operation. Marked -out floor areas, partitions, barriers, signs, labels or other 
appropriate means could be used.  
 
Empty cylinders/home cryogenic vessels after sorting or maintenance, and filled cylinders/home 
cryogenic vessels should be stored under cover, protected from adverse weather conditions. Filled 
cylinders/mobile cryogenic vessels should be stored in a manner that ensures that they will be 
delivered in a clean state, compatible with the environment in which they will be used.  Specific 
storage conditions should be provided as required by the Marketing Authorization (e.g. for gas 
mixtures where phase separation occurs on freezing).  
 
Equipment  
 
Equipment should be designed to ensure the corr ect gas is filled into the correct container. There 
should normally be no cross connections between pipelines carrying different gases. If cross 
connections are needed (e.g. filling equipment of mixtures), qualification should ensure that there is 
no risk of cross contamination between the different gases. In addition, the manifolds should be 
equipped with specific connections. These connections may be subject to international or national 
standards. The use of connections meeting different standards at the same filling site should be 
carefully controlled, as well as the use of adaptors needed in some situations to bypass the specific 
fill connection systems.  
 
Tanks and tankers should be dedicated to a single and defined quality of gas. However, medicinal 
gases may be stored or transported in the same tanks . Other containers used for intermediate storage, 
or tankers, as the same non - medicinal gas, provided that the quality of the latter is at least equal to 
the quality of the medicinal gas and that GMP sta ndards are maintained. In such cases, quality risk 
management should be performed and documented.  
 
A common system supplying gas to medicinal and non -medicinal gas manifolds is only acceptable 
if there is a validated method to prevent backflow from the non-medicinal gas line o the medicinal 
gas line.  Filling manifolds should be dedicated to a single medicinal gas or to a given mixture of 
medicinal gases. In exceptional cases, filling gases used for other medical purposes on manifolds 
dedicated to medicin al gases may be acceptable if justified and performed under control. In these 
cases, the quality of the non -medicinal gas should be at least equal to the required quality of the 
medicinal gas and GMP standards should be maintained. Filling should then be c arried out by 
campaigns.  
 
Repair and maintenance operations (including cleaning and purging) of equipment, should not 
adversely affect the quality of the medicinal gases. In particular, procedures should describe the 
measures to be taken after repair and m aintenance operations involving breaches of the system’s 
integrity. Specifically, it should be demonstrated that the equipment is free from any contamination 
that may adversely affect the quality of the finished product before releasing it for use. Records  
should be maintained.  
 
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 service (after transporting non -medicinal gas in the conditions mentioned in section 12, or after a 
maintenance operation). This should in clude analytical testing.  
 
6.3 DOCUMENTATION  
 
Data included in the records for each batch of cylinders/mobile cryogenic vessels must ensure that 
each filled cylinder is traceable to significant aspects of the relevant filling operations. As 
appropriate, the following should be entered:  
 
a) the name of the product;  
b) batch number;  
c) the date and the time of the filling operations;  
d) identification of the person(s) carrying out each significant step (e.g. line clearance, 
receipt, preparation before filling, filling etc.);  
e) batch(es) reference(s) for the gas(es) used for the filling operation as referred to in 
section 22, including status;  
f) equipment used (e.g. filling manifold);  
g) quantity of cylinders/mobile cryogenic vessels before filling, including individual 
identif ication references and water capacity(ies);  
h) pre-filling operations performed (see section 30);  
i) key parameters that are needed to ensure correct fill at standard conditions;  
j) results of appropriate checks to ensure the containers have been filled;  
k) a sample o f the batch label;  
l) specification of the finished product and results of quality control tests(including 
reference to the calibration status of the test equipment);  
m) quantity  of rejected  cylinders/mobile  cryogenic  vessels, with 
individual identification references and reasons for rejections;  
n) details of any problems or unusual events, and signed authorization for any deviation 
from filling instructions; and  
o) certification statement by the Authorized Person, date and signature.  
 
Records should be maintained for each batch of gas intended to be delivered into hospital tanks. 
These records should, as appropriate, include the following (items to be recorded may vary depending 
on local legislation):  
 
a) name of the product;  
b) batch number;  
c) identification reference for  the tank (tanker) in which the batch is certified;  
d) date and time of the filling operation;  
e) identification of the person(s) carrying out the filling of the tank (tanker);  
f) reference to the supplying tanker (tank), reference to the source gas as applicable;  
g) relevant details concerning the filling operation;  
h) specification of the finished product and results of quality control tests (including 
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 i) details of any problems or unusual events, and signed autho rization for any deviation 
from filling instructions; and  
j) certification statement by the Authorized Person, date and signature.  
 
6.4 PRODUCTION  
 
Transfers and deliveries of cryogenic and liquefied gas  
 
The transfers of cryogenic or liquefied gases from primary  storage, including controls before 
transfers, should be in accordance with validated procedures designed to avoid any contamination. 
Transfer lines should be equipped with non -return valves or other suitable alternatives. Flexible 
connections, and couplin g hoses and connectors should be flushed with the relevant gas before use.  
 
The transfer hoses used to fill tanks and tankers should be equipped with product -specific 
connections. The use of adaptors allowing the connection of tanks and tankers not dedicated to the 
same gases should be adequately controlled.  Deliveries of gas may be added to tanks containing the 
same quality of gas provided that a sample is tested to ensure that the quality of the delivered gas is 
acceptable. This sample may be  taken  from the gas to be delivered or from the receiving tank after 
delivery.  
 
Filling and labeling of cylinders and mobile cryogenic vessels  
 
Before filling cylinders and mobile cryogenic vessels, a batch (batches) of gas(es) should be 
determined, controlled according to specifications and approved for filling.  In the case of continuous 
processes as those mentioned in ‘Principle’, there should be adequate in -process controls to ensure 
that the gas complies with specifications.  
 
Cylinders, mobile cryogenic vess els and valves should conform to appropriate technical 
specifications and any relevant requirements of the Marketing Authorization. They should be 
dedicated to a single medicinal gas or to a given mixture of medicinal gases. Cylinders should be 
colour -code d according to relevant standards. They should preferably be fitted with minimum 
pressure retention valves with non -return mechanism in order to get adequate protection against 
contamination.  
 
Cylinders, mobile cryogenic vessels and valves should be checke d before first use in production, and 
should be properly maintained. Where medical devices have gone through a conformity assessment 
procedure1, the maintenance should address the medical device manufacturer’s instructions.  
 
Checks and maintenance operatio ns should not affect the quality and the safety of the medicinal 
product. The water used for the hydrostatic pressure testing carried out on cylinders should be at least 
of drinking quality.  
 
As part of the checks and maintenance operations, cylinders shou ld be subject to an internal visual 
inspection before fitting the valve, to make sure they are not contaminated with water or other Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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 contaminants. This should be done:  
 
● when they are new and initially put into medicinal gas service;  
● following any hydrostatic statutory pressure test or equivalent test where the valve is removed;  
● whenever the valve is replaced.  
 
After fitting, the valve should be kept closed to prevent any contamination from entering the cylinder. 
If there is any doubt about the internal condition of the cylinder, the valve should be removed and 
the cylinder internally inspected to ensure it has not been contaminated.  
 
Maintenance and repair operations of cylinders, mobile cryogenic vessels and valves are the 
responsibility of the  manufacturer of the medicinal product. If subcontracted, they should only be 
carried out by approved subcontractors, and contracts including technical agreements should be 
established. Subcontractors should be audited to ensure that appropriate standards are maintained.  
 
There should be a system in place to ensure traceability of cylinders, mobile cryogenic vessels and 
valves.  Checks to be performed before filling should include: in the case of cylinders, a check, carried 
out according to defined procedure, to ensure there is a positive residual pressure in each cylinder . If 
the cylinder is fitted with a minimum pressure retention valve, when there is no signal indicating 
there is a positive residual pressure, the correct functioning of the valve s hould be checked, and if the 
valve is shown not to function properly the cylinder should be sent to maintenance . If the cylinder is 
not fitted with a minimum pressure retention valve, when there is no positive residual pressure the 
cylinder should be put a side for additional measures, to make sure it is not contaminated with water 
or other contaminants; additional measures could consist of internal visual inspection followed by 
cleaning using a validated method : 
 
a) a check to ensure that all previous batch labels have been removed;  
b) a check that any damaged product labels have been removed and replaced;  
c) a visual external inspection of each cylinder, mobile cryogenic vessel and valve for dents, arc 
burns, debris, other damage and contamination with oil or grea se; cleaning should be done if 
necessary;  
d) a check of each cylinder or mobile cryogenic vessel outlet connection to determine that it is the 
proper type for the particular gas involved;  
e) a check of the date of the next test to be performed on the valve (in t he case of valves that need 
to be periodically tested);  
f) a check of the cylinders or mobile cryogenic vessels to ensure that any tests required by national 
or international regulations (e.g. hydrostatic pressure test or equivalent for cylinders) have been 
conducted and still is valid; and  
g) a check to determine that each container is colour -coded as specified in the Marketing 
Authorization (colour -coding of the relevant national / international standards).  
 
A batch should be defined for filling operations.  Cylinders which have been returned for refilling 
should be prepared with care in order to minimize risks for contamination in line with the procedures 
defined in the Marketing Authorization. These procedures, which should include evacuation and/or Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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 purging operations, should be validated.  For compressed gases a maximum theoretical impurity of 
500 ppm v/v should be obtained for a filling pressure of 200 bar at 15°C (and equivalent for other 
filling pressures).  
 
Mobile cryogenic vessels that have been returned  for refilling should be prepared with care in order 
to minimize the risks of contamination, in line with the procedures defined in the Marketing 
Authorization. In particular, mobile vessels with no residual pressure should be prepared using a 
validated me thod.  
 
There should be appropriate checks to ensure that each cylinder/mobile cryogenic vessel has been 
properly filled.  Each filled cylinder should be tested for leaks using an appropriate method, prior to 
fitting the tamper evident seal or device (see se ction 36). The test method should not introduce any 
contaminant into the valve outlet and, if applicable, should be performed after any quality sample is 
taken.  
 
After filling, cylinders valves should be fitted with covers to protect the outlets from conta mination. 
Cylinders and mobile cryogenic vessels should be fitted with tamper -evident seals or devices.  Each 
cylinder or mobile cryogenic vessel should be labelled. The batch number and the expiry date may 
be on a separate label.  
 
In the case of medicinal gases produced by mixing two or more different gases (in -line before filling 
or directly into the cylinders); the mixing process should be validated to ensure that the gases are 
properly mixed in every cylinder and that the mixture is homogeneous.  
 
6.5 QUALITY  CONTROL  
 
Each batch of medicinal gas (cylinders, mobile cryogenic vessels, hospital tanks) should be tested in 
accordance with the requirements of the Marketing Authorization and certified.  
 
Unless different provisions are required in the Marketing Author ization, the sampling plan and the 
analysis to be performed should comply, in the case of cylinders with the following requirements.  
 
a) In the case of a single medicinal gas filled via a multi -cylinder manifold, the gas from at least 
one cylinder from each manifold filling cycle should be tested for identity and assay each time 
the cylinders are changed on the manifold.  
 
b) In the case of a single medicinal gas filled into  cylinders one at a time, the gas from at least one 
cylinder of each uninterrupted filling  cycle should be tested for identity and assay. An example 
of an uninterrupted filling cycle is one shift's production using the same personnel, equipment, 
and batch of gas to be filled.  
 
c) In the case of a medicinal gas produced by mixing two or more gases in a cylinder from the 
same manifold, the gas from every cylinder should be tested for assay and identity of each 
component gas. For excipients, if any, testing on identity could be perfor med on one cylinder Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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 per manifold filling cycle (or per uninterrupted filling cycle in case of cylinders filled one at a 
time). Fewer cylinders may be tested in case of a validated  automated filling system.  
 
d) Premixed gases should follow the same principles as single gases when continuous in - line 
testing of the mixture to be filled is performed. Premixed gases should follow the same 
principle as medicinal gases produced by mixing gases in the cylinders when there is no 
continuous in - line testing of the mixt ure to be filled.  
 
e) Testing for water content should be performed unless otherwise justified. Other sampling and 
testing procedures that provide at least equivalent level of quality assurance may be justified.  
 
Unless different provisions are required in th e Marketing Authorization, final testing on mobile 
cryogenic vessels should include a test for assay and identity on each vessel. Testing by batches 
should only be carried out if it has been demonstrated that the critical attributes of the gas remaining 
in each vessel before refilling have been maintained.  
 
Cryogenic vessels retained by customers (hospital tanks or home cryogenic vessels), which are 
refilled in place from dedicated tankers do not need to be sampled after filling, provided that a 
certificate  of analysis on the contents of the tanker accompanies the delivery. However, it should be 
demonstrated that the specification of the gas in the vessels is maintained over the successive 
refilling.  Reference and retention samples are not required, unless o therwise specified.  On-going 
stability studies are not required in case initial stability studies have been replaced by bibliographic 
data.  
 
6.6 TRANSPORTATION OF PACKAGED GASES  
 
Filled gas cylinders and home cryogenic vessels should be protected during transportation so that, in 
particular, they are delivered to customers in a clean state compatible with the environment in which 
they will be used.  
 
GLOSSARY  
 
Definition of terms relating to manufacture of medicinal gases, which are not given in the glossary 
of the current PIC/S Guide to GMP, but which are used in this Annex are given below.  
 
Active substance gas  
Any gas intended to be an active substance for a medicinal product.  
 
Air separation  
Separation of atmospheric air into its constituent gases  using fractional distillation at cryogenic 
temperatures.  
 
Compressed gas  Guidelines on Good Manufacturing Practices on Medical Products_Annexes  
 
 
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 Gas which, when packaged under pressure is entirely gaseous at all temperatures above – 50oC. 
 
Container  
A container is a cryogenic vessel, (tank, tanker or other type of mobile cryo genic vessel), a cylinder, 
a cylinder bundle or any other package that is in direct contact with the gas.  
 
Cryogenic gas  
Gas which liquefies at 1.013 bar at temperatures below –150oC. 
 
Cylinder  
 
Container usually cylindrical suited for compressed, liquefied or dissolved gas, fitted with a device 
to regulate the spontaneous outflow of gas at atmospheric pressure and room temperature.  
 
Cylinder bundle  
An assembly of cylinders, which are fastened together interconnected by a manifold, transported and 
used as a unit.  
 
Evacuate  
To remove the residual gas from a container / system to a pressure less than 1.013 bar using a vacuum 
system.  
 
Gas 
Any substance that is completely gaseous at 1.013 bar and +20oC or has a vapor pressure exceeding 
3 bar at + 50oC.  
 
Home cryogenic vessel  
Mobile cryogenic vessel designed to hold liquid oxygen and dispense gaseous oxygen at patients’ 
home.  
 
Hydrostatic pressure test  
Test performed as required by national or international regulations in order to ensure that pressure 
containers are able to withstand pressures up to the container’s design pressure.  
 
Liquefied gas  
A gas which, when packaged for transport, is partially liquid (or solid) at a temperature above – 50 
0c  
 
Manifold  
Equipment or apparatus designed to enable one o r more gas containers to be emptied and filled at the 
same time.  
 
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 Gaseous impurity coming from a possible backflow that remains after the cylinders pre - treatment 
before filling. The calculation of the maximum theoretical residual impurity is only relevant for 
compressed gases and supposes that these gases act as perfect gases.  
 
Medicinal gas  
Any gas or mixture of gases classified as a medicinal product.  
 
Minimum pressure retention valve  
A cylinder valve, which maintains a positive pressure above atmospheric pressure in a gas cylinder 
after use, in order to prevent internal contamination of the cylinder.  
 
Mobile cryogenic vessel  
Mobile thermally insulated container designed to maintain the contents in a liquid st ate. In the Annex, 
this term does not include tankers . 
 
Non-return valve  
Valve which permits flow in one direction only.  
 
Purge  
To remove the residual gas from a container / system by first pressurizing and then venting  the gas 
used for purging to 1.013 b ar. 
Tank  
Static thermally insulated container designed for the storage of liquefied or cryogenic gas. They are 
also called “Fixed cryogenic vessels”.  
 
Tanker  
In the context of the Annex, thermally insulated containers are  fixed on a vehicle for the transport  of 
liquefied or cryogenic gas.  
 
Valve  
Device for opening and closing containers.  
 
Vent  
To remove the residual gas from a container / system down to 1.013 bar, by opening the container / 
system to the atmosphere .Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 ANNEX 7: MANUFACTURE OF HERBAL MEDICINAL PRODUCTS PRINCIPLE  
 
Because of their often complex and variable nature, control of starting materials, storage and 
processing assume particular importance in the manufacture of herbal medicinal products.  
 
The “starting material” in the manufacture of an herbal medicinal product29   can be a me dicinal plant, 
an herbal substance30 or an herbal preparation. The herbal substance should be of suitable quality and 
supporting data should be provided to the manufacturer of the herbal preparation/herbal medicinal 
product. Ensuring consistent quality of t he herbal substance may require more detailed information 
on its agricultural production. The selection of seeds, cultivation and harvesting conditions represent 
important aspects of the quality of the herbal substance and can influence the consistency of the 
finished product. Recommendations on an appropriate quality assurance system for good agricultural 
and collection practice are provided in national or international guidance documents on Good 
Agricultural and Collection Practice for starting materials of herbal origin31. 
 
This Annex applies to all herbal starting materials: medicinal plants, herbal substances or herbal 
preparations.  
 
Table illustrating the application of Good Practices to the manufacture of herbal  
medicinal products32  
 
Activity  Good 
Agricultura
l and 
Collection 
Practice 
(GACP) # Part II 
of the 
GMP 
Guide 
† Part I 
of the 
GMP 
Guide 
† 
Cultivation, collection and harvesting of 
plants, algae, fungi and lichens, and 
collection of exudates     
Cutting, and drying of plants, algae, 
fungi,  lichens and exudates *     
Expression from plants and distillation**     
                                                 
29 Throughout the annex and unless otherwise specified, the term “herbal medicinal product / preparation” includes 
“traditional herbal medicinal product / preparation”.  
30 The terms herbal substance and herbal preparation are considered to be equivalent to the terms herbal drug and 
herbal drug preparation respectively.  
31 European Medicines Agency (EMA), World Health Organization (WHO) or  equivalent  
32 This table expands in detail the herbal section of Table 1 in Part II of the GMP Guide.  
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 Comminution, processing of exudates, 
extraction from plants, fractionation, 
purification, concentration or 
fermentation of herbal substances     
Further processing into a dosage form  
including packaging as a medicinal 
product     
 
Explanatory Notes  
† The GMP classification of the herbal material is dependent upon the use made of it by the 
manufacturing authorization holder. The material may be classified as an active substance, an 
intermediate or a finished product. It is the responsibility of the man ufacturer of the medicinal product 
to ensure that the appropriate GMP classification is applied.  
 
* Manufacturers should ensure that these steps are carried out in accordance with the marketing 
authorization / registration. For those initial steps that take place in the field, as justified in the 
marketing authorization / registration, the national or international standards of Good Agricultural 
and Collection Practice for starting materials of herbal origin (GACP) # are applicable. GMP is 
applicable to further cutting and drying steps.  
 
** Regarding the expression from plants and distillation, if it is necessary for these activities to be 
an integral part of harvesting to maintain the quality of the product within the approved specifications, 
it is accep table that they are performed in the field, provided that the cultivation is in compliance 
with national or international standards of GACP#. These circumstances should be regarded as 
exceptional and justified in the relevant marketing authorization / regi stration documentation. For 
activities carried out in the field, appropriate documentation, control, and validation according to the 
GMP principles should be assured. Regulatory authorities may carry out GMP inspections of these 
activities in order to asse ss compliance.  
 
1.1 PREMISES  
 
Storage areas  
 
Herbal substances should be stored in separate areas. The storage area should be equipped in such a 
way as to give protection against the entry of insects or other animals, especially rodents. Effective 
measures should be taken to prevent the spread of any such animals and micro -organisms brought in 
with the crude substance, to prevent fermentation or mould growth and to prevent cross - 
contamination. Different enclosed areas should be used to quarantine incoming h erbal substances 
and for the approved herbal substances.  
 
The storage area should be well aerated and the containers should be located in such a way as to 
allow free circulation of air.  Special attention should be paid to the cleanliness and good maintenan ce Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 of the storage areas particularly when dust is generated.  Storage of herbal substances and herbal 
preparations may require special conditions of humidity, temperature or light protection; these 
conditions should be provided and monitored.  
 
Production area  
 
Specific provisions should be made during sampling, weighing, mixing and processing operations of 
herbal substances and herbal preparations whenever dust is generated, to facilitate cleaning and to 
avoid cross -contamination, as for example, dust extr action, dedicated premises, etc.  
 
1.2 EQUIPMENT  
 
The equipment, filtering materials etc. used in the manufacturing process must be compatible with 
the extraction solvent, in order to prevent any release or undesirable absorption of substances  that 
could affect  the product.  
 
1.3 DOCUMENTATION  
 
Specifications for starting materials  
 
Herbal medicinal product manufacturers must ensure that they use only herbal starting materials 
manufactured in accordance with GMP and the Marketing Authorization dossier. Comprehensive 
documentation on audits of the herbal starting material suppliers carried out by, or on behalf of the 
herbal medicinal product manufacturer should be made available. Audit trails for the active substance 
are fundamental to the quality of the starting mater ial. The manufacturer should verify, where 
appropriate, whether the suppliers of the herbal substance / preparation are in compliance with Good 
Agricultural and Collection Practice33 and – if not – apply appropriate controls in line with Quality 
Risk Manage ment (QRM).  To fulfil the specification requirements described in the basic 
requirements of the Guide (Chapter 4), documentation for herbal substances / preparations should 
include:  
 
a. the binomial scientific name of plant (genus, species, subspecies / variety and author 
(e.g. Linnaeus); other relevant information such as the cultivar name and the 
chemotype should also be provided, as appropriate;  
b. details of the source of the plant (country or region of origin and where applicable, - 
cultivation, time of  harvesting, collection procedures, possible pesticides used, possible 
radioactive contamination, etc.);  
c. which part(s) of the plant is/are used;  
d. when a dried plant is used, the drying system should be specified;  
e. a description of the herbal substance and its macro and microscopic examination;  
f. suitable identification tests including, where appropriate, identification tests for 
constituents with known therapeutic activity, or markers. Specific distinctive tests are 
                                                 
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Page 95 of 234 
 required where an herbal substance is liabl e to be adulterated / substituted. A 
reference authentic specimen should be available for identification purposes;  
g. the water content for herbal substances, determined in accordance with the relevant 
Pharmacopoeia;  
h. assay of constituents of known therapeutic  activity or, where appropriate, of markers; 
the methods suitable to determine possible pesticide contamination and limits 
accepted in accordance with relevant Pharmacopoeia methods or, in absence of 
thereof, with an appropriate validated method, unless ot herwise justified;  
i. tests to determine fungal and/or microbial contamination, including aflatoxins, other 
mycotoxins, pest -infestations and limits accepted, as appropriate;  
j. tests for toxic metals and for likely contaminants and adulterants, as appropriate;  
k. tests for foreign materials, as appropriate;  
l. any other additional test according to the relevant Pharmacopoeia general monograph 
on herbal substances or to the specific monograph of the herbal substance, as 
appropriate.  
 
Any treatment used to reduce fungal/microbial contamination or other infestation should be 
documented. Specifications and procedures should be available and should include details of process, 
tests and limits for residues.  
 
Processing instructions  
 
The processing instructions should d escribe the different operations carried out upon the herbal 
substance such as cleaning, drying, crushing and sifting, and include drying time and temperatures, 
and methods used to control cut size or particle size.  In particular, there should be written i nstructions 
and records, which ensure that each container of herbal substance is carefully examined to detect any 
adulteration/substitution or -presence of foreign matter, such as metal or glass pieces, animal parts or 
excrement, stones, sand, etc., or rot and signs of decay.  
 
The processing instructions should also describe security sieving or other methods of removing 
foreign materials and appropriate procedures for cleaning/selection of plant material before the 
storage of the approved herbal substance or  before the start of manufacturing.  For the production of 
an herbal preparation, instructions should include details of solvent, time and temperatures of 
extraction, details of any concentration stages and methods used.  
 
1.4 QUALITY CONTROL  
 
Sampling  
 
Due to the fact that medicinal plant/herbal substances are heterogeneous in nature, their sampling 
should be carried out with special care by personnel with particular expertise. Each batch should be 
identified by its own documentation.  A reference sample of the plant material is necessary, especially 
in those cases where the herbal substance is not described in the relevant Pharmacopoeia. Samples 
of unmilled plant material are required if powders are used.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Quality Control personnel should have particular experti se and experience in herbal substances, 
herbal preparations and/or herbal medicinal products in order to be able to carry out identification 
tests and recognize adulteration, the presence of fungal growth, infestations, non -uniformity within 
a delivery of crude material, etc.  
 
The identity and quality of herbal substances, herbal preparations and herbal medicinal products 
should be determined in accordance with the relevant current national or international guidance on 
quality and specifications of herbal medicinal products and traditional herbal medicinal products and, 
where relevant, to specific pharmacopoeial monographs.  
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 ANNEX 8: SAMPLING OF STARTING AND PACKAGING MATERIALS PRINCIPLE  
 
Sampling is an important operation in which only a small fraction of a batch is taken. Valid 
conclusions on the whole cannot be based on tests which have been carried out on non - representative 
samples. Correct sampling is thus an essential part of a system of Quality Assurance.  
 
Note: Sampling is dealt with in Chapter 6 of the Guide to GMP,  items 6.11 to 6.14. These 
supplementary guidelines give additional guidance on the sampling of starting and packaging 
materials.  
 
8.1 PERSONNEL  
 
Personnel who take samples should receive initial and on -going regular training in the disciplines 
relevant to correct sampling. This training should include:  
 
a. sampling plans;  
b. written sampling procedures;  
c. the techniques and equipment for sampling;  
d. the risks of cross -contamination;  
e. the precautions to be taken with regard to unstable and/or sterile substances;  
f. the importance of considering the visual appearance of materials, containers and labels; and  
g. the importance of recording any unexpected or unusual circumstances.  
 
8.2 STARTING MATERIALS  
 
The identity of a complete batch of starting materials can normally only be ensured if individual 
samples are taken from all the containers and an identity test performed on each sample. It is 
permissible to sample only a proportion of the containers where a validated procedure has been 
established to ensure that no single contain er of starting material will be incorrectly identified on its 
label.  This validation should take account of at least the following aspects:  
 
a. nature and status of the manufacturer and of the supplier and their understanding of 
the GMP requirements of the Pharmaceutical Industry;  
b. the Quality Assurance system of the manufacturer of the starting material;  
c. the manufacturing conditions under which the starting material is produced and 
controlled;  
d. the nature of the starting material and the medicinal products in  which it will be used.  
 
Under such arrangements, it is possible that a validated procedure exempting identity testing of each 
incoming container of starting material could be accepted for:  
a. starting materials coming from a single product manufacturer or plant;  
b. Starting materials coming directly from a manufacturer or in the manufacturer's sealed 
container where there is a history of reliability and regular audits of the manufacturer’s Quality 
Assurance system are conducted by the purchaser (the manufactur er of the medicinal products Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 98 of 234 
 or by an officially accredited body.  
 
It is improbable that a procedure could be satisfactorily validated for:  
a. starting materials supplied by intermediaries such as brokers where the source of manufacture 
is unknown or not audited;  
b. starting materials for use in parenteral products.  
 
The quality of a batch of starting materials may be assessed by taking and testing a representative 
sample. The samples taken for identity testing could be used for this purpose. The number of samples 
taken for the preparation of a representative sample should be determined statistically and specified 
in a sampling plan. The number of individual samples which may be blended to form a composite 
sample should also be defined, taking into account t he nature of the material, knowledge of the 
supplier and the homogeneity of the composite sample.  
 
8.3 PACKAGING MATERIAL  
 
The sampling plan for packaging materials should take account of at least the following: the quantity 
received, the quality required, the nature of the material (e.g. primary packaging materials and/or 
printed packaging materials), the production methods, and the knowledge of Quality Assurance 
system of the packaging materials manufacturer based on audits. The number of samples taken should 
be determined statistically and specified in a sampling plan.Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 99 of 234  ANNEX 9: MANUFACTURE OF LIQUIDS, CREAMS AND OINTMENTS PRINCIPLE  
 
Liquids, creams and ointments may  be particularly susceptible to microbial and other contamination 
during manufacture. Therefore, special measures must be taken to prevent any contamination.  
 
Note: The manufacture of liquids, creams and ointments must be done in accordance with the GMP 
described in the PIC Guide to GMP and with the other supplementary guidelines, where applicable. 
The present guidelines only stress points which are specific to this manufacture.  
 
1.1 PREMISES AND EQUIPMENT  
 
The use of closed systems of processing and transfer is recommended in order to protect the product 
from contamination. Production areas where the products or open clean containers are exposed 
should normally be effectively ventilated with filtered air.  
 
Tanks, containers, pipework and pumps should be design ed and installed so that they may be readily 
cleaned and if necessary sanitized. In particular, equipment design should include a minimum of 
dead -legs or sites where residues can accumulate and promote microbial proliferation.  The use of 
glass apparatus sh ould be avoided wherever possible. High quality stainless steel is often the material 
of choice for product contact parts.  
 
1.2 PRODUCTION  
 
The chemical and microbiological quality of water used in production should be specified and 
monitored. Care should be taken in the maintenance of water systems in order to avoid the risk of 
microbial proliferation. After any chemical sanitization of the water systems, a validated flushing 
procedure should be followed to ensure that the sanitizing agent has been effectivel y removed.  
 
The quality of materials received in bulk tankers should be checked before they are transferred to 
bulk storage tanks.  Care should be taken when transferring materials via pipelines to ensure that they 
are delivered to their correct destination . Materials likely to shed fibres or other contaminants, like 
cardboard or wooden pallets, should not enter the areas where products or clean containers are 
exposed.  
 
Care should be taken to maintain the homogeneity of mixtures, suspensions, etc. during fi lling. 
Mixing and filling processes should be validated. Special care should be taken at the beginning of a 
filling process, after stoppages and at the end of the process to ensure that homogeneity is maintained.  
When the finished product is not immediatel y packaged, the maximum period of storage and the 
storage conditions should be specified and respected.   Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 100 of 234  ANNEX 10: MANUFACTURE OF PRESSURISED METERED DOSE AEROSOL 
PREPARATIONS FOR INHALATION  
 
PRINCIPLE  
 
Manufacture of pressurized aerosol products for inhalation with metering valves requires some 
special provisions arising from the particular nature of this pharmaceutical form. It should occur 
under conditions which minimize microbial and particulate contamination. Assurance of the quality 
of the valve components and, in the case of suspensions, of uniformity is also of particular 
importance.  
 
Note : The manufacture of metered dose aerosols must be done in accordance with the GMP described 
in the PIC Guide to GMP and with the other supplementary guideline s, where applicable. The present 
guidelines only stress points which are specific to this manufacture.  
 
GENERAL  
 
There are presently two common manufacturing and filling methods as follows:  
 
a) Two-shot system (pressure filling). The active ingredient is suspended in a high boiling point 
propellant, the dose is filled into the container, the valve is crimped on and the lower boiling 
point propellant is injected through the valve stem to make up the finished product. The 
suspension of active ingredient in p ropellant is kept cool to reduce evaporation loss.  
b) One-shot process (cold filling). The active ingredient is suspended in a mixture of propellants 
and held either under high pressure and/or at a low temperature. The suspension is then filled 
directly into the container in one shot.  
 
10.1 PREMISES AND EQUIPMENT  
 
Manufacture and filling should be carried out as far as possible in a closed system.  Where products 
or clean components are exposed, the area should be fed with filtered air, should comply with the 
requirements of at least a Grade D environment and should be entered through airlocks.  
 
10.2 PRODUCTION AND QUALITY CONTROL  
 
Metering valves for aerosols are a more complex engineering article than most pharmaceutical 
components. Specifications, sampling and te sting should be appropriate for this situation. Auditing 
the Quality Assurance system of the valve manufacturer is of particular importance.  All fluids (e.g. 
liquid or gaseous propellants) should be filtered to remove particles greater than 0.2 micron. An 
additional filtration where possible immediately before filling is desirable.  
 
Containers and valves should be cleaned using a validated procedure appropriate to the use of the 
product to ensure the absence of any contaminants such as fabrication aids (e.g. lubricants) or undue 
microbiological contaminants. After cleaning, valves sho uld be kept in clean, closed containers and 
precautions taken not to introduce contamination during subsequent handling, e.g. taking samples. Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 101 of 234  Containers should be provided to the filling line in a clean condition or cleaned on line immediately 
before filli ng. 
 
Precautions should be taken to ensure uniformity of suspensions at the point of fill throughout the 
filling process.  When a two -shot filling process is used, it is necessary to ensure that both shots are 
of the correct weight in order to achieve the c orrect composition. For this purpose, 100% weight 
checking at each stage is often desirable.  Controls after filling should ensure the absence of undue 
leakage. Any leakage test should be performed in a way which avoids microbial contamination or 
residual m oisture.  
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Page 102 of 234  ANNEX 11: COMPUTERIZED SYSTEMS  
 
PRINCIPLE  
 
This annex applies to all forms of computerized systems used as part of a GMP regulated activities.  
 
A computerized system is a set of software and hardware components which together fulfil certain 
functionalities. The application should be validated; IT infrastructure should be qualified.  
 
Where a computerized system replaces a manual operation, there should be no resultant decrease in 
product quality, process control or quality assurance. There should be no increase in the overall risk 
of the process.  
 
GENERAL  
 
1.1 Risk Management  
 
Risk management should be applied throughout the lifecycle of the computerized system taking into 
account patient safety, data integrity and product quality. As part of a risk management system, 
decisions on the extent of validation and data integrity controls should be based on a justified and 
documented risk assessment of the computerized system.  
 
1.2 Personnel  
 
There should be close cooperation between all relevant personnel  such as Process Owner, System 
Owner, Authorized Persons and IT. All personnel should have appropriate qualifications, level of 
access and defined responsibilities to carry out their assigned duties.  
 
1.3 Suppliers and Service Providers  
 
When third parties (e.g. suppliers, service providers) are used e.g. to provide, install, configure, 
integrate, validate, maintain (e.g. via remote access), modify or retain a computerized system or 
related service or for data processing, formal agreements must exist between  the manufacturer and 
any third parties, and these agreements should include clear statements of the responsibilities of the 
third party. IT -departments should be considered analogous.  The competence and reliability of a 
supplier are key factors when selec ting a product or service provider. The need for an audit should 
be based on a risk assessment.  
 
Documentation supplied with commercial off -the-shelf products should be reviewed by regulated 
users to check that user requirements are fulfilled.  Quality syst em and audit information relating to 
suppliers or developers of software and implemented systems should be made available to inspectors 
on request.  
 
 
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Page 103 of 234  PROJECT PHASE  
 
The validation documentation and reports should cover the relevant steps of the life cycle. 
Manufacturers should be able to justify their standards, protocols, acceptance criteria, procedures and 
records based on their risk assessment.  
 
Validation documentation should include change control records (if applicable) and reports on any 
deviat ions observed during the validation process.  An up to date listing of all relevant systems and 
their GMP functionality (inventory) should be available.  
For critical systems an up -to-date system description detailing the physical and logical arrangements, 
data flows and interfaces with other systems or processes, any hardware and software pre -requisites, 
and security measures should be available.  
 
User Requirements Specifications should describe the required functions of the computerized system 
and be based on documented risk assessment and GMP impact. User requirements should be 
traceable throughout the life -cycle.  The regulated user should take all reasonable steps to ensure that 
the system has been developed in accordance with an appropriate quality manage ment system. The 
supplier should be assessed appropriately.  
 
For the validation of bespoke or customized computerized systems there should be a process in place 
that ensures the formal assessment and reporting of quality and performance measures for all th e life -
cycle stages of the system.  
 
Evidence of appropriate test methods and test scenarios should be demonstrated. Particularly, system 
(process) parameter limits, data limits and error handling should be considered. Automated testing 
tools and test envir onments should have documented assessments for their adequacy.  If data are 
transferred to another data format or system, validation should include checks that data are not altered 
in value and/or meaning during this migration process.  
 
OPERATIONAL PHASE  
 
1. Data  
 
Computerized systems exchanging data electronically with other systems should include appropriate 
built-in checks for the correct and secure entry and processing of data, in order to minimize the risks.  
 
2. Accuracy Checks  
 
For critical data entered man ually, there should be an additional check on the accuracy of the data. 
This check may be done by a second operator or by validated electronic means. The criticality and 
the potential consequences of erroneous or incorrectly entered data to a system should  be covered by 
risk management.  
 
3. Data Storage  
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Page 104 of 234  Data should be secured by both physical and electronic means against damage. Stored data should 
be checked for accessibility, readability and accuracy. Access to data should be ensured throughout 
the retention  period.  
Regular back -ups of all relevant data should be done. Integrity and accuracy of backup data and the 
ability to restore the data should be checked during validation and monitored periodically.  
 
4. Printouts  
 
It should be possible to obtain clear print ed copies of electronically stored data.  
For records supporting batch release it should be possible to generate printouts indicating if any of 
the data has been changed since the original entry.  
 
5. Audit Trails  
 
Consideration should be given, based on a risk  assessment, to building into the system the creation 
of a record of all GMP -relevant changes and deletions (a system generated "audit trail"). For change 
or deletion of GMP -relevant data the reason should be documented. Audit trails need to be available 
and convertible to a generally intelligible form and regularly reviewed.  
 
6. Change and Configuration Management  
 
Any changes to a computerized system including system configurations should only be made in a 
controlled manner in accordance with a defined procedure.  
 
7. Periodic Evaluation  
 
Computerized systems should be periodically evaluated to confirm that they remain in a valid state 
and are compliant with GMP. Such evaluations should include, where appropriate, the current range 
of functionality, deviatio n records, incidents, problems, upgrade history, performance, reliability, 
security and validation status reports.  
 
8. Security  
 
a. Physical and/or logical controls should be in place to restrict access to computerized system to 
authorized persons. Suitable methods of preventing unauthorized entry to the system may 
include the use of keys, pass cards, personal codes with passwords, biometrics, restricted access 
to computer equipment and data storage areas.  
b. The extent of security controls depends on the critic ality of the computerized system.  
c. Creation, change, and cancellation of access authorizations should be recorded.  
d. Management systems for data and for documents should be designed to record the identity of 
operators entering, changing, confirming or deletin g data including date and time.  
 
9. Incident Management  
 
All incidents, not only system failures and data errors, should be reported and assessed. The root Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 105 of 234  cause of a critical incident should be identified and should form the basis of corrective and preventive 
actions.  
 
10. Electronic Signature  
 
Electronic records may be signed electronically. Electronic signatures are expected to:  
 
a) have the same impact as hand -written signatures within the boundaries of the company,  
b) be permanently linked to their respective record,  
c) include the time and date that they were applied.  
 
11. Batch release  
 
When a computerized system is used for recording certification and batch release, the system should 
allow only Authorized Persons to certify the release of the batches and  it should clearly identify and 
record the person releasing or certifying the batches. This should be performed using an electronic 
signature.  
 
12. Business Continuity  
 
For the availability of computerized systems supporting critical processes, provisions should be made 
to ensure continuity of support for those processes in the event of a system breakdown (e.g. a manual 
or alternative system). The time required to bring the alternative arrangements into use should be 
based on risk and appropriate for a part icular system and the business process it supports. These 
arrangements should be adequately documented and tested.  
 
13. Archiving  
 
Data may be archived. This data should be checked for accessibility, readability and integrity. If 
relevant changes are to be mad e to the system (e.g. computer equipment or programs), then the ability 
to retrieve the data should be ensured and tested.  
 
GLOSSARY  
 
Application  
 
Software installed on a defined platform/hardware providing specific functionality.  
 
Bespoke/Customized computerized system  
 
A computerized system individually designed to suit a specific business process.  
 
Commercial of the shelf software  
 
Software commercially available, whose fitness for use is demonstrated by a broad spectrum of users.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 106 of 234  IT Infrastructure  
 
The hardware and software such as networking software and operation systems, which makes it 
possible for the application to function.  
 
Life cycle  
 
All phases in the life of the system from initial requirements until retirement including design, 
specificat ion, programming, testing, installation, operation, and maintenance.  
 
Process owner  
 
The person responsible for the business process.  
 
System owner  
 
The person responsible for the availability, and maintenance of a computerized system and for the 
security of the data residing on that system.  
 
Third Party  
 
Parties not directly managed by the holder of the manufacturing and/or import authorization.  
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Page 107 of 234  ANNEX 12: USE OF IONISING RADIATION IN THE MANUFACTURE OF MEDICINAL 
PRODUCTS  
 
INTRODUCTION  
 
Ionizing radiation  may be used during the manufacturing process for various purposes including the 
reduction of bioburden and the sterilization of starting materials, packaging components or products 
and the treatment of blood products.  
 
There are two types of irradiation p rocess: Gamma irradiation from a radioactive source and high 
energy Electron irradiation (Beta radiation) from an accelerator.  
 
Gamma irradiation: two different processing modes may be employed:  
 
a) Batch mode: the products is arranged at fixed locations around the radiation source and cannot 
be loaded or unloaded while the radiation source is exposed.  
b) Continuous mode: an automatic system conveys the products into the radiation cell, past the 
exposed radiation source along a defined path and at an appropri ate speed, and out of the cell.  
 
Electron irradiation: the product is conveyed past a continuous or pulsed beam of high energy 
electrons (Beta radiation) which is scanned back and forth across the product pathway.  
 
12.1 RESPONSIBILITIES  
 
Treatment by irradiation may be carried out by the pharmaceutical manufacturer or by an operator of 
a radiation facility under contract (a "contract manufacturer"), both of whom must hold an appropriate 
manufacturing authorization.  
The pharmaceutical manufacturer bears  responsibility for the quality of the product including the 
attainment of the objective of irradiation. The contract operator of the radiation facility bears 
responsibility for ensuring that the dose of radiation required by the manufacturer is delivered to the 
irradiation container (i.e. the outermost container in which the products are irradiated).  
The required dose including justified limits will be stated in the marketing authorization for the 
product.  
 
12.2 DOSIMETRY  
 
Dosimetry is defined as the measuremen t of the absorbed dose by the use of dosimeters. Both 
understanding and correct use of the technique is essential for the validation, commissioning and 
control of the process.  
 
The calibration of each batch of routine dosimeters should be traceable to a national or international 
standard. The period of validity of the calibration should be stated, justified and adhered to.  The same 
instrument should normally be used to establish the calibration curve of the routine dosimeters and 
to measure the change in their absorbance after irradiation. If a different instrument is used, the 
absolute absorbance of each instrument should be established.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Depending on the type of dosimeter used, due account should be taken of possible causes of 
inaccuracy including the ch ange in moisture content, change in temperature; time elapsed between 
irradiation and measurement, and the dose rate.  The wavelength of the instrument used to measure 
the change in absorbance of dosimeters and the instrument used to measure their thickness  should be 
subject to regular checks of calibration at intervals established on the basis of stability, purpose and 
usage.  
 
12.3 VALIDATION OF THE PROCESS  
 
Validation is the action of proving that the process, i.e. the delivery of the intended absorbed dose to 
the product, will achieve the expected results. The requirements for validation are given more fully 
in the note for guidance on "the use of ionizing radiation in the manufacture of medicinal products".  
Validation should include dose mapping to establish t he distribution of absorbed dose within the 
irradiation container when packed with product in a defined configuration.  An irradiation process 
specification should include at least the following:  
a) details of the packaging of the product;  
b) the loading pattern(s) of the product  within the irradiation container.  
 
Particular care needs to be taken, when a mixture of products is allowed in the irradiation container, 
that there is no under -dosing  of dense product or shadowing of other products by dense product. Each 
mixed product arrangement must be specified and validated;  
 
c) the loading pattern of irradiation containers around the source (batch mode) or the pathway 
through the cell (continuous mod e); 
d) maximum and minimum limits of absorbed dose to the product [and associated routine 
dosimetry];  
e) maximum and minimum limits of absorbed dose to the irradiation container and associated 
routine dosimetry to monitor this absorbed dose;  
f) other process parame ters, including dose rate, maximum time of exposure, number of 
exposures, etc.  
 
When irradiation is supplied under contract at least parts (d) and (e) of the irradiation process 
specification should form part of that contract.  
 
12.4 COMMISSIONING OF THE PLANT  
 
GENERAL  
 
Commissioning is the exercise of obtaining and documenting evidence that the irradiation plant will 
perform consistently within predetermined limits when operated according to the process 
specification. In the context of this annex, predetermined limits are the maximum and minimum 
doses designed to be absorbed by the irradiation container. It must not be possible for variations to 
occur in the operation of the plant which give a dose to the container outside these limits without the 
knowledge of th e operator. Commissioning should include the following elements:  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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a. Design;  
b. Dose mapping;  
c. Documentation;  
d. Requirement for re -commissioning.  
 
Gamma irradiators Design  
 
The absorbed dose received by a particular part of an irradiation container at any specific point in the 
irradiator depends primarily on the following factors:  
 
g) the activity and geometry of the source;  
h) the distance from source to container;  
i) the duration of irradiation controlled by the timer setting or conveyor speed;  
j) the composition and density of material, including other products, between the source 
and the particular part of the container.  
 
The total absorbed dose will in addition depend on the path of containers through a continuous 
irradiator or the loading pattern in a batch irradiator, and  on the number of exposure cycles.  For a 
continuous irradiator with a fixed path or a batch irradiator with a fixed loading pattern, and with a 
given source strength and type of product, the key plant parameter controlled by the operator is 
conveyor speed or timer setting.  
 
Dose Mapping  
 
For the dose mapping procedure, the irradiator should be filled with irradiation containers packed 
with dummy products or a representative product of uniform density. Dosimeters should be placed 
throughout a minimum of three loaded irradiation containers which are passed through the irradiator, 
surrounded by similar containers or dummy products. If the product is not uniformly packed, 
dosimeters should be placed in a larger number of containers.  
 
The positioning of dosim eters will depend on the size of the irradiation container. For example, for 
containers up to 1 x 1 x 0.5 m, a three -dimensional 20 cm grid throughout the container including the 
outside surfaces might be suitable. If the expected positions of the minimum and maximum dose are 
known from a previous irradiator performance characterization, some dosimeters could be removed 
from regions of average dose and replaced to form a 10 cm grid in the regions of extreme dose.  
 
The results of this procedure will give min imum and maximum absorbed doses in the product and on 
the container surface for a given set of plant parameters, product density and loading pattern.  
 
Ideally, reference dosimeters should be used for the dose mapping exercise because of their greater 
precision. Routine dosimeters are permissible but it is advisable to place reference dosimeters beside 
them at the expected positions of minimum and maximum dose and at the routine monitoring position 
in each of the replicate irradiation containers. The ob served values of dose will have an associated 
random uncertainty which can be estimated from the variations in replicate measurements.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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The minimum observed dose, as measured by the routine dosimeters, necessary to ensure that all 
irradiation containers re ceive the minimum required dose will be set in the knowledge of the random 
variability of the routine dosimeters used.  Irradiator parameters should be kept constant, monitored 
and recorded during dose mapping. The records, together with the dosimetry resul ts and all other 
records generated should be retained.  
 
Electron Beam Irradiators Design  
 
The absorbed dose received by a particular portion of an irradiated product depends primarily on the 
following factors:  
 
a) the characteristics of the beam, which are: electron energy, average beam current, 
scan width and scan uniformity;  
b) the conveyor speed;  
c) the product composition and density;  
d) the composition, density and thickness of material between the output window and 
the particular portion of product;  
e) the output window to container distance.  
 
Key parameters controlled by the operator are the characteristics of the beam and the conveyor speed.  
 
Dose Mapping  
 
For the dose mapping procedure, dosimeters should be placed between layers of homogeneous 
absorber sheets making up a dummy product, or between layers of representative products of uniform 
density, such that at least ten measurements can be made within the  maximum range of the electrons. 
Reference should also be made to sections 18  
 
Irradiator parameters should be kept constant, monitored and recorded during dose mapping. The 
records, together with the dosimetry results and all other records generated shou ld be retained.  
 
Re-commissioning  
 
Commissioning should be repeated if there is a change to the process or the irradiator which could 
affect the dose distribution to the irradiation container (e.g. change of source pencils). The extent to 
re-commissioning depends on the extent of the change in the irradiator or the load that has taken 
place. If in doubt, re -commission.  
 
12.5 PREMISES  
 
Premises should be designed and operated to segregate irradiated from non - irradiated containers to 
avoid their cross -contaminati on. Where materials are handled within closed irradiation containers, it 
may not be necessary to segregate pharmaceuticals  from non -pharmaceutical materials, provided 
there is no risk of the former being contaminated by the latter. Any possibility of conta mination of Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 111 of 234  the products by radio -nuclide from the source must be excluded.  
 
12.6 PROCESSING  
 
Irradiation containers should be packed in accordance with the specified loading pattern(s) 
established during validation.  During the process, the radiation dose to th e irradiation containers 
should be monitored using validated dosimetry procedures. The relationship between this dose and 
the dose absorbed by the product inside the container must have been established during process 
validation and plant commissioning.  
 
Radiation indicators should be used as an aid to differentiating irradiated from non -irradiated 
containers. They should not be used as the sole means of differentiation or as an indication of 
satisfactory processing.  
 
Processing of mixed loads of containers  within the irradiation cell should only be done when it is 
known from commissioning trials or other evidence that the radiation dose received by individual 
containers remains within the limits specified.  
 
When the required radiation dose is by design give n during more than one exposure or passage 
through the plant, this should be with the agreement of the holder of the marketing authorization and 
occur within a predetermined time period. Unplanned interruptions during irradiation should be 
notified to the holder of the marketing authorization if this extends the irradiation process beyond a 
previously agreed period.  Non-irradiated products must be segregated from irradiated products at all 
times. Methods or doing this include the use of radiation indicators  (31.) and appropriate design of 
premises (28.).  
 
Gamma irradiators  
 
For continuous processing modes, dosimeters should be placed so that at least two are exposed    in 
the irradiation at all times.  For batch modes, at least two dosimeters should be expose d in positions 
related to the minimum dose position.  For continuous process modes, there should be a positive 
indication of the correct position of the source and an interlock between source position and conveyor 
movement. Conveyor speed should be monitore d continuously and recorded.  For batch process 
modes source movement and exposure times for each batch should be monitored and recorded.  For 
a given desired dose, the timer setting or conveyor speed requires adjustment for source decay and 
source additions . The period of validity of the setting or speed should be recorded and adhered to.  
 
Electron Beam Irradiators  
 
A dosimeter should be placed on every container.  There should be continuous recording of average 
beam current, electron energy, scan -width and c onveyor speed. These variables, other than conveyor 
speed, need to be controlled within the defined limits established during commissioning since they 
are liable to instantaneous change.  
 
12.7 DOCUMENTATION  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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The numbers of containers received, irradiated and dispatched should be reconciled with each other 
and with the associated documentation. Any discrepancy should be reported and resolved.  
 
The irradiation plant operator should certify in writing the range of doses received by each irradiated 
container within a batch or delivery.  Process and control records for each irradiation batch should be 
checked and signed by a nominated responsible person and retained. The method and place or 
retention should be agreed between the plant operator and the holder of the marketing authorization.  
 
The documentation associated with the validation and commissioning of the plant should be retained 
for one year after the expiry date or at least five years after the release of the last product processed 
by the plant, whichev er is the longer.  
 
12.8 MICROBIOLOGICAL MONITORING  
 
Microbiological monitoring is the responsibility of the pharmaceutical manufacturer. It may include 
environmental monitoring where a product  is manufactured and pre -irradiation monitoring of the 
product as specified in the marketing authorization.  
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Page 113 of 234  ANNEX 13: MANUFACTURE OF INVESTIGATIONAL MEDICINAL PRODUCTS  
 
PRINCIPLE  
 
Investigational medicinal products should be produced in accordance with the principles and the 
detailed guidelines of Good Manufacturing Practice for Medicinal Products. Other guidelines should 
be taken into account where relevant and as appropriate to the stage of development of the product. 
Procedures need to be flexible to provide for changes as knowledge of the process increases, and 
appropriate to the stage of development of the product.  
 
In clinical trials there may be added risk to participating subjects compared to patients treated with 
marketed products. The application of GMP to the manufacture of investigational medicinal products 
is intended to ensure that trial subjects are not placed at risk, and that the results of clinical trials are 
unaffected by inadequate safety, quality or efficacy arising from unsa tisfactory manufacture. Equally, 
it is intended to ensure that there is consistency between batches of the same investigational medicinal 
product used in the same or different clinical trials, and that changes during the development of an 
investigational m edicinal product are adequately documented and justified.  
 
The production of investigational medicinal products involves added complexity in comparison to 
marketed products by virtue of the lack of fixed routines, variety of clinical trial designs, consequ ent 
packaging designs, and the need, often, for randomization and blinding and increased risk of product 
cross - contamination and mix up. Furthermore, there may be incomplete knowledge of the potency 
and toxicity of the product and a lack of full process v alidation, or, marketed products may be used 
which have been re -packaged or modified in some way.  
 
These challenges require personnel with a thorough understanding of, and training in, the application 
of GMP to investigational medicinal products. Co - opera tion is required with trial sponsors who 
undertake the ultimate responsibility for all aspects of the clinical trial including the quality of 
investigational medicinal products.The increased complexity in manufacturing operations requires a 
highly effectiv e quality system.  
 
The annex also includes guidance on ordering, shipping, and returning clinical supplies, which are at 
the interface with, and complementary to, guidelines on Good Clinical Practice.  
 
1. NON -INVESTIGATIONAL MEDICINAL PRODUCT  
 
Products other than the test product, placebo or comparator may be supplied to subjects participating 
in a trial. Such products may be used as support or escape medication for preventative, diagnostic or 
therapeutic reasons and/or needed to ensure that adequate medical c are is provided for the subject. 
They may also be used in accordance with the protocol to induce a physiological response. These 
products do not fall within the definition of investigational medicinal products and may be supplied 
by the sponsor, or the inv estigator. The sponsor should ensure that they are in accordance with the 
notification/request for authorization to conduct the trial and that they are of appropriate quality for 
the purposes of the trial taking into account the source of the materials, wh ether or not they are the 
subject of a marketing authorization and whether they have been repackaged. The advice and Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 114 of 234  involvement of an Authorized Person is recommended in this task.  
 
2. MANUFACTURING AUTHORIZATION AND RECONSTITUTION  
 
Both the total and partial manufacture of investigational medicinal products, as well as the various 
processes of dividing up, packaging or presentation, is subject to a manufacturing authorization. This 
authorization, however, shall not be required for reconstitution. For t he purpose of this provision, 
reconstitution shall be understood as a simple process of:  
 
a) dissolving or dispersing the investigational medicinal product for administration of the product 
to a trial subject, or,  
b) diluting or mixing the investigational medici nal product(s) with some other substance(s) used as 
a vehicle for the purposes of administering it.  
 
Reconstitution is not mixing several ingredients, including the active substance, together to produce 
the investigational medicinal product.  
 
An investigat ional medicinal product must exist before a process can be defined as reconstitution. 
The process of reconstitution has to be undertaken as soon as practicable before administration.  
 
This process has to be defined in the clinical trial application / IMP dossier and clinical trial protocol, 
or related document, available at the site.  
 
GLOSSARY  
 
Blinding  
A procedure in which one or more parties to the trial are kept unaware of the treatment assignment(s). 
Single -blinding usually refers to the subject(s) bei ng unaware, and double -blinding usually refers to 
the subject(s), investigator(s), monitor, and, in some cases, data analyst(s) being unaware of the 
treatment assignment(s). In relation to an investigational medicinal product, blinding means the 
deliberate  disguising of the identity of the product in accordance with the instructions of the sponsor. 
Unbinding means the disclosure of the identity of blinded products.  
 
Clinical trial  
Any investigation in human subjects intended to discover or verify the clinic al, pharmacological 
and/or other pharmacodynamics effects of an investigational product(s) and/or to identify any 
adverse reactions to an investigational product(s), and/or to study absorption, distribution, 
metabolism, and excretion of one or more investi gational medicinal product(s) with the object of 
ascertaining its/their safety and/or efficacy.  
 
Comparator product  
An investigational or marketed product (i.e. active control), or placebo, used as a reference in a 
clinical trial.  
 
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Page 115 of 234  Investigational medicinal product  
A pharmaceutical form of an active substance or placebo being tested or used as a reference in a 
clinical trial, including a product with a marketing authorization when used or assembled (formulated 
or packaged) in a way different from th e authorized form, or when used for an unauthorized 
indication, or when used to gain further information about the authorized form.  
 
Investigator  
A person responsible for the conduct of the clinical trial at a trial site. If a trial is conducted by a team 
of individuals at a trial site, the investigator is the responsible leader of the team and may be called 
the principal investigator.  
 
Manufacturer/importer of Investigational Medicinal Products  
Any holder of the authorization to manufacture/import . 
 
Order  
Instruction to process, package and/or ship a certain number of units of investigational medicinal 
product(s).  
 
Product Specification File  
A reference file containing, or referring to files containing, all the information necessary to draft the 
detailed wr itten instructions on processing, packaging, quality control testing, batch release and 
shipping of an investigational medicinal product.  
 
Randomization  
The process of assigning trial subjects to treatment or control groups using an element of chance to 
determine the assignments in order to reduce bias.  
 
Randomization Code  
A listing in which the treatment assigned to each subject from the randomization process is identified.  
 
Shipping  
The operation of packaging for shipment and sending of ordered medicinal products for clinical trials.  
 
Sponsor  
An individual, company, institution or organization which takes responsibility for the initiation, 
management and/or financing of a clinical trial.  
 
13.1 QUALITY MANAGEMENT  
 
The Quality System, designed, set up and verified by the manufacturer or importer, should be 
described in written procedures available to the sponsor, taking into account the GMP principles and 
guidelines applicable to investigational medicinal products.  
 
The product specifications and manufactur ing instructions may be changed during development but 
full control and traceability of the changes should be maintained.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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13.2 PERSONNEL  
 
All personnel involved with investigational medicinal products should be appropriately trained in the 
requirements specific to these types of product. Even in cases where the number of staff involved is 
small, there should be, for each batch, separate people responsible for production and quality control.  
 
The Authorized Person should ensure that there are systems in p lace that meet the requirements of 
GMP and have a broad knowledge of pharmaceutical development and clinical trial processes. 
Guidance for the Authorized Person in connection with the certification of investigational medicinal 
products is given in paragrap hs 38 to 41  
 
13.3 PREMISES AND EQUIPMENT  
 
The toxicity, potency and sensitizing potential may not be fully understood for investigational 
medicinal products and this reinforces the need to minimize all risks of cross -contamination. The 
design of equipment and premises, inspection test methods and acceptance limits to be used after 
cleaning should reflect the nature of these risks. Consideration should be given to campaign working 
where appropriate. Account should be taken of the solubility of the product in dec isions about the 
choice of cleaning solvent.  
 
13.4 DOCUMENTATION  
 
Specifications and instructions  
 
Specifications (for starting materials, primary packaging materials, intermediate, bulk products and 
finished products), manufacturing formulae and processing and  packaging instructions should be as 
comprehensive as possible given the current state of knowledge. They should be periodically re -
assessed during development and updated as necessary. Each new version should take into account 
the latest data, current tec hnology used, regulatory and pharmacopoeial requirements, and should 
allow traceability to the previous document. Any changes should be carried out according   to a 
written procedure, which should address any implications for product quality such as stabil ity and 
bio equivalence.  
 
Rationales for changes should be recorded and the consequences of a change on product quality and 
on any on -going clinical trials should be investigated and documented.  
 
Order  
 
The order should request the processing and/or packaging of a certain number of units and/or their 
shipping and be given by or on behalf of the sponsor to the manufacturer. It should be in writing 
(though it may be transmitted by electronic means), and precise enough to avoid any ambiguity. It 
should b e formally authorized and refer to the Product Specification File and the relevant clinical 
trial protocol as appropriate.  
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Page 117 of 234  Product specification file  
 
The Product Specification File (see glossary) should be continually updated as development of the 
product proceeds, ensuring appropriate traceability to the previous versions. It should include, or 
refer to, the following documents:  
 
a) Specifications and analytical methods for starting materials, packaging materials, intermediate, 
bulk and finished produ ct; 
b) Manufacturing methods;  
c) In-process testing and methods;  
d) Approved label copy;  
e) Relevant clinical trial protocols and randomization codes, as appropriate;  
f) Relevant technical agreements with contract givers, as appropriate;  
g) Stability data;  
h) Storage and shipment conditions.  
 
The above listing is not intended to be exclusive or exhaustive. The contents will vary depending on 
the product and stage of development. The information should form the basis for assessment of the 
suitability for certification and release of a particular batch by the Authorized Person and should 
therefore be accessible to him/her. Where different manufacturing steps are carried out at different 
locations under the responsibility of different Authorized Persons, it is acceptable to m aintain 
separate files limited to information of relevance to the activities at the respective locations.  
 
Manufacturing formulae and processing instructions  
 
For every manufacturing operation or supply there should be clear and adequate written instructio ns 
and written records. Where an operation is not repetitive it may not be necessary to produce Master 
Formulae and Processing Instructions. Records are particularly important for the preparation of the 
final version of the documents to be used in routine manufacture once the marketing authorization is 
granted.  
The information in the Product Specification File should be used to produce the detailed written 
instructions on processing, packaging, quality control testing, storage conditions and shipping.  
 
Pack aging instructions  
 
Investigational medicinal products are normally packed in an individual way for each subject 
included in the clinical trial. The number of units to be packaged should be specified prior to the start 
of the packaging operations, includin g units necessary for carrying out quality control and any 
retention samples to be kept. Sufficient reconciliations should take place to ensure the correct 
quantity of each product required has been accounted for at each stage of processing.  
 
Processing, testing and packaging batch records  
 
Batch records should be kept in sufficient detail for the sequence of operations to be accurately 
determined. These records should contain any relevant remarks which justify the procedures used Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 118 of 234  and any changes made, enh ance knowledge of the product and develop the manufacturing operations.  
Batch manufacturing records should be retained at least for the periods specified in relevant 
regulations.  
 
13.5 PRODUCTION  
 
Packaging materials  
 
Specifications and quality control checks s hould include measures to guard against unintentional 
unbinding due to changes in appearance between different batches of packaging materials.  
 
Manufacturing operations  
 
During development critical parameters should be identified and in -process controls primarily used 
to control the process. Provisional production parameters and in -process controls may be deduced 
from prior experience, including that gained from earlier development work.  Careful consideration 
by key personnel is called for in order to fo rmulate the necessary instructions and to adapt them 
continually to the experience gained in production. Parameters identified and controlled should be 
justifiable based on knowledge available at the time  
 
Production processes for investigational medicinal  products are not expected to be validated to the 
extent necessary for routine production but premises and equipment are expected to be qualified. For 
sterile products, the validation of sterilizing processes should be of the same standard as for products 
authorized for marketing. Likewise, when required, virus inactivation/removal and that of other 
impurities of biological origin should be demonstrated, to assure the safety of biotechnologically 
derived products, by following the scientific principles and techniques defined in the available 
guidance in this area.  
 
Validation of aseptic processes presents special problems when the batch size is small; in these cases, 
the number of units filled may be the maximum number filled in production.  If practicable, and 
otherwise consistent with simulating the process, a larger number of units should be filled with media 
to provide greater confidence in the results obtained. Filling and sealing is often a manual or semi -
automated operation presenting great challenges to sterility so enhanced attention should be given to 
operator training, and validating the aseptic technique of individual operators.  
 
Principles applicable to comparator product  
 
If a product is modified, data should be available (e.g. stability, compara tive dissolution, 
bioavailability) to demonstrate that these changes do not significantly alter the original quality 
characteristics of the product.  
The expiry date stated for the comparator product in its original packaging might not be applicable    
to the product where it has been repackaged in a different container that may not offer equivalent 
protection, or be compatible with the product. A suitable use -by date, taking into account the nature 
of the product, the characteristics of the container and th e storage conditions to which the article may 
be subjected, should be determined by or on behalf of the sponsor. Such a date should be justified Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 119 of 234  and must not be later than the expiry date of the original package. There should be compatibility of 
expiry dat ing and clinical trial duration.  
 
Blinding operations  
 
Where products are blinded, systems should be in place to ensure that the blind is achieved and 
maintained while allowing for identification of “blinded” products when necessary, including the 
batch nu mbers of the products before the blinding operation. Rapid identification of product should 
also be possible in an emergency.  
 
Randomization code  
 
Procedures should describe the generation, security, distribution, handling and retention of any 
randomization code used for packaging investigational products, and code -break mechanisms. 
Appropriate records should be maintained.  
 
Packaging  
 
During packaging of investigational medicinal products, it may be necessary to handle different 
products on the  same packaging line at the same time. The risk of product mix up must be minimized 
by using appropriate procedures and/or, specialized equipment as appropriate and relevant staff 
training.  
 
Packaging and labeling of investigational medicinal products are likely to be more complex and more 
liable to errors (which are also harder to detect) than for marketed products, particularly when 
“blinded” products with similar appearance are used. Precautions against mislabeling such as label 
reconciliation, line clea rance, in -process control checks by appropriately trained staff should 
accordingly be intensified.  
 
The packaging must ensure that the investigational medicinal product remains in good condition 
during transport and storage at intermediate destinations. An y opening or tampering of the outer 
packaging during transport should be readily discernible.  
 
Labelling  
 
Table 1 summarizes the contents of articles 26 -30 that follow. The following information should be 
included on labels, unless its absence can be justified, e.g. use of a centralized electronic 
randomization system:  
 
a) name, address and telephone number of the sponsor, contract research organization or 
investigator (the main contact for information on the product, clinical trial and emergency 
unbinding);  
b) pharmaceutical dosage form, route of administration, quantity of dosage units,  and  in  the Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 120 of 234  case of open trials341, the name/identifier and strength/potency;  
c) the batch and/or code number to identify the contents and packaging operation;  
d) a trial  reference code allowing identification of the trial, site, investigator and sponsor if not 
given elsewhere;  
e) the trial subject identification number/treatment number and where relevant, the visit number ; 
f) the name of the investigator (if not included in (a)  or (d));  
g) directions for use (reference may be made to a leaflet or other explanatory document intended 
for the trial subject or person administering the product);  
h) “For clinical trial use only” or similar wording;  
i) the storage conditions;  
j) period of use (use -by date, expiry date or re -test date as applicable), in month/year format and 
in a manner that avoids any ambiguity.  
k) “keep out of reach of children” except when the product is for use in  
l) trials where the product is not taken home by subjects.  
 
The address  and telephone number of the main contact for information on the product, clinical trial 
and for emergency unbinding need not appear on the label where the subject has been given a leaflet 
or card which provides these details and has been instructed to kee p this in their possession at all 
times.  
 
Particulars should appear in the official language(s) of the country in which the investigational 
medicinal product is to be used. The particulars listed in Article 26 should appear on the primary 
packaging and on the secondary packaging (except for the cases described in Articles 29 and 30). 
The requirements with respect to the contents of the label on the primary and secondary packaging 
are summarized in table 1.  Other languages may be included.  
 
When the product  is to be provided to the trial subject or the person administering the medication 
within a primary packaging together with secondary packaging that is intended to remain together, 
and the secondary packaging carries the particulars listed in paragraph 26,  the following information 
should be included on the label of the primary package (or any sealed dosing device that contains the 
primary packaging):  
 
a) name of sponsor, contract research organization or investigator;  
b) pharmaceutical dosage form, route of administration (may be excluded for oral solid dose 
forms), quantity of dosage units and in the case of open label trials, the name/identifier and 
strength/potency;  
c) batch and/or code number to identify the contents and packaging operation;  
d) a trial referenc e code allowing identification of the trial, site, investigator and sponsor if not 
given elsewhere;  
e) the trial subject identification number/treatment number and where relevant, the visit number.  
 
If the primary packaging takes the form of blister packs or small units such as ampoules on which 
                                                 
34 For closed    blinded    trials, the   labelling  should include a statement indicating “placebo or 
[name/identifier] + [strength/potency]”  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 121 of 234  the particulars required in paragraph 26 cannot be displayed, outer packaging should be provided 
bearing a label with those particulars. The immediate container should nevertheless contain the 
following:  
 
a) name of sponsor, contract research organization or investigator;  
b) route of administration (may be excluded for oral solid dose forms) and in the case of open 
label trials, the name/identifier and strength/potency;  
c) batch and/or code number to identify the contents a nd packaging operation;  
d) a trial reference code allowing identification of the trial, site, investigator and sponsor if not 
given elsewhere;  
e) the trial subject identification number/treatment number and where relevant, the visit number.  
 
Symbols or pictograms may be included to clarify certain information mentioned above. Additional 
information, warnings and/or handling instructions may be displayed35. For clinical trials with certain 
characteristics the following particulars should be added to the or iginal container but should not 
obscure the original labelling:  
 
a) name of sponsor, contract research organization or investigator;  
b) trial reference code allowing identification of the trial site, investigator and trial subject.  
 
If it becomes necessary to ch ange the use -by date, an additional label should be affixed to the 
investigational medicinal product. This additional label should state the new use -by date and repeat 
the batch number. It may be superimposed on the old use -by date, but for quality control  reasons, not 
on the original batch number. This operation should be performed at an appropriately authorized 
manufacturing site. However, when justified, it may be performed at the investigational site by or 
under the supervision of the clinical trial sit e pharmacist, or other health care professional in 
accordance with national regulations. Where this is not possible, it may be performed by the clinical 
trial monitor(s) who should be appropriately trained. The operation should be performed in 
accordance w ith GMP principles, specific and standard operating procedures and under contract, if 
applicable, and should be checked by a second person. This additional labelling should be properly 
documented in both the trial documentation and in the batch records.  
 
13.6 QUALITY CONTROL  
 
As processes may not be standardized or fully validated, testing takes on more importance in ensuring 
that each batch meets its specification.  Quality control should be performed in accordance with the 
Product Specification File and in acc ordance with the required information. Verification of the 
effectiveness of blinding should be performed and recorded.  
 
2. Samples are retained to fulfil two purposes; firstly, to provide a sample for analytical testing 
and secondly to provide a specimen of th e finished product. Samples may therefore fall into 
two categories:  
 
Reference sample: a sample of a batch of starting material, packaging material, product contained in 
                                                 
35 E.g. labels for cytoto xic products or for products requiring special storage conditions  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 122 of 234  its primary packaging or finished product which is stored for the purpose of being analyzed should 
the need arise. Where stability permits, reference sampl es from critical intermediate stages (e.g. 
those. labels for cytotoxic products or for products requiring special storage conditions requiring 
analytical testing and release) or intermediates, which are transported outside of the manufacturer’s 
control sho uld be kept.  
Retention sample: a sample of a packaged unit from a batch of finished product for each packaging 
run/trial period. It is stored for identification purposes. For example, presentation, packaging, 
labelling, leaflet, batch number, expiry date s hould the need arise.  
 
In many instances the reference and retention samples will be presented identically, i.e. as fully 
packaged units. In such circumstances, reference and retention samples may be regarded as 
interchangeable.  
 
Reference and retention sa mples of investigational medicinal product, including blinded product 
should be kept for at least two years after completion or formal discontinuation of the last clinical 
trial in which the batch was used, whichever period is the longer.  
 
Consideration sh ould be given to keeping retention samples until the clinical report has been prepared 
to enable confirmation of product identity in the event of, and as part of an investigation into 
inconsistent trial results.  
 
The storage location of Reference and Reten tion samples should be defined in a Technical Agreement 
between the sponsor and manufacturer(s) and should allow timely access by the competent 
authorities.  
 
The reference sample should be of sufficient size to permit the carrying out, on, at least, two 
occasions, of the full analytical controls on the batch in accordance with the IMP dossier submitted 
for authorization to conduct the clinical trial.  
In the case of retention samples, it is acceptable to store information related to the final packaging as 
written or electronic records if such records provide sufficient information. In the case of the latter, 
the system should comply with the requirements of Annex 11.  
 
13.7 RELEASE OF BATCHES  
 
Release of investigational medicinal products (see paragraph 43) should not occur until after the 
Authorized Person has certified that the relevant requirements have been met. The Authorized Person 
should take into account the elements listed in paragraph 40 as appropriate.  
 
Assessment of each batch for certification prior to release may include as appropriate:  
 
a) batch records, including control reports, in -process test reports and release reports 
demonstrating compliance with the product specification file, the order, protocol and 
randomization code. These records should include all deviations or planned changes, and any 
consequent additional checks or tests, and should be completed and endorsed by the staff 
authorized to do so according to the quality system;  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 123 of 234  b) production conditions;  
c) the validation status of facilities, pro cesses and methods;  
d) examination of finished packs;  
e) where relevant, the results of any analyses or tests performed after importation;  
f) stability reports;  
g) the source and verification of conditions of storage and shipment;  
h) audit reports concerning the quality system of the manufacturer;  
i) Documents certifying that the manufacturer is authorized to manufacture investigational 
medicinal products or comparators for export by the appropriate authorities in the country of 
export;  
j) where relevant, regulatory requirements for marketing authorization, GMP  
k) standards applicable and any official verification of GMP compliance;  
l) all other factors of which the QP is aware that are relevant to the quality of the batch.  
 
The relevance of the above elements is affected by the country of origin of the product, the 
manufacturer, and the marketed status of the product (with or without a marketing authorization, in 
the EU or in a third country) and its phase of development.  
 
The sponsor should ensure that the elements taken into account by the Authorized Person when 
certifying the batch are consistent with the required information.  Where investigational medicinal 
products are manufactured and packaged at different sites under the supervision of different 
Authorized Persons, r ecommendations should be followed as applicable.  
 
Where, permitted in accordance with local regulations, packaging or labelling is carried out at the 
investigator site by, or under the supervision of a clinical trials pharmacist, or other health care 
profe ssional as allowed in those regulations, the Authorized Person is not required to certify the 
activity in question. The sponsor is nevertheless responsible for ensuring that the activity is 
adequately documented and carried out in accordance with the princ iples of GMP and should seek 
the advice of the Authorized Person in this regard.  
 
13.8 SHIPPING  
 
Investigational medicinal products should remain under the control of the Sponsor until after 
completion of a two -step procedure: certification by the Authorized Person; and release following 
fulfilment of the relevant requirements. The Sponsor should ensure that the details set out in the 
clinical trial application and considered by the Authorized Person are consistent with what is finally 
accepted by the Competen t Authorities. Suitable arrangements to meet this requirement should be 
established. In practical terms, this can best be achieved through a change control process for the 
Product Specification File and defined in a Technical Agreement between the Authoriz ed Person and 
the Sponsor. Both steps should be recorded and retained in the relevant trial files held by or on behalf 
of the sponsor.  
 
Shipping of investigational products should be conducted according to instructions given by or on 
behalf of the sponsor in the shipping order.  De-coding arrangements should be available to the 
appropriate responsible personnel before investigational medicinal products are shipped to the Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 124 of 234  investigator site.  
 
A detailed inventory of the shipments made by the manufacturer or importer should be maintained.    
It should particularly mention the addressees’ identification.  
 
Transfers of investigational medicinal products from one trial site to another should remain the 
exception. Such transfers should be covered by standard opera ting procedures. The product history 
while outside of the control of the manufacturer, through for example, trial monitoring reports and 
records of storage conditions at the original trial site should be reviewed as part of the assessment of 
the product’s suitability for transfer and the advice of the Authorized Person should be sought. The 
product should be returned to the manufacturer, or another authorized manufacturer for re -labelling, 
if necessary, and certification by an Authorized  Person. Records sho uld be retained and full 
traceability ensured.  
 
13.9 COMPLAINTS  
 
The conclusions of any investigation carried out in relation to a complaint which could arise from 
the quality of the product should be discussed between the manufacturer or importer and the spons or 
(if different). This should involve the Authorized Person and those responsible for the relevant 
clinical trial in order to assess any potential impact on the trial, product development and on subjects.  
 
13.10  RECALLS AND RETURNS  
 
Recalls  
 
Procedures for retrieving investigational medicinal products and documenting this retrieval should 
be agreed by the sponsor, in collaboration with the manufacturer or importer where different. The 
investigator and monitor need to understand their obligations under the re trieval procedure.  
 
The Sponsor should ensure that the supplier of any comparator or other medication to be used in a 
clinical trial has a system for communicating to the Sponsor the need to recall any product supplied.  
 
Returns  
 
Investigational medicinal  products should be returned on agreed conditions defined by the sponsor, 
specified in approved written procedures.  
 
Returned investigational medicinal products should be clearly identified and stored in an 
appropriately controlled, dedicated area. Invento ry records of the returned medicinal products should 
be kept.  
 
13.11  DESTRUCTION  
 
The Sponsor is responsible for the destruction of unused and/or returned investigational medicinal 
products. Investigational medicinal products should therefore not be destroyed without prior written 
authorization by the Sponsor.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 125 of 234   
The delivered, used and recovered quantities of product should be recorded, reconciled and verified 
by or on behalf of the sponsor for each trial site and each trial period. Destruction of unused 
investigational medicinal products should be carried out for a given trial site or a given trial period 
only after any discrepancies have been investigated and satisfactorily explained and the reconciliation 
has been accepted. Recording of destruction oper ations should be carried out in such a manner that 
all operations may be accounted for. The records should be kept by the Sponsor.  
 
When destruction of investigational medicinal products takes place a dated certificate of, or receipt 
for destruction, shoul d be provided to the sponsor. These documents should clearly identify, or allow 
traceability to, the batches and/or patient numbers involved and the actual quantities destroyed.  
 
13.12   SUMMARY OF LABELING DETAILS  
 
a) name, address and telephone number of the sponsor, contract research organization or 
investigator (the main contact for information on the product, clinical trial and emergency 
unbinding);  
b) pharmaceutical dosage form, route of administration, quantity of dosage units, and in the case 
of open trials36, the name/identifier and strength/potency;  
c) the batch and/or code number to identify the contents and packaging operation;  
d) a trial reference code allowing identification of the trial, site, investigator and sponsor if not 
given elsewhere;  
e) the trial subject identification number /Treatment number and where relevant, the visit number;  
f) the name of the investigator (if not included in or (d);  
g) directions for use (reference may be made to a leaflet or other explanatory document intended 
for the trial subject or person administering the product  
h) “for clinical trial use only” or similar wording;  
i)  the storage conditions; period of use (use -by date, expiry date or re - test date as applicable), in 
month/year format and in a manner that avoids any ambiguit y. 
j) “keep out of reach of children” except when the product is for use in trials where the product 
is not taken home by subjects.  
                                                 
36 When the outer packaging carries the particulars listed in Article 26.  
 Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 126 of 234  GENERAL CASE  
 
For both the primary and secondary packaging (§26)  
 
PRIMARY PACKAGE  
 
Where Primary and secondary packaging remain  together throughout (§29)37 
 
PRIMARY PACKAGE  
 
Blisters or small packaging units  (§30)  
 
The pharmaceutical dosage form and quantity of dosage units may be omitted.  
  
                                                 
37 Route of administration may be excluded for oral solid dose forms  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 127 of 234  ANNEX 14: MANUFACTURE OF MEDICINAL PRODUCTS DERIVED FROM HUMAN 
BLOOD OR PLASMA  
 
GLOSSARY  
 
Blood  
Blood38 means whole blood collected from a single (human) donor and processed either for 
transfusion or for further manufacturing.  
 
Blood component  
A blood component39 means a therapeutic constituent of blood (red cells, white cells, platelets and 
plasma) that can be prepared by various methods, using conventional blood bank methodology (e.g. 
centrifugation, filtration, freezing). This does not include haematopoietic progenitor cells.  
 
Blood establishment  
A blood establishment40 is any structure or body that is responsible for any aspect of the collection 
and testing of human blood and blood components, whatever their intended  
purpose, and their processing, storage and distribution when intended for transfusion.  
 
Blood products  
A blood product41 means any therapeutic product derived from human blood or plasma.  
 
Fractionation, fractionation plant  
Fractionation is the manufacturing process in a plant (fractionation plant) during which plasma 
components are separated/purified by various physical and chemical m ethods such as e.g. 
precipitation, chromatography.  
 
Good Practice guidelines  
Good practice guidelines give interpretation on the national standards and specifications defined for 
quality systems in blood establishments42. 
 
Medicinal products derived from human blood or human plasma  
Medicinal products derived from human blood or human plasma43 are medicinal products based on 
blood constituents which are prepared industrially by public or  
private establishments.  
 
Plasma for fractionation  
Plasma for fractionat ion is the liquid part of human blood remaining after separation of the cellular 
elements from blood collected in a container containing an anticoagulant, or separated by continuous 
                                                 
38 For EU/EEA as referred to in Directive 2002/98 /EC (Art. 3a)  
39 For EU/EEA as referred to in Directive 2002/98/EC (Art. 3b)  
40 For EU/EEA as referred to in Directive 2002/98/EC (Art. 3e)  
41 For EU/EEA as referred to in Directive 2002/98/EC  (Art. 3c)  
42 For EU/EEA as established in the Annex of Directive 2005/62/EC  
43 For EU/EEA as referred to as referred to in Directive 2001/83/EC (Art. 1 No. 10)  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 128 of 234  filtration or centrifugation of anti -coagulated blood in an apheresis proc edure; it is intended for the 
manufacture of plasma derived medicinal products, in particular albumin, coagulation factors and 
immunoglobulins of human origin and specified in the European (or other relevant) Pharmacopoeia 
(Ph. Eur.) monograph “Human Plasm a for fractionation” (0853).  
 
Plasma Master File (PMF)  
A Plasma Master File44 is a stand -alone document, which is separate from the dossier for marketing 
authorization. It provides all relevant detailed information on the characteristics of the entire human  
plasma used as a starting material and/or a raw material for the manufacture of sub/intermediate 
fractions, constituents of the excipients and active substances, which are part of plasma, derived 
medicinal products or medical devices.  
 
Processing  
Processi ng45 means any step in the preparation of blood components  that is carried out between the 
collection of blood and the issuing of a blood component, e.g. separation and freezing of blood 
components. In this Annex, processing in addition refers to those oper ations performed at the blood 
establishment that are specific to plasma to be used for fractionation.  
 
Responsible Person (RP)  
A person responsible for ensuring  that each batch of (biological) active substance or medicinal 
product has been manufactured and  checked in compliance with the laws in force and in accordance 
with the specifications and/or requirements of the marketing authorization. The RP is equivalent to 
the EU term “Qualified Person”46. 
 
Responsible Person (RP) for blood establishment  
A person r esponsible for ensuring that every unit of blood or blood components has been collected 
and tested, processed, stored and distributed in compliance with the laws in force. This term is 
equivalent to the EU term “Responsible Person”47. 
 
Contract fractionatio n program  
This is a contract fractionation in a national plant of a fractionator/manufacturer, using starting 
material from other countries and manufacturing products not intended for the national market.  
 
SCOPE  
 
The provisions of this Annex apply to medicinal products derived from human blood or plasma, 
fractionated in or imported into the country. The Annex applies also to the starting material (e.g. 
human plasma) for these products. In line with national legislation11 the requirements may apply 
also for stable derivatives of human blood or human plasma (e.g. Albumin) incorporated into medical 
devices.  
This Annex defines specific Good Manufacturing Practices (GMP) requirements for collection, 
                                                 
44 For EU/EEA as referred to in Directive 2001/83/EC (Annex I, Part III, No. 1.1.a)  
45 For EU/EEA as according to the terminology of directive 2005/62/EC  
46 For EU/E EA, see Article 48 of Directive 2001/83/EC and Article 52 of Directive 2001/82/EC.  
47 For EU/EEA, see Article 9 of Directive 2002/98/EC  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 129 of 234  processing, storage and transport of human plasma used for fractionation and for the manufacture of 
medicinal products derived from human blood or plasma.  
The Annex addresses specific provisions for when starting material is imported from other countries 
and for contract fractionation programs for other countries.  
The Annex does not apply to blood components intended for transfusion.  
 
PRINCIPLES  
 
Medicinal products derived from human blood or plasma (and their active substances which are used 
as starting materials) must comply with the principles and guidelines of Good Manufacturing 
Practice48 as well as the relevant marketing authorization. They are considered to be biological 
medicinal products and the starting materials include biological substances, such as cells or fluids 
(including blood or plasma) of human origin. Certain special feature s arise from the biological nature 
of the source material. For example, disease - transmitting agents, especially viruses, may 
contaminate the source material. The quality and safety of these products relies therefore on the 
control of source materials and their origin as well as on the subsequent manufacturing procedures, 
including infectious marker testing, virus removal and virus inactivation.  
 
In principle active substances used as starting material for medicinal products must comply with the 
principles and guidelines of Good Manufacturing Practice (see 2.1). For starting materials derived 
from human blood and plasma national49 or international requirements for blood establishments 
involved in the collection, preparation and testing are to be followed. Col lection, preparation and 
testing must be performed in accordance with an appropriate quality system50 and for which standards 
and specifications are defined. Furthermore, the national51 or international requirements on 
traceability and serious adverse reacti ons and serious adverse event notifications from the donor to 
the recipient should be applied. Reference is hereby made to international guidelines as defined in 
the addendum. In addition, the monographs of the relevant Pharmacopoeia52 are to be observed.  
 
Starting material for the manufacture of medicinal products derived from human blood or plasma 
imported from other countries and intended for use or distribution within the country must meet the 
national53 standards.  
 
In the case of contract fractionation p rograms the starting material imported from other countries 
must comply with the national or equivalent54 quality and safety requirements for blood components. 
The activities conducted within the country must fully comply with GMP.  Consideration should be 
                                                 
48 For EU/EEA this is laid down in Commission Directive 2003/94/EC and the EU  
49 For EU/EEA requirement for the collection and testing are defined in Directive 2002/98/EC.  
50 For EU/EEA standards and specifications for quality systems are defined in the  Annex of Directive 2005/62/EC and 
interpreted in the Good Practice guidelines referred to in Article 2 (2) of Directive 2005/ 62/EC.  
51 For EU/EEA requirements on traceability and serious adverse reactions and serious adverse event notifications are 
defined in Directive 2005/61/EC.  
52 For EU/EEA this is the European Pharmacopoeia as defined in Directive 2002/98/EC.  
53 For EU/EEA ref erence is made to the quality and safety requirements as laid down in Directive 2002/98/EC and in 
Annex V of Directive 2004/33/EC.  
54 For EU/EEA considerations should be given to the Community standards and specifications relating to a quality 
system for bl ood establishments set out in Commission Directive 2005/62/EC and the traceability requirements and  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 130 of 234  given to national55 standards and specifications relating to a quality system for blood establishments, 
the traceability requirements and notification of serious adverse reactions and events and the relevant 
WHO guidelines and recommendations as listed in t he addendum.  
 
All subsequent steps after collection and testing (e.g. processing (including separation), freezing, 
storage and transport to the manufacturer) must therefore be done in accordance with the principles 
and guidelines of Good Manufacturing Prac tice20. Normally, these activities would be carried out 
under the responsibility of a Responsible Person in an establishment with a manufacturing 
authorization. Where specific processing steps in relation to plasma for fractionation take place in a 
blood e stablishment, the specific appointment of a Responsible Person may, however, not be 
proportionate given the presence and responsibility of a Responsible Person of the blood 
establishment. To address this particular situation and to ensure the legal respons ibilities of the 
Responsible Person are properly addressed, the fractionation plant/manufacturer should establish a 
contract in accordance with Chapter 7 of the GMP Guide with the blood establishment that defines 
respective responsibilities and the detaile d requirements in order to ensure compliance. The 
Responsible Person of the blood establishment and the Responsible Person of the 
fractionation/manufacturing plant (see 3.5) should be involved in drawing up this contract. The 
Responsible Person should ensu re that audits are performed to confirm that the blood establishment 
complies with the contract notification of serious adverse reactions and events as set out in 
Commission Directive 2005/61/EC.  
 
Depending on national legislation, specific requirements fo r documentation and other arrangements 
relating to the starting material of plasma -derived medicinal products are defined in the Plasma 
Master File.  
 
14.1 QUALITY MANAGEMENT  
 
Quality management should govern all stages from donor selection in the blood establishment up to 
delivery of the finished product by the finished product manufacturer. Traceability of each donation 
up to and including the delivery of plasma to the fractionation plant should be ensured by the blood 
establishment through accurate ide ntification procedures, record maintenance and an appropriate 
labeling system according to national or international requirements, and should be maintained during 
further manufacturing and distribution of final products by the manufacturer.  
 
Blood or plasm a used as source  material for the manufacture of medicinal products must be collected 
and processed by blood establishments and be tested in laboratories which apply quality systems in 
accordance with national56 or international standards. Reference is mad e to documents listed in the 
addendum. The blood establishments have to be authorized and subject to regular inspections by a 
national competent authority57. Contract fractionation programs have to be notified to the competent 
authority by the manufacturer58. 
                                                 
55 For EU/EEA the requirements of Directive 2001/83/EC apply.  
 
56 For EU/EEA reference is made to Directive 2005/61/EC and to Directive 2005/62/EC.  
57 For EU/ EEA reference is made to Directive 2005/62/EC.  
58 For EU/EEA as referred to in Directive 2002/98/EC  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 131 of 234   
If plasma is imported from other countries it should only be purchased from approved suppliers (e.g. 
blood establishments, including external warehouses). They should be named in the specifications 
for starting materials as defined by the fractionation plant/manufacturer, and be accepted by the 
competent authority (e.g. following an inspection) of the importing country and by the Responsible 
Person of the importing fractionation plant. Certification and release of plasma (plasma for 
fractionation) as sta rting material is mentioned in section 6.8.  
 
Supplier qualification, including audits, should be performed by the fractionation plant/manufacturer 
of the finished product including test laboratory according to written procedures. Re -qualification of 
suppli ers should be performed at regular intervals taking a risk -based approach into account.  
 
The fractionation plant/manufacturer of the finished product should establish written contracts with 
the supplying blood establishments. As a minimum the following key  aspects should be addressed: 
definition of duties and respective responsibilities:  
 
a) quality system and documentation requirements  
b) donor selection criteria and testing  
c) requirements for the separation of blood into blood components/plasma  
d) freezing of plasma  
e) storage and transport of plasma  
f) Traceability and post donation / collection information (including adverse events).  
 
The test results of all units supplied by the blood establishment should be available to the 
fractionation plant/manufacturer of the medicinal product. In addition, any fractionation step 
subcontracted should be defined in a written contract.  
 
A formal change control system should be in place to plan, evaluate and document all changes that 
may affect the quality or safety of the products, or traceability. The potential impact of proposed 
changes should be evaluated. The need for additional testing and validation, especially viral 
inactivation and removal steps, should be determined.  An adequate safety strategy should be in place 
to minimize the risk from infectious agents and emerging infectious agents. This strategy should 
involve a risk assessment that:  
 
i) Defines an inventory holding time (internal quarantine time) before processing the plasma i.e. to 
remove look back units.  
ii)  Considers all aspects of virus reduction and/or testing for infectious agents or surrogates.  
iii) Consider  the virus reduction capabilities, the pool size and other relevant aspects of the 
manufacturing processes.  
 
14.2 TRACEABILITY AND POST COLLECTION MEASURES  
 
There must be a system in place that enables each donation to be traced, from the donor and the 
donation via the blood establishment through to the batch of medicinal product and vice versa.  
                                                 
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Page 132 of 234  Responsibilities for traceability of the product should  be defined (there should be no gaps):  
 
a) from the donor and the donation in the blood establishment to the fractionation plant (this is 
the responsibility of the RP of the blood establishment);  
b) from the fractionation plant to the manufacturer of the medicinal product and any secondary 
facility, whether a manufacturer of a medicinal product or of a medical device (this is the 
responsibility of the RP).  
 
Data needed for full traceability must be stored according to national legislation59. The contracts (as 
mentioned in 3.5) between the blood establishments (including testing laboratories) and the 
fractionation plant/manufacturer should ensure that traceability and post collection measures cover 
the complete chain from the collection of the plasma to all manufacturers responsible for release of 
the final products.  
 
The blood establishments should notify the fractionating plant/manufacturer of any event which may 
affect the quality or safety of the product including serious adverse events and reactions60 and other 
relevant information found subsequent to donor acceptance or release of the plasma, e.g. look back 
information61 (post -collection information). Where the fractionation plant/manufacturer is located in 
another country, the information should be forwar ded to the manufacturer responsible for release in 
the country of any product manufactured from the plasma concerned. In both cases, if relevant for 
the quality or safety of the final product, this information should be forwarded to the competent 
authority62 responsible for the fractionation plant/manufacturer as required by national legislation.  
 
The notification procedure as described in 4.5 also applies when an inspection of a blood 
establishment by a competent authority leads to a withdrawal of an existi ng license/certificate/ 
approval.  The management of post -collection information should be described in standard operating 
procedures and taking into account obligations and procedures for informing the competent 
authorities. Post -collection measures should  be available as defined in national or relevant 
international recommendations63. 
 
The blood establishment and the fractionation/manufacturer should inform each other if, following 
donation:  
 
It is found that the donor did not meet the relevant donor health  criteria;  
a. A subsequent donation from a donor previously found negative for viral markers is 
found positive for any of the viral markers;  
b. It is discovered that testing for viral markers has not been carried out according to 
agreed procedures;  
c. The donor has  developed an infectious disease caused by an agent potentially 
                                                 
59 Plasma units donated by donors during a defined period (as defined on a national / EU basis) before it is found that a 
donation from a high -risk donor should have been excluded from processing, e.g. due to a positive test result.  
60 For EU/EEA this is for at least 30 years according to Article 4 of Directive 2005/61/EC  
61 For EU/EEA reference is made to in Annex II part A and Annex III -part A of Directive 2005/61/EC.  
62 Information that appears if a subsequent donation from a donor previously found negative for viral markers is found 
positive for any of the viral markers or any other risk factors which may induce a viral infection  
63 For EU/EEA this is the co mpetent authority as referred to in Directive 2001/83/EC.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 133 of 234  transmissible by plasma -derived products (HBV, HCV, HAV and other non -A, non -
B, non -C hepatitis viruses, HIV -1 and 2 and other agents in the light of current 
knowledge);  
d. The donor develops Cre utzfeldt -Jakob disease (CJD or vCJD);  
e. The recipient of blood or a blood component develops post -transfusion infection 
which implicates or can be traced back to the donor.  
 
In the event of any of the above, a re -assessment of the batch documentation should always be carried 
out. The need for withdrawal of the given batch should be carefully considered, taking into account 
criteria such as the transmissible agent involved, the size of the pool, the time period between 
donation and sero -conversion, the nature of the product and its manufacturing method.  
 
14.3 PREMISES AND EQUIPMENT  
 
In order to minimize microbiological contamination or the introduction of foreign material into the 
plasma pool, thawing and pooling of plasma units should be performed in an area confor ming at least 
to the Grade D requirements defined in Annex 1 of the PIC/S GMP Guide. Appropriate clothing 
should be worn including face masks and gloves. All other open manipulations during the 
manufacturing process should be done under conditions conformi ng to the appropriate requirements 
of Annex 1 of the PIC/S GMP Guide.  
 
Environmental monitoring should be performed regularly, especially during the ‘opening’ of plasma 
containers, and during subsequent thawing and pooling processes in accordance with Annex 1 of the 
PIC/S GMP Guide.  
 
In the production of plasma -derived medicinal products, appropriate viral inactivation or removal 
procedures are used and steps should be taken to prevent cross contamination of treated with 
untreated products. Dedicated an d distinct premises and equipment should be used for manufacturing 
steps before and after viral inactivation treatment.  
 
To avoid placing routine manufacture at risk of contamination from viruses used during validation 
studies, the validation of methods fo r virus reduction should not be conducted in production facilities. 
Validation should be performed according to international recommendations64. 
 
14.4 MANUFACTURING  
 
Starting material  
 
The starting material should comply with the requirements of all relevant monographs of the relevant 
Pharmacopoeia and of the conditions laid down in the respective marketing authorization dossier 
                                                 
64 For EU/EEA reference is made to the "Note for Guidance on Virus Validation Studies: The Design, Contribution 
and Interpretation of Studies validating the Inactivation and Removal of Viruses" in it s current version as adopted by 
the Committee for Medicinal Products for Human Use (CHMP) and published by the European Medicines Agency. 
Current version at date of publication: CHMP/BWP/268/95 (see  3.5) between the blood establishment and the 
fractionati ng plant/manufacturer and controlled through the quality system.  
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Page 134 of 234  (including the Plasma Master File if applicable). These req uirements should be defined in the written 
contract.  
 
Starting material imported for contract fractionation programs should comply with the requirements . 
Depending on the type of collection (i.e. either whole blood collection or automated apheresis) 
differ ent processing steps may be required. All processing steps (e.g. centrifugation and/or 
separation, sampling, labelling, freezing) should be defined in written procedures.  
 
Any mix -ups of units and of samples, especially during labelling, as well as any con tamination, e.g. 
when cutting the tube segments/sealing the containers, must be avoided.  Freezing is a critical step 
for the recovery of proteins that are labile in plasma, e.g. clotting factors. Freezing should therefore 
be performed as soon as possible a fter collection (see the European Pharmacopoeia Monograph No 
0853 "Human Plasma for Fractionation" and where relevant, monograph No 1646 "Human Plasma 
pooled and treated for virus inactivation", or other relevant Pharmacopoeia), following a validated 
metho d. The storage and transport of blood or plasma at any stage in the transport chain to the 
fractionation plant should be defined and recorded. Any deviation from the defined temperature 
should be notified to the fractionation plant. Qualified equipment and  validated procedures should 
be used.  
 
Certification/release of plasma for fractionation as starting material  
 
Plasma for fractionation should only be released, i.e. from a quarantine status, through systems and 
procedures that assure the quality needed for the manufacture of the finished product. It should only 
be distributed to the plasma fractionation plant/manufacturer after it has been documented by the 
Responsible Person of the blood establishment (or in case of blood/plasma collection in other 
coun tries by a person with equivalent responsibilities and qualifications) that the plasma for 
fractionation does comply with the requirements and specifications defined in the respective written 
contracts and that all steps have been performed in accordance w ith Good Practice and GMP 
Guidelines, as appropriate.  
 
On entering the fractionation plant, the plasma units should be released for fractionation under the 
responsibility of the Responsible Person. The Responsible Person should confirm that the plasma 
complies with the requirements of all relevant monographs and the conditions laid down in the 
respective marketing authorization dossier (including the Plasma Master File if applicable) or, in case 
of plasma to be used for contract fractionation programs, with the requirements . 
 
Processing of plasma for fractionation  
 
The steps used in the fractionation process vary according to product and manufacturer and usually 
include several fractionation/purification procedures, some of which may contribute to the 
inactivation and/or removal of potential contamination.  Requirements for the processes of pooling, 
pool sampling and fractionation/purification and virus inactivation/removal should be defined and 
followed thoroughly.  
 
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Page 135 of 234  The methods used in the viral inacti vation process should be undertaken with strict adherence to 
validated procedures and in compliance with the methods used in the virus validation studies. 
Detailed investigation of failures in virus inactivation procedures should be performed. Adherence 
to the validated production process is especially important in the virus reduction procedures as any 
deviation could result in a safety risk for the final product. Procedures which take this risk into 
consideration should be in place.  
 
Any reprocessing or re working may only be performed after a quality risk management exercise has 
been performed and using processing steps as defined in the relevant marketing authorization.  A 
system for clearly segregating/distinguishing between products or intermediates which  have 
undergone a process of virus reduction, from those which have not, should be in place.  
 
Depending on the outcome of a thorough risk management process (taking into consideration 
possible differences in epidemiology) production in campaigns including clear segregation and 
defined validated cleaning procedures should be adopted when plasma/intermediates of different 
origins is processed at the same plant. The requirement for such measures should be based on 
international recommendations65. The risk manag ement process should consider whether it is 
necessary to use dedicated equipment in the case of contract fractionation programs.  
 
For intermediate products intended to be stored, a shelf -life should be defined based on stability data.  
The storage and transport of intermediate and finished medicinal products at any stage of the transport 
chain should be specified and recorded. Qualified equipment and validated procedures should be 
used.  
 
14.5 QUALITY CONTROL  
 
Testing requirements for viruses or other infecti ous agents should be considered in the light of 
knowledge emerging on infectious agents and on the availability of appropriate, validated test 
methods.  
 
The first homogeneous plasma pool (e.g. after separation of the cryoprecipitate from the plasma pool) 
should be tested using validated test methods of suitable sensitivity and specificity, according to the 
relevant Pharmacopoeia monographs66 
 
 
14.6 RELEASE OF INTERMEDIATE AND FINISHED PRODUCTS  
 
Only batches derived from plasma pools tested and found negative for  virus markers / antibodies and 
found in compliance with the relevant Pharmacopoeia monographs, including any specific virus cut -
off limits, and with the approved specifications (e.g. Plasma Master File if applicable), should be 
released.  
 
                                                 
65 For EU/EEA, see Guidelines on Epidemiological Data on Blood Transmissible Infections, 
EMEA/CPMP/BWP/125/04.  
66 For EU/EEA reference is made to the relevant European Pharmacopoeia monographs  (e.g. No 0853).  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 136 of 234  The release of intermediates intended for further in -house processing or delivery to a different site 
and the release of finished products should be performed by the Responsible Person and in 
accordance with the approved marketing authorization.  The release of intermedia tes and final 
products used in contract fractionation programs should be performed by the Responsible Person on 
the basis of standards agreed with the contract giver and compliance with PIC/S GMP standards.  
 
14.7 RETENTION OF PLASMA POOL SAMPLES  
 
One plasma pool may be used to manufacture more than one batch and/or product. Retention samples 
and corresponding records from every pool should be kept for at least one year after the expiry date 
of the finished medicinal product with the longest shelf -life derived  from the pool.  
 
14.8 DISPOSAL OF WASTE  
 
There should be written procedures for the safe and documented storage and disposal of waste, 
disposable and rejected items (e.g. contaminated units, units from infected donors, out of date blood, 
plasma, intermediate or  finished products).  
 
ADDENDUM  
 
The Addendum lists EU -specific directives and guidelines which give further guidance on specific 
topics or must be implemented by EU/EEA Member States.  
 
Addendum  
 
A) EU/EEA Member States have been obliged to implement the following Directives and guidelines:  
 
1. for collection and testing of blood and blood components:  
Directive/Guideline
s Title  Scope  
Directive 
2002/98/EC of the 
European Parliament 
and of the Council  Setting standards of 
quality and safety for 
the collection,  testing, 
processing, storage and 
distribution of human 
blood and blood 
components, amending 
Directive 2001/83/E C.  Art.2 Defines 
standards of 
quality and safety 
for the collection 
and testing of 
human blood and 
blood 
components, 
whatever their 
intended pu rpose, 
and for their 
processing, 
storage and 
distribution when 
intended for Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 137 of 234  transfusion.  
Commission 
Directive 
2004/33/EC  Implementing Directive 
2002/98/EC of the 
European Parliament 
and of the Council as 
regards certain technical 
requirements for blood 
and blood components  Defines the 
provision of 
information to 
prospective 
donors and 
information 
required from 
donors (Part A 
and B, Annex II), 
eligibility of 
donors (Annex 
III), storage, 
transport and 
distribution 
conditions for 
blood and blood 
components 
(Annex IV), as 
well as quality 
and safety 
requirements for 
blood and blood 
components 
(Annex V).  
 
Commission 
Directive 2005/61/EC  Implementing 
Directive 2002/98/EC 
of the European 
Parliament and of the 
Council as regards 
traceability 
requirements and 
notification of serious 
adverse reactions and 
events.  Defines 
traceability 
requirements for 
blood 
establishments, 
donors, blood and 
blood 
components, and 
for the final 
destination of 
each unit, 
whatever the 
intended purpose. 
It further defines Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 138 of 234  the reportin g 
requirements in 
the event of 
serious adverse 
events and 
reactions.  
Commission 
Directive 2005/62/EC  Implementing 
Directive 2002/98/EC 
of the European 
Parliament and of the 
Council as regards 
Community standards 
and specifications 
relating to a quality 
system for blood 
establishments.  Defines the 
implementation 
of quality system 
standards and 
specifications as 
referred to in 
article 47 of 
Directive 
2001/83/EC.  
 
2. for collection and regulatory submission of data/information for plasma for fractionation:  
 
Directive/ 
Guidelines  Title  Scope  
Directive 
2001/83/EC of the 
European Parliament 
and the Council  On the Community 
Code relating to 
medicinal products for 
human use.  Art. 2 Medicinal 
products for 
human use 
intended to be 
placed on the 
market in 
Member Sta tes 
and either 
prepared 
industrially or 
manufactured by 
a method 
involving an 
industrial 
process, covering 
medicinal 
products derived 
from human 
blood or human 
plasma.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 139 of 234  Commission 
Directive 
2003/63/EC  Amending Directive 
2001/83/EC of the 
European Parliament 
and of the Council on 
the Community code 
relating to medicinal 
products for human use; 
Amending the Annex on 
documentation of 
medicinal products   
Commission 
Directive 
2003/94/EC  Laying down the 
principles and 
guidelines of good 
manufacturing practice 
in respect of medicinal 
products for human use 
and investigational 
medicinal products for 
human use  Art. 1 Principles 
and guidelines of 
good 
manufacturing 
practice in 
respect of 
medicinal 
products for 
human use and 
investigational 
medicinal 
produc ts for 
human use  
EU Guidelines to 
Good Manufacturing 
Practice  Giving interpretation  on 
the principles and 
guidelines on GMP  
  
 
EMEA/CHMP/BWP
/ 37 
94/03 Rev.1, 15. 
Nov.  
2006  Guideline on the 
Scientific data 
requirements for a 
Plasma Master File 
(PMF) Revision 1   
EMEA/CPMP/BWP
/ 12 
5/04 EMEA  
Guideline  Guideline on 
Epidemiological Data 
on Blood Transmissible 
Infections   
B. Other relevant documents:  
 
Document  Title  Scope  
PE 005  PIC/S GMP Guide for 
blood establishments  Guidance for 
GMP for blood 
establishments  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Page 140 of 234  Recommendation 
No. R (95) 15  
(Council of Europe)  Guide to the Preparation, 
use and quality assurance 
of blood components   
World Health 
Organization  
WHO Technical  
Report Series No 
941, 2007; Annex 4  WHO Recommendations 
for the  
production, control and 
regulation  
of human plasma for 
fractionation  Guidance on the 
production,  
control and 
regulation of 
human  
plasma for 
fractionation,  
adopted by the 
56th meeting of 
the WHO Expert 
Committee on  
Biological 
Standardization,  
24-28 October 
2005  
   
World Health  
Organization,  
WHO  
Technical  
Report Series, No.  
961, 2011; Annex 4  WHO guidelines on 
Good  
Manufacturing Practices 
for blood  
establishments   
  
 
Reference should be made to the latest revisions of these documents for current guidance.Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 ANNEX 15: QUALIFICATION AND VALIDATION  
 
PRINCIPLE  
 
This Annex describes the principles of qualification and validation which are applicable to the 
facilities; equipment, utilities and processes used for the manufacture of medicinal products and may 
also be used as supplementary optional guidance for active subs tances without introduction of 
additional requirements to Part II. It is a GMP requirement that manufacturers control the critical 
aspects of their particular operations through qualification and validation over the life cycle of the 
product and process. A ny planned changes to the facilities, equipment, utilities and processes, which 
may affect the quality of the product, should be formally documented and the impact on the validated 
status or control strategy assessed. Computerized systems used for the manu facture of medicinal 
products should also be validated according to the requirements of Annex 11. The relevant concepts 
and guidance presented in ICH Q8, Q9, Q10 and Q11 should also be taken into account.  
 
GENERAL  
 
A quality risk management approach should  be applied throughout the lifecycle of a medicinal 
product. As part of a quality risk management system, decisions on the scope and extent of 
qualification and validation should be based on a justified and documented risk assessment of the 
facilities, equ ipment, utilities and processes. Retrospective validation is no longer considered an 
acceptable approach.  
 
Data supporting qualification and/or validation studies which were obtained from sources outside of 
the manufacturers own programmes may be used prov ided that this approach has been justified and 
that there is adequate assurance that controls were in place throughout the acquisition of such data.  
 
15.1 ORGANISING AND PLANNING FOR QUALIFICATION AND VALIDATION.  
 
All qualification and validation activities should be planned and take the life cycle of facilities, 
equipment, utilities, process and product into consideration.  Qualification and validation activities 
should only be performed by suitably trained personnel who follow approved procedures.  
 
Qualifica tion/validation personnel should report as defined in the pharmaceutical quality system 
although this may not necessarily be to a quality management or a quality assurance function. 
However, there should be appropriate quality oversight over the whole vali dation life cycle.  
 
The key elements of the site qualification and validation program should be clearly defined and 
documented in a validation master plan (VMP) or equivalent document.  The VMP or equivalent 
document should define the qualification/validati on system and include or reference information on 
at least the following:  
 
a) Qualification and Validation policy;  
b) The organizational structure including roles and responsibilities for qualification and validation Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 activities;  
c) Summary of the facilities, equipment, systems, processes on site and the qualification and 
validation status;  
d) Change control and deviation management for qualification and validation; Guidance on 
developing acceptance criteria;  
e) References to existing documents;  
f) The qualification and  validation strategy, including requalification, where applicable.  
 
For large and complex projects, planning takes on added importance and separate validation plans 
may enhance clarity.  A quality risk management approach should be used for qualification and 
validation activities. In light of increased knowledge and understanding from any changes during the 
project phase or during commercial production, the risk assessments should be repeated, as required. 
The way in which risk assessments are used to supp ort qualification and validation activities should 
be clearly documented.  Appropriate checks should be incorporated into qualification and validation 
work to ensure the integrity of all data obtained.  
 
15.2 DOCUMENTATION INCLUDING VMP  
 
Good documentation practi ces are important to support knowledge management throughout the 
product lifecycle.  All documents generated during qualification and validation should be approved 
and authorized by appropriate personnel as defined in the pharmaceutical quality system.  
 
The inter-relationship between documents in complex validation projects should be clearly defined.  
Validation protocols should be prepared which defines the critical systems, attributes and parameters 
and the associated acceptance criteria.  
 
Qualification doc uments may be combined together, where appropriate, e.g. installation qualification 
(IQ) and operational qualification (OQ).  Where validation protocols and other documentation are 
supplied by a third party providing validation services, appropriate personn el at the manufacturing 
site should confirm suitability and compliance with internal procedures before approval. Vendor 
protocols may be supplemented by additional documentation/test protocols before use.  
 
Any significant changes to the approved protocol d uring execution, e.g. acceptance criteria, operating 
parameters etc., should be documented as a deviation and be scientifically justified.  Results which 
fail to meet the pre -defined acceptance criteria should be recorded as a deviation, and be fully 
invest igated according to local procedures. Any implications for the validation should be discussed 
in the report.  
 
The review and conclusions of the validation should be reported and the results obtained summarized 
against the acceptance criteria. Any subsequent changes to acceptance criteria should be scientifically 
justified and a final recommendation made as to the outcome of the validation.  
 
A formal release for the next stage in the qualification and validation process should be authorized 
by the r elevant responsible personnel either as part of the validation report approval or as a separate Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 summary document. Conditional approval to proceed to the next qualification stage can be given 
where certain acceptance criteria or deviations have not been ful ly addressed and there is a 
documented assessment that there is no significant impact on the next activity.  
 
15.3 QUALIFICATION STAGES FOR EQUIPMENT, FACILITIES, UTILITIES AND 
SYSTEMS.  
 
Qualification activities should consider all stages from initial development of the user requirements 
specification through to the end of use of the equipment, facility, utility or system. The main stages 
and some suggested criteria (although this depends on individual project circumstances and may be 
different) which c ould be included in each stage are indicated below:  
 
User requirements specification (URS)  
 
The specification for equipment, facilities, utilities or systems should be defined in a URS and/or a 
functional specification. The essential elements of quality ne ed to be built in at this stage and any 
GMP risks mitigated to an acceptable level. The URS should be a point of reference throughout the 
validation life cycle.  
 
Design qualification (DQ)  
 
The next element in the qualification of equipment, facilities, utilities, or systems is DQ where the 
compliance of the design with GMP should be demonstrated and documented. The requirements of 
the user requirements specification should be verified during the design qualification.  
 
Factory acceptance testing (FAT) /Si te acceptance testing (SAT)  
 
Equipment, especially if incorporating novel or complex technology, may be evaluated, if applicable, 
at the vendor prior to delivery.  Prior to installation, equipment should be confirmed to comply with 
the URS/ functional speci fication at the vendor site, if applicable.  Where appropriate and justified, 
documentation review and some tests could be performed at the FAT or other stages without the need 
to repeat on site at IQ/OQ if it can be shown that the functionality is not affe cted by the transport and 
installation.  FAT may be supplemented by the execution of a SAT following the receipt of equipment 
at the manufacturing site.  
 
Installation qualification (IQ)  
 
IQ should be performed on equipment, facilities, utilities, or systems.  IQ should include, but is not 
limited to the following:  
 
a) Verification of the correct installation of components, instrumentation, equipment, pipe work 
and services against the engineering drawings and specifications;  
b) Verification of the correct installation against pre -defined criteria;  
c) Collection and collation of supplier operating and working instructions and maintenance Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 requirements;  
d) Calibration of instrumentation;  
e) Verification of the materials of construction.  
 
Operational qualification (OQ)  
 
OQ normally follows IQ but depending on the complexity of the equipment, it may be performed as 
a combined Installation/Operation Qualification (IOQ).  OQ should include but is not limited to the 
following:  
a) Tests that have been developed from the knowledge  of processes, systems and equipment to 
ensure the system is operating as designed;  
b) Tests to confirm upper and lower operating limits, and/or “worst case” conditions.  
 
The completion of a successful OQ should allow the finalization of standard operating an d cleaning 
procedures, operator training and preventative maintenance requirements.  
 
Performance qualification (PQ)  
 
PQ should normally follow the successful completion of IQ and OQ. However, it may in some cases 
be appropriate to perform it in conjunction  with OQ or Process Validation.  
PQ should include, but is not limited to the following:  
Tests, using production materials, qualified substitutes or simulated product proven to have 
equivalent behavior under normal operating conditions with worst case batch  sizes. The frequency 
of sampling used to confirm process control should be justified;  
Tests should cover the operating range of the intended process, unless documented evidence from 
the development phases confirming the operational ranges is available.  
 
15.4 RE-QUALIFICATION  
 
Equipment, facilities, utilities and systems should be evaluated at an appropriate frequency to confirm 
that they remain in a state of control.  
Where re -qualification is necessary and performed at a specific time period, the period should be 
justified and the criteria for evaluation defined. Furthermore, the possibility of small changes over 
time should be assessed.  
 
15.5 PROCESS VALIDATION  
 
General  
 
The requirements and principles outlined in this section are applicable to the manufacture of all 
pharmaceutical dosage forms. They cover the initial validation of new processes, subsequent 
validation of modified processes, site transfers and ongoing process verification. It is implicit in this 
annex that a robust product development process is in place to enable successful process validation. 
Section 5 should be used in conjunction with relevant guidelines on Process  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Validation.  
 
A guideline on Process Validation is intended to provide guidance on the information and data to be 
provided in the regulatory submission only. However, GMP requirements for process validation 
continue throughout the lifecycle of the process.  This approach should be applied to link product and 
process development. It will ensure validation of the commercial manufacturin g process and 
maintenance of the process in a state of control during routine commercial production.  
 
Manufacturing processes may be developed using a traditional approach or a continuous verification 
approach. However, irrespective of the approach used, p rocesses must be shown to be robust and 
ensure consistent product quality before any product is released to the market. Manufacturing 
processes using the traditional approach should undergo a prospective validation programme 
wherever possible prior to cert ification of the product. Retrospective validation is no longer an 
acceptable approach.  
 
Process validation of new products should cover all intended marketed strengths and sites of 
manufacture. Bracketing could be justified for new products based on exten sive process knowledge 
from the development stage in conjunction with an appropriate ongoing verification programme.  
For the process validation of products, which are transferred from one site to another or within the 
same site, the number of validation ba tches could be reduced by the use of a bracketing approach. 
However, existing product knowledge, including the content of the previous validation, should be 
available. Different strengths, batch sizes and pack sizes/ container types may also use a bracketi ng 
approach if justified.  
 
For the site transfer of legacy products, the manufacturing process and controls must comply with 
the marketing authorization and meet current standards for marketing authorization for that product 
type. If necessary, variations to the marketing authorization should be submitted.  
 
Process validation should establish whether all quality attributes and process parameters, which are 
considered important for ensuring the validated state and acceptable product quality, can be 
consisten tly met by the process. The basis by which process parameters and quality attributes were 
identified as being critical or non -critical should be clearly documented, taking into account the 
results of any risk assessment activities.  
 
Normally batches manufa ctured for process validation should be the same size as the intended 
commercial scale batches and the use of any other batch sizes should be justified or specified in other 
sections of the GMP guide.  Equipment, facilities, utilities and systems used for p rocess validation 
should be qualified. Test methods should be validated for their intended use.  
 
For all products irrespective of the approach used, process knowledge from development studies or 
other sources should be accessible to the manufacturing site,  unless otherwise justified, and be the 
basis for validation activities.  
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 For process validation batches, production, development, or other site transfer personnel may be 
involved. Batches should only be manufactured by trained personnel in accordance with  GMP using 
approved documentation. It is expected that production personnel are involved in the manufacture of 
validation batches to facilitate product understanding.  
 
The suppliers of critical starting and packaging materials should be qualified prior to the manufacture 
of validation batches; otherwise a justification based on the application of quality risk management 
principles should be documented.  
 
It is especially important that the underlying process knowledge for the design space justification (if 
used) and for development of any mathematical models (if used) to confirm a process control strategy 
should be available.  Where validation batches are released to the market this should be pre -defined.  
 
The conditions under which they are produced should fu lly comply with GMP, with the validation 
acceptance criteria, with any continuous process verification criteria (if used) and with the marketing 
authorization or clinical trial authorization.  For the process validation of investigational medicinal 
products  (IMP), please refer to Annex 13.  
 
Concurrent validation  
 
In exceptional circumstances, where there is a strong benefit -risk ratio for the patient, it may be 
acceptable not to complete a validation programme before routine production starts and concurrent 
validation could be used. However, the decision to carry out concurrent validation must be justified, 
documented in the VMP for visibility and approved by Authorized Personnel.  
 
Where a concurrent validation approach has been adopted, there should be suffi cient data to support 
a conclusion that any given batch of product is uniform and meets the defined acceptance criteria. 
The results and conclusion should be formally documented and available to the Authorized Person 
prior to certification of the batch.  
 
Traditional process validation  
 
In the traditional approach, a number of batches of the finished product are manufactured under 
routine conditions to confirm reproducibility.  The number of batches manufactured and the number 
of samples taken should be base d on quality risk management principles, allow the normal range of 
variation and trends to be established and provide sufficient data for evaluation. Each manufacturer 
must determine and justify the number of batches necessary to demonstrate a high level o f assurance 
that the process is capable of consistently delivering a quality  product.  
 
Without prejudice to 5.19, it is generally considered acceptable that a minimum of three consecutive 
batches manufactured under routine conditions could constitute a val idation of the process. An 
alternative number of batches may be justified taking into account whether standard methods of 
manufacture are used and whether similar products or processes are already used at the site. An initial 
validation exercise with three  batches may need to be supplemented with further data obtained from Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 subsequent batches as part of an on -going process verification exercise.  
 
A process validation protocol should be prepared which defines the critical process parameters (CPP), 
critical quality attributes (CQA) and the associated acceptance criteria which should be based on 
development data or documented process knowledge.  Process validation protocols should include, 
but are not limited to the following:  
 
a). A short description of the process and a reference to the respective Master Batch Record;  
b). Functions and responsibilities;  
c). Summary of the CQAs to be investigated;  
d). Summary of CPPs and their associated limits;  
e). Summary of other (non -critical) attributes and parameters which will be inve stigated or 
monitored during the validation activity, and the reasons for their inclusion;  
f). List of the equipment/facilities to be used (including measuring/monitoring/recording 
equipment) together with the calibration status;  
g). List of analytical methods and  method validation, as appropriate;  
h). Proposed in -process controls with acceptance criteria and the reason(s) why each in -process 
control is selected;  
i). Additional testing to be carried out, with acceptance criteria;  
j). Sampling plan and the rationale behind it;  
k). Methods for recording and evaluating results;  
l). Process for release and certification of batches (if applicable).  
 
Continuous process verification  
 
For products developed by a quality by design approach, where it has been scientifically established 
during development that the established control strategy provides a high degree of assurance of 
product quality, then continuous process verification can be used as an alternative to traditional 
process validation.  
 
The method by which the process will be verifie d should be defined. There should be a science based 
control strategy for the required attributes for incoming materials, critical quality attributes and 
critical process parameters to confirm product realization. This should also include regular evaluatio n 
of the control strategy. Process Analytical Technology and multivariate statistical process control 
may be used as tools. Each manufacturer must determine and justify the number of batches necessary 
to demonstrate a high level of assurance that the proce ss is capable of consistently delivering quality 
product.  The general principles laid down in 5.1 – 5.14 above still apply.  
 
Hybrid approach  
 
A hybrid of the traditional approach and continuous process verification could be used where there 
is a substantia l amount of product and process knowledge and understanding which has been gained 
from manufacturing experience and historical batch data.  
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 This approach may also be used for any validation activities after changes or during ongoing process 
verification even though the product was initially validated using a traditional approach.  
 
Ongoing Process Verification during Lifecycle  
 
Paragraphs 5.28 -5.32 are applicable to all three approaches to process validation mentioned above, 
i.e. traditional, continuous and hybrid.  
 
Manufacturers should monitor product quality to ensure that a state of control is maintained 
throughout the product lifecycle with the relevant process trends evaluated.  
 
The extent and frequency of ongoing process verification should be revie wed periodically. At any 
point throughout the product lifecycle, it may be appropriate to modify the requirements taking into 
account the current level of process understanding and process performance.  
 
Ongoing process verification should be conducted under an approved protocol or equivalent 
documents and a corresponding report should be prepared to document the results obtained. 
Statistical tools should be used, where appropriate, to support any conclusions with regard to the 
variability and capability  of a given process and ensure a state of control.  
 
Ongoing process verification should be used throughout the product lifecycle to support the validated 
status of the product as documented in the Product Quality Review. Incremental changes over time 
should also be considered and the need for any additional actions, e.g. enhanced sampling, should be 
assessed.  
 
15.6 VERIFICATION OF TRANSPORTATION  
 
Finished medicinal products, investigational medicinal products, bulk product and samples should 
be transported from manufacturing sites in accordance with the conditions defined in the marketing 
authorization, the approved label, product specification file or as justified by the manufacturer.  
 
It is recognized that verification of transportation may be challenging due to the variable factors 
involved however, transportation routes should be clearly defined. Seasonal and other variations 
should also be considered during verification of transport  
 
A risk assessment should be performed to consider the impact of variabl es in the transportation 
process other than those conditions which are continuously controlled or monitored, e.g. delays 
during transportation, failure of monitoring devices, topping up liquid nitrogen, product susceptibility 
and any other relevant factors . 
 
Due to the variable conditions expected during transportation, continuous monitoring and recording 
of any critical environmental conditions to which the product may be subjected should be performed, 
unless otherwise justified.  
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 15.7 VALIDATION OF PACKAGING  
 
Variation in equipment processing parameters especially during primary packaging may have a 
significant impact on the integrity and correct functioning of the pack, e.g. blister strips, sachets and 
sterile components; therefore, primary and secondary packa ging equipment for finished and bulk 
products should be qualified.  
 
Qualification of the equipment used for primary packing should be carried out at the minimum and 
maximum operating ranges defined for the critical process parameters such as temperature, m achine 
speed and sealing pressure or for any other factors.  
 
15.8 QUALIFICATION OF UTILITIES  
 
The quality of steam, water, air, other gases etc. should be confirmed following installation using the 
qualification steps described in section 3 above.  The period and extent of qualification should reflect 
any seasonal variations, if applicable, and the intended use of the utility.  
 
A risk assessment should be carried out where there may be direct contact with the product, e.g. 
heating, ventilation and air -condition ing (HVAC) Systems or indirect contact such as through heat 
exchangers to mitigate any risks of failure.  
 
15.9 VALIDATION OF TEST METHODS  
 
All analytical test methods used in qualification, validation or cleaning exercises should be validated 
with an appropriate detection and quantification limit, where necessary, as defined in Chapter 6 of 
the PIC/S GMP guide Part I.  Where microbial testing of product is carried out, the method should be 
validated to confirm that the product does not influence the rec overy of microorganisms.  
 
Where microbial testing of surfaces in clean rooms is carried out, validation should be performed on 
the test method to confirm that sanitizing agents do not influence the recovery of microorganisms.  
 
15.10  CLEANING VALIDATION  
 
Cleaning  validation should be performed in order to confirm the effectiveness of any cleaning 
procedure for all product contact equipment. Simulating agents may be used with appropriate 
scientific justification. Where similar types of equipment are grouped togethe r, a justification of the 
specific equipment selected for cleaning validation is expected.  
 
A visual check for cleanliness is an important part of the acceptance criteria for cleaning validation. 
It is not generally acceptable for this criterion alone to b e used. Repeated cleaning and retesting until 
acceptable residue results are obtained is not considered an acceptable approach.  
 
It is recognized that a cleaning validation programme may take some time to complete and validation 
with verification after eac h batch may be required for some products e.g. investigational medicinal Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 products. There should be sufficient data from the verification to support a conclusion that the 
equipment is clean and available for further use.  
 
Validation should consider the leve l of automation in the cleaning process. Where an automatic 
process is used, the specified normal operating range of the utilities and equipment should be 
validated.  
 
For all cleaning processes an assessment should be performed to determine the variable fa ctors which 
influence cleaning effectiveness and performance, e.g. operators, the level of detail in procedures 
such as rinsing times etc. If variable factors have been identified, the worst case situations should be 
used as the basis for cleaning validati on studies.  
 
Limits for the carryover of product residues should be based on a toxicological evaluation67. The 
justification for the selected limits should be documented in a risk assessment which includes all the 
supporting references. Limits should be est ablished for the removal of any cleaning agents used. 
Acceptance criteria should consider the potential cumulative effect of multiple items of equipment 
in the process equipment train.  
 
a) Therapeutic macromolecules and peptides are known to degrade and denature when 
exposed to pH extremes and/or heat, and may become pharmacologically inactive. A 
toxicological evaluation may therefore not be applicable in these circumstances  
b) If it is not feasible to test for specific product residues, other representative  parameters 
may be selected, e.g. total organic carbon (TOC) and conductivity.  
 
The risk presented by microbial and endotoxin contamination should be considered during the 
development of cleaning validation protocols.  The influences of the time between man ufacture and 
cleaning and the time between cleaning and use should be taken into account to define dirty and clean 
hold times for the cleaning process.  
 
Where campaign manufacture is carried out, the impact on the ease of cleaning at the end of the 
campaig n should be considered and the maximum length of a campaign (in time and/or number of 
batches) should be the basis for cleaning validation exercises.  
 
 
Where a worst case product approach is used as a cleaning validation model, a scientific rationale 
should be provided for the selection of the worst case product and the impact of new products to the 
site assessed. Criteria for determining the worst case may include solubility, clean ability, toxicity, 
and potency.  
 
Cleaning validation protocols should specify or reference the locations to be sampled, the rationale 
for the selection of these locations and define the acceptance criteria.  Sampling should be carried out 
by swabbing and/or rinsing or by other means depending on the production equipment. The sampling 
                                                 
67 In the EU/EEA, this is the EMA Guideline on setting health based exposure limits for use in risk identification in the 
manufacture of different medicinal products in shared facilities  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 materials and method should not influence the result. Recovery should be shown to be possible from 
all product contact materials sampled in the equipment with all the sampling methods used.  
 
The cleaning procedure should be performed an appropriate number of times based on a risk 
assessment and meet the acceptance criteria in order to prove that the cleaning method is validated.  
 
Where a cleaning process is ineffective or is not appropriate for some equipment, dedicated 
equipment or other  appropriate measures should be used for each product as indicated in chapters 3 
and 5 of the PIC/S GMP Guide.  
 
Where manual cleaning of equipment is performed, it is especially important that the effectiveness 
of the manual process should be confirmed at a justified frequency.  
 
15.11  CHANGE CONTROL  
 
The control of change is an important part of knowledge management and should be handled within 
the pharmaceutical quality system.  
 
Written procedures should be in place to describe the actions to be taken if a planned change is 
proposed to a starting material, product component, process, equipment, premises, product range, 
method of production or testing, batch size, design space or any other change during the lifecycle 
that may affect product quality or reprodu cibility.  
 
Where design space is used, the impact on changes to the design space should be considered against 
the registered design space within the marketing authorization and the need for any regulatory actions 
assessed.  
 
Quality risk management should be used to evaluate planned changes to determine the potential 
impact on product quality, pharmaceutical quality systems, documentation, validation, regulatory 
status, calibration, maintenance and on any other system to avoid unintended consequences and to  
plan for any necessary process validation, verification or requalification efforts.  
 
 
Changes should be authorized and approved by the responsible persons or relevant functional 
personnel in accordance with the pharmaceutical quality system.  
 
Supporting data, e.g. copies of documents, should be reviewed to confirm that the impact of the 
change has been demonstrated prior to final approval.  Following implementation, and where 
appropriate, an evaluation of the effectiveness of change Should be carried out t o confirm that the 
change has been successful.  
 
GLOSSARY  
 
Definitions of terms relating to qualification and validation which are not given in other sections of Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 the current PIC/S Guide to GMP are given below.  
 
Bracketing approach  
A science and risk based validation approach such that only batches on the extremes of certain 
predetermined and justified design factors, e.g. strength, batch size, and/or pack size, are tested during 
process validation. The design assumes that validation of any intermediate leve ls is represented by 
validation of the extremes. Where a range of strengths is to be validated, bracketing could be 
applicable if the strengths are identical or very closely related in composition, e.g. for a tablet range 
made with different compression we ights of a similar basic granulation, or a capsule range made by 
filling different plug fill weights of the same basic composition into different size capsule shells. 
Bracketing can be applied to different container sizes or different fills in the same con tainer closure 
system.  
 
Change Control  
A formal system by which qualified representatives of appropriate disciplines review proposed or 
actual changes that might affect the validated status of facilities, systems, equipment or processes. 
The intent is to d etermine the need for action to ensure and document that the system is maintained 
in a validated state.  
 
Cleaning Validation  
Cleaning validation is documented evidence that an approved cleaning procedure will reproducibly 
remove the previous product or cle aning agents used in the equipment below the scientifically set 
maximum allowable carryover level.  
 
Cleaning verification  
The gathering of evidence through chemical analysis after each batch/campaign to show that the 
residues of the previous product or cle aning agents have been reduced below the scientifically set 
maximum allowable carryover level.  
 
Concurrent Validation  
Validation carried out in exceptional circumstances, justified on the basis of significant patient 
benefit, where the validation protocol is executed concurrently with commercialization of the 
validation batches.  
 
Continuous process verification  
An alternative approach to process validation in which manufacturing process performance is 
continuously monitored and evaluated. (ICH Q8)  
 
Control Strategy  
A planned set of controls, derived from current product and process understanding that ensures 
process performance and product quality. The controls can include parameters and attributes related 
to drug substance and drug product materials and com ponents, facility and equipment operating 
conditions, in -process controls, finished product specifications, and the associated methods and 
frequency of monitoring and control. (ICH Q10)  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Critical process parameter (CPP)  
A process parameter whose variabilit y has an impact on a critical quality attribute and therefore 
should be monitored or controlled to ensure the process produces the desired quality. (ICH Q8)  
 
Critical quality attribute (CQA)  
A physical, chemical, biological or microbiological property or c haracteristic that should be within 
an approved limit, range or distribution to ensure the desired product quality. (ICH Q8)  
 
Design qualification (DQ)  
The documented verification that the proposed design of the facilities, systems and equipment is 
suitabl e for the intended purpose.  
 
Design Space  
The multidimensional combination and interaction of input variables, e.g. material attributes, and 
process parameters that have been demonstrated to provide assurance of quality. Working within the 
design space is not considered as a change. Movement out of the design space is considered to be a 
change and would normally initiate a regulatory post approval change process. Design space is 
proposed by the applicant and is subject to regulatory assessment and approval.  (ICH Q8)  
 
Installation Qualification (IQ)  
The documented verification that the facilities, systems and equipment, as installed or modified, 
comply with the approved design and the manufacturer’s recommendations.  
 
Knowledge management  
A systematic approach  to acquire, analyze, store and disseminate information. (ICH Q10)  
 
Lifecycle  
All phases in the life of a product, equipment or facility from initial development or use through to 
discontinuation of use.  
 
Ongoing Process Verification (also known as continu ed process verification)  
Documented evidence that the process remains in a state of control during commercial manufacture.  
 
Operational Qualification (OQ)  
The documented verification that the facilities, systems and equipment, as installed or modified, 
perform as intended throughout the anticipated operating ranges.  
 
Performance Qualification (PQ)  
The documented verification that systems and equipment can perform effectively and reproducibly 
based on the approved process method and product specification.  
 
Process Validation  
The documented evidence that the process, operated within established parameters, can perform Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 effectively and reproducibly to produce a medicinal product meeting its predetermined specifications 
and quality attributes.  
 
Product realizati on 
Achievement of a product with the quality attributes to meet the needs of patients, health care 
professionals and regulatory authorities and internal customer requirements. (ICH Q10)  
 
Prospective Validation  
Validation carried out before routine producti on of products intended for sale.  
 
Quality by design  
A systematic approach that begins with predefined objectives and emphasizes product and process 
understanding and process control, based on sound science and quality risk management.  
 
Quality risk management  
A systematic process for the assessment, control, communication and review of risks to quality across 
the lifecycle. (ICH Q9)  
 
Simulated agents  
A material that closely approximates the physical and, where practical, the chemical characteristics,  
e.g. viscosity, particle size, pH etc., of the product under validation.  
 
State of control  
A condition in which the set of controls consistently provides assurance of acceptable process 
performance and product quality.  
 
Traditional approach  
A product deve lopment approach where set points and operating ranges for process parameters are 
defined to ensure reproducibility.  
 
User requirements Specification (URS)  
The set of owner, user, and engineering requirements necessary and sufficient to create a feasible 
design meeting the intended purpose of the system.  
 
Worst Case  
A condition or set of conditions encompassing upper and lower processing limits and circumstances, 
within standard operating procedures, which pose the greatest c h a n c e of product or process  failure 
when compared to ideal conditions. Such conditions do not necessarily induce product or process 
failure.  
 
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 ANNEX 16: QUALIFIED PERSON AND BATCH RELEASE  
 
SCOPE  
 
This Annex provides guidance on the certification by an Authorized Person and on batch release of 
medicinal products for human or veterinary use . 
 
GENERAL PRINCIPLES  
 
The ultimate responsibility for the performance of a medicinal product over its lifetime, its safety, 
quality and efficacy, lies with the marketing authorization holder (MAH). However, the Authorized 
Person is responsible for ensuring that each individual batch has been manufactured and checked in 
compliance with national requirements in accordance with the requirements of the marketing 
authorization (MA) and with Good Ma nufacturing Practice (GMP).  
 
The process of batch release comprises of:  
 
a. The checking of the manufacture and testing of the batch in accordance with defined release 
procedures.  
b. The certification of the finished product batch performed by an Authorized Person signifying 
that the batch is in compliance with GMP and the requirements of its MA. This represents the 
quality release of the batch.  
c. The transfer to saleable stock, and/or export of the finished batch of product which should take 
into account the c ertification performed by the Authorized Person. If this transfer is performed 
at a site other than that where certification takes place, then the arrangement should be 
documented in a written agreement between the sites.  
 
The purpose of controlling batch  release is notably to ensure that:  
 
a. The batch has been manufactured and checked in accordance with the requirements of its MA.  
b.  The batch has been manufactured and checked in accordance with the principles and guidelines 
of GMP.  
c. Any other relevant legal requirements are taken into account.  
d. In the event that a quality defect as referred to in Chapter 8 of PIC/S GMP Guide, Part I, needs 
to be investigated or a batch recalled, to ensure that any Authorized Persons involved in the 
certification or confirmation1 and any relevant records are readily identifiable.  
 
1.1 THE PROCESS OF CERTIFICATION  
 
Each batch of finished product must be certified by an authorized Person before being released for 
sale, supply or export. Certification can only be performed by an authorized Person of the 
manufacturer and/or importer which are described in the MA.  
 
Any Authorized Person involved in the certification or confirmation of a batch must have detailed Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 knowledge of the steps for which they are taking responsibility. The authorized Persons should be 
able to prove their continuous training regarding the product ty pe, production processes, technical 
advances and changes to GMP.  
 
There may be several sites involved in the various stages of manufacture, importation, testing and 
storage of a batch before it undergoes certification. Regardless of how many sites are inv olved, the 
authorized Person performing certification of the finished product must ensure that all necessary steps 
have been completed under accepted pharmaceutical quality systems to assure compliance of the 
batch with GMP, the MA and any other national r equirements where certification is taking place.  
 
a) Information required for the confirmation, where authorized Person responsibilities 
for the batch are being transferred between sites, is recommended in Appendix I to 
this Annex.  
b) The contents of a batch cer tificate for medicinal products are recommended in 
Appendix II to this Annex. The content of a batch certificate may differ from 
Appendix II as required under national law or as required to facilitate arrangements 
between National Competent Authorities.  
 
Each manufacturing site must have at least one authorized Person .  Where the site only undertakes 
partial manufacturing operations in relation to a batch, then an authorized Person at that site must at 
least confirm that the operations undertaken by the si te have been performed in accordance with GMP 
and the terms of the written agreement detailing the operations for which the site is responsible.  
 
If the Authorized Person is responsible for providing confirmation of compliance for those operations 
with th e relevant MA, then the Authorized Person should have access to the necessary details of the 
MA. 
 
The Authorized Person who performs certification of the finished product batch should assume full 
responsibility for all stages of manufacture of the batch or this responsibility may be shared with 
other Authorized Persons who have provided confirmation fo r specified steps in the manufacture and 
control of a batch. These could be other Authorized Persons who are operating under the same 
manufacturing authorization holder or operating under different manufacturing authorization holders.  
 
Any sharing of resp onsibilities amongst Authorized Persons in relation to compliance of a batch must 
be defined in a written agreement. This document should detail responsibility for assessment of the 
impact any deviation(s) has/have on compliance of the batch with GMP and t he MA.  
 
For medicinal products manufactured outside the jurisdiction of a National Competent Authority, 
physical importation and certification are the final stages of manufacturing which precede the transfer 
to saleable stock of the batch, depending on nat ional law.  
 
The process of certification as described in Section 1 of this Annex, applies to all medicinal products 
intended to be released within domestic markets, or for export, irrespective of the complexity of the 
supply chain and the global locations of manufacturing sites involved.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 In accordance with the principles described in Section 1.4 of this Annex and the law in each 
jurisdiction, the Authorized Person certifying the finished medicinal product batch may take account 
of the confirmation by, and s hare defined responsibilities with, other Authorized Persons in relation 
to any manufacturing or importation operations taking place at other sites in the same jurisdiction 
and other manufacturing authorization holders defined in the relevant MA.  
 
Conditio ns of storage and transport for the batch and the sample, if sent separately, should be taken 
into account by the Authorised Person before certification of a batch.  The Authorised Person 
certifying the finished product is responsible for ensuring that each  finished medicinal product batch 
has been manufactured in accordance with GMP and the MA. The Authorised Person is also 
responsible for ensuring that the finished medicinal product batch has undergone testing required 
upon importation in accordance with n ational law.  
 
If sampling of imported product is necessary, it should be fully representative of the batch. Samples 
may either be taken after arrival in the jurisdiction of the National Competent Authority, or be taken 
at the manufacturing site located in another jurisdiction in accordance with national law and a 
technically justified approach which is documented within the company’s quality system. 
Responsibilities in relation to the sampling should be defined in a written agreement between the 
sites. Any samples taken outside the National Competent Authority jurisdiction should be shipped 
under equivalent transport conditions as the batch that they represent.  
 
Where sampling is performed at a manufacturing site located in another jurisdiction, the technical 
justification should include a formal Quality Risk Management process to identify and manage any 
risks associated with this approach. This should be fully documented and include at least the 
following elements:  
a. Audit of the manufacturing activity  including any sampling activity in the other jurisdiction 
and evaluation of subsequent transportation steps of both the batch and samples to ensure that 
the samples are representative of the imported batch.  
b. A comprehensive scientific study, including data  to support any conclusions that samples taken 
in the other jurisdiction are representative of the batch after importation. This study should at 
least include:  
 
i. description of the sampling process in the other jurisdiction;  
ii. description of the transported conditions of the sample and the imported batch. Any 
differences should be justified;  
iii. comparative analysis of samples taken in the other jurisdiction and samples taken 
after importation; and consideration of the time interval between sampling and 
importati on of the batch and generation of data to support appropriate defined limits.  
 
c. Provision for random periodic analysis of samples taken after importation to justify ongoing 
reliance on samples taken in another jurisdiction.  
d. A review of any unexpected result  or confirmed out of specification result.  
 
These may have implications for reliance on sampling performed at a manufacturing site located in Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 another jurisdiction and should be notified to the National Competent Authority for the site where 
certification is performed. Such an occurrence should be regarded as a potential quality defect and 
investigated in line with the guidance in Chapter 8 of the PIC/S  
 
GMP Guide, Part I.  
 
Different imported finished product batches may originate from the same bulk product  batch. If 
testing upon importation is required (see 1.5.4), the Authorized Person(s) certifying the different 
finished product batches may base their decision on the quality control testing of the first imported 
finished batch provided that a justificatio n has been documented based on Quality Risk Management 
principles.  
 
This should take into account the provisions of paragraph 1.5.6 in relation to reliance on any samples 
taken in another jurisdiction. Evidence should be available to ensure that the integr ity and identity of 
the imported finished product batch has been established through documented verification of at least 
the following:  
 
a) relevant requirements for storage of the bulk product prior to packaging have been satisfied;  
b) The finished product batch has been stored and transported under the required conditions; the 
consignment has remained secure and there is no evidence of tampering during storage or 
transportation;  
c) correct identification of the product has been established; and the sample(s) t ested are 
representative of all finished product batches derived from the bulk batch.  
 
The Authorized Person must ensure that the following operational responsibilities are fulfilled prior 
to certification of a batch:  
 
a) Certification is permitted under the terms of any authorization by the national competent 
authority. Any additional duties and requirements of national law are complied with.  
b) Certification is recorded in accordance with this Annex and in accordance with national  law. 
 
In addition, the Authorized Person has responsibility for ensuring points 1.7.1 to 1.7.21 are secured. 
These tasks may be delegated to appropriately trained personnel or third parties. It is recognized that 
the Authorized Person will need to rely on the pharmaceutical qual ity system and the Authorized 
Person should have on -going assurance that this reliance is well founded.  
 
a. All activities associated with manufacture and testing of the medicinal product have been 
conducted in accordance with the principles and guidelines of  GMP.  
b. The entire supply chain of the active substance and medicinal product up to the stage of 
certification is documented and available for the Authorized Person. This should include the 
manufacturing sites of the starting materials and packaging material s for the medicinal product 
and any other materials deemed critical through a risk assessment of the manufacturing process. 
The document should preferably be in the format of a comprehensive diagram, where each 
party, including subcontractors of critical s teps such as the sterilization of components and Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 equipment for aseptic processing, are included.  
c. All audits of sites involved in the manufacture and the testing of the medicinal products and in 
the manufacture of the active substance have been carried out and that the audit reports are 
available to the Authorised Person performing the certification.  
d. All sites of manufacture, analysis and certification are compliant with the terms of the MA for 
the intended jurisdiction.  
e. All manufacturing activities and test ing activities are consistent with those described in the 
MA. 
f. The source and specifications of starting materials and packaging materials used in the batch 
are compliant with the MA. Supplier quality management systems are in place that ensures 
only materi als of the required quality have been supplied.  
g. For medicinal products, the active substances have been manufactured in accordance with 
GMP and, where required, distributed in accordance with Good Distribution Practice (GDP) 
for Active Substances.  
h. Active s ubstances used in the manufacture of medicinal products for human use shall only be 
imported if the active substances comply with the following requirements:  
 
i. the active substances have been manufactured in accordance with standards of GMP 
and, where applicable, distributed in accordance with Good Distribution Practice 
according to national law; and  
ii. there is evidence of GMP compliance of the manufacturer of the active substance in 
accordance with national  law. 
 
i. The excipients used to manufacture a medicinal product have been manufactured with an 
appropriate good manufacturing practice. Where applicable, this shall be in accordance with PI 
045-1: Guidelines on the formalized risk assessment for ascertaining the appropriate good 
manufacturing practice  for excipients of medicinal products for human use.  
j. When relevant, the TSE (Transmissible Spongiform Encephalopathy) status of all materials 
used in batch manufacture is compliant with the terms of the MA.  
k. All records are complete and endorsed by appropri ate personnel. All required in -process 
controls and checks have been made.  
l. All manufacturing and testing processes remain in the validated state. Personnel are trained and 
qualified as appropriate.  
m. Finished product quality control (QC) test data complies with the Finished Product 
Specification described in the MA, or where authorized, the Real Time Release Testing 
program.  
n. Any regulatory post -marketing commitments relating to manufacture or testing of the product 
have been addressed. On -going stability dat a continues to support certification.  
o. 1.7.15 The impact of any change to product manufacturing or testing has been evaluated and 
any additional checks and tests are complete.  
p. All investigations pertaining to the batch being certified (including out of spec ification and out 
of trend investigations) have been completed to a sufficient level to support certification.  
q. A batch should not be certified if there are any on -going complaints, investigations or recalls 
that may have impact on the batch.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 r. The required t echnical agreements are in place.  
s. The self -inspection program is active and current.  
t. The appropriate arrangements for distribution and shipment are in place.  
u. Where required in national law, safety features have been affixed to the packaging enabling 
wholes ale distributors and persons authorized or entitled to supply medicinal products to the 
public to:  
 
i. verify the authenticity of the medicinal product;  
ii. identify individual packs; and  
iii. verify, via a device, of whether the outer packaging has been tampered with.  
 
For certain products, special guidance may apply, such as PIC/S GMP Guide Annex 2: Manufacture 
of Biological active substances and Medicinal Products for Human Use, and Annex 3: Manufacture 
of Radiopharmaceuticals.  
 
In the case of parallel importation and parallel distribution, any repackaging operation carried out on 
a batch which has already been released must be approved by the competent authority of the intended 
market, as applicable under national law.  
 
a. Prior to certification of a repacked batch the Authorised Person should confirm 
compliance with national requirements for parallel importation and rules for parallel 
distribution.  
b. The Authorized Person, who is responsible for the certification of the batch in the 
MA of the repackaged  finished product, certifies that the repackaging has been 
performed in accordance with the relevant authorization pertaining to the repackaged 
product and GMP.  
 
Recording of Authorized Person certification  
 
The certification of a medicinal product is reco rded by the Authorized Person in the document 
provided for that purpose. The record should show that each production batch satisfies the following 
provisions:  
 
a. Each batch of medicinal products has been manufactured and checked in compliance with 
national law and in accordance with the requirements of the marketing authorization.  
b. In the case of medicinal products coming from another jurisdiction each production batch has 
a full qualitative analysis, a quantitative analysis of at least all the active substan ces and all the 
other tests or checks necessary to ensure the quality of medicinal products in accordance with 
the requirements of the marketing authorization. Such testing is also performed in the importing 
country where required in national law.  
c. In the c ase of medicinal products imported from another jurisdiction, where appropriate 
arrangements have been made with the exporting jurisdiction to ensure that the manufacturer 
of the medicinal product applies standards of good manufacturing practice at least e quivalent 
to those laid down by the national competent authority, and to ensure that the controls referred Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 to under point (b) have been carried out in the exporting country, the Authorized person may 
be relieved of responsibility for carrying out those con trols.  
d. The record must be kept up to date as operations are carried out and must remain at the disposal 
of the agents of the National Competent Authority the longer of one year after expiry of the 
batch or five years unless otherwise specified in national law. 
 
The control report referred to in 1.10.1 or another proof for release for sale, supply, or export, based 
on an equivalent system, should be made available for the batch in order to be exempted from further 
controls when entering another National Comp etent Authority jurisdiction.  
 
1.2 RELYING ON GMP ASSESSMENTS BY THIRD PARTIES, E.G. AUDITS  
 
In some cases, the Authorized Person will rely on the correct functioning of the pharmaceutical 
quality system of sites involved in the manufacture of the product and this may be derived from audits 
conducted by third parties.  
 
Relying on assessment by third parties, e.g. audits should be in accordance with Chapter 7 of the 
PIC/S GMP Guide in order to appropriately define, agree and control any outsourced activity.  
 
Special focus should be given to the approval of audit reports:  
a) The audit report should address general GMP requirements, as for example the quality 
management system, all relevant production and quality control procedures related to the 
supplied product, e.g. active substance manufacturing, quality control testing, primary 
packaging, etc. All audited areas should be accurately described resulting in a detailed report 
of the audit.  
b) It should be determined whether the manufacture and quality control of the a ctive substance 
and medicinal product complies with GMP or in case of manufacture in another jurisdiction, 
GMP at least equivalent to that of each National Competent Authority.  
c) In case of outsourced activities compliance with the MA should be verified. The  Authorized 
Person should ensure that a written final assessment and approval of third party audit reports 
have been made. The Authorized Person should have access to all documentation which 
facilitates review of the audit outcome and continued reliance on  the outsourced activity.  
d) Outsourced activities with critical impact on product quality should be defined in accordance 
with the principles of Quality Risk Management as described in Annex 20 of the PIC/S GMP 
Guide. According to this, the Authorized Person  should be aware of the outcome of an audit 
with critical impact on the product quality before certifying the relevant batches.  
e) Repeated audits should be performed in accordance with the principles of Quality Risk 
Management.  
 
1.3 HANDLING OF UNEXPECTED DEVIATIONS  
 
Provided registered specifications for active substances, excipients, packaging materials and 
medicinal products are met, an Authorized Person may consider confirming compliance or certifying 
a batch where an unexpected deviation concerning the manufacturi ng process and/or the analytical Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 control methods from details contained within the MA and/or GMP has occurred.  
 
The deviation should be thoroughly investigated and the root cause corrected. This may require the 
submission of a variation to the MA for the continued manufacture of the product.  
 
The impact of the deviation should be assessed in accordance with a quality risk management process 
using an appropriate approach such as described in Annex 20 of the PIC/S GMP Guide. The quality 
risk management proce ss should include the following;  
 
a. Evaluation of the potential impact of the deviation on quality, safety or efficacy of 
the batch(es) concerned and conclusion that the impact is negligible.  
b. Consideration of the need to include the affected batch(es) in the  ongoing stability 
programme.  
c. In the case of biological medicinal products, consideration that any deviations from 
the approved process can have an unexpected impact on safety and efficacy.  
 
Taking account that responsibilities may be shared between more than one Authorized Person 
involved in the manufacture and control of a batch, the Authorized Person performing certification 
of a batch of medicinal product should be aware of and take into consideration any deviations which 
have the potential to impact c ompliance with GMP and/or compliance with the MA.  
 
THE RELEASE OF A BATCH  
 
Batches of medicinal products should only be released for sale or supply to the market after 
certification by an Authorized Person as described above. Until a batch is certified, it  should remain 
at the site of manufacture or be shipped under quarantine to another site which has been approved 
for that purpose by the relevant National Competent Authority.  
 
Safeguards to ensure that uncertified batches are not transferred to saleable s tock should be in place 
and may be physical in nature, e.g. the use of segregation and labelling or electronic in nature, e.g. 
the use of validated computerized systems. When uncertified batches are moved from one authorized 
site to another, the safeguards  to prevent premature release should remain.  
 
The steps necessary to notify Authorized Person certification to the site where the transfer to saleable 
stock is to take place should be defined within a technical agreement. Such notification by an 
Authorized  Person to the site should be formal and unambiguous and should be subject to the 
requirements of Chapter 4 of the PIC/S GMP Guide, Part I.  National law may require a specific 
release for the local market (market release) by the MAH which takes into consid eration the 
certification of the finished product by the manufacturer.  
 
GLOSSARY  
 
Certain words and phrases in this annex are used with the particular meanings defined below. 
Reference should also be made to the Glossary in the main part of the PIC/S  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Certification of the finished product batch  
The certification in a document by an Authorized Person, as defined in this annex, and represents the 
quality release of the batch before the batch is released for sale or distribution.  
 
Confirmation (Confirm and co nfirmed have equivalent meanings)  
A signed statement by an Authorised Person that a process or test has been conducted in accordance 
with GMP and the relevant marketing authorisation or clinical trial authorisation, product 
specification file and/or techni cal agreement, as applicable, as agreed in writing with the Authorised 
Person responsible for certifying the finished product batch before release. The Authorised Person 
providing a confirmation takes responsibility for those activities being confirmed.  
 
Finished product batch  
 
With reference to the control or test of the finished product, a finished medicinal product batch is an 
entity which comprises all the units of a pharmaceutical form which are made from the same initial 
quantity of material and have undergone the same series of manufacturing and/or sterilization 
operations or, in the case of a continuous production process, all the units manufactured in a given 
period of time. In the context of this annex the term in particular denotes the batch of pr oduct in its 
final pack for release to the market.  
Importer  
Any holder of the authorization to import as required by national law.  
 
Jurisdiction  
A jurisdiction is a territory within which a court or government agency is exercising its power. A 
jurisdiction  can be e.g. a State (whether internationally recognized or not) or a region.  
 
APPENDIX I  
 
Recommended content of the confirmation of the partial manufacturing of a medicinal product  
 
[LETTER HEAD OF MANUFACTURER WHO CARRIED OUT THE MANUFACTURING  
ACTIVITY]  
 
1. Name of the product and description of the manufacturing stage (e.g. paracetamol 500 mg 
tablets, primary packaging into blister packs).  
2. Batch number.  
3. Name and address of the site carrying out the partial manufacturing.  
4. Reference to the Technical Quality Agreement (in accordance with Chapter 7 of the PIC/S 
GMP Guide).  
5. Confirmation statement. hereby confirm that the manufacturing stages referred to in the 
Technical Quality Agreement have been carried out in full compliance with the GMP 
requirements of the [insert jurisdiction] and the terms described in the Agreement for  ensuring 
compliance with the requirements of the Marketing Authorization(s) as provided by [Contract Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 Giver/manufacturer certifying and releasing the batch].  
6. Name of the Authorized Person confirming the partial manufacturing.  
7. Signature of Authorized Person  confirming the partial manufacturing.  
8. Date of signature.  
 
APPENDIX II  
 
Recommended content of the Batch Certificate for Medicinal Products  
 
[LETTER HEAD OF THE BATCH CERTIFYING AND RELEASING MANUFACTURER]  
 
1. Name, strength/potency, dosage form and package size (identical to the text on the finished 
product package).  
2. Batch number of the finished product.  
3. Name of the destination country/countries of the batch.  
4. Certification statement.  
 
I hereby certify that all the manufacturing stages of this batch of finished product  
have been carried out in full compliance with the GMP requirements of the [insert  
jurisdiction] and [as applicable] with the requirements of the Marketing  
Authorization(s) of the destination country/countries.  
 
5. Name of the Authorized Perso n certifying the batch.  
6. Signature of the Authorized Person certifying the batch.  
7. Date of signature.  
 
ANNEX 17: PARAMETRIC RELEASE  
 
PRINCIPLE  
 
The definition of Parametric Release used in this Annex is based on that proposed by the European 
Organization for  Quality: "A system of release that gives the assurance that the product is of the 
intended quality based on information collected during the manufacturing process and on the 
compliance with specific GMP requirements related to Parametric Release."  
Paramet ric release should comply with the basic requirements of GMP, with applicable annexes and 
the following guidelines.  
 
17.1 PARAMETRIC RELEASE  
 
It is recognized that a comprehensive set of in -process tests and controls may provide greater 
assurance of the finished product meeting specification than finished product testing.  
 
Parametric release may be authorized for certain specific parameters as an alternative to routine 
testing of finished products. Authorization for parametric release should be given, ref used or Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 withdrawn jointly by those responsible for assessing products together with the GMP inspectors.  
 
17.2 PARAMETRIC RELEASE FOR STERILE PRODUCTS  
 
This section is only concerned with that part of Parametric Release which deals with the routine 
release of fi nished products without carrying out a sterility test. Elimination of the sterility test is 
only valid on the basis of successful demonstration that predetermined, validated sterilizing 
conditions have been achieved.  
 
A sterility test only provides an opportunity to detect a major failure of the sterility assurance system 
due to statistical limitations of the method.  Parametric release can be authorized if the data 
demonstrating correct processing of the batch provides sufficient assurance, on its own, that the 
process designed and validated to ensure the sterility of the product has been delivered.  
 
At present Parametric release can only be approved for products terminally sterilized in their final 
container.  Fertilization methods according to European (or other relevant) Pharmacopoeia 
requirements using steam, dry heat and ionizing radiation may be considered for parametric release.  
 
It is unlikely that a completely new product would be considered as suitable for Parametric Release 
because a period of s atisfactory sterility test results will form part of the acceptance criteria. There 
may be cases when a new product is only a minor variation, from the sterility assurance point of 
view, and existing sterility test data from other products could be conside red as relevant :  
 
1. A risk analysis of the sterility assurance system focused on an evaluation of releasing non - 
sterilized products should be performed.  
2. The manufacturer should have a history of good compliance with GMP.  
3. The history of non -sterility of products and of results of sterility tests carried out on the product 
in question together with products processed through the same or a similar sterility assurance 
system should be taken into consideration when evaluating GMP compliance.  
4. A qualified exper ienced sterility assurance engineer and a qualified microbiologist should 
normally be present on the site of production and sterilization.  
5. The design and original validation of the product should ensure that integrity can be maintained 
under all relevant c onditions.  
6. The change control system should require review of change by sterility assurance personnel.  
7. There should be a system to control microbiological contamination in the product before 
sterilization.  
8. There should be no possibility for mix ups between  sterilised and non sterilised products. 
Physical barriers or validated electronic systems may provide such assurance.  
9. The sterilization records should be checked for compliance to specification by at least two 
independent systems. These systems may consis t of two people or a validated computer system 
plus a person.  
10. The following additional items should be confirmed prior to release of each batch of product.  
 
i. All planned maintenance and routine checks have been completed in the sterilizer used.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 ii. All repairs and modifications have been approved by the sterility assurance engineer and 
microbiologist.  
iii. All instrumentation was in calibration.  
iv. The sterilizer had a current validation for the product load processed.  
 
Once parametric release has been granted, decision s for release or rejection of a batch should be 
based on the approved specifications. Non -compliance with the specification for parametric release 
cannot be overruled by a pass of a sterility test.  
 
Parametric Release  
A system of release that gives the assurance that the product is of the intended quality based on 
information collected during the manufacturing process and on the compliance with specific GMP 
requirements related to Parametric Release.  
 
Sterility Assurance System  
The sum total of the arran gements made to assure the sterility of products. For terminally sterilized 
products these typically include the following stages:  
 
a) Product design.  
b) Knowledge of and, if possible, control of the microbiological condition of starting materials 
and process aids (e.g. gases and lubricants).  
c) Control of the contamination of the process of manufacture to avoid the ingress of 
microorganisms and their multiplication in the product. This is usually accomplished by 
cleaning and sanitization of product contact surfac es, prevention of aerial contamination by 
handling in clean rooms, use of process control time limits and, if applicable, filtration stages.  
d) Prevention of mix up between sterile and non -sterile product streams. e) Maintenance of 
product integrity.  
f) The ster ilization process.  
g) The totality of the Quality System that contains the Sterility Assurance System e.g. change 
control, training, written procedures, release checks, planned preventative maintenance, failure 
mode analysis, prevention of human error, valida tion calibration, etc.  
 
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 ANNEX 18: REFERENCE AND RETENTION SAMPLES  
 
SCOPE  
 
This Annex to the Guide to Good Manufacturing Practice for Medicinal Products (“the GMP Guide”) 
gives guidance on the taking and holding of reference samples of starting materials,  packaging 
materials or finished products and retention samples of finished products.  
Specific requirements for investigational medicinal products are given in Annex to the Guide.  
This annex also includes guidance on the taking of retention samples for parallel imported / 
distributed medicinal products.  
 
PRINCIPLE  
 
Samples are retained to fulfil two purposes; firstly, to provide a sample for analytical testing and 
secondly to provide a specimen of the fully finished product. Samples may therefore fall in to two 
categories:  
 
Reference sample: a sample of a batch of starting material, packaging material or finished product 
which is stored for the purpose of being analyzed should the need arise during the shelf life of the 
batch concerned. Where stability per mits, reference samples from critical intermediate stages (e.g. 
those requiring analytical testing and release) or intermediates that are transported outside of the 
manufacturer’s control should be kept.  
 
Retention sample: a sample of a fully packaged unit  from a batch of finished product. It is stored for 
identification purposes. For example, presentation, packaging, labelling, patient information leaflet, 
batch number, expiry date should the need arise during the shelf life of the batch concerned. There 
may be exceptional circumstances where this requirement can be met without retention of duplicate 
samples e.g. where small amounts of a batch are packaged for different markets or in the production 
of very expensive medicinal products.  
 
For finished product s, in many instances the reference and retention samples will be presented 
identically, i.e. as fully packaged units. In such circumstances, reference and retention samples may 
be regarded as interchangeable.  
 
It is necessary for the manufacturer, importer  or site of batch release, as specified under section 7 and 
8, to keep reference and/or retention samples from each batch of finished product and, for the 
manufacturer to keep a reference sample from a batch of starting material (subject to certain 
excepti ons see 3.2 below) and/or intermediate product. Each packaging site should keep reference 
samples of each batch of primary and printed packaging materials. Availability of printed materials 
as part of the reference and/or retention sample of the finished p roduct can be accepted.  
 
The reference and/or retention samples serve as a record of the batch of finished product or starting 
material and can be assessed in the event of, for example, a dosage form quality complaint, a query 
relating to compliance with the marketing authorizatio n, a labelling/ packaging query or Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 pharmacovigilance report.  Records of traceability of samples should be maintained and be available 
for review by competent authorities.  
 
1.1 DURATION OF STORAGE  
 
Reference and retention samples from each batch of finished pro duct should be retained for at least 
one year after the expiry date. The reference sample should be contained in its finished primary 
packaging or in packaging composed of the same material as the primary container in which the 
product is marketed (for vet erinary medicinal products other than immunologicals, see also Annex 
4, paragraphs 8 and 9).  
 
Unless a longer period is required under the law of the country of manufacture (whose competent 
authority is a PIC/S Member), samples of starting materials (other  than solvents, gases or water used 
in the manufacturing process) should be retained for at least two years after the release of product. 
That period may be shortened if the period of stability of the material, as indicated in the relevant 
specification, i s shorter. Packaging materials should be retained for the duration of the shelf life of 
the finished product concerned.  
 
1.2 SIZE OF REFERENCE AND RETENTION SAMPLES  
 
The reference sample should be of sufficient size to permit the carrying out, on, at least, two 
occasions, of the full analytical controls on the batch in accordance with the Marketing Authorization 
File which has been assessed and approved by the relevant Competent Authority / Authorities. Where 
it is necessary to do so, unopened packs should be  used when carrying out each set of analytical 
controls. Any proposed exception to this should be justified to, and agreed with, the relevant 
competent authority.  
 
Where applicable, national requirements relating to the size of reference samples and, if ne cessary, 
retention samples should be followed.  Reference samples should be representative of the batch of 
starting material, intermediate product or finished product from which they are taken. Other samples 
may also be taken to monitor the most stressed pa rt of a process (e.g. beginning or end of a process). 
Where a batch is packaged in two, or more, distinct packaging operations, at least one retention 
sample should be taken from each individual packaging operation. Any proposed exception to this 
should be  justified to, and agreed with, the relevant competent authority.  
 
It should be ensured that all necessary analytical materials and equipment are still available, or are 
readily obtainable, in order to carry out all tests given in the specification until one year after expiry 
of the last batch manufactured.  
 
1.3 STORAGE CONDITIONS  
 
Storage conditions should be in accordance with the marketing authorization (e.g. refrigerated 
storage where relevant).  
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1.4 WRITTEN AGREEMENTS  
 
Where the marketing authorization holder is not the same legal entity as the site(s) responsible or 
batch release, the responsibility for taking and storage of reference/retention samples should be 
defined in a written agreement between the two parties in accordance with Chapter 7 of the P IC/S 
Guide to Good Manufacturing Practice. This applies also where any manufacturing or batch release 
activity is carried out at a site other than that with overall responsibility for the batch and the 
arrangements between each different site for the takin g and keeping of reference and retention 
samples should be defined in a written agreement.  
 
The Authorized Person who certifies a batch for sale should ensure that all relevant reference and 
retention samples are accessible at all reasonable times. Where necessary, the arrangements for such 
access should be defined in a written agreement.  Where more than one site is involved in the 
manufacture of a finished product, the availability of written agreements is key to controlling the 
taking and location of ref erence and retention samples.  
 
1.5 REFERENCE SAMPLES – GENERAL POINTS  
 
Reference samples are for the purpose of analysis and, therefore, should be conveniently available to 
a laboratory with validated methodology. For starting materials and packaging materials  used for 
medicinal products, this is the original site of manufacture of the finished product. For finished 
products, this is the original site of manufacture. 7.2 […] *68 
 
1.6 RETENTION SAMPLES – GENERAL POINTS  
 
A retention sample should represent a batch of finished products as distributed and may need to be 
examined in order to confirm non -technical attributes for compliance with the marketing 
authorization or national legislation. The retention samples should p referably be stored at the site 
where the Authorized Person (AP) certifying the finished product batch is located.  
 
Retention samples should be stored at the premises of an authorized manufacturer in order to permit 
ready access by the Competent Authority.  Where more than one manufacturing site is involved in 
the manufacture importation/packaging/testing/batch release, as appropriate of a product, the 
responsibility for taking and storage of retention samples should be defined in a written agreeme nt(s) 
between the parties concerned.  
 
1.7 REFERENCE AND RETENTION SAMPLES FOR PARALLEL IMPORTED / 
PARALLEL DISTRIBUTED PRODUCTS  
 
This section is only applicable if the national legislation deals with parallel imported / parallel 
distributed products.  
                                                 
68 *This Section is specific to the EU GMP Guide and h as not been adopted by PIC/S.  
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Where the secondary packaging is not opened, only the packaging material used needs to be retained, 
as there is no, or little, risk of product mix -up. 
 
Where the secondary packaging is opened, for example, to replace the carton or patient information 
leaflet, th en one retention sample, per packaging operation, containing the product should be taken, 
as there is a risk of product mix -up during the assembly process. It is important to be able to identify 
quickly who is responsible in the event of a mix -up (original  manufacturer or parallel import 
assembler), as it would affect the extent of any resulting recall.  
 
1.8 REFERENCE AND RETENTION SAMPLES IN THE CASE OF CLOSEDOWN OF A 
MANUFACTURER  
 
When  a manufacturer closes down and the manufacturing authorization is surrendered, revoked, or 
ceases to exist, it is probable that many unexpired batches of medicinal products manufactured by 
that manufacturer remain on the market. In order for those batches  to remain on the market, the 
manufacturer should make detailed arrangements for transfer of reference and retention samples (and 
relevant GMP documentation) to an authorized storage site. The manufacturer should satisfy the 
Competent Authority that the ar rangements for storage are satisfactory and that the samples can, if 
necessary, be readily accessed and analyzed.  
 
If the manufacturer is not in a position to make the necessary arrangements this may be delegated to 
another manufacturer. The Marketing Auth orization holder (MAH) is responsible for such delegation 
and for the provision of all necessary information to the Competent Authority. In addition, the MAH 
should, in relation to the suitability of the proposed arrangements for storage of reference and 
retention samples, consult with the competent authority of each country in which any unexpired batch 
has been placed on the market.10.3  
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 ANNEX 19: QUALITY RISK MANAGEMENT  
 
FOREWORD AND SCOPE OF APPLICATIONS  
 
The new GMP Annex 19 corresponds to ICH Q9 guideline on Quality Risk Management. It provides 
guidance on a systematic approach to quality risk management facilitating compliance with GMP 
and other quality requirements. It includes principles to be used and options for process es, methods 
and tools which may be used when applying a formal quality risk management approach.  
 
To ensure coherence, GMP Part I, Chapter 1 on Quality Management, has been revised to include 
aspects of quality risk management within the quality system fra mework. A similar revision is 
planned for Part II of the Guide. Other sections of the GMP Guide may be adjusted to include aspects 
of quality risk management in future broader revisions of those sections.  
 
With the revision of the chapters on quality management in GMP Parts I and II quality risk 
management becomes an integral part of a manufacturer’s quality system. Annex 19 itself is not 
intended, however, to create any new regulatory expectations; it provi des an inventory of 
internationally acknowledged risk management methods and tools together with a list of potential 
applications at the discretion of manufacturers.  
 
INTRODUCTION  
 
Risk management principles are effectively utilized in many areas of busine ss and government 
including finance, insurance, occupational safety, public health, pharmacovigilance, and by agencies 
regulating these industries. Although there are some examples of the use of quality risk management 
in the pharmaceutical industry today,  they are limited and do not represent the full contributions that 
risk management has to offer. In addition, the importance of quality systems has been recognized in 
the pharmaceutical industry and it is becoming evident that quality risk management is a valuable 
component of an effective quality system.  
 
It is commonly understood that risk is defined as the combination of the probability of occurrence of 
harm and the severity of that harm. However, achieving a shared understanding of the application of 
risk management among diverse stakeholders is difficult because each stakeholder might perceive 
different potential harms, place a different probability on each harm occurring and attribute different 
severities to each harm. In relation to pharmaceuticals,  although there are a variety of stakeholders, 
including patients and medical practitioners as well as government and industry, the protection of the 
patient by managing the risk to quality should be considered of prime importance.  
 
The manufacturing and u se of a drug (medicinal) product, including its components, necessarily 
entail some degree of risk. The risk to its quality is just one component of the overall risk. It is 
important to understand that product quality should be maintained throughout the pr oduct lifecycle 
such that the attributes that are important to the quality of the drug (medicinal) product remain 
consistent with those used in the clinical studies. An effective quality risk management approach can 
further ensure the high quality of the d rug (medicinal) product to the patient by providing a proactive Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 means to identify and control potential quality issues during development and manufacturing. 
Additionally, use of quality risk management can improve the decision making if a quality problem 
arises. Effective quality risk management can facilitate better and more informed decisions, can 
provide regulators with greater assurance of a company’s ability to deal with potential risks and can 
beneficially affect the extent and level of direct regulat ory oversight.  
 
The purpose of this document is to offer a systematic approach to quality risk management. It serves 
as a foundation or resource document that is independent of, yet supports, other ICH Quality 
documents and complements existing quality pra ctices, requirements, standards, and guidelines 
within the pharmaceutical industry and regulatory environment. It specifically provides guidance on 
the principles and some of the tools of quality risk management that can enable more effective and 
consisten t risk based decisions, both by regulators and industry, regarding the quality of drug 
substances and drug (medicinal) products across the product lifecycle. It is not intended to create any 
new expectations beyond the current regulatory requirements.  
 
It is neither always appropriate nor always necessary to use a formal risk management process (using 
recognized tools and/ or internal procedures e.g. standard operating procedures). The use of informal 
risk management processes (using empirical tools and/ or  internal procedures) can also be considered 
acceptable.  
 
Appropriate use of quality risk management can facilitate but does not obviate industry’s obligation 
to comply with regulatory requirements and does not replace appropriate communications between 
industry and regulators.  
 
SCOPE  
 
This guideline provides principles and examples of tools for quality risk management that can be 
applied to different aspects of pharmaceutical quality. These aspects include development, 
manufacturing, distribution, and the inspection and submission/review processes throughout the 
lifecycle of drug substances, drug (medicinal) products, biological and biotechnological products 
(including the use of raw materials, solvents, excipients, packaging and labeling materials in drug 
(medicinal) products, biological and biotechnological products).  
 
PRINCIPLES OF QUALITY RISK MANAGEMENT  
 
Two primary principles of quality risk management are:  
 
a) The evaluation of the risk to quality should be based on scientific knowledge and ultimately 
link to the protection of the patient; and  
b) The level of effort, formality and documentation of the quality risk management process should 
be commensurate with the level of risk.  
 
 
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 19.1 GENERAL QUALITY RISK MANAGEMENT PROCESS  
 
Quality risk management is a systematic process for the assessment, control, communication 
and review of risks to the quality of the drug (medicinal) product across the product lifecycle. A 
model for quality risk management is outlined in the diagram (Figure 1). Other models could be 
used. The emphasis on each component of the framework might differ from case to case but a 
robust process will incorporate consideration of all the elements at a level of detail that is 
commensurate with the specific risk.  
 
Decision nodes are not shown in the diagram above because decisions can occur at any point in the 
process. These decisions might be to return to the previous step and seek further information, to 
adjust the risk models or even to terminate the risk management process based upon informati on that 
supports such a decision. Note: “unacceptable” in the flowchart does not only refer to statutory, 
legislative or regulatory requirements, but also to the need to revisit the risk assessment process.  
 
Responsibilities  
 
Quality risk management activi ties are usually, but not always, undertaken by interdisciplinary teams. 
When teams are formed, they should include experts from the appropriate areas (e.g. quality unit, 
business development, engineering, regulatory affairs, production operations, sales a nd marketing, 
legal, statistics and clinical) in addition to individuals who are knowledgeable about the quality risk 
management process.  
 
Decision makers should:  
 
-take responsibility for coordinating quality risk management across various functions and 
departments of their organization; and  
 
-assure that a quality risk management process is defined, deployed and reviewed and that adequate 
resources are available.  
 
Initiating a Quality Risk Management Process  
 
Quality risk management should include systematic processes designed to coordinate, facilitate and 
improve science -based decision making with respect to risk. Possible steps used to initiate and plan 
a quality risk management process might include the following:  
 
a) Define the problem and/or risk question, including pertinent assumptions identifying the 
potential for risk  
b) Assemble background information and/ or data on the potential hazard, harm or human health 
impact relevant to the risk assessment  
c) Identify a leader and necessary resources  
d) Specify  a timeline, deliverables and appropriate level of decision making for the risk 
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Risk Assessment  
 
Risk assessment consists of the identification of hazards and the analysis and evaluation of risks 
associated with exposure to those hazards (as defined below). Quality risk assessments begin with a 
well-defined problem description or risk question. When the risk in question is well defined, an 
appropriate risk management tool (see examples in section 5) and the types of information nee ded to 
address the risk question will be more readily identifiable. As an aid to clearly defining the risk(s) 
for risk assessment purposes, three fundamental questions are often helpful:  
 
a) What might go wrong?  
b) What is the likelihood (probability) it will go  wrong?  
c) What are the consequences (severity)?  
 
Risk identification is a systematic use of information to identify hazards referring to the risk question 
or problem description. Information can include historical data, theoretical analysis, informed 
opinions, and the concerns of stakeholders. Risk identification addresses the “What might go 
wrong?” question, including identifying the possible consequences. This provides the basis for 
further steps in the quality risk management process.  
 
Risk analysis  is the estimation of the risk associated with the identified hazards. It is the qualitative 
or quantitative process of linking the likelihood of occurrence and severity of harms. In some risk 
management tools, the ability to detect the harm (detectability ) also factors in the estimation of risk.  
 
Risk evaluation compares the identified and analyzed risk against given risk criteria. Risk evaluations 
consider the strength of evidence for all three of the fundamental questions.  
 
In doing an effective risk ass essment, the robustness of the data set is important because it determines 
the quality of the output. Revealing assumptions and reasonable sources of uncertainty will enhance 
confidence in this output and/or help identify its limitations.  
 
Uncertainty is due to a combination  of incomplete knowledge about a process and its expected or 
unexpected variability. Typical sources of uncertainty include gaps in knowledge gaps in 
pharmaceutical science and process understanding, sources of harm (e.g. , failure modes of a process, 
sources of variability), and probability of detection of problems.  
 
The output of a risk assessment is either a quantitative estimate of risk or a qualitative description of 
a range of risk. When risk is expressed quantitative ly, a numerical probability is used. Alternatively, 
risk can be expressed using qualitative descriptors, such as “high”, “medium”, or “low”, which should 
be defined in as much detail as possible. Sometimes a "risk score" is used to further define descripto rs 
in risk ranking. In quantitative risk assessments, a risk estimate provides the likelihood of a specific 
consequence, given a set of risk - generating circumstances. Thus, quantitative risk estimation is 
useful for one particular consequence at a time. A lternatively, some risk management tools use a 
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 of relative risk. The intermediate steps within a scoring process can sometimes employ quantitative 
risk es timation.  
 
Risk Control  
 
Risk control includes decision making to reduce and/or accept risks. The purpose of risk control is to 
reduce the risk to an acceptable level. The amount of effort used for risk control should be 
proportional to the significance of  the risk. Decision makers might use different processes, including 
benefit -cost analysis, for understanding the optimal level of risk control.  
 
Risk control might focus on the following questions:  
 
a) Is the risk above an acceptable level?  
b) What can be done to reduce or eliminate risks?  
c) What is the appropriate balance among benefits, risks and resources?  
d) Are new risks introduced as a result of the identified risks being controlled?  
 
Risk reduction focuses on processes for mitigation or avoidance of quality ri sk when it exceeds a 
specified (acceptable) level (see Fig. 1). Risk reduction might include actions taken to mitigate the 
severity and probability of harm. Processes that improve the detectability of hazards and quality risks 
might also be used as part of  a risk control strategy. The implementation of risk reduction measures 
can introduce new risks into the system or increase the significance of other existing risks. Hence, it 
might be appropriate to revisit the risk assessment to identify and evaluate any  possible change in 
risk after implementing a risk reduction process.  
 
Risk acceptance is a decision to accept risk. Risk acceptance can be a formal decision to accept the 
residual risk or it can be a passive decision in which residual risks are not specif ied. For some types 
of harms, even the best quality risk management practices might not entirely eliminate risk. In these 
circumstances, it might be agreed that an appropriate quality risk management strategy has been 
applied and that quality risk is reduc ed to a specified (acceptable) level. This (specified) acceptable 
level will depend on many parameters and should be decided on a case -by-case basis.  
 
Risk Communication  
 
Risk communication is the sharing of information about risk and risk management between the 
decision makers and others. Parties can communicate at any stage of the risk management process 
(see Fig. 1: dashed arrows). The output/result of the quality risk management process should be 
appropriately communicated and documented (see Fig. 1: solid arrows). Communications might 
include those among interested parties; e.g., regulators and industry, industry and the patient, within 
a company, industry or regulatory authority, etc. The included information might relate to the 
existence, nature,  form, probability, severity, acceptability, control, treatment, detectability or other 
aspects of risks to quality. Communication need not be carried out for each and every risk acceptance. 
Between the industry and regulatory authorities, communication co ncerning quality risk management 
decisions might be effected through existing channels as specified in regulations and guidance.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Risk Review  
 
Risk management should be an ongoing part of the quality management process. A mechanism to 
review or monitor events should be implemented.  The output/results of the risk management process 
should be reviewed to take into account new knowledge and experience. Once a quality risk 
management process has been initiated, that process should continue to be utilized for  events that 
might impact the original quality risk management decision, whether these events are planned (e.g. 
results of product review, inspections, audits, change control) or unplanned (e.g. root cause from 
failure investigations, recall). The frequenc y of any review should be based upon the level of risk. 
Risk review might include reconsideration of risk acceptance decisions (section 4.4).  
 
19.2 RISK MANAGEMENT METHODOLOGY  
 
Quality risk management supports a scientific and practical approach to decision -making. It provides 
documented, transparent and reproducible methods to accomplish steps of the quality risk 
management process based on current knowledge about assessing the probability, severity and 
sometimes detectability of the risk.  
 
Traditionally, risks  to quality have been assessed and managed in a variety of informal ways 
(empirical and/ or internal procedures) based on, for example, compilation of observations, trends 
and other information. Such approaches continue to provide useful information that m ight support 
topics such as handling of complaints, quality defects, deviations and allocation of resources.  
 
Additionally, the pharmaceutical industry and regulators can assess and manage risk using 
recognized risk management tools and/ or internal proced ures (e.g., standard operating procedures). 
Below is a non -exhaustive list of some of these tools :  
 
a) Basic risk management facilitation methods (flowcharts, check sheets etc.)  
b) Failure Mode Effects Analysis (FMEA)  
c) Failure Mode, Effects and Criticality Analysis (FMECA)  
d) Fault Tree Analysis (FTA)  
e) Hazard Analysis and Critical Control Points (HACCP)  
f) Hazard Operability Analysis (HAZOP)  
g) Preliminary Hazard Analysis (PHA)  
h) Risk ranking and filtering  
i) Supporting statistical tools  
 
It might be appropriate to adapt these tools for use in specific areas pertaining to drug substance and 
drug (medicinal) product quality. Quality risk management methods and the supporting statistical 
tools can be used in combination (e.g. Probabilistic Risk Assessment). Combined use prov ides 
flexibility that can facilitate the application of quality risk management principles.  
 
The degree of rigor and formality of quality risk management should reflect available knowledge and Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 be commensurate with the complexity and/ or criticality of the issue to be addressed.  
 
19.3 INTEGRATION OF QUALITY RISK MANAGEMENT INTO INDUSTRY AND 
REGULATORY OPERATIONS  
 
Quality risk management is a process that supports science -based and practical decisions when 
integrated into quality systems (see Annex II). As outlined in the introduction, appropriate use of 
quality risk management does not obviate industry’s obligation to comply with regulatory 
requirements. However, effective quality risk management can facilitate better and more informed 
decisions, can provid e regulators with greater assurance of a company’s ability to deal with potential 
risks, and might affect the extent and level of direct regulatory oversight. In addition, quality risk 
management can facilitate better use of resources by all parties.  
 
Training of both industry and regulatory personnel in quality risk management processes provides 
for greater understanding of decision -making processes and builds confidence in quality risk 
management outcomes.  
 
Quality risk management should be integrated int o existing operations and documented 
appropriately. Annex II provides examples of situations in which the use of the quality risk 
management process might provide information that could then be used in a variety of pharmaceutical 
operations. These examples  are provided for illustrative purposes only and should not be considered 
a definitive or exhaustive list. These examples are not intended to create any new expectations beyond 
the requirements laid out in the current regulations.  
 
Examples for industry an d regulatory operations (see Annex II):  
Quality management.  
 
Examples for industry operations and activities (see Annex II):  
 
a) Development  
b) Facility, equipment and utilities  
c) Materials management  
d) Production  
e) Laboratory control and stability testing  
f) Packaging and labelling  
 
Examples for regulatory operations (see Annex II):  
 
a) Inspection and assessment activities  
 
While regulatory decisions will continue to be taken on a regional basis, a common understanding 
and application of quality risk management principles could facilitate mutual confidence and promote 
more consistent decisions among regulators on the basis of  the same information. This collaboration 
could be important in the development of policies and guidelines that integrate and support quality Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 risk management practices.  
 
GLOSSARY  
 
Decision maker(s)  
Person(s) with the competence and authority to make appropriate and timely quality risk management 
decisions  
 
Detectability  
The ability to discover or determine the existence, presence, or fact of a hazard  
 
Harm  
damage to health, including the damage that can occur from loss of product quality or availabil ity 
 
Hazard  
The potential source of harm (ISO/IEC Guide 51)  
 
Product Lifecycle  
All phases in the life of the product from the initial development through marketing until the 
product’s discontinuation  
 
Quality  
The degree to which a set of inherent propert ies of a product, system or process fulfils requirements 
(see ICH Q6a definition specifically for "quality" of drug substance and drug (medicinal) products.)  
Quality risk management  
A systematic process for the assessment, control, communication and review  of risks to the quality 
of the drug (medicinal) product across the product lifecycle  
 
Quality system  
The sum of all aspects of a system that implements quality policy and ensures that quality objectives 
are met.  
 
Requirements   
The explicit or implicit needs or expectations of the patients or their surrogates (e.g. health care 
professionals, regulators and legislators). In this document, “requirements” refers not only to 
statutory, legislative, or regulatory requirements, but also to such needs and expec tations.  
 
Risk  
the combination of the probability of occurrence of harm and the severity of that harm (ISO/IEC 
Guide 51)  
 
Risk acceptance  
The decision to accept risk (ISO Guide 73)  
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 Risk analysis  
The estimation of the risk associated with the identified ha zards  
 
Risk assessment  
A systematic process of organizing information to support a risk decision to be made within a risk 
management process. It consists of the identification of hazards and the analysis and evaluation of 
risks associated with exposure to those hazards.  
 
Risk communication  
The sharing of information about risk and risk management between the decision maker and other 
stakeholders  
 
Risk control  
Actions implementing risk management decisions (ISO Guide 73) Risk evaluation – the comparison 
of the estimated risk to given risk criteria using a quantitative or qualitative scale to determine the 
significance of the risk  
 
Risk identification  
The systematic use of information to identify potential sources of harm (hazards) referring to the risk 
question or problem description  
 
Risk management  
The systematic application of quality management policies, procedures, and practices to the tasks of 
assessing, controlling, communicating and reviewing risk  
 
Risk reduction  
Actions taken to lessen the prob ability of occurrence of harm and the severity of that harm  
 
Risk review  
Review or monitoring of output/results of the risk management process considering (if appropriate) 
new knowledge and experience about the risk  
 
Severity  
A measure of the possible cons equences of a hazard  
 
Stakeholder  
Any individual, group or organization that can affect, be affected by, or perceive itself to be affected 
by a risk. Decision makers might also be stakeholders. For the purposes of this guideline, the primary 
stakeholders are the patient, healthcare professional, regulatory authority, and industry  
 
Trend  
A statistical term referring to the direction or rate of change of a variable(s)  
 
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 REFERENCES  
 
1. ICH Q8 Pharmaceutical development  
2. ISO/IEC Guide 73:2002 - Risk Management - Vocabulary - Guidelines for use in Standards  
3. ISO/IEC Guide 51:1999 - Safety Aspects - Guideline for their inclusion in standards Process 
Mapping by the American Productivity & Quality Center 2002, ISBN 1928593739 IEC 61025 
- Fault Tree Analysis (FTA)  
4. IEC 6 0812 Analysis Techniques for system reliability —Procedures for failure mode and 
effects analysis (FMEA)  
5. Failure Mode and Effect Analysis, FMEA from Theory to Execution, 2nd Edition 2003, D. H. 
Stamatis, ISBN 0873895983  
6. Guidelines for Failure Modes and Effe cts Analysis (FMEA) for Medical Devices, 2003 
Dyadem Press ISBN 0849319102  
7. The Basics of FMEA, Robin McDermott, Raymond J. Mikulak, Michael R. Beauregard 1996 
ISBN 0527763209  
8. WHO Technical Report Series No 908, 2003 Annex 7 Application of Hazard Analysis a nd 
Critical Control Point (HACCP) methodology to pharmaceuticalsIEC 61882 - Hazard 
Operability Analysis (HAZOP)  
9. ISO 14971:2000 - Application of Risk Management to Medical Devices ISO 7870:1993 - 
Control Charts  
10. ISO 7871:1997 - Cumulative Sum Charts ISO 7966:1993 - Acceptance Control Charts ISO 
8258:1991 - Shewhart Control Charts  
11. What is Total Quality Control? The Japanese Way, Kaoru Ishikawa (Translated by David J. 
Liu), 1985, ISBN 0139524339  
 
APPENDIX I: RISK MANAGEMENT METHODS AND TOOLS  
 
The purpose of  this appendix is to provide a general overview of and references for some of the 
primary tools that might be used in quality risk management by industry and regulators. The 
references are included as an aid to gain more knowledge and detail about the part icular tool. This is 
not an exhaustive list. It is important to note that no one tool or set of tools is applicable to every 
situation in which a quality risk management procedure is used.  
 
1. Basic Risk Management Facilitation Methods  
 
Some of the simple techniques that are commonly used to structure risk management by organizing 
data and facilitating decision -making are:  
 
a) Flowcharts  
b) Check Sheets  
c) Process Mapping  
d) Cause and Effect Diagrams (also called an Ishikawa diagram or fish bone diagram)  
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 2. Failure Mode Effects Analysis (FMEA)  
 
FMEA (see IEC 60812) provides for an evaluation of potential failure modes for processes and their 
likely effect on outcomes and/or product performance. Once failure modes are established, risk 
reduction can be used to eliminate, c ontain, reduce or control the potential failures. FMEA relies on 
product and process understanding. FMEA methodically breaks down the analysis of complex 
processes into manageable steps. It is a powerful tool for summarizing the important modes of failure,  
factors causing these failures and the likely effects of these failures.  
 
Potential Areas of Use(s)  
 
FMEA can be used to prioritize risks and monitor the effectiveness of risk control activities.  
 
FMEA can be applied to equipment and facilities and might be used to analyze a manufacturing 
operation and its effect on product or process. It identifies elements/operations within the system that 
render it vulnerable. The output/ results of FMEA can be used as a basis for design or further analysis 
or to guide resource deployment.  
 
3. Failure Mode, Effects and Criticality Analysis (FMECA)  
 
FMEA might be extended to incorporate an investigation of the degree of severity of the 
consequences, their respective probabilities of occurrence, and their detectability, there by becoming 
a Failure Mode Effect and Criticality Analysis (FMECA; see IEC 60812). In order for such an 
analysis to be performed, the product or process specifications should be established.  FMECA can 
identify places where additional preventive actions mig ht be appropriate to minimize risks.  
 
Potential Areas of Use(s)  
 
FMECA application in the pharmaceutical industry should mostly be utilized for failures and risks 
associated with manufacturing processes; however, it is not limited to this application. The output of 
an FMECA is a relative risk “score” for each failure mode, which is used to rank the modes on a 
relative risk basis.  
 
4. Fault Tree Analysis (FTA)  
 
The FTA tool (see IEC 61025) is an approach that assumes failure of the functionality of a product 
or process. This tool evaluates system (or subsystem) failures one at a time but can combine multiple 
causes of failure by identifying causal chains. The results are represented pictorially in the form of a 
tree of fault modes. At each level in the tree, com binations of fault modes are described with logical 
operators (AND, OR, etc.). FTA relies on the experts’ process understanding to identify causal 
factors.  
 
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 Potential Areas of Use(s)  
 
FTA can be used to establish the pathway to the root cause of the failu re. FTA can be used to 
investigate complaints or deviations in order to fully understand their root cause and to ensure that 
intended improvements will fully resolve the issue and not lead to other issues (i.e. solve one problem 
yet cause a different probl em). Fault Tree Analysis is an effective tool for evaluating how multiple 
factors affect a given issue. The output of an FTA includes a visual representation of failure modes. 
It is useful both for risk assessment and in developing monitoring programs.  
 
5. Hazard Analysis and Critical Control Points (HACCP)  
 
HACCP is a systematic, proactive, and preventive tool for assuring product quality, reliability, and 
safety (see WHO Technical Report Series No 908, 2003  
Annex 7). It is a structured approach that applies technical and scientific principles to analyze, 
evaluate, prevent, and control the risk or adverse consequence(s) of hazard(s) due to the design, 
development, production, and use of products.  
 
HACCP consists of the following seven steps:  
 
A. conduct a  hazard analysis and identify preventive measures for each step of the process;  
B. determine the critical control points;  
C. establish critical limits;  
D. establish a system to monitor the critical control points;  
E. establish the corrective action to be taken when mo nitoring indicates that the critical control 
points are not in a state of control;  
F. Establish a system  to verify that the HACCP system is working effectively and establish  a 
record -keeping system.  
 
Potential Areas of Use(s)  
 
HACCP might be used to identify and manage risks associated with physical, chemical and biological 
hazards (including microbiological contamination). HACCP is most useful when product and process 
understanding is sufficiently comprehensive to support identification of critical control po ints. The 
output of a HACCP analysis is risk management information that facilitates monitoring of critical 
points not only in the manufacturing process but also in other life cycle phases.  
 
6. Hazard Operability Analysis (HAZOP)  
 
HAZOP (see IEC 61882) is bas ed on a theory that assumes that risk events are caused by deviations 
from the design or operating intentions. It is a systematic brainstorming technique for identifying 
hazards using so -called “guide -words”. “Guide -words” (e.g., No, More, Other Than, Part  of, etc.) are 
applied to relevant parameters (e.g., contamination, temperature) to help identify potential deviations 
from normal use or design intentions. It often uses a team of people with expertise covering the design 
of the process or product and its  application.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 Potential Areas of Use(s)  
 
HAZOP can be applied to manufacturing processes, including outsourced production and 
formulation as well as the upstream suppliers, equipment and facilities for drug substances and drug 
(medicinal) products. It has also been used primarily in the pharmaceutical industry for evaluating 
process safety hazards. As is the case with HACCP, the output of a HAZOP analysis is a list of 
critical operations for risk management. This facilitates regular monitoring of critical p oints in the 
manufacturing process.  
 
7. Preliminary Hazard Analysis (PHA)  
 
PHA is a tool of analysis based on applying prior experience or knowledge of a hazard or failure to 
identify future hazards, hazardous situations and events that might cause harm, as w ell as to estimate 
their probability of occurrence for a given activity, facility, product or system. The tool consists of: 
1) the identification of the possibilities that the risk event happens, 2) the qualitative evaluation of 
the extent of possible inju ry or damage to health that could result and 3) a relative ranking of the 
hazard using a combination of severity and likelihood of occurrence, and 4) the identification of 
possible remedial measures.  
 
Potential Areas of Use(s)  
 
PHA might be useful when ana lyzing existing systems or prioritizing hazards where circumstances 
prevent a more extensive technique from being used. It can be used for product, process and facility 
design as well as to evaluate the types of hazards for the general product type, then t he product class, 
and finally the specific product. PHA is most commonly used early in the development of a project 
when there is little information on design details or operating procedures; thus, it will often be a 
precursor to further studies. Typically , hazards identified in the PHA are further assessed with other 
risk management tools such as those in this section.  
 
8. Risk Ranking and Filtering  
 
Risk ranking and filtering is a tool for comparing and ranking risks. Risk ranking of complex systems 
typically requires evaluation of multiple diverse quantitative and qualitative factors for each risk. The 
tool involves breaking down a basic risk question into as many components as needed to capture 
factors involved in the risk. These factors are combine d into a single relative risk score that can then 
be used for ranking risks. “Filters,” in the form of weighting factors or cut - offs for risk scores, can 
be used to scale or fit the risk ranking to management or policy objectives.  
 
Potential Areas of Use( s) 
 
Risk ranking and filtering can be used to prioritize manufacturing sites for inspection/audit by 
regulators or industry. Risk ranking methods are particularly helpful in situations in which the 
portfolio of risks and the underlying consequences to be m anaged are diverse and difficult to compare 
using a single tool. Risk ranking is useful when management needs to evaluate both quantitatively -Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 assessed and qualitatively -assessed risks within the same organizational framework.  
 
9. Supporting Statistical Tools  
 
Statistical tools can support and facilitate quality risk management. They can enable effective data 
assessment, aid in determining the significance of the data set(s), and facilitate more reliable decision 
making. A listing of some of the principal stati stical tools commonly used in the pharmaceutical 
industry is provided:  
 
Control Charts, for example:  
 
a) Acceptance Control Charts (see ISO 7966)  
b) Control Charts with Arithmetic Average and Warning Limits (see ISO 7873)  
c) Cumulative Sum Charts (see ISO 7871)  
d) Shewhart Control Charts (see ISO 8258)  
e) Weighted Moving Average (ii) Design of Experiments (DOE) (iii) Histograms  
f) Pareto Charts  
g) Process Capability Analysis  
 
APPENDIX II: POTENTIAL APPLICATIONS FOR QUALITY RISK MANAGEMENT  
 
This Appendix is intended to identify potential uses of quality risk management principles and tools 
by industry and regulators. However, the selection of particular risk management tools is completely 
dependent upon specific facts and circumstances. These examples are provided for il lustrative 
purposes and only suggest potential uses of quality risk management. This Annex is not intended to 
create any new expectations beyond the current regulatory requirements.  
 
1. Quality Risk Management as Part of Integrated Quality Management  
 
Documentation  
 
1. To review current interpretations and application of regulatory expectations  
2. To determine the desirability of and/or develop the content for SOPs, guidelines, etc.  
 
Training and education  
 
To determine the appropriateness of initial and/or ongoing training sessions based on education, 
experience and working habits of staff, as well as on a periodic assessment of previous training (e.g., 
its effectiveness)  
To identify the training, experience, qualifications and physical abilities that allow personnel to 
perform an operation reliably and with no adverse impact on the quality of the product  
 
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 Quality defects  
 
To provide the basis for identifying, evaluating, and communicating the potential quality impact of 
a suspected quality defect, complaint, trend, deviation, investigation, out of specification result, etc.  
To facilitate risk communications and determine appropriate action to address significant product 
defects, in conjunction with regulatory authorities (e.g., recall)  
 
Auditing/Ins pection  
 
To define the frequency and scope of audits, both internal and external, taking into account factors 
such as:  
 
a) Existing legal requirements  
b) Overall compliance status and history of the company or facility  
c) Robustness of a company’s quality risk management activities  
d) Complexity of the site  
e) Complexity of the manufacturing process  
f) Complexity of the product and its therapeutic significance  
g) Number and significance of quality defects (e.g. recall)  
h) Results of previous audits/inspections  
i) Major changes of  building, equipment, processes, key personnel  
j) Experience with manufacturing of a product (e.g. frequency, volume, number of batches)  
k) Test results of official control laboratories  
 
Periodic review  
 
a) To select, evaluate and interpret trend results of data within the product quality review  
b) To interpret monitoring data (e.g., to support an assessment of the appropriateness of 
revalidation or changes in sampling)  
c) Change management / change control  
d) To manage changes based on knowledge and information accumulate d in pharmaceutical 
development and during manufacturing  
e) To evaluate the impact of the changes on the availability of the final product  
f) To evaluate the impact on product quality of changes to the facility, equipment, material, 
manufacturing process or tech nical transfers  
g) To determine appropriate actions preceding the implementation of a change, e.g., additional 
testing, (re)qualification, (re)validation or communication with regulators  
 
Continual improvement  
 
To facilitate continual improvement in processes  throughout the product lifecycle  
 
2. Quality Risk Management as Part of Regulatory Operations Inspection and assessment 
activities  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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a) To assist with resource allocation including, for example, inspection planning and frequency, 
and inspection and assessment intensity . 
b) To evaluate the significance of, for example, quality defects, potential recalls and inspectional 
findings.  
c) To determine the appropriateness and type of post -inspection regulatory follow - up. 
d) To evaluate information submitted by industry including pharmaceutical development 
information.  
 
To evaluate impact of proposed variations or changes  
 
To identify risks which should be communicated between inspectors and assessors to facilitate better 
understanding of how risks can be or are controlle d (e.g. parametric release, Process Analytical 
Technology (PAT)).  
 
3. Quality Risk Management as Part of Development  
 
a) To design a quality product and its manufacturing process to consistently deliver the intended 
performance of the product (see ICH Q8)  
b) To enhance knowledge of product performance over a wide range of material attributes (e.g. 
particle size distribution, moisture content, flow properties), processing options and process 
parameters  
c) To assess the critical attributes of raw materials, solvents, Active Pharmaceutical Ingredient 
(API) starting materials, APIs, excipients, or packaging materials  
d) To establish appropriate specifications, identify critical process parameters and establish 
manufacturing controls (e.g., using information from pharmaceuti cal development studies 
regarding the clinical significance of quality attributes and the ability to control them during 
processing)  
 
To decrease variability of quality attributes:  
 
a) reduce product and material defects  
b) reduce manufacturing defects  
c) To assess  the need for additional studies (e.g., bioequivalence, stability) relating to scale up 
and technology transfer  
d) To make use of the “design space” concept  
 
4. Quality Risk Management for Facilities, Equipment and Utilities  
 
Design of facility / equipment  
 
a) To determine appropriate zones when designing buildings and facilities, e.g., flow of material 
and personnel  
b) minimize contamination  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 c) pest control measures  
d) prevention of mix -ups 
e) open versus closed equipment  
f) clean rooms versus isolator technologies  
g) dedicated or segregated facilities / equipment  
 
To determine appropriate product contact materials for equipment and containers (e.g., selection of 
stainless steel grade, gaskets, lubricants)  
To determine appropriate utilities (e.g., steam, gases, power source, compressed air, heating, 
ventilation and air conditioning (HVAC), water)  
To determine appropriate preventive maintenance for associated equipment (e.g., inventory of 
necessary spare parts)  
 
Hygiene aspects in facilities  
 
To protect the product from environ mental hazards, including chemical, microbiological, and 
physical hazards (e.g., determining appropriate clothing and gowning, hygiene concerns)  
To protect the environment (e.g., personnel, potential for cross -contamination) from hazards related 
to the pro duct being manufactured  
Qualification of facility/equipment/utilities  
 
To determine the scope and extent of qualification of facilities, buildings, and production equipment 
and/or laboratory instruments (including proper calibration methods)  
 
Cleaning of equipment and environmental control  
 
To differentiate efforts and decisions based on the intended use (e.g. multi - versus single - purpose, 
batch versus continuous production)  
To determine acceptable (specified) cleaning validation limits Calibration/preven tive maintenance  
To set appropriate calibration and maintenance schedules Computer systems and computer controlled 
equipment  
To select the design of computer hardware and software (e.g., modular, structured, fault tolerance)  
 
To determine the extent of validation, e.g.:  
 
a) identification of critical performance parameters  
b) selection of the requirements and design  
c) code review  
d) the extent of testing and test methods  
e) reliability of electronic records and signatures  
 
5. Quality Risk Management as Part of Materials Management  
 
Assessment and evaluation of suppliers and contract manufacturers  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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To provide a comprehensive evaluation of suppliers and contract manufacturers (e.g., auditing, 
supplier quality agreements)  
 
Starting material  
 
To assess differences and possible quality risks associated with variability in starting materials (e.g., 
age, route of synthesis).  
 
Use of materials  
 
To determine whether it is appropriate to use material under quarantine (e.g., for further internal 
processing)  
To determine appropriateness of reprocessing, reworking, use of returned goods  
 
Storage, logistics and distribution conditions  
 
To assess the adequacy of arrangements to ensure maintenance of appropriate storage and transport 
conditions (e.g., temperature, humidity, co ntainer design)  
To determine the effect on product quality of discrepancies in storage or transport conditions (e.g. 
cold chain management) in conjunction with other ICH guidelines  
To maintain infrastructure (e.g. capacity to ensure proper shipping conditi ons, interim storage, 
handling of hazardous materials and controlled substances, customs clearance)  
To provide information for ensuring the availability of pharmaceuticals (e.g. ranking risks to the 
supply chain)  
 
6. Quality Risk Management as Part of Production  
 
Validation  
 
To identify the scope and extent of verification, qualification and validation activities (e.g., analytical 
methods, processes, equipment and cleaning methods  
To determine the extent for follow -up activities (e.g., sampling, monitoring and re -validation)  
To distinguish between critical and non -critical process steps to facilitate design of a validation study  
 
In-process sampling & testing  
 
To evaluate the frequency and extent of in -process control testing (e.g., to justify red uced testing 
under conditions of proven control)  
To evaluate and justify the use of process analytical technologies (PAT) in conjunction with 
parametric and real time release  
 
Production planning  
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 To determine appropriate production planning (e.g. dedicate d, campaign and concurrent production 
process sequences)  
 
7. Quality Risk Management as Part of Laboratory Control and Stability Studies  
 
Out of specification results  
 
To identify potential root causes and corrective actions during the investigation of out of  
specification results, Retest period / expiration date  
To evaluate adequacy of storage and testing of intermediates, excipients and starting materials  
 
8. Quality Risk Management as Part of Packaging and Labelling Design of packages  
 
To design the secondary package for the protection of primary packaged product (e.g., to ensure 
product authenticity, label legibility)  
 
Selection of container closure system :  
 
To determine the critical parameters of the container closure system Label controls  
To design label co ntrol procedures based on the potential for mix -ups involving different product 
labels, including different versions of the same label  
 
GLOSSARY  
 
Action limit  
Established criteria, requiring immediate follow -up and corrective action if exceeded.  
 
Air lock  
An enclosed space with two or more doors, and which is interposed between two or more rooms, e.g. 
of differing class of cleanliness, for the purpose of controlling the air -flow between those rooms when 
they need to be entered. An air -lock is designed for a nd used by either people or goods.  
 
Alert limit  
Established criteria giving early warning of potential drift from normal conditions which are not 
necessarily grounds for definitive corrective action but which require follow -up investigation.  
 
Authorized person  
Person recognized by the authority as having the necessary basic scientific and technical background 
and experience.  
 
Batch (or lot)  
A defined quantity of starting material, packaging material or product processed in one process or 
series of process es so that it could be expected to be homogeneous.  
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 Note : To complete certain stages of manufacture, it may be necessary to divide a batch into a number 
of sub batches, which are later brought together to form a final homogeneous batch. In the case of 
continuous manufacture, the batch must correspond to a defined fraction of the production, 
characterized by its intended homogeneity.  
 
For the control of the finished product, a batch of a medicinal products comprises all the units of a 
pharmaceutical form whi ch are made from the same initial mass of material and have undergone a 
single series of manufacturing operations or a single sterilization operation or, in the case of a 
continuous production process, all the units manufactured in a given period of time.  
 
Batch number (or lot number)  
A distinctive combination of numbers and/or letters which specifically identifies a batch.  
 
Biogenerator  
A contained system, such as a fermenter, into which biological agents are introduced along with other 
materials so as to affect their multiplication or their production of other substances by reaction with 
the other materials. Biogenerators are generally fitted with devices for regulation, control, 
connection, material addition and material withdrawal.  
 
Biological agents  
Microorganisms, including genetically engineered microorganisms, cell cultures and endoparasites, 
whether pathogenic or not.  
 
Bulk product  
Any product which has completed all processing stages up to, but not including, final packaging.  
 
Calibration  
The set of  operations which establish, under specified conditions, the relationship between values 
indicated by a measuring instrument or measuring system, or values represented by material measure, 
and the corresponding known values of a reference standard.  
 
Cell b ank 
Cell bank system: A cell bank system is a system whereby successive batches of a product are 
manufactured by culture in cells derived from the same master cell bank (fully characterized for 
identity and absence of contamination). A number of containers  from the master cell bank are used 
to prepare a working cell bank. The cell bank system is validated for a passage level or number of 
population doublings beyond that achieved during routine production.  
 
Master cell bank:  
A culture of (fully characterized ) cells distributed into containers in a single operation, processed 
together in such a manner as to ensure uniformity and stored in such a manner as to ensure stability. 
A master cell bank is usually stored at -70°C or lower.  
 
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 Working cell bank:  
A culture of cells derived from the master cell bank and intended for use in the preparation of 
production cell cultures. The working cell bank is usually stored at -70°C or lower.  
 
Cell culture  
The result from the in -vitro growth of cells isolated from mult icellular organisms.  
 
Clean area  
An area with defined environmental control of particulate and microbial contamination constructed 
and used in such a way as to reduce the introduction, generation and retention of contaminants within 
the area.  
 
Note : The different degrees of environmental control are defined in the Supplementary Guidelines 
for the Manufacture of sterile medicinal products.  
 
Clean/contained area  
An area constructed and operated in such a manner that will achieve the aims of both a clean are a 
and a contained area at the same time.  
 
Containment  
The action of confining a biological agent or other entity within a defined space.  
 
Primary containment: A system of containment which prevents the escape of a biological agent into 
the immediate workin g environment. It involves the use of closed containers or safety biological 
cabinets along with secure operating procedures.  
 
Secondary containment: A system of containment which prevents the escape of a biological agent 
into the external environment or i nto other working areas. It involves the use of rooms with specially 
designed air handling, the existence of airlocks and/or sterilizes for the exit of materials and secure 
operating procedures. In many cases it may add to the effectiveness of primary cont ainment.  
 
Contained area  
An area constructed and operated in such a manner (and equipped with appropriate air handling and 
filtration) so as to prevent contamination of the external environment by biological agents from 
within the area.  
 
Controlled area  
An area constructed and operated in such a manner that some attempt is made to control the 
introduction of potential contamination (an air supply approximating to grade D may be appropriate), 
and the consequences of accidental release of living organisms. Th e level of control exercised should 
reflect the nature of the organism employed in the process. At a minimum, the area should be 
maintained at a pressure negative to the immediate external environment and allow for the efficient 
removal of small quantities  of airborne contaminants.  
Computerized system  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 A system including the input of data, electronic processing and the output of information to be used 
either for reporting or automatic control.  
 
Cross contamination  
Contamination of a starting material or of a  product with another material or product.  
 
Crude plant (vegetable drug)  
Fresh or dried medicinal plant or parts thereof.  
 
Cryogenic vessel  
A container designed to contain liquefied gas at extremely low temperature.  
Cylinder  
A container designed to contain  gas at a high pressure.  
 
Exotic organism  
A biological agent where either the corresponding disease does not exist in a given country or 
geographical area, or where the disease is the subject of prophylactic measures or an eradication 
programme undertaken in the given country or geographical area.  
 
Finished product  
A medicinal product which has undergone all stages of production, including packaging in its final 
container.  
 
Herbal medicinal products  
Medicinal products containing, as active ingredients, excl usively plant material and/or vegetable drug 
preparations.  
 
Infected  
Contaminated with extraneous biological agents and therefore capable of spreading infection.  
 
In-process control  
Checks performed during production in order to monitor and if necessary to  adjust the process to 
ensure that the product conforms to its specification. The control of the environment or equipment 
may also be regarded as a part of in - process control.  
 
Intermediate product  
Partly processed material which must undergo further manu facturing steps before it becomes a bulk 
product.  
 
Liquifiable gases  
Those which, at the normal filling temperature and pressure, remain as a liquid in the cylinder.  
 
Manifold  
Equipment or apparatus designed to enable one or more gas containers to be fille d simultaneously Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 from the same source.  
 
Manufacture  
All operations of purchase of materials and products, Production, Quality Control, release, storage, 
distribution of medicinal products and the related controls.  
 
Manufacturer  
Holder of a manufacturing au thorization.  
 
 
Media fill  
Method of evaluating an aseptic process using a microbial growth medium. (Media fills are 
synonymous to simulated product fills, broth trials, broth fills etc.).  
 
Medicinal plant  
Plant the whole or part of which is used for pharmaceutical purpose.  
 
Medicinal products  
Any medicine or similar product intended for human use, which is subject to control under health 
legislation in the manufacturing or importing State.  
 
Packaging  
All operations, including filling and labelling, wh ich a bulk product has to undergo in order to become 
a finished product.  
 
Note:  Sterile filling would not normally be regarded as part of packaging, the bulk product being the 
filled, but not finally packaged, primary containers.  
 
Packaging material  
Any m aterial employed in the packaging of medicinal products, excluding any outer packaging used 
for transportation or shipment. Packaging materials are referred to as primary or secondary according 
to whether or not they are intended to be in direct contact wi th the product.  
 
Procedures  
Description of the operations to be carried out, the precautions to be taken and measures to be applied 
directly or indirectly related to the manufacture of medicinal products.  
 
Production  
All operations involved in the preparat ion of a medicinal product, from receipt of materials, through 
processing and packaging, to its completion as a finished product.  
 
Qualification  
Action of proving that any equipment works correctly and actually leads to the expected results. The 
word validation is sometimes widened to incorporate the concept of qualification.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Quality control  
See Chapter 1.  
 
Quarantine  
The status of starting or packaging materials, intermediate, bulk or finished products isolated  
physically or by other effective means whilst awaiting a decision on their release or refusal.  
 
Radiopharmaceutical  
"Radiopharmaceutical" means any medicinal product which, when ready for use, contains one or 
more radionuclides (radioactive isotopes) included for a pharmaceutical purpose.  
 
Reco nciliation  
A comparison, making due allowance for normal variation, between the amount of product or 
materials theoretically and actually produced or used.  
 
Record  
See Chapter 4.  
 
Recovery  
The introduction of all or part of previous batches of the required  quality into another batch at a 
defined stage of manufacture.  
 
Reprocessing  
The reworking of all or part of a batch of product of an unacceptable quality from a defined stage of 
production so that its quality may be rendered acceptable by one or more additional operations.  
 
Return  
Sending back to the manufacturer or distributor of a medicinal product which may or may not present 
a quality defect.  
 
Seed lot  
Seed lot system: A seed lot system is a system according to which successive batches of a product  
are derived from the same master seed lot at a given passage level. For routine production, a working 
seed lot is prepared from the master seed lot. The final product is derived from the working seed lot 
and has not undergone more passages from the master  seed lot than the vaccine shown in clinical 
studies to be satisfactory with respect to safety and efficacy. The origin and the passage history of 
the master seed lot and the working seed lot are recorded.  
 
Master seed lot:  
A culture of a micro -organism d istributed from a single bulk into containers in a single operation in 
such a manner as to ensure uniformity, to prevent contamination and to ensure stability. A master 
seed lot in liquid form is usually stored at or below -70°C. A freeze - dried master see d lot is stored 
at a temperature known to ensure stability.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Working seed lot:  
A culture of a micro -organism derived from the master seed lot and intended for use in production. 
Working seed lots are distributed into containers and stored as described abo ve for master seed lots.  
 
Specification  
See Chapter 4.  
Starting material  
Any substance used in the production of medicinal products, but excluding packaging materials.  
 
Sterility  
Sterility is the absence of living organisms. The conditions of the sterility  tests are given in the 
European (or other relevant) Pharmacopoeia. *  
 
Validation  
Action of proving, in accordance with the principles of Good Manufacturing Practice, that any 
procedure, process, equipment, material, activity or system actually leads to th e expected results (see 
also qualification).  
 
* The procedures and precautions employed should be such as to give a theoretical level of not more 
than one living micro -organism in 106 units in the final product.  
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 ANNEX 21: MODEL GUIDANCE FOR THE STORAGE A ND TRANSPORT OF TIME AND 
TEMPERATURE -SENSITIVE PHARMACEUTICAL PRODUCTS.  
 
Background  
 
These guidelines set out the principal requirements for the safe storage and distribution of time - and 
temperature -sensitive pharmaceutical products (TTSPPs). They are based upon existing regulations 
and best practice guidance from a wide range of international sources (see References), while 
accepting that local legislation and regulations will continue to take precedence. The target audience 
includes regulators, logist icians and pharmaceutical professionals in industry, government and the 
international agencies.  
 
The document has been prepared in close consultation with the WHO Task Force on Regulatory 
Oversight on Pharmaceutical Cold Chain Management which has been cen tral to the review process. 
A full list of members is given at the end of this annex.  
 
The intention is that the guidance in this document should be directly applicable in less -developed 
countries as well as in the industrialized world. To this end, supple mentary materials will be 
developed to show how the requirements can practicably be achieved, particularly in resource - 
constrained settings. Experience with vaccine supply chain assessments in many less -developed 
countries demonstrates that the mandatory standards set out in this document can be achieved, and 
that some countries are also capable of meeting many of the optional requirements.  
 
The document is designed to give a balanced overview of the major aspects of good storage and 
distribution practice for TTSPPs. As such it deliberately includes references to requirements which 
can be found in general guides to good manufacturing practice (GMP), good storage practice (GSP) 
and good distribution practice (GDP). The purpose is not to supplant these source  materials, but to 
ensure that the reader is aware of the relevant GMP, GSP and GDP implications when seen from the 
particular and specialized perspective of TTSPP management.  
 
Key to conventions used  
 
The following conventions are used in the requirements  clauses:  
 
The imperative voice is used to denote a mandatory or highly desirable requirement. For example: 
“Ensure that…”, “Provide…” and the like.  
The words “where possible” or “preferably” are used to denote an optional but desirable requirement.  
Many clauses are followed by a brief explanation setting out the underlying reason for including the 
clause.  
 
 
 
 
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 GLOSSARY  
 
Active systems  
Actively powered systems using electricity or other fuel source to maintain a temperature controlled 
environment inside an  insulated enclosure under thermostatic regulation (e.g. cold rooms, 
refrigerators, temperature -controlled trucks, refrigerated ocean and air containers).  
 
Change control  
The processes and procedures to manage system changes.  
 
Common carrier  
A seller of distribution services.  
 
Controlled or hazardous time - and temperature -sensitive pharmaceutical products  
Time - and temperature -sensitive pharmaceutical products (TTSPPs) with high illicit value: poisons, 
narcotics, psychotropic products, inﬂammable or expl osive substances and radioactive materials.  
 
Dunnage  
Loose packing material used to protect TTSPPs from damage during transport.  
 
External distribution  
Transport of TTSPPs through various steps in the customer’s supply chain (i.e. transport from a 
pharmace utical manufacturer’s distribution center to commercial customers (including wholesalers, 
retailers and buying groups), to clinical facilities or direct to the patient).  
 
Installation Qualiﬁcation  
The process of obtaining and documenting evidence that equi pment has been provided and installed 
in accordance with its speciﬁcations and that it functions within predetermined limits when operated 
in accordance with the operating instructions.  
 
Internal distribution  
Transport of a TTSPP within a pharmaceutical ma nufacturer’s internal supply chain (i.e. all internal 
transports from manufacturing facility to packaging facility to warehouse to distribution centre).  
 
Net storage capacity  
The total volume available for storing TTSPPs, taking account of the type of load  support system 
employed (ﬂoor -standing pallets, adjustable pallet racking or shelving units), as modiﬁed by the 
utilization factor that can be achieved in the store.  
 
Passive systems  
Systems which maintain a temperature -controlled environment inside an in sulated enclosure, with or 
without thermostatic regulation, using a ﬁnite amount of pre -conditioned coolant in the form of 
chilled or frozen gel packs, phase change materials, dry ice or others.  
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 Includes birds, bats, rodents and insects whose uncontrolled presence affects hygiene and cleanliness.  
 
Pharmaceutical product  
Any product intended for human use or veterinary product intended for administration to food -
producing animals, presented in its ﬁnished dosage form, that is subject to control by pharmaceutical 
legislation in either the exporting or the importing state and includes products for which a prescription 
is required, products which may be sold to patients without a prescription, biologicals and vaccines. 
It does not, however, include medical devices.1  
 
Deﬁnition from Revision of WHO good distribution practices for pharmaceutical products. In: WHO 
Expert Committee on Speciﬁcations for Pharmaceutical Preparations. Forty -fourth report. Geneva, 
World Health Organization, 2010 (WHO Technica l Report Series, No. 957), Annex 5.  
 
Qualiﬁcation  
Documented testing that demonstrates, with a high degree of assurance, that a speciﬁc process will 
meet its predetermined acceptance criteria.2  
 
Refrigeration equipment  
The term “refrigeration” or “refriger ation equipment” means any equipment whose purpose is to 
lower air and product temperatures and/or to control relative humidity.  
 
Service Level Agreement (SLA)  
A service level agreement or contract is a negotiated agreement between the customer and service  
provider that deﬁnes the common understanding about materials or service quality speciﬁcations, 
responsibilities, guarantees and communication mechanisms. It can either be legally binding, or an 
information agreement. The SLA may also specify the target a nd minimum level performance, 
operation or other service attributes.3  
 
Standard Operating Procedure (SOP)  
A set of instructions having the force of a directive, covering those features of operations that lend 
themselves to a deﬁnite or standardized procedu re without loss of effectiveness.  
 
Storage temperature  
The temperature range listed on the TTSPP label, and within the regulatory documentation, for  
long-term storage.  
 
Storage unit temperature/humidity distribution  
The range and pattern of temperatures and/or humidity within a temperature - controlled storage unit 
during normal operation.  
 
Suspect Product  
A TTSPP whose presentation and/or pharmacological formulation indicates that it has not been 
manufactured by the company named on the packaging. A TTSPP  that shows visible or 
pharmacological evidence of tampering.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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Temperature -Controlled  
Includes any environment in which the temperature is actively or passively controlled at a level 
different from that of the surrounding environment within precise predeﬁn ed limits.  
 
Temperature Excursion  
An excursion event in which a TTSPP is exposed to temperatures outside the range(s) prescribed for 
storage and/or transport. Temperature ranges for  
 
1. Deﬁnition from the Parenteral Drug Association (PDA) Technical Report No.  39, 2007.  
2. Deﬁnition from International Air Transport Association (IATA), Chapter 17, 9th ed., June 
2009. storage and transport may be the same or different; they are determined by the product 
manufacturer, based on stability data.  
 
Temperature -modiﬁed  
Includes any environment in which the temperature is predictably maintained at a level different from 
that of the surrounding environment, but is not actively or passively controlled within precise 
predeﬁned limits.  
 
Time - and Temperature -Sensitive Pharmac eutical Product (TTSPP)  
Any pharmaceutical good or product which, when not stored or transported within predeﬁned 
environmental conditions and/or within predeﬁned time limits, is degraded to the extent that it no 
longer performs as originally intended.  
 
Transport temperature proﬁle  
Anticipated ambient temperature variation and duration to which a TTSPP may be exposed during 
transport.  
 
Utilization factor  
The percentage of the total volume available for storing TTSPPs that can reliably be achieved in 
practic e, taking account of the types of stock -keeping unit (SKU), the types of load support system 
and the stock management systems used in the store.  
 
Validation  
Documented testing performed under highly controlled conditions, demonstrating that processes, 
meth ods, and systems consistently produce results meeting predetermined acceptance criteria.  
 
1. Importation  
 
a.  Port handling and customs clearance  
 
i. Port of entry  
 
Import TTSPPs through a port of entry that is equipped to handle such products. Where this is not Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 possible, ensure that arrangements are in place to provide the necessary level of protection and 
security.  
 
Reason: To minimize the risk of damage.  
 
ii. Ofﬂoading  
 
As soon as possible after arrival, remove TTSPP shipments from the wharf or airport apron to a safe 
and suitable temperature -controlled storage location.  
 
1. Deﬁnition from PDA Technical Report No. 39, 2007.Reason: To minimize the risk of theft and 
to avoid exposure to adverse ambient conditions.  
 
iii. Temporary storage at port of entry  
 
Store TTSPP shipments in a secure warehouse under the conditions recommended by the product 
manufacturer, until the shipment has been authorized for removal by customs.5  
 
Reason: To avoid risk of theft or damage during temporary storage.  
 
iv. Customs clearance  
 
Draw up pr ocedures and memoranda of understanding to ensure that TTSPP shipments are cleared 
through customs as rapidly as possible. This can be facilitated by a pre -clearance procedure carried 
out by the local health agency, clearing agent or freight forwarder in c ollaboration with customs. 
Alternatively, the clearance process should be conducted by customs staff, supported by personnel 
with suitable pharmaceutical training, especially when clearance involves the opening and resealing 
of temperature - controlled pack aging.  
 
Reason: To avoid delays during customs clearance that may cause temperature excursions and 
place TTSPPs at risk.  
 
2. WAREHOUSING SITES  
 
a. Site layout  
 
i. Natural hazards  
 
Select and/or develop storage sites to minimize risks from natural hazards such as ﬂoods, landslides 
and earthquakes and extreme weather conditions such as hurricanes and tornadoes.  
 
Reason: To protect against loss of valuable pharmaceutical products, to ensure continued supply 
to patients in the market and to protect personnel working i n the store.  
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 b. Site access  
 
Provide vehicular access to storage buildings sufﬁcient to accommodate the largest vehicles visiting 
the site, including emergency vehicles.  
 
Reason: To ensure convenient operation of the facility.  
 
In some situations, arrangements can be made for formal customs clearance to take place away from 
the port of entry — for example, at a national vaccine store. In situations where the port of entry is 
not equipped with suitable cold storage facilities, thi s can reduce the risk of temperature excursions.  
 
c. Site security  
 
Provide perimeter protection to ensure security of the grounds and storage buildings against 
anticipated risks.  
 
Reason: To protect against vandalism, theft and other illegal incursions. Security arrangements 
should be appropriate to the site location and the value of goods stored there.  
 
d. Site cleanliness  
 
Keep the site free of accumulated dust, dirt, waste and debris. Ensure that pests are kept under control 
within the site area. Collect waste in designated closed containers and arrange for safe disposal at 
frequent intervals.  
 
Reason: To help protect storage buildings against ingress by dust, dirt and pests.  
 
3. STORAGE BUILDINGS  
 
a. Construction standards  
 
Construct or procure storage buildings that are:  
 
i. purpose -designed for the storage of TTSPPs, or well -adapted for this purpose;  
ii. designed to suit the prevailing climate, making maximum use of passive heating, cooling and 
ventilation;  
iii. designed and equipped to minimize the consumption of  electricity and other fuel sources;  
iv. constructed using materials and ﬁnishes that are robust, easy to clean and which are selected to 
minimize long -term maintenance;  
v. constructed using locally available materials and building technologies; and  
vi. built to mini mize hiding and nesting places for pests.  
 
Reasons: Storage in unsuitable and poorly -designed buildings places TTSPPs at risk and increases 
storage costs. Buildings constructed using inappropriate materials and technologies are difﬁcult Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 to operate and main tain in resource -constrained settings.  
 
b. Accommodation and layout  
 
Ensure that the storage buildings are well laid out and contain all the necessary storage areas, goods 
assembly, receiving and dispatch bays and ofﬁce accommodation needed for efﬁcient operation of 
the TTSPP store.  
 
4. LOADING AND RECEIVING BAYS  
 
a. Loading bays  
 
Ensure that receiving and dispatch bays are designed to avoid conﬂict between incoming and 
outgoing goods and are protected from direct sunlight, dust, dirt, rain, snow and wind, and from 
extremes of heat, cold and solar radiation that could damage TTSPPs, and measures are taken to 
minimize pest activity in these areas.  
 
Reason: Protection against damage and maintenance of product quality.  
 
b. Receiving bays  
 
Provide receiving areas with suitable equipment to clean reusable transport containers after their 
contents have been unloaded, and before the containers are stored for re -use. 
 
Reason: Protection against contamination of outgoing TTSPPs.  
 
5.  GOODS ASSEMBLY AND QUARANTINE AREAS  
 
a. Goods assembly areas  
 
Provide sufﬁcient space to receive, assemble and pack TTSPPs for dispatch under temperature -
modiﬁed conditions. Preferably, these areas should be physically close to the temperature -controlled 
storage area.  
Reason: Protection of TTSPPs during arrival, order assembly and dispatch.  
b. Holding area for incoming goods  
 
Provide a temperature -controlled holding area for incoming TTSPPs pending their acceptance into 
the main storage area. The holding area may be a physically separated zone, or it may be deﬁned 
using a suitable stock control information system, or by a combination arrangement. Where goods 
are held in bond in the warehouse, awaiting customs clearance, they must be physically separated 
and secured.  
 
Reason: Incoming items may need ins pection and/or regulatory clearance, including laboratory 
testing.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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c. Quarantine area  
 
Provide a quarantine area for the isolation of returned, faulty, recalled and otherwise withdrawn 
goods pending a decision on disposal or re -stocking by the qualiﬁed person or department. Materials 
within quarantine areas must be clearly identiﬁed with their status.  
 
i. with temperature control, for items returned for re -stocking; with temperature control, for items 
recalled for testing;  
ii. without temperature control, for items awaiting disposal.  
 
The quarantine area may be a physically separated zone, or it may be deﬁned using a suitable stock 
control information system, or by a combination arrangement.  
 
Reason: Items for re -stocking, testing and disposal should be kept se parate to avoid the risk of 
inappropriate use.  
 
6. ENVIRONMENTAL CONTROL OF ANCILLARY AREAS  
 
Ensure, where possible, that ancillary areas where TTSPPs are temporarily held during arrival, order 
assembly or dispatch are:  
 
i. maintained within the temperature range speciﬁed for the goods being handled;  
ii. maintained within the humidity range speciﬁed for goods that are adversely affected by high 
relative humidity and are not sufﬁciently protected by their packaging;6  
iii. protected from undue exposure to direct sunligh t; 
iv. protected from the weather;  
v. protected against dust, dirt and waste accumulation;  
vi. adequately ventilated;  
vii. adequately lit to enable operations to be carried out accurately and safely;  
viii. monitored during the times when TTSPPs are handled; and monitored during  the times when 
TTSPPs are handled (see 4.5.1 -4.5.4.  
 
Reason: Protection of TTSPP quality during arrival, order assembly or dispatch.  
 
7. BUILDING SECURITY  
 
a. General building security  
 
Ensure that buildings used to store TTSPPs have sufﬁcient security to prevent unauthorized access 
and to prevent misappropriation of goods.  
 
Reason: To protect against vandalism, theft and other illegal incursions. Security arrangements 
should be appropriate to the site location and to the value of goods stored there.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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b. Contr olled and hazardous substances areas  
 
Ensure that all areas that are used to store controlled or hazardous TTSPPs are:  
 
Six (6) Active environmental control of ancillary areas may not be needed if all TTSPPs are kept in 
temperature - controlled packaging and/or humidity -protective packaging when passing through these 
areas. dedicated, securely locked facilities that comply fully with all legislative and regulatory 
requirements applicable in the country where the store is located;  
 
i. only accessible to author ized staff;  
ii. protected by automatic intruder and/or ﬁre and smoke, and/or chemical and/or radiological 
sensor alarm systems appropriate to the type(s) of product being stored;7  
iii. designed to be explosion -proof, where explosive TTSPPs are stored; and  
iv. continuou sly monitored by security staff.  
 
Reason: Protection of property and life.  
 
8. FIRE PROTECTION  
 
a. Fire protection equipment  
 
Provide suitable ﬁre detection and ﬁre -ﬁghting equipment, including ﬁre hydrants, in all TTSPP 
storage areas and ensure that:  
 
i. systems and equipment are appropriate for the class of occupancy and product storage 
arrangements and are approved by the local ﬁre authority; and  
ii. equipment is regularly serviced in accordance with the equipment manufacturers’ 
recommendations and local regulations . 
 
Reason: Protection of property and life.  
 
b. Fire prevention, detection and control procedures  
 
Follow standard operating procedures (SOPs) for ﬁre prevention, detection and control. Train staff 
and carry out regular ﬁre drills. Prohibit smoking in all areas.  
 
Reason: Protection of property and life.  
 
9. BUILDING HYGIENE  
 
a. Building cleanliness  
 
Implement a cleaning programme for all areas:  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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i. do not allow the accumulation of dust, dirt and waste, including packaging waste;  
ii. take precautions against spillage or breakage, and cross -contamination;  
 
Zoned sprinkler systems are recommended to control ﬁres and to localize product damage in the 
event of system activation.  
 
Explosion -proof stores must have a blast roof or wall. Preferably, explosive substances should be  
stored in an independent building, well separated from the main store. collect waste in designated 
closed containers and arrange for safe disposal at frequent intervals;  
 
i. do not permit consumption of food or beverages other than in designated areas; and  
ii. maintain cleaning records to demonstrate compliance.  
 
Reason: Protection against damage and contamination of TTSPPs and to minimize the risk of pest 
infestation.  
 
b. Pest control  
 
Implement a programme to keep all areas free of pests. This should include enclosed receiving and 
loading bays. Maintain records to demonstrate compliance with a robust pest control programme.  
 
Reason: Protection against damage and contamination of TTSPPs.  
 
10. POWER SUPPLY  
 
a. Uninterrupted power supply  
 
Where possible, and where necessary,9 ensure that all temperature - controlling equipment for TTSPP 
storage (i.e. refrigerators, freezers, building management systems, heating, ventilation and air -
conditioning (HVAC) systems, compressors, air -handling units, monitoring systems, alar ms and 
related computer equipment) are connected to an uninterrupted power supply (UPS) system. Where 
a generator and associated control equipment is used it should:  
 
i. be able to manage the combined start -up load of all connected temperature -controlling and  
temperature -monitoring equipment;  
ii. not exceed the deﬁned parameters of the mains power supply;  
iii. be equipped with automatic mains failure start -up and automatic shutdown when power is 
restored; and  
iv. have adequate fuel tank capacity and sufﬁcient fuel to cover  a prolonged power outage. 
Regularly test and service UPS equipment and generators. Maintain records to demonstrate 
compliance.  
 
Reason: Loss prevention.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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UPS systems may be unnecessary in countries with a very reliable electricity supply. In smaller store s 
in countries where electricity is only available for a limited period each day, or is entirely absent, an 
alternative approach to UPS is to use refrigeration equipment with extended holdover capacity, for 
example, ice -lined refrigerators, or gas, kerosen e or solar -powered refrigerators.  
 
The installed capacity of the UPS system can be minimized by ﬁtting electronic controls which 
reduce compressor start -up loads.  
 
b. Power failure contingency plan  
 
Develop and maintain a contingency plan to protect TTSPPs in  the event of power failure which 
places products at risk. Alternative emergency cooling systems (e.g. liquid nitrogen or dry ice) are 
acceptable.  
 
Reason: Loss prevention.  
 
c. Building Maintenance  
 
Implement a planned preventive maintenance programme to ensure that storage buildings and 
building utilities are well maintained. Keep records to demonstrate compliance with the programme.  
 
Reason: To ensure that storage buildings continue to protect stored products against damage.  
 
11. TEMPERATURE -CONTROLLED STORA GE 
 
a. Normative references  
 
i. EN 60068 -3 parts 5, 6, 7 and 11: Environmental testing. Guidance. Conﬁrmation of the 
performance of temperature chambers  
ii. International Air Transport Association (IATA) Perishable cargo regulations chapter 17. 10th 
ed, July 2010  
iii. USP <1079> Good storage and shipping practices  
iv. USP <1118> Monitoring devices — time, temperature and humidity 67890 - . 
 
b. Storage capacity of temperature -controlled stores  
 
Ensure that the net storage capacity of the temperature -controlled stores is sufﬁcient to accommodate 
peak TTSPP stock levels and their associated transit temperature protection components (i.e. freezer 
blocks, ﬂexible ice blankets, refrigerated gel packs, phase change materials and insulated packaging, 
if retained), under correct temperature conditions and in a manner which enables efﬁcient and correct 
stock management operations to take place.  
 
Reason: To avoid the risks associated with overstocking and to ensure that good warehousing Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 practices can be adopted (i.e. ﬁrst in -ﬁrst ou t (FIFO) or earliest expiry -ﬁrst out (EEFO)). 
Overstocking makes FIFO or EEFO handling difﬁcult or impossible and hinders accurate 
physical stock counts . 
 
c. Temperature -controlled storage  
 
Ensure that TTSPPs are stored in temperature -controlled rooms, cold rooms, freezer rooms, 
refrigerators and freezers which comply with the following requirements. Temperature -controlled 
rooms, cold rooms and freezer rooms should be:  
 
i. capable of maintaining the temperature range deﬁned by the system set points over the full  
annual ambient temperature range experienced at the store location;  
ii. preferably equipped with an auto -defrost circuit which has a minimal effect on temperature 
within the unit during the defrost cycle and maintains temperature within speciﬁcation for this 
period;  
iii. equipped with a low temperature protection circuit in cold climates where there is a risk of 
breaching the low temperature set point for TTSPPs that are damaged by exposure to low 
temperatures;  
iv. connected to a UPS as described in clause 3.9.1;  
v. equip ped with a calibrated continuous temperature monitoring system with sensors located at 
points representing greatest temperature variability and temperature extremes;  
vi. preferably equipped with continuous humidity monitoring devices with sensors located at 
points representing humidity extremes;  
vii. equipped with alarms to indicate temperature excursions and/or refrigeration failure;  
viii. ﬁtted with lockable doors, or an access control system, as necessary; locks must have a safety 
device so that doors can be freely ope ned from the inside; and  
ix. qualiﬁed as deﬁned in clause 4.7.  
 
 
Refrigerators and freezers should be:  
 
i. purpose -designed for the storage of TTSPPs; household -style units are only acceptable if they 
have been independently tested and found to comply with the temperature control requirements 
of a recognized standard for pharmaceutical refrigerators and freezers;11  
ii. capable of maintaining the temperature range speciﬁed by the TTSPP manufacturer over the 
full annual ambient temperature range experienced at the sto rage site;  
iii. equipped with calibrated temperature monitoring devices appropriate to the level of risk but 
preferably capable of continuous recording and with sensor(s) located at a point or points within 
the cabinet which most accurately represents the tempe rature proﬁle of the equipment during 
normal operation;  
iv. preferably equipped with alarms to indicate temperature excursions and/ or refrigeration 
failure;  
v. ﬁtted with lockable doors or lids, or access control system, as necessary; and  
vi. qualiﬁed and/or tested as deﬁned in clause 4.7.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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For example, WHO PQS standards for refrigerators and freezers are available at: 
http://www.who.int/immunization_standards/vaccine_quality/pqs_e03_fridges_freezers/en/index.ht
ml  
 
Reason: To maintain labelled TTSPP storage temperatures during long - term storage.  
 
d. Temperature -controlled storage for controlled and hazardous products  
 
Ensure that controlled and hazardous TTSPPs are securely stored:  
 
i. Provide dedicated temperature -controlled rooms, cold rooms, freezer rooms, refrigerators and 
freezers for these TTSPPs, in separate secure areas, as described in clause 3.6.2.  
ii. Alternatively, but only if acceptable to the regulatory authority, bulk stocks of TTSPPs with 
high illicit -value may be stored in a securely locked section of a general temperature -controlled 
storage area.  
 
Reason: To protect this category of TTSPPs against theft and mis use and to safeguard workers 
and general storage areas in the event of an accident involving hazardous substances.  
 
12. TEMPERATURE AND HUMIDITY CONTROL AND MONITORING IN STORAGE  
 
a. Temperature control  
 
Provide thermostatic temperature control systems for all temperature - controlled rooms, cold rooms, 
freezer rooms, refrigerators and freezers, used to store TTSPPs. Comply with the following minimum 
requirements:  
 
i. system able continuously to maintain air temperatures within the set point limits throughout 
the validated storage volume;  
ii. control sensors accurate to ± 0.5 °C or better;  
iii. control sensors calibrated as described in clause 4.10.1;  
iv. control sensors located in areas where greatest variability in temperature is expected to occur 
in order to maximize availab le safe storage volume;  
v. control sensors positioned at the hot and cold spots determined by temperature mapping, even 
if affected by door opening, unless recommendations are being made not to store products in 
such areas; and  
vi. control sensors independent of the temperature monitoring system.  
 
b. Temperature monitoring  
 
Provide air temperature monitoring systems and devices for all temperature - controlled rooms, cold 
rooms, freezer rooms, refrigerators and freezers, used to store TTSPPs. Comply with the following  
minimum requirements:  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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General requirements  
 
i. Monitoring sensors accurate to ± 0.5 °C or better for electronic devices and  
ii. ± 1 °C or better for alcohol, bi -metal gas or vapour pressure thermometers. Monitoring sensors 
calibrated as described in clause 4.10.1.  
iii. Monitoring sensors located in areas where greatest variability in temperature is expected to 
occur within the qualiﬁed and/or tested storage volume as deﬁned in clause 4.7.  
iv. Monitoring sensors positioned so as to be minimally affected by transient e vents such as door 
opening.  
v. Temperature monitoring devices, temperature traces or electronic temperature records 
manually checked at least twice a day, in the morning and evening, seven days a week, 
including public holidays.  
 
Temperature -controlled rooms,  cold rooms and freezer rooms  
 
i. Provide a temperature record with a minimum recording frequency of six times per hour for 
each monitoring sensor position.  
ii. Provide documentation for each monitoring sensor position which can be stored and accessed.  
iii. Continue to operate independently in the event of a power failure.12  
 
Refrigerators and freezers  
 
i. Preferably, connect refrigerators and freezers to a multipoint monitoring system with a 
minimum recording frequency of six times per hour for each sensor position which can operate 
independently in the event of a power failure.  
ii. Alternatively use battery -powered portable temperature monitoring devices with a minimum 
recording frequency of six times per hour.  
iii. The least preferred option is a thermometer or maximum/mini mum thermometer.  
iv. Provide documentation for each appliance which can be stored and accessed.  
 
Reasons: To maintain labelled TTSPP temperatures during long -term storage. Thermometers 
provide only limited and discontinuous temperature information. For this re ason, continuous 
recording devices are preferable.  
 
c. Humidity control  
 
Provide humidity control in temperature -controlled rooms that are used to store TTSPPs which are 
adversely affected by high relative humidity and are not sufﬁciently protected by their packaging. 
Such products are typically labelled “store in a dry place”, or carry similar wording and require a 
humidity -controlled environment.  
 
Where there is no UPS, the autonomy period for the device should be matched to the maximum 
length of anticipate d power outages.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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d. Humidity monitoring  
 
Provide humidity monitoring systems and devices in temperature -controlled rooms that are used to 
store TTSPPs which require a humidity -controlled environment. Comply with the following 
minimum requirements:  
 
i. sensors accurate to ± 5% RH;  
ii. sensors calibrated as per clause 4.10.2;  
iii. sensors located to monitor worst -case humidity levels within the qualiﬁed storage volume 
deﬁned in clause 4.7;  
iv. sensors positioned so as to be minimally affected by transient events such as door opening;  
v. provides a humidity record with a minimum recording frequency of six times per hour for each 
sensor position;  
vi. provides documentation for each sensor position which can be stored and accessed; and  
vii. continues to operate independently in the event of a power failure.13  
 
Reason: To maintain labelled TTSPP humidity conditions during long -term storage.  
 
13. ALARM SYSTEMS  
 
a. Temperature alarms  
 
Provide temperature alarm systems for temperature -controlled rooms, cold rooms, freezer rooms, 
refrigerators and freezers, used to store TTSPPs. Comply with the following minimum requirements:  
 
General requirements  
 
i. Sensors accurate to ± 0.5 °C.  
ii. Sensors calibrated as described in clause 4.10.1.  
iii. Sensors located to monitor worst -case temperatures within the validated storage volume 
deﬁned in clause 4.7; where the alarm system is not integrated with the temperature monitoring 
system, sensors should be located close to the temperature monitoring sensors.  
iv. Sensors positioned so as to be minimally affected by transient even ts such as door opening.  
 
b. Temperature -controlled rooms, cold rooms and freezer rooms  
 
i. High/low alarms set points to trigger appropriately located visual alarm(s).  
ii. Preferably there should also be appropriately located audible alarm(s) in addition to the visual 
alarm(s).  
 
Where there is no UPS the autonomy period for the device should be matched to the maximum length 
of anticipated power outages. Preferably there should be an automatic telephone dial -up or SMS text 
warning system to alert on -call personnel  when an alarm is triggered outside working hours.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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c. Refrigerators and freezers  
 
Preferably there should be a visual and/or audible alarm system; this may be integrated with a 
portable continuous temperature monitoring device.  
 
Reason: Loss prevention.  
 
d. Hum idity alarms  
 
Provide humidity alarm systems for temperature -controlled rooms used to store TTSPPs that require 
a humidity -controlled environment. Comply with the following minimum requirements:  
 
i. sensors accurate to ± 5% relative humidity (RH);  
ii. sensors calibrated as described in clause 4.10.2;  
iii. sensors located to monitor worst -case humidity levels within the validated storage volume 
deﬁned in clause 4.7; where the alarm system is not integrated with the humidity monitoring 
system, sensors should be locate d close to the humidity monitoring sensors;  
iv. sensors positioned so as to be minimally affected by transient events such as door opening;  
v. high/low alarms set points to trigger appropriately located visual alarm(s);  
vi. preferably there should also be appropriate ly located audible alarm(s) in addition to the visual 
alarm(s); and  
vii. preferably there should be an automatic telephone dial -up or SMS text warning system to alert 
on-call personnel when an alarm is triggered outside working hours.  
Reason: Loss prevention.  
 
14. QUALICATION OF TEMPERATURE -CONTROLLED STORES  
 
Qualify new temperature -controlled storage areas and new refrigeration equipment before it becomes 
operational. The qualiﬁcation procedure should:  
 
i. demonstrate the air temperature proﬁle throughout the storage area or equipment cabinet, when 
empty and in a normal loaded condition;  
ii. deﬁne zones which should not be used for storage of TTSPPs (for example areas in close 
proximity to cooling coils, cold air streams or heat sources); and  
iii. demonstrate the time taken for  temperatures to exceed the designated limits in the event of 
power failure.  
 
Fully document the initial qualiﬁcation. Carry out additional qualiﬁcation exercises whenever 
modiﬁcations are made to the storage area that may increase loading or affect air ci rculation, or when 
changes are made to the refrigeration equipment, such as a change in the set point. Consider the need 
for requaliﬁcation whenever temperature and/or humidity monitoring shows unexplained variability 
that is greater than normal.  
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 Qualiﬁca tion may not be required for equipment which requires little or no site assembly or 
commissioning, such as vaccine refrigerators and freezers that have been independently tested and 
found suitable for the storage of TTSPPs. Independent testing must be carr ied out between the chosen 
set points and under the ambient temperature conditions to which the equipment will be exposed 
during operation. Prequaliﬁed equipment of this type must be correctly installed in each location in 
accordance with written guidance.  
 
Reason: To ensure that labelled TTSPP temperatures can be maintained during long -term storage 
and that the facility can demonstrate to the regulatory authorities and other interested parties that 
due diligence has been observed.  
 
15. CLEANLINESS OF TEMPERATURE -CONTROLLED STORES  
 
Implement a cleaning and decontamination programme for all temperature - controlled rooms:  
i. Ensure that ﬂoor areas are fully accessible for cleaning. Do not store goods directly on the ﬂoor.  
ii. Do not permit storage of any non -pharmaceutical products except transport -related items such 
as icepacks, gel packs and the like.  
iii. Do not allow the accumulation of dust, dirt and waste, including packaging waste.  
iv. Take precautions against spillage or breakage, and cross -contamination.  
v. Do not allow accumulation of frost and ice, particularly ice contaminated by spillages.  
vi. Collect waste in designated closed containers and arrange for safe disposal at frequent intervals.  
vii. Maintain cleaning records to demonstrate compliance.  
viii. Reason: Protection agai nst damage and contamination of TTSPPs and hazards to workers, 
arising from spillage or breakage.  
a. Refrigeration equipment maintenance  
 
Implement a maintenance programme for all temperature -controlled rooms, cold rooms, freezer 
rooms, refrigerators and freezers:  
 
i. Carry out regular planned preventive maintenance on all temperature - controlling equipment. 
Make arrangements to ensure that emergency maintenance is carried out within a time period 
that does not place TTSPPs at risk of damage.  
ii. Ensure that ther e is a contingency plan to move products stored in non - functioning equipment 
to a safe location before damage to the product occurs in the event that equipment cannot be 
repaired in a timely manner.  
iii. Maintain records to demonstrate compliance.  
 
Reason: Los s prevention.  
 
16. CALIBRATION AND VERIFICATION OF CONTROL AND MONITORING 
DEVICES  
 
a. Calibration of temperature control and monitoring devices  
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 Calibrate devices against a certiﬁed, traceable reference standard at least once a year, unless 
otherwise justiﬁed. Calibration should demonstrate the accuracy of the unit across the entire 
temperature range over which the device is designed to be used. Single -use devices that are supplied 
with a manufacturer’s calibration certiﬁcate do not need to be re -calibrated.  
 
b. Calibration of humidity control and monitoring devices  
 
Calibrate devices against a certiﬁed, traceable reference standard at least once a year unless otherwise 
justiﬁed. Single -use devices that are supplied with a manufacturer’s calibration certiﬁcate do not need 
to be re -calibrated.  
 
c. Alarm equipment veriﬁcation  
 
Check functionality of temperature and humidity alarms at least once every six months at the 
designated set points. Maintain records to demonstrate compliance.  
 
Reason: To ensure that labelled TTSPP storage temperatures and humidity control can be 
maintained during long -term storage and that the store can demonstrate to the regulatory 
authorities and other interested parties that due diligence has been observed.  
 
17. MATERIALS HANDLING  
 
a. Materials handling equipment  
 
Where powered materials handling equipment is used in temperature - controlled rooms, cold rooms 
or freezer rooms, select equipment which is certiﬁed for safe use in conﬁned spaces.  
 
Reason: Protection of the workforce.  
 
18. TRANSPORT AND DELIVERY  
 
a. Normative references  
 
i. Directive 94/62/EC. European Parliament and Council Directive of 20 December 1994 on 
packaging and packaging waste.1994.  
ii. EN 13428:2004. Packaging. Requirements speciﬁc to manufacturing and composition. 
Prevention by source r eduction.  
iii. EN 13430:2004. Packaging. Requirements for packaging recoverable by material recycling.  
iv. EN 13431:2004. Packaging. Requirements for packaging recoverable in the form of energy 
recovery, including speciﬁcation of minimum inferior caloriﬁc value.  
v. EN 13432:2000. Packaging. Requirements for packaging recoverable through composting and 
biodegradation. Test scheme and evaluation criteria for the ﬁnal acceptance of packaging.  
vi. IATA Perishable Cargo Regulations Chapter 17, 9th Edition, July 2009.  
vii. Isothermal and refrigerating containers for health products — Thermal performance Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 qualiﬁcation method.  
viii. ISTA — 5B: Focused Simulation Guide for Thermal Performance Testing of Temperature 
Controlled Transport Packaging.  
ix. ISTA — 7D: Thermal Controlled Transpor t Packaging for Parcel Delivery System Shipment. 
Basic Requirements: atmospheric conditioning, vibration and shock testing.  
x. WHO Technical Report Series, No. 937, 2006. Annex 5: Good distribution practices for 
pharmaceutical products.  
 
b. Product stability pro ﬁles 
 
Transport TTSPPs in such a manner that transport temperatures meet local regulatory requirements 
at the sending and receiving sites and/or so that temperature excursions above or below the 
manufacturer’s labelled storage temperature range do not adversely affect product quality. Product 
stability data must demonstrate the acceptable temperature excursion time during transport.  
 
Reason: Protection of TTSPPs against degradation.  
 
c. Transport route proﬁling and qualiﬁcation  
Proﬁle and qualify transport  routes:  
 
i. Select the most suitable methods for protecting TTSPPs against anticipated ambient 
temperature and humidity conditions throughout the year.  
ii. Use suitable methods, including published standards, weather data, laboratory tests and ﬁeld 
tests to select suitable transport equipment and shipping containers. Reason: To ensure that 
TTSPPs can be safely transported within the transport temperature proﬁle deﬁned for each 
product and that compliance can be demonstrated to the regulatory authorities and o ther 
interested parties.  
 
19. TEMPERATURE -CONTROLLED TRANSPORT  
 
a. Air and sea transport  
 
Ensure that any carrier contracted to transport TTSPPs by air or by sea operates under the terms of a 
formal service level agreement (SLA) drawn up between the parties. The carrier is to be made 
responsible for maintaining load temperatures within the transport temperature proﬁle deﬁned for 
each product.  
 
Reason: To ensure that the carrier is made responsible for maintaining load temperatures within 
the transport temperature proﬁle deﬁned for each product and that compliance can be 
demonstrated to the contracting organization, the regulatory authorities and other interested 
parties.  
 
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 b. Temperature -controlled road vehicles operated by common carriers  
 
Temperature control in vehicles operated by a common carrier must be qualiﬁed and the details and 
responsibilities for this process should be set out in a formal SLA drawn up between the parties.  
 
Reason: To ensure that the carrier is made responsible for maintaining load temper atures within 
the transport temperature proﬁle deﬁned for each product and that compliance can be 
demonstrated to the contracting organization, the regulatory authorities and other interested 
parties.  
 
c. Temperature -controlled road vehicles generally  
 
Ensure  that temperature -controlled road vehicles used for the transport of TTSPPs are:  
 
i. capable of maintaining the temperature range deﬁned by the system set points over the full 
annual ambient temperature range experienced over known distribution routes and when the 
vehicle is in motion, or parked with the main engine stopped;  
ii. equipped with a low temperature protection circuit in cold climates where there is a risk of 
breaching the low temperature set point for TTSPPs that are damaged by exposure to low 
tempe ratures;  
iii. equipped with calibrated temperature monitoring devices with sensors located at points 
representing temperature extremes;  
iv. equipped with alarms to alert the driver in the event of temperature excursions and/or 
refrigeration unit failure;  
v. ﬁtted with  doors with security seals and/or security locks that protect against unauthorized 
access during transit;  
vi. qualiﬁed as deﬁned in clause 6.6; and  
vii. regularly calibrated and maintained and records kept to demonstrate compliance.  
 
Reason: To ensure that TTSPPs c an be safely transported within the transport temperature proﬁle 
deﬁned for each product and that compliance can be demonstrated to the regulatory authorities 
and other interested parties.  
 
d. Transport of controlled TTSPPs and TTSPPs with high illicit value  
 
Ensure that controlled TTSPPs and TTSPPs with high illicit value are transported in the following 
manner:  
 
i. Transport practices comply with all relevant local legislation and regulations.  
ii. Vehicles are equipped with lockable doors and an intruder alarm.  
iii. Vehicles use unique seal lock indicating devices such as cable seal locks with unique identiﬁers 
that are tamper -resistant to protect against unauthorized access during transit.14  
iv. Security -cleared delivery drivers are employed.  
v. All deliveries are documente d and tracked.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 vi. Signed dispatch and arrival records are kept.  
vii. Shipments are ﬁtted with security equipment appropriate to the product being transported and 
the assessed security risk, such as global positioning system (GPS) devices located in the 
vehicle and /or hidden in the product.  
viii. Drivers are informed about the perishability of the product and the maximum acceptable 
transport time.  
 
Reason: To prevent theft and misappropriation of this category of TTSPP and to ensure the 
security and safety of the driver.  
 
20. TEMPERATURE AND HUMIDITY CONTROL AND MONITORING DURING 
TRANSIT  
 
a. Temperature control in temperature -controlled road vehicles  
 
Provide thermostatic temperature control systems for all temperature - controlled vehicles used to 
transport TTSPPs. Comply with the following minimum requirements:  
i. system able continuously to maintain air temperatures within the set point limits throughout 
the validated storage volume deﬁned in clause 6.6;  
ii. control sensors accurate to ± 0.5 °C;  
iii. control sensors calibrated as describe d in clause 6.7.1; Refer to ISO/PAS 17712: Freight 
containers — Mechanical seals.  
iv. control sensors located to control worst -case temperatures in order to maximize available safe 
storage volume;  
v. control sensors positioned in the return air stream; and  
vi. control sensors independent of the temperature monitoring system.  
 
b. Temperature monitoring in temperature -controlled road vehicles  
 
Provide air temperature monitoring systems and devices for vehicles used to transport TTSPPs. 
Comply with the following minimum requirements:  
 
i. monitoring sensors accurate to ± 0.5 °C;  
ii. monitoring sensors calibrated as described in clause 6.7.2;  
iii. monitoring sensors located to monitor worst -case temperatures within the qualiﬁed storage 
zone deﬁned in clause 6.6;  
iv. monitoring sensors positioned so as to monitor worst -case positions;  
v. provide a temperature record with a minimum recording frequency of six times per hour for 
each sensor position;15 and  
vi. provide documentation which can be stored and accessed.  
vii. Establish transit temper ature speciﬁcations and document transit temperatures for every 
internal and external shipment.  
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 c. Humidity monitoring in temperature -controlled road vehicles  
 
Preferably provide humidity monitoring systems and devices for temperature - controlled vehicles 
which are used to transport TTSPPs that require a humidity -controlled environment. Systems and 
devices should comply with the following minimum requirements:  
 
i. sensors accurate to ± 5% RH;  
ii. sensors calibrated as described in clause 6.7.3;  
iii. sensors located to monitor worst -case humidity levels within the qualiﬁed storage zone deﬁned 
in clause 6.6;  
iv. sensors positioned so as to be minimally affected by transient events such as door opening;  
v. provide a humidity record with a minimum recording frequency of six times per hour for each 
sensor position; and  
vi. provide documentation which can be stored and accessed.  
vii. Establish transit humidity speciﬁcations and document transit humidity conditions for internal 
and external shipments where required.  
 
15 Recording frequency sho uld take account of the storage capacity of the data logger and the 
expected transport period.  
d. Temperature monitoring in passive and active shipping containers  
 
Use chemical or electronic freeze indicators, electronic loggers (with or without alarms) and/or other 
suitable indicators to monitor temperature and/or humidity exposure during internal distribution. 
Preferably use these devices for external distribution. Monitor and document indicator status upon 
arrival.  
 
Reason: To ensure that TTSPPs can be  safely transported within the transport temperature proﬁle 
deﬁned for each product and that compliance can be demonstrated to the regulatory authorities 
and other interested parties.  
 
e. Qualiﬁcation of temperature -controlled road vehicles  
 
Where temperature -controlled vehicles are directly owned and/or operated, qualify each vehicle 
before it becomes operational, wherever possible. The qualiﬁcation procedure should:  
i. demonstrate that the air temperature distribution is maintained within the limits speciﬁed 
throughout the temperature -controlled compartment for both air and product temperatures for 
commonly used load layouts and at the ambient temperature extremes anticipated during 
normal operation over known routes;  
ii. demonstrate the humidity distribu tion throughout the temperature - controlled compartment for 
commonly used load layouts, where products are being transported that require a humidity -
controlled environment;  
iii. deﬁne zones within the vehicle’s payload area which should not be packed with TTSPP s (for 
example areas in close proximity to cooling coils or cold air streams);  
iv. demonstrate the time taken for temperatures to exceed the designated maximum in the event Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 that the temperature -controlling unit fails; and  
v. document the qualiﬁcation exercise.  
 
An alternative approach is to perform an initial full qualiﬁcation on each trailer/refrigeration unit 
type combined with an installation qualiﬁcation (IQ) for each example when a new vehicle becomes 
operational.  
Carry out additional qualiﬁcation exercises whenever signiﬁcant modiﬁcations are made to the 
vehicle. Consider the need for requaliﬁcation whenever temperature and/or humidity monitoring 
shows unexplained variability that is greater than normal.  
 
Reason: To ensure that TTSPPs can be safely transport ed within the transport temperature proﬁle 
deﬁned for each product and that compliance can be demonstrated to the regulatory authorities 
and other interested parties. Calibration and veriﬁcation of transport monitoring devices  
 
21. CALIBRATION OF TRANSPORT TEM PERATURE CONTROL DEVICES  
 
Calibrate devices against a certiﬁed, traceable reference standard at least once a year, unless 
otherwise justiﬁed.  
a. Calibration of transport temperature monitoring devices  
 
Calibrate devices against a certiﬁed, traceable reference  standard at least once a year, unless 
otherwise justiﬁed.  
 
b. Calibration of transport humidity monitoring devices  
 
Calibrate devices against a certiﬁed, traceable, reference standard at least once a year, unless 
otherwise justiﬁed.  
 
c. Veriﬁcation of transport  alarm equipment  
 
Check functionality of temperature and humidity alarms at the designated set points. Check 
functionality of security alarm systems. Carry out these checks at least once a year, unless otherwise 
justiﬁed.  
Maintain records to demonstrate compliance.  
 
Reason: To ensure that TTSPPs can be safely transported within the transport temperature 
proﬁle deﬁned for each product and that compliance can be demonstrated to the regulatory 
authorities and other interested parties.  
 
22. SHIPPING CONTAINERS  
 
a. Container selection generally  
 
Select shipping containers that:  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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i. comply with applicable national and international standards relevant to the product type and 
the chosen transport route and mode(s);  
ii. protect personnel and the general public from hazards arising from spillage, leakage or 
excessive internal pressure;  
iii. protect the product being transported against mechanical damage and the anticipated ambient 
temperature range that will be encountered in transit; and  
iv. can be closed in a manner that allows the recipient of the consignment to establish that the 
product has not been tampered with during transport.  
 
Reason: Quality assurance and safety.  
 
b. Uninsulated containers  
 
i. Ensure that uninsulated containers are correctly used, in a manner which protects their contents: 
transport uninsulated containers in a qualiﬁed temperature -controlled environment such as an 
actively or passively temperature -controlled vehicle;  
ii. ensure that the transport system is able to maintain the temperature of the TTSPP within the 
produc t’s stability proﬁle as stated by the product manufacturer and/or to maintain the TTSPP 
within the transit temperature speciﬁcation requirements speciﬁed by the regulatory authorities 
at both the sending and receiving locations.  
 
Reason: Quality assurance and safety.  
 
c. Qualiﬁcation of insulated passive containers  
 
Qualify insulated passive containers, including any and all necessary ancillary packaging such as 
temperature stabilizing medium, dry ice, ice or gel packs, cool water packs or warm packs, phase 
change materials, partitions, bubble wrap and dunnage:  
 
i. ensure that the qualiﬁed packaging system is capable of maintaining the TTSPP within the 
temperature range needed to meet the product stability proﬁle as stated by the product 
manufacturer. Container qualiﬁcation should include full details of the packaging assembly, 
the thermal conditioning regime and the minimum and maximum shipping volume, weight and 
thermal mass that can safely be accommodated in the container. Qualiﬁcation should also 
include the correct placement of temperature monitors where these are used;  
ii. take account of the transport route and of the anticipated ambient temperature proﬁle over the 
duration of transport, measured from the point of departure to the point of arrival in the 
recipi ent’s temperature -controlled store.  
 
Reason: To ensure that TTSPPs can safely be transported within the transport temperature proﬁle 
deﬁned for each product and that compliance can be demonstrated to the regulatory authorities 
and other interested parties.  
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 d. Qualiﬁcation of active containers  
 
Qualify active containers:  
 
i. ensure that the container is capable of maintaining the TTSPP within the temperature range 
needed to meet the product stability proﬁle as stated by the product manufacturer;  
ii. take account of the transport route and of the anticipated ambient temperature proﬁle over the 
duration of transport, measured from the point of departure to the point of arrival in the 
recipient’s temperature - controlled store.  
 
Reason: To ensure that TTSPPs can be safel y transported within the transport temperature proﬁle 
deﬁned for each product and that compliance can be demonstrated to the regulatory authorities 
and other interested parties. Shipping container packing  
 
Pack TTSPP shipping containers to:  
 
i. the exact speciﬁed conﬁguration to ensure that the correct TTSPP temperature range is 
maintained;  
ii. minimize the risk of theft and fraud and assure the recipient that the goods have not been 
tampered with while in transit, for example by using locked containers or shr ink-wrapped 
pallets;  
iii. minimize the risk of mechanical damage during transport;  
iv. protect freeze -sensitive products against temperatures below 0 °C when frozen packs are used;  
v. protect products against light, moisture and contamination or attack by microorganis ms and 
pests;  
vi. protect products against adverse effects when dry ice is used as a coolant;  
vii. clearly label containers to identify the correct transport temperature range and to show correct 
orientation for handling; and  
viii. ensure that packages containing dangero us goods (including dry ice) are labelled in compliance 
with relevant transport regulations and requirements.  
 
Reason: To ensure that shipping containers are systematically used in the manner deﬁned during 
the container qualiﬁcation process and that this can be demonstrated to the regulatory authorities 
and other interested parties.  
 
e. Product handling during packing and transport  
 
Handle TTSPPs correctly during packing and transport:  
 
i. pack TTSPPs in an area set aside for the assembly and packaging of these products as speciﬁed 
in clause 3.3.1;  
ii. take precautions against spillage or breakage, contamination and cross - contamination;  
iii. deliver TTSPPs to outside recipients by the most suitable mode(s) of transport available in 
order to minimize delivery time; and  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 iv. ensure that patients receiving TTSPP deliveries are given clear advice on correct storage of the 
product before use.  
 
Reason: To maintain TTSPP quality during transport.  
 
f. Cleaning road vehicles and transport containers  
 
Implement a cleaning and decontamination programme for all road vehicles and reusable shipping 
containers used to transport TTSPPs:  
 
i. ensure that all internal surfaces of load compartments are regularly cleaned;do not allow the 
accumulation of dust, dirt and waste, including packaging waste in load compartments, or in 
reusable shipping containers;  
ii. take precautions against spillage or breakage, and cross -contamination;  
iii. do not allow accumulation of frost and ice in refrigerated vehicles, particularly ice 
contaminated by spillage s; and  
iv. collect waste in designated closed containers and arrange for safe disposal at frequent intervals.  
v. Maintain cleaning records for vehicles and reusable shipping containers to demonstrate 
compliance.  
 
Reason: Protection against damage and contaminatio n of TTSPPs and hazards to workers arising 
from spillage or breakage.  
 
23. TRANSPORT OF RETURNED AND RECALLED TTSPPS  
 
a. Transport of returned TTSPPs  
 
Ensure that that returned TTSPPs are transported under the same conditions as those used for the 
initial delivery:  
 
i. the sender and recipient must work together so that that the product is maintained within the 
temperature range needed to meet the manufacturer’s stated product stability proﬁle;  
ii. take account of the anticipated ambient temperature proﬁle over the duration of transport, 
measured from the point of departure to the point of return; and  
iii. quarantine returned TTSPPs in temperature -controlled storage pending a decision by the 
quality control department or qualiﬁed person to dispose of the product or to  return it to stock.  
 
Reason: To ensure that returned and recalled TTSPPs are maintained within the correct transport 
temperature proﬁle so that they can safely be re -stocked if a decision to do so is made.  
 
b. Transport of recalled TTSPPs  
 
Ensure that recalled TTSPPs are:  
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 i. marked for disposal as either “recalled” or “withdrawn”;  
ii. transported back from the recipient and quarantined under secure conditions pending a ﬁnal 
decision on disposal as described in clause 8.6.3.  
24. LABELLING  
 
Normative references: IATA Perishable Cargo Regulations Chapter 179th Edition, July 
2009. Clauses 17.10.5 and 17.10.6.  
 
a. Labelling generally  
 
Label internal shipping and external distribution containers containing TTSPPs as follows:  
 
i. identify the product in accordance with all national and international labelling requirements 
relevant to the container content, transport route and mode(s);  
ii. identify hazardous products in accordance with relevant national and international labelling 
conventions; and  
iii. indicate the appropriate tempera ture and humidity ranges within which the product is to be 
transported and/or stored.  
 
b. Labelling air -freighted shipments  
 
In cases where TTSPPs are to be air -freighted, the package(s) should be labelled using the standard 
International Air Transport Association (IATA) time and temperature -sensitive symbol, in 
accordance with the conditions outlined in Chapter 17 of the IATA Perishable Cargo Regulations. 
Apply the label to the outer surface of individual shipping packages, overpacks or bulk containers.  
 
Reason: To ensure that products are correctly and safely handled at all points in the supply 
chain.  
 
25. STOCK MANAGEMENT  
 
STOCK CONTROL SYSTEMS  
 
a. General stock control systems and procedures  
 
TTSPP stock control systems and procedures meet the following minimum requirements:  
 
i. allow access only to authorized persons;  
ii. record all receipts and dispatches;  
iii. record batch numbers and expiry dates;  
iv. record short -dated and expired products;  
v. record product status (i.e. released, quarantined, hold, reject);  
vi. record all  product returns, recalls, withdrawals, damage and disposals;  
vii. manage the issue of products in EEFO order; and  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 viii. take regular physical inventories and reconcile stock records with the actual physical count.  
 
Investigate and report on stock discrepancies in accordance with agreed procedures. Preferably 
physical counts should be made at least twice a year.  
Reason: To ensure that accurate and complete stock records are kept at all times.  
 
b. Stock control procedures for controlled and hazardous TTSPPs  
 
In additio n to the requirements set out in clause 8.1.1, implement the following procedures:  
 
i. Institute a customer veriﬁcation process to ensure that all recipients of these products are 
authorized to receive them.  
ii. Maintain stock records which speciﬁcally identify products in these categories.  
iii. Carry out regular audits and make audit reports available to the responsible authorities.  
iv. Comply with all record -keeping procedures speciﬁed in local legislation and regulations. 
Retain product transaction and delivery records  for at least the minimum time period required 
by local regulations.  
 
Reason: To ensure that accurate and complete stock records are kept at all times and to satisfy the 
requirements of the regulatory authorities.  
 
INCOMING GOODS  
 
c. Product arrival checks  
 
Check and record the following for all incoming TTSPPs:  
 
i. product name, item code (identiﬁer), strength, and batch/lot number;  
ii. quantity received against order;  
iii. name and address of the supplying site;  
iv. examine containers for tampering, damage or contamination;  
v. examine expiry dates — accept short -dated products only if prior agreement has been reached 
with the supplier; do not accept products that have expired or which are so close to their expiry 
date that this date is likely to occur before use b y the consumer;  
vi. delays encountered during transport;  
vii. status of any attached temperature recording device(s) and/or time/ temperature indicators; and  
viii. verify that required storage and transport conditions have been maintained.  
 
d. Actions following arrival chec ks 
 
i. Enter product details, including product name/number, strength, batch numbers, quantities 
received, expiry dates and acceptance status into the stock recording system.  
ii. Store checked goods under the correct temperature and security regime immediately upon 
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 iii. Quarantine defective or potentially defective products, products with incomplete or missing 
paperwork, products that experienced unacceptable temperature excursions during transport, 
or products suspected to be counterfeit. Do not release unt il checks have been completed 
satisfactorily.  
iv. All unacceptable temperature excursions should be evaluated to determine their effect on the 
product.  
v. Report any defects to the supplying store or holder of the marketing authorization.  
vi. Do not transfer to salea ble stock until all relevant disposition procedures have been completed.  
 
Reason: To ensure that incoming TTSPPs are in acceptable condition, accurately recorded and 
correctly stored and that defective and/or incorrect shipments are followed up with the supplier.  
 
OUTGOING GOODS (EXTERNAL DELIVERIES)  
 
e. Management of outgoing goods  
 
Implement outgoing goods procedures to ensure that:  
 
i. Transport vehicle conformity, including conformity with SLA or quality assurance (QA) 
agreements, is checked before loading goods.  
ii. Expired products are never issued.  
iii. Products with short expiry dates are not issued unless the recipient accepts that they can be 
consumed before the expiry date is reached.  
iv. Products are distributed in strict EEFO order unless a product -based time -temperature exposure 
indicator, such as a vaccine vial monitor, demonstrates that a batch should be distributed ahead 
of its EEFO order.  
v. Details of any temperature monitoring devices packed with the external distributions are 
recorded.  
vi. Details of outgoing pr oducts, including product name/number, strength, batch numbers, expiry 
dates and quantities distributed, are entered into the stock recording system.  
 
f. Actions following dispatch  
 
Monitor TTSPPs following dispatch in order to:  
 
i. trace products to their intended destination;  
ii. record and retain records to provide assurance of goods arrival status. A suitable delivery report 
from the carrier is an acceptable alternative; and  
iii. take appropriate action in the event of returns, recalls or complaints.  
 
Reason: To ensure that outgoing TTSPPs are in acceptable condition, that short -dated stock does 
not accumulate in the store and that evidence is kept to demonstrate that correct quantities are 
distributed and received in good condition.  
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 g. Product complaint procedures  
 
Manage product complaints as follows:  
 
i. If a product defect is discovered or suspected in a batch of TTSPPs, cooperate with the 
regulatory authority to determine whether other batches are affected and recall products if 
required to do so by the regulatory authority.  
ii. Where complaints or defects relate to a product or its packaging, immediately notify the holder 
of the marketing authorization for the product.  
iii. Where complaints or defects arise as a result of errors or omissions within the organization, 
immedia tely evaluate the causes and take remedial measures to prevent a recurrence.  
iv. Record all complaints and the remedial actions taken. Monitor and analyse trends in the 
complaint records.  
 
Reason: Protection of the public and of the reputation of the supplying  organization.  
 
SUSPECT PRODUCT PROCEDURES  
 
h. Suspect products  
 
Implement systems for identifying and managing suspect products found in the supply chain as 
follows:  
 
i. Physically segregate any suspect TTSPPs found in the supply chain and store securely until 
legal investigations are complete.  
ii. Label them clearly as “Not for use” or other similar phrase;  
iii. Immediately notify the regulatory authority or authorities and any other relevant authorities, as 
well as the holder of the marketing authorization of the produ ct. 
iv. Cooperate with regulatory authorities to assist with investigating the source of suspect products 
and implement appropriate remedial action(s).  
v. Document the decision -making process for disposal or return of condemned or defective 
TTSPPs and make these records available to the relevant authorities.  
 
Reason: Protection of the public, protection of legitimate suppliers and manufacturers and 
conformity with regulatory requirements.  
 
26. PRODUCT RETURN, RECALL, WITHDRAWAL AND DISPOSAL PROCEDURES  
a. Return procedures  
 
Manage product returns as follows:  
 
i. Quarantine returned TTSPPs in a suitable temperature -controlled area and under the security 
conditions applicable to the product type.  
ii. Do not return to saleable stock unless storage and transport temperature conditions after Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 dispatch from the distribution site have been fully veriﬁed and documented, including the return 
leg to the distribution site. Where appropriate, obtain written advic e from the holder of the 
marketing authorization regarding handling and/or disposal of the returned TTSPP.  
iii. If returned stock is re -issued, distribute in EEFO order or in accordance with the exposure 
status of any product -mounted time -temperature indicator device.  
iv. Quarantine returned TTSPPs that have been exposed to unacceptable storage and/or transport 
temperatures and mark for disposal.  
v. Maintain records of all returned TTSPPs.  
Reason: Protection of the public . 
b. Recall procedures  
 
Manage product recalls as follows:  
 
i. Conduct urgent and non -urgent TTSPP recalls in accordance with an agreed emergency plan.  
ii. Notify the local regulatory authority or authorities.  
iii. Notify overseas regulatory counterparts where the product has been exported.  
iv. Notify all affected customers as applicable.  
v. Quarantine any remaining inventory of recalled TTSPPs and mark for further investigation 
before disposal.  
vi. Maintain records of all TTSPP recalls, including reconciliation of quantity sold, quantity 
returned, quantity remaining or quantity consumed.  
 
Reason: Protection of the public and conformity with regulatory requirements.  
 
c. Disposal procedures  
 
Manage product awaiting board of survey or disposal as follows:  
 
i. Ensure that rejected and/or recalled or withdrawn TTSPPs cannot be used, released or cause 
contamination to other products. Store separately from other products, in accordance with local 
regulations, to await destruction or return to the supplier.  
ii. Safely dispose of rejected and/or recalled/withdrawn products in accordance  with local 
regulations, including where relevant, regulations covering the disposal of hazardous and 
controlled drugs.  
iii. Maintain disposal records.  
 
Reason: Protection of the public and the environment.  
d. Traceability or stock tracking  
 
Ensure that stock and distribution records enable traceability, or stock tracking, of TTSPPs from the 
point of supply to the end -user or patient. Traceability should include records of the temperature 
exposure of the product during internal shipping and storage. These records s hould include:  
 
i. for incoming goods: status of shipping indicators used (if any), status of product -based time -Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 temperature indicators (if any) and physical condition of goods and time of receipt;  
ii. for outgoing goods: type of shipping indicators used (if any), status of product -based time -
temperature indicators (if any) and physical condition of goods and time of dispatch.  
iii. Monitor, record, and investigate discrepancies.  
 
Reason: To demonstrate that TTSPPs have been correctly distributed and to facilitate p roduct 
recalls and detect theft and fraud.  
27. GENERAL PROCEDURES AND RECORD -KEEPING  
 
a. Emergencies and contingency planning  
 
Make contingency arrangements for the safe storage of TTSPPs in the event of emergencies, 
including, but not conﬁned to:  
 
i. extended power  supply outages;  
ii. equipment failure; and  
iii. vehicle breakdown during transport of TTSPPs.  
 
Prepare action plans to deal with products subjected to temperature excursions and ensure that the 
responsible staff know, and have rehearsed, the appropriate actions to  be taken in the event of the 
identiﬁed emergency scenarios.  
 
Reason: Loss prevention.  
 
28. GENERAL RECORD -KEEPING  
 
a. Record -keeping  
 
Maintain comprehensive records and ensure that they are laid out in an orderly fashion and are easy 
to check.  
Paper records must  be: 
 
i. stored and maintained so that they are accessible and easily retrievable;  
ii. labelled, dated and ﬁled for easy identiﬁcation;  
iii. protected against deterioration and loss due to ﬁre, ﬂood or other hazards;  
iv. kept secure and protected against unauthorized access; and  
v. signed and dated by authorized persons and not changed without due authorization.  
 
Computer records must be:  
 
i. logically ﬁled for easy identiﬁcation and retrieval;  
ii. kept secure and protected against unauthorized access;  
iii. where feasible, manually signed, dated and scanned or when electronically archived dated, 
encrypted and with check -sum;16  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 iv. regularly backed -up and archived on media that are independent of the record -keeping 
computer system(s). Back -up media may be a separate secure server, a separ ate hard disc, a 
ﬂash drive or other digital media appropriate to the scale of the operation.  
 
b. Content of records  
Ensure that the following traceability data is recorded for each TTSPP batch number, as applicable:  
i. status of product on arrival;  
ii. temperature and humidity records including records of excursions outside labelled storage 
and/or transit temperature speciﬁcation conditions;  
iii. general TTSPP stock transactions, including purchase and sale records;  
iv. controlled drug audits;  
v. audits for products with high i llicit value;  
vi. audits for hazardous products;  
vii. stock tracking;  
viii. return, recall, withdrawal and disposal reports, where relevant;  
ix. product complaint reports, where relevant; and  
x. counterfeit product reports, where relevant.  
 
Maintain all records in accordance with local legislation and regulations.  
 
c. Record review and retention  
 
i. Ensure that records are reviewed and approved on a regular basis by a designated member of 
the quality management team.  
ii. Ensure that records are accessible for review by end -users, the regulatory authority and other 
interested parties.  
iii. Retain records for the minimum period required under local legislation, but for not less than 
three years.  
 
Reason: Internal quality control , transparency and external inspection by the regulatory 
authorities and other interested parties.  
 
Electronic records from data loggers are usually encrypted and protected by check -sums. This ensures 
compliance with FDA Title 21 CFR Part 11: Electronic Re cords; Electronic Signatures; Final Rule 
(1997). Temperature and humidity records  
 
d. Temperature records  
 
Monitor and record storage temperatures in all temperature -controlled rooms, cold rooms, freezer 
rooms, refrigerators and freezers, as follows:  
 
i. Check and record temperatures at least twice daily — in the morning and evening — and 
preferably continuously.  
ii. Review temperature records monthly and take action to rectify systematic excursions.  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 iii. Systematically ﬁle temperature records for each storage environmen t or piece of equipment to 
ensure traceability. Keep records for at least one year after the end of the shelf -life of the stored 
material or product, or as long as required by national legislation.  
 
e. Humidity records  
 
When storing products which are adversely affected by high relative humidity (see clause 4.5.3), 
monitor and record humidity levels in all temperature -controlled rooms as follows:  
 
i. Record humidity at least twice every 24 hours or preferably continuously.  
ii. Check humidity records daily.  
iii. Review humidity records monthly and take action to rectify systematic excursions.  
iv. Systematically ﬁle humidity records for each temperature -controlled room to ensure 
traceability.  
 
Keep records for at least one year after the end of the shelf -life of the st ored material or product, or 
as long as required by national legislation.  
 
Reason: Internal quality assurance and availability of records for review by the regulatory 
authorities and other interested parties.  
 
29. ENVIRONMENTAL MANAGEMENT  
 
a. Normative references  
 
i. ISO 14001: 2004. Environmental management systems — Requirements with guidance for use.  
ii. The Montreal Protocol on Substances that Deplete the Ozone Layer.  
iii. UNEP, 2000.  
 
b. Environmental management of refrigeration equipment  
 
Ensure that all new refrigeration equipment for temperature -controlled storage and transport is 
speciﬁed to: use refrigerants that comply with the Montreal Protocol;  
 
i. minimize or eliminate the use of refrigerants with high global warming potential (GWP); and  
ii. minimize CO2 emissions during o peration.  
 
Select equipment to minimize whole -life environmental impact and employ best practice to eliminate 
leakage of refrigerant into the environment during installation, maintenance and decommissioning of 
refrigeration equipment.  
 
Reason: Compliance w ith international protocols and accords on climate change and 
environmental protection.  
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30. QUALITY MANAGEMENT  
 
a. Normative references  
 
i. ICH, 2005: ICH Harmonized Tripartite Guideline: Quality risk management Q9  
ii. ISO 9000:2005. Quality management systems — Fundamentals and vocabulary  
iii. ISO 9001:2008. Quality management systems — Requirements  
iv. ISO 9004:2000. Quality management systems — Guidelines for performance improvements  
v. ISO 10005:2005. Quality management systems — Guidelines for quality plans  
vi. ISO 19011:200 2. Guidelines for quality and/or environmental management systems auditing  
 
b. Organizational structure  
 
Establish, document and maintain an organizational structure for the TTSPP storage and shipping 
and distribution operations which clearly identiﬁes all key management responsibilities, and the 
personnel who are accountable.  
 
Reason: Quality management.  
 
c. Quality system  
 
Establish, document and maintain a quality system for the management of TTSPPs including, the 
following, as applicable:  
 
i. standard quality system(s) and associated auditing procedures;  
ii. written procedures and speciﬁcations;  
iii. record storage, record retention and record destruction programme;  
iv. risk management;  
v. calibration programme;  
vi. stability programme;  
vii. qualiﬁcation and validation programme;  
viii. devia tion and root cause investigation programme;  
ix. corrective and preventive action (CAPA) procedures;  
x. training programme;  
xi. periodic temperature -controlled process assessment;  
xii. change control programme;  
xiii. maintenance programme;  
xiv. management controls;  
xv. product return and recall/withdrawal policies, including emergency recalls;  
xvi. product complaint policies;  
xvii. material destruction programme;  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 xviii. warehouse and storage programme;  
xix. shipping and distribution programme;  
xx. notiﬁcation systems for regulatory agencies; boards of health and  ministries of health; and  
xxi. self-inspection programme and continuous quality improvement.  
 
Carry out annual reviews of the quality management system to ensure that it remains appropriate, 
relevant, and effective.  
 
Reason: Quality assurance.  
 
d. Self-inspections  
 
Conduct regular self -inspections to ensure continuing compliance with quality management 
standards GSP and GDP; record results, follow -up with the corrective actions needed to rectify areas 
of non -compliance and document the changes made.  
 
e. Contractors subject to service level agreements  
 
Ensure that every contractor with whom there is an SLA provides periodic evidence of compliance 
with the GSP and/or GDP standards incorporated into the SLA.  
 
Reason: To demonstrate compliance with applicable quality management standards.  
 
31. MANAGEMENT OF DOCUMENTS AND STANDARD OPERATING 
PROCEDURES  
 
a. Standard operating procedures  
 
Develop and maintain SOPs covering correct storage, internal shipping and external distribution of 
TTSPPs, including, but not limited to, the following topics:  
security, including management of controlled and hazardous TTSPPs;  
 
i. safe handling of TTSPPs;  
ii. temperature monitoring;  
iii. calibration of temperature and humidity monitoring devices and alarm systems;  
iv. qualiﬁcation and validation procedures, including temperature mapping;  
v. maintenance of controlled -temperature equipment;  
vi. facility cleaning and pest control;  
vii. facility maintenance;  
viii. product arrival (receiving) procedures and records;  
ix. stock storage and warehousing procedures (p ut away, replenishment, order fulﬁlment, 
packing);  
x. stock control procedures and records;  
xi. distribution procedures and records;  Guidelines on Good Manufacturing Practices on Medical Products _ Annexes  
 
 
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 xii. management of temperature excursions;  
xiii. product return and recall/withdrawal procedures and records;  
xiv. product complaint procedures an d records;  
xv. safe disposal of damaged, expired and quarantined products and records which are no longer 
required;  
xvi. temperature -controlled packaging and route qualiﬁcation;  
xvii. temperature -controlled vehicle operation, including management of security locks and seals;  
xviii. emergency response procedures; and  
xix. environmental management.  
 
Ensure that all documents are clear and unambiguous and that document change control procedures 
are in place as speciﬁed in clause 11.5.  
 
Reason: Quality management and staff training.  
 
b. Document control  
 
Ensure that all quality manuals, SOPs and similar documents are:  
 
i. authorized by an appropriate person;  
ii. recorded in a document register;  
iii. regularly reviewed and kept up to date, with all changes recorded and authorized;  
iv. version controlled;  
v. issued to all relevant personnel; and  
vi. withdrawn when superseded.  
 
Withdraw superseded documents and retain record copies for document history ﬁles and for the 
minimum period(s) required by the regulatory authorities and for duty -of-care purposes.  
 
Reason: Good quality management practice.  
 
32. PERSONNEL/TRAINING  
 
a. General training  
 
Provide regular and systematic training for all relevant personnel responsible for storage, loading and 
unloading areas used for non -hazardous TTSPPs, covering the following:  
 
i. applicable pharmaceutical legislation and regulations;  
ii. SOPs and safety issues; and  
iii. response to emergencies.  
 
Ensure that each employee understands his or her speciﬁc responsibilities. Provide similar training 
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 to demonstrate compliance and regularly evaluate the effectiveness of training programmes.  
 
Reason: To ensure that all relevant personnel are competent to carry out their duties.  
b. Specialist training  
 
In addition to the training described in clause 12.1.1, provide regular and systematic additional 
training for relevant personnel responsible for storage, loading and unloading of controlled or 
hazardous TTSPPs. Training should cover the following:  
 
i. applicable legislation and regulations;  
ii. security and safety risks; and  
iii. response to emergencies.  
 
Ensure that each employee understands his or her speciﬁc responsibilities. Maintain training records 
to demonstrate compliance and perform effectiveness checks  on training. Provide similar training for 
drivers who are responsible for transporting these substances  to ensure that all relevant personnel are 
competent to handle controlled or hazardous . 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ENDORSEMENT  OF THE  GUIDELINES