#286

Good Manufacturing Practice for Active 

Pharmaceutical Ingredients Used in 

Veterinary Medicinal Products

VICH GL60

Guidance for Industry

Draft Guidance 

This guidance document is being distributed for comment purposes only.

Submit comments on this draft guidance by the dated provided in the Federal Register notice 

announcing the availability of the draft guidance. Submit electronic comments to

https://www.regulations.gov. Submit written comments to the Dockets Management Staff 

(HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 

20852. All comments should be identified with docket number FDA-2023-D-4761. 

For further information regarding this document, contact Mai Huynh, Center for Veterinary 

Medicine (HFV-140), Food and Drug Administration, 7500 Standish Place, Rockville MD 

20855, 240-402-0669, email: Mai.Huynh@fda.hhs.gov. 

Additional copies of this draft guidance document may be requested from the Policy and 

Regulations Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 

7500 Standish Place, Rockville MD 20855, and may be viewed on the Internet at 

https://www.fda.gov/animal-veterinary, https://www.fda.gov/regulatory-information/search-fdaguidance-documents, or http://www.regulations.gov. 

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Veterinary Medicine (CVM)

January 2024
VICH GL60 (QUALITY: GMP FOR API) 

September 2023

 For consultation at Step 4

GOOD MANUFACTURING PRACTICE FOR 

ACTIVE PHARMACEUTICAL INGREDIENTS 

USED IN VETERINARY MEDICINAL 

PRODUCTS

Recommended for Consultation at Step 4 of the VICH Process

In September 2023

by the VICH Steering Committee

This Guideline has been developed by the appropriate VICH Expert Working Group and will be subject to 

consultation by the parties, in accordance with the VICH Process. At Step 7 of the Process the final draft will 

be recommended for adoption to the regulatory bodies of the European Union, Japan and USA.
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Table of Contents

1. INTRODUCTION................................................................................................................ 1

1.1 Objective ...................................................................................................................... 1

1.2 Regulatory Applicability ............................................................................................ 2

1.3 Scope............................................................................................................................. 2

2. QUALITY MANAGEMENT .............................................................................................. 5

2.1 Principles ..................................................................................................................... 5

2.2 Responsibilities of the Quality Unit(s) ...................................................................... 5

2.3 Responsibility for Production Activities ................................................................... 6

2.4 Internal Audits (Self Inspection) ............................................................................... 7

2.5 Product Quality Review ............................................................................................. 7

3. PERSONNEL ....................................................................................................................... 7

3.1 Personnel Qualifications ............................................................................................. 7

3.2 Personnel Hygiene ....................................................................................................... 8

3.3 Consultants .................................................................................................................. 8

4. BUILDINGS AND FACILITIES ....................................................................................... 8

4.1 Design and Construction ............................................................................................ 8

4.2 Utilities ......................................................................................................................... 9

4.3 Water .......................................................................................................................... 10

4.4 Containment .............................................................................................................. 10

4.5 Lighting ...................................................................................................................... 11

4.6 Sewage and Refuse .................................................................................................... 11

4.7 Sanitation and Maintenance .................................................................................... 11

5. PROCESS EQUIPMENT ................................................................................................. 12

5.1 Design and Construction .......................................................................................... 12

5.2 Equipment Maintenance and Cleaning .................................................................. 12

5.3 Calibration ................................................................................................................. 13

5.4 Computerized Systems ............................................................................................. 14

6. DOCUMENTATION AND RECORDS .......................................................................... 14

6.1 Documentation System and Specifications ............................................................. 14

6.2 Equipment Cleaning and Use Record ..................................................................... 15
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6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging 

Materials .................................................................................................................... 16

6.4 Master Production Instructions (Master Production and Control Records) ...... 16

6.5 Batch Production Records (Batch Production and Control Records) ................. 17

6.6 Laboratory Control Records ................................................................................... 18

6.7 Batch Production Record Review ............................................................................ 19

7. MATERIALS MANAGEMENT ...................................................................................... 19

7.1 General Controls ....................................................................................................... 19

7.2 Receipt and Quarantine ........................................................................................... 19

7.3 Sampling and Testing of Incoming Production Materials .................................... 20

7.4 Storage ....................................................................................................................... 21

7.5 Re-evaluation ............................................................................................................. 21

8. PRODUCTION AND IN-PROCESS CONTROLS ........................................................ 21

8.1 Production Operations ............................................................................................. 21

8.2 Time Limits................................................................................................................ 22

8.3 In-process Sampling and Controls .......................................................................... 22

8.4 Blending Batches of Intermediates or APIs ............................................................ 23

8.5 Contamination Control ............................................................................................ 24

9. PACKAGING AND IDENTIFICATION LABELING OF APIs AND 

INTERMEDIATES ........................................................................................................... 24

9.1 General ....................................................................................................................... 24

9.2 Packaging Materials ................................................................................................. 25

9.3 Label Issuance and Control ..................................................................................... 25

9.4 Packaging and Labeling Operations ....................................................................... 25

10. STORAGE AND DISTRIBUTION .................................................................................. 26

10.1 Warehousing Procedures ......................................................................................... 26

10.2 Distribution Procedures ........................................................................................... 26

11. LABORATORY CONTROLS ......................................................................................... 27

11.1 General Controls ....................................................................................................... 27

11.2 Testing of Intermediates and APIs .......................................................................... 28

11.3 Validation of Analytical Procedures - see section 12. Validation. ........................ 29

11.4 Certificates of Analysis ............................................................................................. 29

11.5 Stability Monitoring of APIs .................................................................................... 29
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11.6 Expiry and Retest Dating ......................................................................................... 30

11.7 Reserve/Retention Samples ...................................................................................... 30

12. VALIDATION.................................................................................................................... 31

12.1 Validation Policy ....................................................................................................... 31

12.2 Validation Documentation ....................................................................................... 31

12.3 Qualification .............................................................................................................. 32

12.4 Approaches to Process Validation ........................................................................... 32

12.5 Process Validation Program .................................................................................... 33

12.6 Periodic Review of Validated Systems .................................................................... 33

12.7 Cleaning Validation .................................................................................................. 34

12.8 Validation of Analytical Methods ............................................................................ 35

13. CHANGE CONTROL ....................................................................................................... 35

14. REJECTION AND RE-USE OF MATERIALS ............................................................. 36

14.1 Rejection .................................................................................................................... 36

14.2 Reprocessing .............................................................................................................. 36

14.3 Reworking .................................................................................................................. 36

14.4 Recovery of Materials and Solvents ........................................................................ 37

14.5 Returns ....................................................................................................................... 37

15. COMPLAINTS AND RECALLS ..................................................................................... 37

16. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES) .................... 38

17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND 

RELABELERS ................................................................................................................... 39

17.1 Applicability .............................................................................................................. 39

17.2 Traceability of Distributed APIs and Intermediates ............................................. 39

17.3 Quality Management ................................................................................................ 40

17.4 Repackaging, Relabeling and Holding of APIs and Intermediates ...................... 40

17.5 Stability ...................................................................................................................... 40

17.6 Transfer of Information ........................................................................................... 40

17.7 Handling of Complaints and Recalls ....................................................................... 40

17.8 Handling of Returns ................................................................................................. 41

18. SPECIFIC GUIDANCE FOR APIS MANUFACTURED BY CELL 

CULTURE/FERMENTATION ........................................................................................ 41

18.1 General ....................................................................................................................... 41
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18.2 Cell Bank Maintenance and Record Keeping ........................................................ 43

18.3 Cell Culture/Fermentation ....................................................................................... 43

18.4 Harvesting, Isolation and Purification .................................................................... 44

18.5 Viral Removal/Inactivation steps ............................................................................ 44

19. APIs FOR USE IN CLINICAL TRIALS......................................................................... 45

19.1 General ....................................................................................................................... 45

19.2 Quality ........................................................................................................................ 45

19.3 Equipment and Facilities .......................................................................................... 46

19.4 Control of Raw Materials ......................................................................................... 46

19.5 Production ................................................................................................................. 46

19.6 Validation................................................................................................................... 46

19.7 Changes ...................................................................................................................... 46

19.8 Laboratory Controls ................................................................................................. 47

19.9 Documentation .......................................................................................................... 47

20. GLOSSARY........................................................................................................................ 47

21. REFERENCES ................................................................................................................... 51
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Good Manufacturing Practice for Active Pharmaceutical

Ingredients Used in Veterinary Medicinal Products

VICH GL60

Draft Guidance for Industry

This draft guidance, when finalized, will represent the current thinking of the Food and Drug 

Administration (FDA or Agency) on this topic. It does not establish any rights for any person 

and is not binding on FDA or the public. You can use an alternative approach if it satisfies the 

requirements of the applicable statutes and regulations. To discuss an alternative approach, 

contact the FDA staff responsible for this guidance as listed on the title page. 

1. INTRODUCTION

1.1 Objective

This document (guidance) is intended to provide guidance regarding good manufacturing 

practice (GMP) for the manufacturing of active pharmaceutical ingredients (APIs) under an 

appropriate system for managing quality. It is also intended to help ensure that APIs meet the 

requirements for quality and purity that they purport or are represented to possess. 

In this guidance “manufacturing” is defined to include all operations of receipt of materials, 

production, packaging, repackaging, labeling, relabeling, quality control, release, storage, and 

distribution of APIs and the related controls. In this guidance the term “should” indicates 

recommendations that are expected to be appropriate in most situations, unless shown not to be 

applicable or an alternative is provided that demonstrates at least an equivalent level of quality 

assurance. For the purposes of this guidance, the terms “current good manufacturing practices” 

and “good manufacturing practices” are equivalent. 

The guidance as a whole does not cover safety aspects for the personnel engaged in the 

manufacture of the active substances. While animal welfare and environmental risk are not 

specifically covered by this guidance, international, national, and regional standards 

implemented in the country/region where the active substance is manufactured, where it is used 

in the production of a veterinary medicinal product, and where such a veterinary medicinal 

product is marketed must be observed. Measures to prevent or minimize discharge of active 

substances into the environment should also be taken into account and relevant international, 

national, and regional standards implemented. 

This guidance is not intended to define registration/filing requirements or modify pharmacopeial 

requirements. This guidance does not affect the ability of the responsible regulatory agency to 

establish specific registration/filing requirements regarding APIs within the context of 
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marketing/manufacturing authorizations or drug applications. All commitments in 

registration/filing documents must be met.

In general, FDA’s guidance documents do not establish legally enforceable responsibilities. 

Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only 

as recommendations, unless specific regulatory or statutory requirements are cited. The use of 

the word should in Agency guidances means that something is suggested or recommended, but 

not required. 

1.2 Regulatory Applicability

Within the world community, materials may vary as to the legal classification as an API. When 

a material is classified as an API in the region or country in which it is manufactured or used in a 

drug product, it should be manufactured according to this guidance. 

- In the case of ectoparasiticides for veterinary use, other standards than this guidance, 

that ensure that the material is of appropriate quality, may be used in some regions. 

- In some regions, where the concept of “equivalent guidance” may not be applicable, 

adherence to the GMP concepts as described in this guidance is recommended.

1.3 Scope

This guidance applies to the manufacture of APIs for use in veterinary medicinal products. It 

applies to the manufacture of sterile APIs only up to the point immediately prior to the APIs 

being rendered sterile. The sterilization and aseptic processing of sterile APIs are not covered by 

this guidance, but should be performed in accordance with GMP guidances for veterinary 

medicinal products as defined by local authorities. 

This guidance covers APIs that are manufactured by chemical synthesis, extraction, cell 

culture/fermentation, by recovery from natural sources, or by any combination of these 

processes. Specific guidance for APIs manufactured by cell culture/fermentation is described in 

section 18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation. 

This guidance excludes all vaccines, whole cells, whole blood and plasma, blood and plasma 

derivatives (plasma fractionation), and gene therapy APIs. However, it does include APIs that 

are produced using blood or plasma as raw materials. Note that cell substrates (mammalian, 

plant, insect, or microbial cells, tissue or animal sources including transgenic animals) and early 

process steps may be subject to GMP but are not covered by this guidance. In addition, the 

guidance does not apply to veterinary medical gases and bulk-packaged veterinary medicinal 

products. 
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Section 19. APIs for Use in Clinical Trials contains guidance that only applies to the 

manufacture of APIs used in the production of veterinary medicinal products specifically for 

clinical trials (veterinary investigational medicinal products) conducted according to Guidance 

for Industry (GFI) #85 (VICH GL9), “Good Clinical Practice.”1

An “API Starting Material” is a raw material, intermediate, or an API that is used in the 

production of an API and that is incorporated as a significant structural fragment into the 

structure of the API. An API Starting Material can be an article of commerce, a material 

purchased from one or more suppliers under contract or commercial agreement, or produced inhouse. API Starting Materials normally have defined chemical properties and structure.

The company should designate and document the rationale for the point at which production of 

the API begins. For synthetic processes, this is known as the point at which “API Starting 

Materials” are entered into the process. For other processes (e.g., fermentation, extraction, 

purification, etc.), this rationale should be established on a case-by-case basis. Table 1. 

Application of the Guidance to API Manufacturing gives guidance on the point at which the API 

Starting Material is normally introduced into the process.

From this point on, appropriate GMP as defined in this guidance should be applied to these 

intermediate and/or API manufacturing steps. This would include the validation of critical 

process steps determined to impact the quality of the API. However, it should be noted that the 

fact that a company chooses to validate a process step does not necessarily define that step as 

critical.

The guidance in this document would normally be applied to the steps shown in gray in Table 1. 

It does not imply that all steps shown should be completed. The stringency of GMP in API 

manufacturing should increase as the process proceeds from early API steps to final steps, 

purification, and packaging. Physical processing of APIs, such as granulation, coating, or 

physical manipulation of particle size (e.g., milling, micronizing), should be conducted at least to 

the standards of this guidance. 

This GMP guidance does not apply to steps prior to the introduction of the defined “API Starting 

Material.” 

1 https://www.fda.gov/media/70333/download (May 2001)
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 Table 1. Application of this Guidance to API Manufacturing

Type of 

Manufacturing

Application of this guidance to steps (shown in grey with an asterisk) used in 

this type of manufacturing

Chemical

Manufacturing

Production of

the API

Starting 

Material

*Introduction

of the API

Starting

Material into

process

*Production of

Intermediate(s)

*Isolation

and

purification

*Physical

processing

and

packaging

API derived 

from animal 

sources

Collection of

organ, fluid, or

tissue

Cutting, 

mixing,

and/or

initial 

processing

*Introduction 

of the API

Starting

Material into

process

*Isolation

and

purification

*Physical

processing

and

packaging

API extracted

from plant

sources

Collection of

plants

Cutting and

initial

extraction(s)

*Introduction 

of the API

Starting

Material into

process

*Isolation

and

purification

*Physical

processing

and

packaging

Herbal extracts

used as API

Collection of

plants

Cutting and

initial

extraction

*Further

extraction

*Physical

processing

and

packaging

API consisting 

of comminuted 

or powdered 

herbs

Collection of

plants and/or

cultivation and

harvesting

Cutting/

comminuting

*Physical

processing

and

packaging

Biotechnology:

fermentation/

cell culture

Establishment

of master cell

bank and

working cell

bank

*Maintenance

of working

cell bank

*Cell culture

and/or

fermentation

*Isolation

and

purification

*Physical

processing

and

packaging

“Classical”

Fermentation to

produce an API

Establishment

of cell bank

Maintenance

of the cell

bank

*Introduction 

of the cells into

fermentation

*Isolation

and

purification

*Physical

processing

and

packaging
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2. QUALITY MANAGEMENT

2.1 Principles

2.10 Quality should be the responsibility of all persons involved in manufacturing. 

2.11 Each manufacturer should establish, document, and implement an effective system for 

managing quality that involves the active participation of management and appropriate 

manufacturing personnel. 

2.12 The system for managing quality should encompass the organizational structure, 

procedures, processes, and resources, as well as activities necessary to ensure 

confidence that the API will meet its intended specifications for quality and purity. All 

quality related activities should be defined and documented. 

2.13 There should be a quality unit(s) that is independent of production and that fulfills both 

quality assurance (QA) and quality control (QC) responsibilities. This can be in the 

form of separate QA and QC units or a single individual or group, depending upon the 

size and structure of the organization.

2.14 The persons authorized to release intermediates and APIs should be specified.

2.15 All quality-related activities should be recorded at the time they are performed.

2.16 Any deviation from established procedures should be documented and explained. 

Critical deviations should be investigated, and the investigation and its conclusions 

should be documented. 

2.17 No materials should be released or used before the satisfactory completion of 

evaluation by the quality unit(s) unless there are appropriate systems in place to allow 

for such use (e.g., release under quarantine as described in section 10.20 or the use of 

raw materials or intermediates pending completion of evaluation). 

2.18 Procedures should exist for notifying responsible management in a timely manner of 

regulatory inspections, serious GMP deficiencies, product defects, and related actions 

(e.g., quality-related complaints, recalls, regulatory actions, etc.).

2.2 Responsibilities of the Quality Unit(s)

2.20 The quality unit(s) should be involved in all quality-related matters.

2.21 The quality unit(s) should review and approve all appropriate quality-related 

documents. 

2.22 The main responsibilities of the independent quality unit(s) should not be delegated. 

These responsibilities should be described in writing and should include but not 

necessarily be limited to:
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1. Releasing or rejecting all APIs. Releasing or rejecting intermediates for use 

outside the control of the manufacturing company; 

2. Establishing a system to release or reject raw materials, intermediates, 

packaging and labeling materials;

3. Reviewing completed batch production and laboratory control records of 

critical process steps before release of the API for distribution;

4. Making sure that critical deviations are investigated and resolved; 

5. Approving all specifications and master production instructions; 

6. Approving all procedures impacting the quality of intermediates or APIs;

7. Making sure that internal audits (self-inspections) are performed;

8. Approving intermediate and API contract manufacturers;

9. Approving changes that potentially impact intermediate or API quality; 

10. Reviewing and approving validation protocols and reports; 

11. Making sure that quality-related complaints are investigated and resolved;

12. Making sure that effective systems are used for maintaining and calibrating 

critical equipment;

13. Making sure that materials are appropriately tested and the results are 

reported; 

14. Making sure that there is stability data to support retest or expiry dates and 

storage conditions on APIs and/or intermediates where appropriate; and

15. Performing product quality reviews (as defined in section 2.5 Product Quality 

Review).

2.3 Responsibility for Production Activities

The responsibility for production activities should be described in writing, and should include 

but not necessarily be limited to:

1. Preparing, reviewing, approving, and distributing the instructions for the production of 

intermediates or APIs according to written procedures;

2. Producing APIs and, when appropriate, intermediates according to pre-approved 

instructions;

3. Reviewing all production batch records and ensuring that these are completed and 

signed; 

4. Making sure that all production deviations are reported and evaluated and that critical 

deviations are investigated and the conclusions are recorded; 

5. Making sure that production facilities are clean and, when appropriate, disinfected;

6. Making sure that the necessary calibrations are performed and records kept;
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7. Making sure that the premises and equipment are maintained and records kept;

8. Making sure that validation protocols and reports are reviewed and approved; 

9. Evaluating proposed changes in product, process, or equipment; and 

10. Making sure that new and, when appropriate, modified facilities and equipment are 

qualified. 

2.4 Internal Audits (Self Inspection)

2.40 In order to verify compliance with the principles of GMP for APIs, regular internal 

audits should be performed in accordance with an approved schedule. 

2.41 Audit findings and corrective actions should be documented and brought to the 

attention of responsible management of the firm. Agreed corrective actions should be 

completed in a timely and effective manner.

2.5 Product Quality Review

2.50 Regular quality reviews of APIs should be conducted with the objective of verifying 

the consistency of the process. Such reviews should normally be conducted and 

documented annually and should include at least: 

- A review of critical in-process control and critical API test results;

- A review of all batches that failed to meet established specification(s);

- A review of all critical deviations or non-conformances and related 

investigations; 

- A review of any changes carried out to the processes or analytical methods; 

- A review of results of the stability monitoring program;

- A review of all quality-related returns, complaints, and recalls; and

- A review of adequacy of corrective actions.

2.51 The results of this review should be evaluated and an assessment made of whether 

corrective action or any revalidation should be undertaken. Reasons for such corrective 

action should be documented. Agreed corrective actions should be completed in a 

timely and effective manner.

3. PERSONNEL

3.1 Personnel Qualifications

3.10 There should be an adequate number of personnel qualified by appropriate education, 

training and/or experience to perform and supervise the manufacturing, 

packaging/labeling, testing, and storage of intermediates and APIs.
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3.11 The responsibilities of all personnel engaged in the manufacturing, packaging/labeling, 

testing, and storage of intermediates and APIs should be specified in writing. 

3.12 Training should be regularly conducted by qualified individuals and should cover, at a 

minimum, the particular operations that the employee performs and GMP as it relates to 

the employee's functions. Records of training should be maintained. Training should 

be periodically assessed.

3.2 Personnel Hygiene

3.20 Personnel should practice good sanitation and health habits. 

3.21 Personnel should wear clean clothing suitable for the manufacturing activity with which 

they are involved and this clothing should be changed when appropriate. Additional 

protective apparel, such as head, face, hand, and arm coverings, should be worn when 

necessary to protect intermediates and APIs from contamination.

3.22 Personnel should avoid direct contact with intermediates or APIs. 

3.23 Smoking, eating, drinking, chewing, and the storage of food should be restricted to 

certain designated areas separate from the manufacturing areas.

3.24 Personnel suffering from an infectious disease or having open lesions on the exposed 

surface of the body should not engage in activities that could result in compromising 

the quality of APIs. Any person shown at any time (either by medical examination or 

supervisory observation) to have an apparent illness or open lesions should be excluded 

from activities where the health condition could adversely affect the quality of the APIs 

until the condition is corrected or qualified medical personnel determine that the 

person's inclusion would not jeopardize the safety or quality of the APIs. 

3.3 Consultants

3.30 Consultants advising on the manufacture and control of intermediates or APIs should 

have sufficient education, training, and experience, or any combination thereof, to 

advise on the subject for which they are retained. 

3.31 Records should be maintained stating the name, address, qualifications, and type of 

service provided by these consultants. 

4. BUILDINGS AND FACILITIES

4.1 Design and Construction

4.10 Buildings and facilities used in the manufacture of intermediates and APIs should be 

located, designed, and constructed to facilitate cleaning, maintenance, and operations as 

appropriate to the type and stage of manufacture. Facilities should also be designed to 

minimize potential contamination. Where microbiological specifications have been 
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established for the intermediate or API, facilities should also be designed to limit 

exposure to objectionable microbiological contaminants as appropriate. 

4.11 Buildings and facilities should have adequate space for the orderly placement of 

equipment and materials to prevent mix-ups and contamination.

4.12 Where the equipment itself (e.g., closed or contained systems) provides adequate 

protection of the material, such equipment can be located outdoors.

4.13 The flow of materials and personnel through the building or facilities should be 

designed to prevent mix-ups or contamination. 

4.14 There should be defined areas or other control systems for the following activities:

- Receipt, identification, sampling, and quarantine of incoming materials, pending 

release or rejection;

- Quarantine before release or rejection of intermediates and APIs;

- Sampling of intermediates and APIs;

- Holding rejected materials before further disposition (e.g., return, reprocessing, 

or destruction); 

- Storage of released materials;

- Production operations;

- Packaging and labeling operations; and

- Laboratory operations.

4.15 Adequate, clean washing and toilet facilities should be provided for personnel. T hese 

washing facilities should be equipped with hot and cold water as appropriate, soap or 

detergent, air driers or single service towels. The washing and toilet facilities should be 

separate from, but easily accessible to, manufacturing areas. Adequate facilities for 

showering and/or changing clothes should be provided, when appropriate. 

4.16 Laboratory areas/operations should normally be separated from production areas. 

Some laboratory areas, in particular those used for in-process controls, can be located in 

production areas, provided the operations of the production process do not adversely 

affect the accuracy of the laboratory measurements, and the laboratory and its 

operations do not adversely affect the production process or intermediate or API. 

4.2 Utilities

4.20 All utilities that could impact on product quality (e.g., steam, gases, compressed air, 

and heating, ventilation and air conditioning) should be qualified and appropriately 

monitored and action should be taken when limits are exceeded. Drawings for these 

utility systems should be available.
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4.21 Adequate ventilation, air filtration and exhaust systems should be provided, where 

appropriate. These systems should be designed and constructed to minimize risks of 

contamination and cross-contamination and should include equipment for control of air 

pressure, microorganisms (if appropriate), dust, humidity, and temperature, as 

appropriate to the stage of manufacture. Particular attention should be given to areas 

where APIs are exposed to the environment. 

4.22 If air is recirculated to production areas, appropriate measures should be taken to 

control risks of contamination and cross-contamination. 

4.23 Permanently installed pipework should be appropriately identified. This can be 

accomplished by identifying individual lines, documentation, computer control 

systems, or alternative means. Pipework should be located to avoid risks of 

contamination of the intermediate or API. 

4.24 Drains should be of adequate size and should be provided with an air break or a suitable 

device to prevent back-siphonage, when appropriate. 

4.3 Water 

4.30 Water used in the manufacture of APIs should be demonstrated to be suitable for its 

intended use. 

4.31 Unless otherwise justified, process water should, at a minimum, meet World Health 

Organization (WHO) guidelines for drinking (potable) water quality.

4.32 If drinking (potable) water is insufficient to ensure API quality, and tighter chemical 

and/or microbiological water quality specifications are called for, appropriate 

specifications for physical/chemical attributes, total microbial counts, objectionable 

organisms and/or endotoxins should be established. 

4.33 Where water used in the process is treated by the manufacturer to achieve a defined 

quality, the treatment process should be validated and monitored with appropriate 

action limits.

4.34 Where the manufacturer of a non-sterile API either intends or claims that it is suitable 

for use in further processing to produce a sterile veterinary medicinal product, it may be 

required in some regions that water used in the final isolation and purification steps 

should be monitored and controlled for total microbial counts, objectionable organisms, 

and endotoxins. 

4.4 Containment

4.40 Dedicated production areas, which can include facilities, air handling equipment and/or 

process equipment, should be employed in the production of highly sensitizing 

materials, such as penicillins or cephalosporins, unless cleaning procedures are 

established, implemented, and maintained to prevent cross-contamination. 
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4.41 Dedicated production areas should also be considered when material of an infectious 

nature or high pharmacological activity or toxicity is involved (e.g., certain steroids or 

cytotoxic anti-cancer agents) unless validated inactivation and/or cleaning procedures 

are established and maintained.

4.42 Appropriate measures should be established and implemented to prevent crosscontamination from personnel, materials, etc., moving from one dedicated area to 

another. 

4.43 Any production activities (including weighing, milling, or packaging) of highly toxic 

non-pharmaceutical materials, such as herbicides and pesticides should not be 

conducted using the buildings and/or equipment being used for the production of APIs. 

Handling and storage of these highly toxic non-pharmaceutical materials should be 

separate from APIs.

4.44 A comprehensive and effective quality system incorporating adequate quality controls 

and quality risk management should be used for determining the necessity for and the 

extent to which all areas can be shared and to mitigate the associated risk of cross 

contamination.

4.5 Lighting

4.50 Adequate lighting should be provided in all areas to facilitate cleaning, maintenance, 

and proper operations. 

4.6 Sewage and Refuse

4.60 Sewage, refuse, and other waste (e.g., solids, liquids, or gaseous by-products from 

manufacturing) in and from buildings and the immediate surrounding area should be 

disposed of in a safe, timely, and sanitary manner. Containers and/or pipes for waste 

material should be clearly identified.

4.7 Sanitation and Maintenance

4.70 Buildings used in the manufacture of intermediates and APIs should be properly 

maintained and repaired and kept in a clean condition. 

4.71 Written procedures should be established assigning responsibility for sanitation and 

describing the cleaning schedules, methods, equipment, and materials to be used in 

cleaning buildings and facilities. 

4.72 When necessary, written procedures should also be established for the use of suitable 

rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing 

agents to prevent the contamination of equipment, raw materials, packaging/labeling

materials, intermediates, and APIs.
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5. PROCESS EQUIPMENT

5.1 Design and Construction

5.10 Equipment used in the manufacture of intermediates and APIs should be of appropriate 

design and adequate size, and suitably located for its intended use, cleaning, 

sanitization (where appropriate), and maintenance.

5.11 Equipment should be constructed so that surfaces that contact raw materials, 

intermediates, or APIs do not alter the quality of the intermediates and APIs beyond the 

official or other established specifications.

5.12 Production equipment should only be used within its qualified operating range. 

5.13 Major equipment (e.g., reactors, storage containers) and permanently installed 

processing lines used during the production of an intermediate or API should be 

appropriately identified. 

5.14 Any substances associated with the operation of equipment, such as lubricants, heating 

fluids, or coolants, should not contact intermediates or APIs so as to alter their quality 

beyond the official or other established specifications. Any deviations from this should 

be evaluated to ensure that there are no detrimental effects upon the fitness for purpose 

of the material. Wherever possible, food grade lubricants and oils should be used. 

5.15 Closed or contained equipment should be used whenever appropriate. Where open 

equipment is used, or equipment is opened, appropriate precautions should be taken to 

minimize the risk of contamination.

5.16 A set of current drawings should be maintained for equipment and critical installations 

(e.g., instrumentation and utility systems).

5.2 Equipment Maintenance and Cleaning

5.20 Schedules and procedures (including assignment of responsibility) should be 

established for the preventative maintenance of equipment.

5.21 Written procedures should be established for cleaning of equipment and its subsequent 

release for use in the manufacture of intermediates and APIs. Cleaning procedures 

should contain sufficient details to enable operators to clean each type of equipment in 

a reproducible and effective manner. These procedures should include: 

- Assignment of responsibility for cleaning of equipment; 

- Cleaning schedules, including, where appropriate, sanitizing schedules; 

- A complete description of the methods and materials, including dilution of 

cleaning agents used to clean equipment; 

- When appropriate, instructions for disassembling and reassembling each article 

of equipment to ensure proper cleaning;
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- Instructions for the removal or obliteration of previous batch identification;

- Instructions for the protection of clean equipment from contamination prior to 

use;

- Inspection of equipment for cleanliness immediately before use, if practical; and

- Establishing the maximum time that may elapse between the completion of 

processing and equipment cleaning, when appropriate. 

5.22 Equipment and utensils should be cleaned, stored, and, where appropriate, sanitized or 

sterilized to prevent contamination or carry-over of a material that would alter the 

quality of the intermediate or API beyond the official or other established 

specifications.

5.23 Where equipment is assigned to continuous production or campaign production of 

successive batches of the same intermediate or API, equipment should be cleaned at 

appropriate intervals to prevent build-up and carry-over of contaminants (e.g., 

degradants or objectionable levels of micro-organisms).

5.24 Non-dedicated equipment should be cleaned between production of different materials 

to prevent cross-contamination. 

5.25 Acceptance criteria for residues and the choice of cleaning procedures and cleaning 

agents should be defined and justified. 

5.26 Equipment should be identified as to its contents and its cleanliness status by 

appropriate means.

5.3 Calibration

5.30 Control, weighing, measuring, monitoring, and test equipment that is critical for 

ensuring the quality of intermediates or APIs should be calibrated according to written 

procedures and an established schedule.

5.31 Equipment calibrations should be performed using standards traceable to certified 

standards, if existing. 

5.32 Records of these calibrations should be maintained.

5.33 The current calibration status of critical equipment should be known and verifiable. 

5.34 Instruments that do not meet calibration criteria should not be used. 

5.35 Deviations from approved standards of calibration on critical instruments should be 

investigated to determine if these could have had an impact on the quality of the 

intermediate(s) or API(s) manufactured using this equipment since the last successful 

calibration.
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5.4 Computerized Systems

5.40 GMP related computerized systems should be validated. The depth and scope of 

validation depends on the diversity, complexity, and criticality of the computerized 

application. 

5.41 Appropriate installation qualification and operational qualification should demonstrate 

the suitability of computer hardware and software to perform assigned tasks. 

5.42 Commercially available software that has been qualified does not require the same level 

of testing. If an existing system was not validated at time of installation, a retrospective 

validation could be conducted if appropriate documentation is available. 

5.43 Computerized systems should have sufficient controls to prevent unauthorized access 

or changes to data. There should be controls to prevent omissions in data (e.g., system 

turned off and data not captured). There should be a record of any data change made, 

the previous entry, who made the change, and when the change was made. 

5.44 Written procedures should be available for the operation and maintenance of 

computerized systems. 

5.45 Where critical data are being entered manually, there should be an additional check on 

the accuracy of the entry. This can be done by a second operator or by the system 

itself.

5.46 Incidents related to computerized systems that could affect the quality of intermediates 

or APIs or the reliability of records or test results should be recorded and investigated.

5.47 Changes to the computerized system should be made according to a change procedure 

and should be formally authorized, documented, and tested. Records should be kept of 

all changes, including modifications and enhancements made to the hardware, software, 

and any other critical component of the system. These records should demonstrate that 

the system is maintained in a validated state.

5.48 If system breakdowns or failures would result in the permanent loss of records, a backup system should be provided. A means of ensuring data protection should be 

established for all computerized systems. 

5.49 Data can be recorded by a second means in addition to the computer system. 

6. DOCUMENTATION AND RECORDS

6.1 Documentation System and Specifications

6.10 All documents related to the manufacture of intermediates or APIs should be prepared, 

reviewed, approved, and distributed according to written procedures. Such documents 

can be in paper or electronic form. 
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6.11 The issuance, revision, superseding, and withdrawal of all documents should be 

controlled with maintenance of revision histories. 

6.12 A procedure should be established for retaining all appropriate documents (e.g., 

development history reports, scale-up reports, technical transfer reports, process 

validation reports, training records, production records, control records, and distribution 

records). The retention periods for these documents should be specified. 

6.13 All production, control, and distribution records should be retained for at least 1 year 

after the expiry date of the batch. For APIs with retest dates, records should be retained 

for at least 3 years after the batch is completely distributed.

6.14 When entries are made in records, these should be made indelibly in spaces provided 

for such entries, directly after performing the activities, and should identify the person 

making the entry. Corrections to entries should be dated and signed and leave the 

original entry still readable.

6.15 During the retention period, originals or copies of records should be readily available at 

the establishment where the activities described in such records occurred. Records that 

can be promptly retrieved from another location by electronic or other means are 

acceptable.

6.16 Specifications, instructions, procedures, and records can be retained either as originals 

or as true copies such as photocopies, microfilm, microfiche, or other accurate 

reproductions of the original records. Where reduction techniques such as 

microfilming or electronic records are used, suitable retrieval equipment and a means to 

produce a hard copy should be readily available. 

6.17 Specifications should be established and documented for raw materials, intermediates 

where necessary, APIs, and labeling and packaging materials. In addition, 

specifications may be appropriate for certain other materials, such as process aids, 

gaskets, or other materials used during the production of intermediates or APIs that 

could critically impact on quality. Acceptance criteria should be established and 

documented for in-process controls. 

6.18 If electronic signatures are used on documents, they should be authenticated and secure. 

6.2 Equipment Cleaning and Use Record

6.20 Records of major equipment use, cleaning, sanitization and/or sterilization, and 

maintenance should show the date, time (if appropriate), product, and batch number of 

each batch processed in the equipment, and the person who performed the cleaning and 

maintenance.

6.21 If equipment is dedicated to manufacturing one intermediate or API, then individual 

equipment records are not necessary if batches of the intermediate or API follow in 
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traceable sequence. In cases where dedicated equipment is employed, the records of 

cleaning, maintenance, and use can be part of the batch record or maintained separately.

6.3 Records of Raw Materials, Intermediates, API Labeling and Packaging Materials

6.30 Records should be maintained including: 

- The name of the manufacturer, identity and quantity of each shipment of each 

batch of raw materials, intermediates, or labeling and packaging materials for 

APIs; the name of the supplier; the supplier's control number(s), if known, or 

other identification number; the number allocated on receipt; and the date of 

receipt;

- The results of any test or examination performed and the conclusions derived 

from this;

- Records tracing the use of materials;

- Documentation of the examination and review of API labeling and packaging 

materials for conformity with established specifications; and

- The final decision regarding rejected raw materials, intermediates, or API 

labeling and packaging materials.

6.31 Master (approved) labels should be maintained for comparison to issued labels. 

6.4 Master Production Instructions (Master Production and Control Records)

6.40 To ensure uniformity from batch to batch, master production instructions for each 

intermediate and API should be prepared, dated, and signed by one person and 

independently checked, dated, and signed by a person in the quality unit(s). 

6.41 Master production instructions should include: 

- The name of the intermediate or API being manufactured and an identifying 

document reference code, if applicable;

- A complete list of raw materials and intermediates designated by names or 

codes sufficiently specific to identify any special quality characteristics;

- An accurate statement of the quantity or ratio of each raw material or 

intermediate to be used, including the unit of measure. Where the quantity is 

not fixed, the calculation for each batch size or rate of production should be 

included. Variations to quantities should be included where they are justified; 

- The production location and major production equipment to be used; 

- Detailed production instructions, including the:

- sequences to be followed,

- ranges of process parameters to be used,
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- sampling instructions and in-process controls with their acceptance 

criteria, where appropriate,

- time limits for completion of individual processing steps and/or the total 

process, where appropriate; and

- expected yield ranges at appropriate phases of processing or time;

- Where appropriate, special notations and precautions to be followed, or crossreferences to these; and

- The instructions for storage of the intermediate or API to ensure its suitability 

for use, including the labeling and packaging materials and special storage 

conditions with time limits, where appropriate.

6.5 Batch Production Records (Batch Production and Control Records)

6.50 Batch production records should be prepared for each intermediate and API and should 

include complete information relating to the production and control of each batch. The 

batch production record should be checked before issuance to ensure that it is the 

correct version and a legible accurate reproduction of the appropriate master production 

instruction. If the batch production record is produced from a separate part of the 

master document, that document should include a reference to the current master 

production instruction being used. 

6.51 These records should be numbered with a unique batch or identification number, dated 

and signed when issued. In continuous production, the product code, together with the 

date and time, can serve as the unique identifier until the final number is allocated.

6.52 Documentation of completion of each significant step in the batch production records 

(batch production and control records) should include: 

- Dates and, when appropriate, times; 

- Identity of major equipment (e.g., reactors, driers, mills, etc.) used;

- Specific identification of each batch, including weights, measures, and batch 

numbers of raw materials, intermediates, or any reprocessed materials used 

during manufacturing; 

- Actual results recorded for critical process parameters;

- Any sampling performed; 

- Signatures of the persons performing and directly supervising or checking each 

critical step in the operation;

- In-process and laboratory test results;

- Actual yield at appropriate phases or times;

- Description of packaging and label for intermediate or API;

- Representative label of API or intermediate if made commercially available;
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- Any deviation noted, its evaluation, investigation conducted (if appropriate) or 

reference to that investigation if stored separately; and

- Results of release testing.

6.53 Written procedures should be established and followed for investigating critical 

deviations or the failure of a batch of intermediate or API to meet specifications. The 

investigation should extend to other batches that may have been associated with the 

specific failure or deviation.

6.6 Laboratory Control Records 

6.60 Laboratory control records should include complete data derived from all tests 

conducted to ensure compliance with established specifications and standards, 

including examinations and assays, as follows: 

- A description of samples received for testing, including the material name or 

source, batch number or other distinctive code, date sample was taken, and, 

where appropriate, the quantity and date the sample was received for testing; 

- A statement of or reference to each test method used;

- A statement of the weight or measure of sample used for each test as described 

by the method; data on or cross-reference to the preparation and testing of 

reference standards, reagents, and standard solutions; 

- A complete record of all raw data generated during each test, in addition to 

graphs, charts, and spectra from laboratory instrumentation, properly identified 

to show the specific material and batch tested;

- A record of all calculations performed in connection with the test, including, for 

example, units of measure, conversion factors, and equivalency factors; 

- A statement of the test results and how they compare with established 

acceptance criteria;

- The signature of the person who performed each test and the date(s) the tests 

were performed; and

- The date and signature of a second person showing that the original records 

have been reviewed for accuracy, completeness, and compliance with 

established standards.

6.61 Complete records should also be maintained for:

- Any modifications to an established analytical method;

- Periodic calibration of laboratory instruments, apparatus, gauges, and recording 

devices;

- All stability testing performed on APIs; and

- Out-of-specification (OOS) investigations
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6.7 Batch Production Record Review

6.70 Written procedures should be established and followed for the review and approval of 

batch production and laboratory control records, including packaging and labeling, to 

determine compliance of the intermediate or API with established specifications before 

a batch is released or distributed.

6.71 Batch production and laboratory control records of critical process steps should be 

reviewed and approved by the quality unit(s) before an API batch is released or 

distributed. Production and laboratory control records of non-critical process steps can 

be reviewed by qualified production personnel or other units following procedures 

approved by the quality unit(s). 

6.72 All deviation, investigation, and OOS reports should be reviewed as part of the batch 

record review before the batch is released.

6.73 The quality unit(s) can delegate to the production unit the responsibility and authority 

for release of intermediates, except for those shipped outside the control of the 

manufacturing company. 

7. MATERIALS MANAGEMENT

7.1 General Controls

7.10 There should be written procedures describing the receipt, identification, quarantine, 

storage, handling, sampling, testing, and approval or rejection of materials. 

7.11 Manufacturers of intermediates and/or APIs should have a system for evaluating the 

suppliers of critical materials.

7.12 Materials should be purchased against an agreed specification, from a supplier or 

suppliers approved by the quality unit(s). 

7.13 If the supplier of a critical material is not the manufacturer of that material, the name 

and address of that manufacturer should be known by the intermediate and/or API 

manufacturer.

7.14 Changing the source of supply of critical raw materials should be treated according to 

section 13. Change Control. 

7.2 Receipt and Quarantine

7.20 Upon receipt and before acceptance, each container or grouping of containers of 

materials should be examined visually for correct labeling (including correlation 

between the name used by the supplier and the in-house name, if these are different), 

container damage, broken seals, and evidence of tampering or contamination. 
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Materials should be held under quarantine until they have been sampled, examined or 

tested as appropriate, and released for use.

7.21 Before incoming materials are mixed with existing stocks (e.g., solvents or stocks in 

silos), they should be identified as correct, tested, if appropriate, and released. 

Procedures should be available to prevent discharging incoming materials wrongly into 

the existing stock.

7.22 If bulk deliveries are made in non-dedicated tankers, there should be ensurance of no 

cross-contamination from the tanker. Means of providing this ensurance could include 

one or more of the following: 

- certificate of cleaning; 

- testing for trace impurities; and/or 

- audit of the supplier.

7.23 Large storage containers, and their attendant manifolds, filling and discharge lines 

should be appropriately identified. 

7.24 Each container or grouping of containers (batches) of materials should be assigned and 

identified with a distinctive code, batch, or receipt number. This number should be 

used in recording the disposition of each batch. A system should be in place to identify 

the status of each batch.

7.3 Sampling and Testing of Incoming Production Materials

7.30 At least one test to verify the identity of each batch of material should be conducted, 

with the exception of the materials described below in section 7.32. A supplier's 

Certificate of Analysis can be used in place of performing other tests, provided that the 

manufacturer has a system in place to evaluate suppliers. 

7.31 Supplier approval should include an evaluation that provides adequate evidence (e.g., 

past quality history) that the manufacturer can consistently provide material meeting 

specifications. Full analyses should be conducted on at least three batches before 

reducing in-house testing. However, as a minimum, a full analysis should be 

performed at appropriate intervals and compared with the Certificates of Analysis. 

Reliability of Certificates of Analysis should be checked at regular intervals.

7.32 Processing aids, hazardous or highly toxic raw materials, other special materials, or 

materials transferred to another unit within the company’s control do not need to be 

tested if the manufacturer’s Certificate of Analysis is obtained, showing that these raw 

materials conform to established specifications. Visual examination of containers, 

labels, and recording of batch numbers should help in establishing the identity of these 

materials. The lack of on-site testing for these materials should be justified and 

documented. 

7.33 Samples should be representative of the batch of material from which they are taken. 
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Sampling methods should specify the number of containers to be sampled, which part 

of the container to sample, and the amount of material to be taken from each container. 

The number of containers to sample and the sample size should be based upon a 

sampling plan that takes into consideration the criticality of the material, material 

variability, past quality history of the supplier, and the quantity needed for analysis. 

7.34 Sampling should be conducted at defined locations and by procedures designed to 

prevent contamination of the material sampled and contamination of other materials.

7.35 Containers from which samples are withdrawn should be opened carefully and 

subsequently reclosed. They should be marked to indicate that a sample has been 

taken. 

7.4 Storage 

7.40 Materials should be handled and stored in a manner to prevent degradation, 

contamination, and cross-contamination.

7.41 Materials stored in fiber drums, bags, or boxes should be stored off the floor and, when 

appropriate, suitably spaced to permit cleaning and inspection. 

7.42 Materials should be stored under conditions and for a period that have no adverse affect 

on their quality, and should normally be controlled so that the oldest stock is used first. 

7.43 Certain materials in suitable containers can be stored outdoors, provided identifying 

labels remain legible and containers are appropriately cleaned before opening and use.

7.44 Rejected materials should be identified and controlled under a quarantine system 

designed to prevent their unauthorized use in manufacturing. 

7.5 Re-evaluation 

7.50 Materials should be re-evaluated as appropriate to determine their suitability for use 

(e.g., after prolonged storage or exposure to heat or humidity). 

8. PRODUCTION AND IN-PROCESS CONTROLS

8.1 Production Operations

8.10 Raw materials for intermediate and API manufacturing should be weighed or measured 

under appropriate conditions that do not affect their suitability for use. Weighing and 

measuring devices should be of suitable accuracy for the intended use. 

8.11 If a material is subdivided for later use in production operations, the container receiving 

the material should be suitable and should be so identified that the following 

information is available:

- Material name and/or item code;
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- Receiving or control number; 

- Weight or measure of material in the new container; and

- Re-evaluation or retest date if appropriate.

8.12 Critical weighing, measuring, or subdividing operations should be witnessed or 

subjected to an equivalent control. Prior to use, production personnel should verify that 

the materials are those specified in the batch record for the intended intermediate or 

API.

8.13 Other critical activities should be witnessed or subjected to an equivalent control. 

8.14 Actual yields should be compared with expected yields at designated steps in the 

production process. Expected yields with appropriate ranges should be established 

based on previous laboratory, pilot scale, or manufacturing data. Deviations in yield 

associated with critical process steps should be investigated to determine their impact 

or potential impact on the resulting quality of affected batches.

8.15 Any deviation should be documented and explained. Any critical deviation should be 

investigated. 

8.16 The processing status of major units of equipment should be indicated either on the 

individual units of equipment or by appropriate documentation, computer control 

systems, or alternative means.

8.17 Materials to be reprocessed or reworked should be appropriately controlled to prevent 

unauthorized use. 

8.2 Time Limits

8.20 If time limits are specified in the master production instruction (see section 6.41), these 

time limits should be met to ensure the quality of intermediates and APIs. Deviations 

should be documented and evaluated. Time limits may be inappropriate when 

processing to a target value (e.g., pH adjustment, hydrogenation, drying to 

predetermined specification) because completion of reactions or processing steps are 

determined by in-process sampling and testing. 

8.21 Intermediates held for further processing should be stored under appropriate conditions 

to ensure their suitability for use.

8.3 In-process Sampling and Controls

8.30 Written procedures should be established to monitor the progress and control the 

performance of processing steps that cause variability in the quality characteristics of 

intermediates and APIs. In-process controls and their acceptance criteria should be 

defined based on the information gained during the development stage or historical 

data.
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8.31 The acceptance criteria and type and extent of testing can depend on the nature of the 

intermediate or API being manufactured, the reaction or process step being conducted, 

and the degree to which the process introduces variability in the product’s quality. Less 

stringent in-process controls may be appropriate in early processing steps, whereas 

tighter controls may be appropriate for later processing steps (e.g., isolation and 

purification steps).

8.32 Critical in-process controls (and critical process monitoring), including the control 

points and methods, should be stated in writing and approved by the quality unit(s). 

8.33 In-process controls can be performed by qualified production department personnel and 

the process adjusted without prior quality unit(s) approval if the adjustments are made 

within pre-established limits approved by the quality unit(s). All tests and results 

should be fully documented as part of the batch record. 

8.34 Written procedures should describe the sampling methods for in-process materials, 

intermediates, and APIs. Sampling plans and procedures should be based on 

scientifically sound sampling practices.

8.35 In-process sampling should be conducted using procedures designed to prevent 

contamination of the sampled material and other intermediates or APIs. Procedures 

should be established to ensure the integrity of samples after collection.

8.36 OOS investigations are not normally needed for in-process tests that are performed for 

the purpose of monitoring and/or adjusting the process. 

8.4 Blending Batches of Intermediates or APIs

8.40 For the purpose of this document, blending is defined as the process of combining 

materials within the same specification to produce a homogeneous intermediate or API. 

In-process mixing of fractions from single batches (e.g., collecting several centrifuge 

loads from a single crystallization batch) or combining fractions from several batches 

for further processing is considered to be part of the production process and is not 

considered to be blending. 

8.41 OOS batches should not be blended with other batches for the purpose of meeting 

specifications. Each batch incorporated into the blend should have been manufactured 

using an established process and should have been individually tested and found to 

meet appropriate specifications prior to blending.

8.42 Acceptable blending operations include but are not limited to: 

- Blending of small batches to increase batch size. 

- Blending of tailings (i.e., relatively small quantities of isolated material) from 

batches of the same intermediate or API to form a single batch.
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8.43 Blending processes should be adequately controlled and documented and the blended 

batch should be tested for conformance to established specifications where appropriate.

8.44 The batch record of the blending process should allow traceability back to the 

individual batches that make up the blend. 

8.45 Where physical attributes of the API are critical (e.g., APIs intended for use in solid 

oral dosage forms or suspensions), blending operations should be validated to show 

homogeneity of the combined batch. Validation should include testing of critical 

attributes (e.g., particle size distribution, bulk density, and tap density) that may be 

affected by the blending process.

8.46 If the blending could adversely affect stability, stability testing of the final blended 

batches should be performed. 

8.47 The expiry or retest date of the blended batch should be based on the manufacturing 

date of the oldest tailings or batch in the blend. 

8.5 Contamination Control 

8.10 Residual materials can be carried over into successive batches of the same intermediate 

or API if there is adequate control. Examples include residue adhering to the wall of a 

micronizer, residual layer of damp crystals remaining in a centrifuge bowl after 

discharge, and incomplete discharge of fluids or crystals from a processing vessel upon 

transfer of the material to the next step in the process. Such carryover should not result 

in the carryover of degradants or microbial contamination that may adversely alter the 

established API impurity profile.

8.11 Production operations should be conducted in a manner that will prevent contamination 

of intermediates or APIs by other materials.

8.12 Precautions to avoid contamination should be taken when APIs are handled after 

purification.

9. PACKAGING AND IDENTIFICATION LABELING OF APIs AND 

INTERMEDIATES

9.1 General

9.10 There should be written procedures describing the receipt, identification, quarantine, 

sampling, examination and/or testing and release, and handling of packaging and 

labeling materials.

9.11 Packaging and labeling materials should conform to established specifications. Those 

that do not comply with such specifications should be rejected to prevent their use in 

operations for which they are unsuitable. 
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9.12 Records should be maintained for each shipment of labels and packaging materials 

showing receipt, examination, or testing, and whether accepted or rejected. 

9.2 Packaging Materials 

9.20 Containers should provide adequate protection against deterioration or contamination of 

the intermediate or API that may occur during transportation and recommended 

storage.

9.21 Containers should be clean and, where indicated by the nature of the intermediate or 

API, sanitized to ensure that they are suitable for their intended use. These containers 

should not be reactive, additive, or absorptive so as to alter the quality of the 

intermediate or API beyond the specified limits.

9.22 If containers are re-used, they should be cleaned in accordance with documented 

procedures and all previous labels should be removed or defaced. 

9.3 Label Issuance and Control

9.30 Access to the label storage areas should be limited to authorized personnel. 

9.31 Procedures should be used to reconcile the quantities of labels issued, used, and 

returned and to evaluate discrepancies found between the number of containers labeled 

and the number of labels issued. Such discrepancies should be investigated, and the 

investigation should be approved by the quality unit(s). 

9.32 All excess labels bearing batch numbers or other batch-related printing should be 

destroyed. Returned labels should be maintained and stored in a manner that prevents 

mix-ups and provides proper identification. 

9.33 Obsolete and out-dated labels should be destroyed. 

9.34 Printing devices used to print labels for packaging operations should be controlled to 

ensure that all imprinting conforms to the print specified in the batch production record.

9.35 Printed labels issued for a batch should be carefully examined for proper identity and 

conformity to specifications in the master production record. The results of this 

examination should be documented. 

9.36 A printed label representative of those used should be included in the batch production 

record. 

9.4 Packaging and Labeling Operations

9.40 There should be documented procedures designed to ensure that correct packaging 

materials and labels are used.
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9.41 Labeling operations should be designed to prevent mix-ups. There should be physical 

or spatial separation from operations involving other intermediates or APIs.

9.42 Labels used on containers of intermediates or APIs should indicate the name or 

identifying code, the batch number of the product, and storage conditions, when such 

information is critical to ensure the quality of intermediate or API.

9.43 If the intermediate or API is intended to be transferred outside the control of the 

manufacturer’s material management system, the name and address of the 

manufacturer, quantity of contents, and special transport conditions and any special 

legal requirements should also be included on the label. For intermediates or APIs with 

an expiry date, the expiry date should be indicated on the label and Certificate of 

Analysis. For intermediates or APIs with a retest date, the retest date should be 

indicated on the label and/or Certificate of Analysis.

9.44 Packaging and labeling facilities should be inspected immediately before use to ensure 

that all materials not needed for the next packaging operation have been removed. This 

examination should be documented in the batch production records, the facility log, or 

other documentation system.

9.45 Packaged and labeled intermediates or APIs should be examined to ensure that 

containers and packages in the batch have the correct label. This examination should 

be part of the packaging operation. Results of these examinations should be recorded 

in the batch production or control records. 

9.46 Intermediate or API containers that are transported outside of the manufacturer's 

control should be sealed in a manner such that, if the seal is breached or missing, the 

recipient will be alerted to the possibility that the contents may have been altered.

10. STORAGE AND DISTRIBUTION

10.1 Warehousing Procedures

10.10 Facilities should be available for the storage of all materials under appropriate 

conditions (e.g., controlled temperature and humidity when necessary). Records should 

be maintained of these conditions if they are critical for the maintenance of material 

characteristics.

10.11 Unless there is an alternative system to prevent the unintentional or unauthorized use of 

quarantined, rejected, returned, or recalled materials, separate storage areas should be 

assigned for their temporary storage until the decision as to their future use has been

taken. 

10.2 Distribution Procedures

10.20 APIs and intermediates should only be released for distribution to third parties after 

they have been released by the quality unit(s). APIs and intermediates can be 

transferred under quarantine to another unit under the company’s control when 
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authorized by the quality unit(s) and if appropriate controls and documentation are in 

place.

10.21 APIs and intermediates should be transported in a manner that does not adversely affect 

their quality. 

10.22 Special transport or storage conditions for an API or intermediate should be stated on 

the label.

10.23 The manufacturer should ensure that the contract acceptor (contractor) for 

transportation of the API or intermediate knows and follows the appropriate transport 

and storage conditions.

10.24 A system should be in place by which the distribution of each batch of intermediate 

and/or API can be readily determined to permit its recall.

11. LABORATORY CONTROLS

11.1 General Controls

11.10 The independent quality unit(s) should have at its disposal adequate laboratory 

facilities.

11.11 There should be documented procedures describing sampling, testing, approval or 

rejection of materials, and recording and storage of laboratory data. Laboratory records 

should be maintained in accordance with section 6.6 Laboratory Control Records. 

11.12 All specifications, sampling plans, and test procedures should be scientifically sound 

and appropriate to ensure that raw materials, intermediates, APIs, and labels and 

packaging materials conform to established standards of quality and/or purity. 

Specifications and test procedures should be consistent with those included in the 

registration/filing. There can be specifications in addition to those in the 

registration/filing. Specifications, sampling plans, and test procedures, including 

changes to them, should be drafted by the appropriate organizational unit and reviewed 

and approved by the quality unit(s). 

11.13 Appropriate specifications should be established for APIs in accordance with accepted 

standards and consistent with the manufacturing process. The specifications should 

include a control of the impurities (e.g., organic impurities, inorganic impurities, and 

residual solvents). If the API has a specification for microbiological purity, appropriate 

action limits for total microbial counts and objectionable organisms should be 

established and met. If the API has a specification for endotoxins, appropriate action 

limits should be established and met. 

11.14 Laboratory controls should be followed and documented at the time of performance. 

Any departures from the above-described procedures should be documented and 

explained. 
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11.15 Any out-of-specification result obtained should be investigated and documented 

according to a procedure. This procedure should require analysis of the data, 

assessment of whether a significant problem exists, allocation of the tasks for corrective 

actions, and conclusions. Any resampling and/or retesting after OOS results should be 

performed according to a documented procedure. 

11.16 Reagents and standard solutions should be prepared and labeled following written 

procedures. “Use by” dates should be applied as appropriate for analytical reagents or 

standard solutions.

11.17 Primary reference standards should be obtained as appropriate for the manufacture of 

APIs. The source of each primary reference standard should be documented. Records 

should be maintained of each primary reference standard’s storage and use in 

accordance with the supplier’s recommendations. Primary reference standards obtained 

from an officially recognized source are normally used without testing if stored under 

conditions consistent with the supplier’s recommendations. 

11.18 Where a primary reference standard is not available from an officially recognized 

source, an “in-house primary standard” should be established. Appropriate testing 

should be performed to establish fully the identity and purity of the primary reference 

standard. Appropriate documentation of this testing should be maintained. 

11.19 Secondary reference standards should be appropriately prepared, identified, tested, 

approved, and stored. The suitability of each batch of secondary reference standard 

should be determined prior to first use by comparing against a primary reference 

standard. Each batch of secondary reference standard should be periodically 

requalified in accordance with a written protocol. 

11.2 Testing of Intermediates and APIs

11.20 For each batch of intermediate and API, appropriate laboratory tests should be 

conducted to determine conformance to specifications. 

11.21 An impurity profile describing the identified and unidentified impurities present in a 

typical batch produced by a specific controlled production process should normally be 

established for each API. The impurity profile should include the identity or some 

qualitative analytical designation (e.g., retention time), the range of each impurity 

observed, and classification of each identified impurity (e.g., inorganic, organic, 

solvent). The impurity profile is normally dependent upon the production process and 

origin of the API. Impurity profiles are normally not necessary for APIs from herbal or 

animal tissue origin. Biotechnology considerations are covered in GFI #177 (VICH 

GL40), “Specifications: Test Procedures and Acceptance Criteria for New

Biotechnological/Biological Veterinary Medicinal Products.”2

2 https://www.fda.gov/media/69907/download (June 2006)
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11.22 The impurity profile should be compared at appropriate intervals against the impurity 

profile in the regulatory submission or compared against historical data in order to 

detect changes to the API resulting from modifications in raw materials, equipment 

operating parameters, or the production process. 

11.23 Appropriate microbiological tests should be conducted on each batch of intermediate 

and API where microbial quality is specified.

11.3 Validation of Analytical Procedures - see section 12. Validation. 

11.4 Certificates of Analysis

11.40 Authentic Certificates of Analysis should be issued for each batch of intermediate or 

API on request. 

11.41 Information on the name of the intermediate or API including where appropriate its 

grade, the batch number, and the date of release should be provided on the Certificate 

of Analysis. For intermediates or APIs with an expiry date, the expiry date should be 

provided on the label and Certificate of Analysis. For intermediates or APIs with a 

retest date, the retest date should be indicated on the label and/or Certificate of 

Analysis.

11.42 The Certificate should list each test performed in accordance with compendial or 

customer requirements, including the acceptance limits, and the numerical results 

obtained (if test results are numerical).

11.43 Certificates should be dated and signed by authorized personnel of the quality unit(s) 

and should show the name, address, and telephone number of the original 

manufacturer. Where the analysis has been carried out by a repacker or reprocessor, 

the Certificate of Analysis should show the name, address, and telephone number of the 

repacker/reprocessor and a reference to the name of the original manufacturer.

11.44 If new Certificates are issued by or on behalf of repackers/reprocessors, agents, or 

brokers, these Certificates should show the name, address, and telephone number of the 

laboratory that performed the analysis. They should also contain a reference to the 

name and address of the original manufacturer and to the original batch Certificate, a 

copy of which should be attached. 

11.5 Stability Monitoring of APIs

11.50 A documented, on-going testing program should be designed to monitor the stability 

characteristics of APIs, and the results should be used to confirm appropriate storage 

conditions and retest or expiry dates. 

11.51 The test procedures used in stability testing should be validated and be stability 

indicating. 
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11.52 Stability samples should be stored in containers that simulate the market container. For 

example, if the API is marketed in bags within fiber drums, stability samples can be 

packaged in bags of the same material and in smaller-scale drums of similar or identical 

material composition to the market drums.

11.53 Normally the first three commercial production batches should be placed on the 

stability monitoring program to confirm the retest or expiry date. However, where data 

from previous studies show that the API is expected to remain stable for at least 2 

years, fewer than three batches can be used.

11.54 Thereafter, at least one batch per year of API manufactured (unless none is produced 

that year) should be added to the stability monitoring program and tested at least 

annually to confirm the stability.

11.55 For APIs with short shelf-lives, testing should be done more frequently. For example, 

for those biotechnological/biologic and other APIs with shelf-lives of 1 year or less, 

stability samples should be obtained and should be tested monthly for the first 3 

months, and at 3-month intervals after that. When data exist that confirm that the 

stability of the API is not compromised, elimination of specific test intervals (e.g., 9-

month testing) can be considered.

11.56 Where appropriate, the stability storage conditions should be consistent with the VICH 

guidelines on stability. 

11.6 Expiry and Retest Dating

11.60 When an intermediate is intended to be transferred outside the control of the 

manufacturer’s material management system and an expiry or retest date is assigned, 

supporting stability information should be available (e.g., published data, test results). 

11.61 An API expiry or retest date should be based on an evaluation of data derived from 

stability studies. Common practice is to use a retest date, not an expiration date.

11.62 Preliminary API expiry or retest dates can be based on pilot scale batches if (1) the pilot 

batches employ a method of manufacture and procedure that simulates the final process 

to be used on a commercial manufacturing scale; and (2) the quality of the API 

represents the material to be made on a commercial scale.

11.63 A representative sample should be taken for the purpose of performing a retest. 

11.7 Reserve/Retention Samples

11.10 The packaging and holding of reserve samples is for the purpose of potential future 

evaluation of the quality of batches of API and not for future stability testing purposes. 

11.11 Appropriately identified reserve samples of each API batch should be retained for 1 

year after the expiry date of the batch assigned by the manufacturer, or for 3 years after 

distribution of the batch, whichever is the longer. For APIs with retest dates, similar 
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reserve samples should be retained for 3 years after the batch is completely distributed 

by the manufacturer.

11.12 The reserve sample should be stored in the same packaging system in which the API is 

stored or in one that is equivalent to or more protective than the marketed packaging 

system. Sufficient quantities should be retained to conduct at least two full compendial 

analyses or, when there is no pharmacopoeial monograph, two full specification 

analyses.

12. VALIDATION

12.1 Validation Policy

12.10 The company's overall policy, intentions, and approach to validation, including the 

validation of production processes, cleaning procedures, analytical methods, in-process 

control test procedures, computerized systems, and persons responsible for design, 

review, approval, and documentation of each validation phase, should be documented. 

12.11 The critical parameters/attributes should normally be identified during the development 

stage or from historical data, and the ranges necessary for the reproducible operation 

should be defined. This should include: 

- Defining the API in terms of its critical product attributes;

- Identifying process parameters that could affect the critical quality attributes of 

the API; and 

- Determining the range for each critical process parameter expected to be used 

during routine manufacturing and process control. 

12.12 Validation should extend to those operations determined to be critical to the quality and 

purity of the API.

12.2 Validation Documentation

12.20 A written validation protocol should be established that specifies how validation of a 

particular process will be conducted. The protocol should be reviewed and approved 

by the quality unit(s) and other designated units. 

12.21 The validation protocol should specify critical process steps and acceptance criteria as 

well as the type of validation to be conducted (e.g., retrospective, prospective, 

concurrent) and the number of process runs. 

12.22 A validation report that cross-references the validation protocol should be prepared, 

summarizing the results obtained, commenting on any deviations observed, and 

drawing the appropriate conclusions, including recommending changes to correct 

deficiencies.
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12.23 Any variations from the validation protocol should be documented with appropriate 

justification.

12.3 Qualification

12.30 Before starting process validation activities, appropriate qualification of critical 

equipment and ancillary systems should be completed. Qualification is usually carried 

out by conducting the following activities, individually or combined: 

- Design Qualification (DQ): documented verification that the proposed design 

of the facilities, equipment, or systems is suitable for the intended purpose. 

- Installation Qualification (IQ): documented verification that the equipment or 

systems, as installed or modified, comply with the approved design, the 

manufacturer’s recommendations, and/or user requirements.

- Operational Qualification (OQ): documented verification that the equipment or 

systems, as installed or modified, perform as intended throughout the 

anticipated operating ranges.

- Performance Qualification (PQ): documented verification that the equipment 

and ancillary systems, as connected together, can perform effectively and 

reproducibly based on the approved process method and specifications. 

12.4 Approaches to Process Validation

12.40 Process Validation (PV) is the documented evidence that the process, operated within 

established parameters, can perform effectively and reproducibly to produce an 

intermediate or API meeting its predetermined specifications and quality attributes.

12.41 There are three approaches to validation. Prospective validation is the preferred 

approach, but there are exceptions where the other approaches can be used. These 

approaches and their applicability are listed below.

12.42 Prospective validation should normally be performed for all API processes as defined 

in section 12.12. Prospective validation performed on an API process should be 

completed before the commercial distribution of the final drug product manufactured 

from that API.

12.43 Concurrent validation can be conducted when data from replicate production runs are 

unavailable because only a limited number of API batches have been produced, API 

batches are produced infrequently, or API batches are produced by a validated process 

that has been modified. Prior to the completion of concurrent validation, batches can 

be released and used in final drug product for commercial distribution based on 

thorough monitoring and testing of the API batches. 

12.44 An exception can be made for retrospective validation for well-established processes 

that have been used without significant changes to API quality due to changes in raw 
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materials, equipment, systems, facilities, or the production process. This validation 

approach may be used where:

(1) Critical quality attributes and critical process parameters have been identified;

(2) Appropriate in-process acceptance criteria and controls have been established;

(3) There have not been significant process/product failures attributable to causes 

other than operator error or equipment failures unrelated to equipment 

suitability; and 

(4) Impurity profiles have been established for the existing API.

12.45 Batches selected for retrospective validation should be representative of all batches 

made during the review period, including any batches that failed to meet specifications, 

and should be sufficient in number to demonstrate process consistency. Retained 

samples can be tested to obtain data to retrospectively validate the process.

12.5 Process Validation Program

12.50 The number of process runs for validation should depend on the complexity of the 

process or the magnitude of the process change being considered. For prospective and 

concurrent validation, three consecutive successful production batches should be used 

as a guide, but there may be situations where additional process runs are warranted to 

prove consistency of the process (e.g., complex API processes or API processes with 

prolonged completion times). For retrospective validation, generally data from 10 to 30 

consecutive batches should be examined to assess process consistency, but fewer 

batches can be examined if justified.

12.51 Critical process parameters should be controlled and monitored during process 

validation studies. Process parameters unrelated to quality, such as variables controlled 

to minimize energy consumption or equipment use, need not be included in the process 

validation. 

12.52 Process validation should confirm that the impurity profile for each API is within the 

limits specified. The impurity profile should be comparable to or better than historical 

data and, where applicable, the profile determined during process development or for 

batches used for pivotal clinical and toxicological studies.

12.6 Periodic Review of Validated Systems

12.60 Systems and processes should be periodically evaluated to verify that they are still 

operating in a valid manner. Where no significant changes have been made to the 

system or process, and a quality review confirms that the system or process is 

consistently producing material meeting its specifications, there is normally no need for 

revalidation. 
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12.7 Cleaning Validation

12.70 Cleaning procedures should normally be validated. In general, cleaning validation 

should be directed to situations or process steps where contamination or carryover of 

materials poses the greatest risk to API quality. For example, in early production it 

may be unnecessary to validate equipment cleaning procedures where residues are 

removed by subsequent purification steps.

12.71 Validation of cleaning procedures should reflect actual equipment usage patterns. If 

various APIs or intermediates are manufactured in the same equipment and the 

equipment is cleaned by the same process, a representative intermediate or API can be 

selected for cleaning validation. This selection should be based on the solubility and 

difficulty of cleaning and the calculation of residue limits based on potency, toxicity, 

and stability.

12.72 The cleaning validation protocol should describe the equipment to be cleaned, 

procedures, materials, acceptable cleaning levels, parameters to be monitored and 

controlled, and analytical methods. The protocol should also indicate the type of 

samples to be obtained and how they are collected and labeled. 

12.73 Sampling should include swabbing, rinsing, or alternative methods (e.g., direct 

extraction), as appropriate, to detect both insoluble and soluble residues. The sampling 

methods used should be capable of quantitatively measuring levels of residues 

remaining on the equipment surfaces after cleaning. Swab sampling may be 

impractical when product contact surfaces are not easily accessible due to equipment 

design and/or process limitations (e.g., inner surfaces of hoses, transfer pipes, reactor 

tanks with small ports or handling toxic materials, and small intricate equipment such 

as micronizers and microfluidizers).

12.74 Validated analytical methods having sensitivity to detect residues or contaminants 

should be used. The detection limit for each analytical method should be sufficiently 

sensitive to detect the established acceptable level of the residue or contaminant. The 

method’s attainable recovery level should be established. Residue limits should be 

practical, achievable, verifiable, and based on the most deleterious residue. Limits can 

be established based on the minimum known pharmacological, toxicological, or 

physiological activity of the API or its most deleterious component. 

12.75 Equipment cleaning/sanitization studies should address microbiological and endotoxin 

contamination for those processes where there is a need to reduce total microbiological 

count or endotoxins in the API, or other processes where such contamination could be 

of concern (e.g., non-sterile APIs used to manufacture sterile products).

12.76 Cleaning procedures should be monitored at appropriate intervals after validation to 

ensure that these procedures are effective when used during routine production. 

Equipment cleanliness can be monitored by analytical testing and visual examination, 

where feasible. Visual inspection can allow detection of gross contamination 
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concentrated in small areas that could otherwise go undetected by sampling and/or 

analysis.

12.8 Validation of Analytical Methods

12.80 Analytical methods should be validated unless the method employed is included in the 

relevant pharmacopoeia or other recognized standard reference. The suitability of all 

testing methods used should nonetheless be verified under actual conditions of use and 

documented. 

12.81 Methods should be validated to include consideration of characteristics included within 

the VICH guidelines on validation of analytical methods. The degree of analytical 

validation performed should reflect the purpose of the analysis and the stage of the API 

production process. 

12.82 Appropriate qualification of analytical equipment should be considered before starting 

validation of analytical methods. 

12.83 Complete records should be maintained of any modification of a validated analytical 

method. Such records should include the reason for the modification and appropriate 

data to verify that the modification produces results that are as accurate and reliable as 

the established method. 

13. CHANGE CONTROL

13.10 A formal change control system should be established to evaluate all changes that may 

affect the production and control of the intermediate or API.

13.11 Written procedures should provide for the identification, documentation, appropriate 

review, and approval of changes in raw materials, specifications, analytical methods, 

facilities, support systems, equipment (including computer hardware), processing steps, 

labeling and packaging materials, and computer software. 

13.12 Any proposals for GMP relevant changes should be drafted, reviewed, and approved by 

the appropriate organizational units, and reviewed and approved by the quality unit(s). 

13.13 The potential impact of the proposed change on the quality of the intermediate or API 

should be evaluated. A classification procedure may help in determining the level of 

testing, validation, and documentation needed to justify changes to a validated process. 

Changes can be classified (e.g., as minor or major) depending on the nature and extent 

of the changes, and the effects these changes may impart on the process. Scientific 

judgement should determine what additional testing and validation studies are 

appropriate to justify a change in a validated process. 

13.14 When implementing approved changes, measures should be taken to ensure that all 

documents affected by the changes are revised.
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13.15 After the change has been implemented, there should be an evaluation of the first 

batches produced or tested under the change. 

13.16 The potential for critical changes to affect established retest or expiry dates should be 

evaluated. If necessary, samples of the intermediate or API produced by the modified 

process can be placed on an accelerated stability program and/or can be added to the 

stability monitoring program.

13.17 Current dosage form manufacturers should be notified of changes from established 

production and process control procedures that can impact the quality of the API. 

14. REJECTION AND RE-USE OF MATERIALS

14.1 Rejection

14.10 Intermediates and APIs failing to meet established specifications should be identified as 

such and quarantined. These intermediates or APIs can be reprocessed or reworked as 

described below. The final disposition of rejected materials should be recorded. 

14.2 Reprocessing

14.20 Introducing an intermediate or API, including one that does not conform to standards or 

specifications, back into the process and reprocessing by repeating a crystallization step 

or other appropriate chemical or physical manipulation steps (e.g., distillation, 

filtration, chromatography, milling) that are part of the established manufacturing 

process is generally considered acceptable. However, if such reprocessing is used for a 

majority of batches, such reprocessing should be included as part of the standard 

manufacturing process. 

14.21 Continuation of a process step after an in-process control test has shown that the step is 

incomplete is considered to be part of the normal process. This is not considered to be 

reprocessing.

14.22 Introducing unreacted material back into a process and repeating a chemical reaction is 

considered to be reprocessing unless it is part of the established process. Such 

reprocessing should be preceded by careful evaluation to ensure that the quality of the 

intermediate or API is not adversely impacted due to the potential formation of byproducts and over-reacted materials.

14.3 Reworking

14.30 Before a decision is taken to rework batches that do not conform to established 

standards or specifications, an investigation into the reason for non-conformance should 

be performed.

14.31 Batches that have been reworked should be subjected to appropriate evaluation, testing, 

stability testing if warranted, and documentation to show that the reworked product is 

of equivalent quality to that produced by the original process. Concurrent validation is 
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often the appropriate validation approach for rework procedures. This allows a 

protocol to define the rework procedure, how it will be carried out, and the expected 

results. If there is only one batch to be reworked, then a report can be written and the 

batch released once it is found to be acceptable.

14.32 Procedures should provide for comparing the impurity profile of each reworked batch 

against batches manufactured by the established process. Where routine analytical 

methods are inadequate to characterize the reworked batch, additional methods should 

be used. 

14.4 Recovery of Materials and Solvents 

14.40 Recovery (e.g., from mother liquor or filtrates) of reactants, intermediates, or the API is 

considered acceptable, provided that approved procedures exist for the recovery and the 

recovered materials meet specifications suitable for their intended use.

14.41 Solvents can be recovered and reused in the same processes or in different processes, 

provided that the recovery procedures are controlled and monitored to ensure that 

solvents meet appropriate standards before reuse or co-mingling with other approved 

materials.

14.42 Fresh and recovered solvents and reagents can be combined if adequate testing has 

shown their suitability for all manufacturing processes in which they may be used. 

14.43 The use of recovered solvents, mother liquors, and other recovered materials should be 

adequately documented. 

14.5 Returns

14.50 Returned intermediates or APIs should be identified as such and quarantined. 

14.51 If the conditions under which returned intermediates or APIs have been stored or 

shipped before or during their return or the condition of their containers casts doubt on 

their quality, the returned intermediates or APIs should be reprocessed, reworked, or 

destroyed, as appropriate.

14.52 Records of returned intermediates or APIs should be maintained. For each return, 

documentation should include: 

- Name and address of the consignee; 

- Intermediate or API, batch number, and quantity returned; 

- Reason for return; and 

- Use or disposal of the returned intermediate or API

15. COMPLAINTS AND RECALLS

15.10 All quality-related complaints, whether received orally or in writing, should be 
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recorded and investigated according to a written procedure. 

15.11 Complaint records should include: 

- Name and address of complainant; 

- Name (and, where appropriate, title) and phone number of person submitting the 

complaint; 

- Complaint nature (including name and batch number of the API);

- Date complaint is received;

- Action initially taken (including dates and identity of person taking the action); 

- Any follow-up action taken;

- Response provided to the originator of complaint (including date response sent); 

and 

- Final decision on intermediate or API batch or lot.

15.12 Records of complaints should be retained in order to evaluate trends, product-related 

frequencies, and severity with a view to taking additional, and if appropriate, immediate 

corrective action.

15.13 There should be a written procedure that defines the circumstances under which a recall 

of an intermediate or API should be considered.

15.14 The recall procedure should designate who should be involved in evaluating the 

information, how a recall should be initiated, who should be informed about the recall, 

and how the recalled material should be treated.

15.15 In the event of a serious or potentially life-threatening situation, local, national, and/or 

international authorities should be informed and their advice sought. 

16. CONTRACT MANUFACTURERS (INCLUDING LABORATORIES)

16.10 All contract manufacturers (including laboratories) should comply with the GMP 

recommended in this guidance. Special consideration should be given to the prevention 

of cross-contamination and to maintaining traceability. 

16.11 Contract manufacturers (including laboratories) should be evaluated by the contract 

giver to ensure GMP compliance of the specific operations occurring at the contract 

sites.

16.12 There should be a written and approved contract or formal agreement between the 

contract giver and the contract acceptor that defines in detail the GMP responsibilities, 

including the quality measures, of each party. 
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16.13 The contract should permit the contract giver to audit the contract acceptor’s facilities 

for compliance with GMP.

16.14 Where subcontracting is allowed, the contract acceptor should not pass to a third party 

any of the work entrusted to him under the contract without the contract giver’s prior 

evaluation and approval of the arrangements. 

16.15 Manufacturing and laboratory records should be kept at the site where the activity 

occurs and be readily available.

16.16 Changes in the process, equipment, test methods, specifications, or other contractual 

requirements should not be made unless the contract giver is informed and approves the 

changes.

17. AGENTS, BROKERS, TRADERS, DISTRIBUTORS, REPACKERS, AND 

RELABELERS

17.1 Applicability

17.10 This section applies to any party other than the original manufacturer who may trade 

and/or take possession, repack, relabel, manipulate, distribute, or store an API or 

intermediate.

17.11 All agents, brokers, traders, distributors, repackers, and relabelers should comply with 

GMP as defined in this guidance. 

17.2 Traceability of Distributed APIs and Intermediates

17.20 Agents, brokers, traders, distributors, repackers, or relabelers should maintain complete 

traceability of APIs and intermediates that they distribute. Documents that should be 

retained and available include:

- Identity of original manufacturer; 

- Address of original manufacturer; 

- Purchase orders; 

- Bills of lading (transportation documentation); 

- Receipt documents; 

- Name or designation of API or intermediate; 

- Manufacturer’s batch number; 

- Transportation and distribution records; 

- All authentic Certificates of Analysis, including those of the original 

manufacturer; and 

- Retest or expiry date
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17.3 Quality Management

17.30 Agents, brokers, traders, distributors, repackers, or relabelers should establish, 

document, and implement an effective system of managing quality, as specified in 

section 2. Quality Management. 

17.4 Repackaging, Relabeling and Holding of APIs and Intermediates

17.40 Repackaging, relabeling, and holding of APIs and intermediates should be performed 

under appropriate GMP controls, as recommended in this guidance, to avoid mix-ups 

and loss of API or intermediate identity or purity.

17.41 Repackaging should be conducted under appropriate environmental conditions to avoid 

contamination and cross-contamination. 

17.5 Stability

17.50 Stability studies to justify assigned expiration or retest dates should be conducted if the 

API or intermediate is repackaged in a different type of container than that used by the 

API or intermediate manufacturer.

17.6 Transfer of Information

17.60 Agents, brokers, distributors, repackers, or relabelers should transfer all quality or 

regulatory information received from an API or intermediate manufacturer to the 

customer, and from the customer to the API or intermediate manufacturer.

17.61 The agent, broker, trader, distributor, repacker, or relabeler who supplies the API or 

intermediate to the customer should provide the name of the original API or 

intermediate manufacturer and the batch number(s) supplied.

17.62 The agent should also provide the identity of the original API or intermediate 

manufacturer to regulatory authorities upon request. The original manufacturer can 

respond to the regulatory authority directly or through its authorized agents, depending 

on the legal relationship between the authorized agents and the original API or 

intermediate manufacturer. (In this context “authorized” refers to authorized by the 

manufacturer.) 

17.63 The specific guidance for Certificates of Analysis included in section 11.4 Certificates 

of Analysis should be met. 

17.7 Handling of Complaints and Recalls

17.70 Agents, brokers, traders, distributors, repackers, or relabelers should maintain records 

of complaints and recalls, as specified in section 15. Complaints and Recalls, for all 

complaints and recalls that come to their attention.
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17.71 If the situation warrants, the agents, brokers, traders, distributors, repackers, or 

relabelers should review the complaint with the original API or intermediate 

manufacturer in order to determine whether any further action, either with other 

customers who may have received this API or intermediate or with the regulatory 

authority, or both, should be initiated. The investigation into the cause for the 

complaint or recall should be conducted and documented by the appropriate party. 

17.72 Where a complaint is referred to the original API or intermediate manufacturer, the 

record maintained by the agents, brokers, traders, distributors, repackers, or relabelers 

should include any response received from the original API or intermediate 

manufacturer (including date and information provided). 

17.8 Handling of Returns

17.80 Returns should be handled as specified in Section 14.52. The agents, brokers, traders, 

distributors, repackers, or relabelers should maintain documentation of returned APIs 

and intermediates.

18. SPECIFIC GUIDANCE FOR APIs MANUFACTURED BY CELL 

CULTURE/FERMENTATION

18.1 General

18.10 This section is intended to address specific controls for APIs or intermediates 

manufactured by cell culture or fermentation using natural or recombinant organisms 

and that have not been covered adequately in the previous sections. It is not intended to 

be a stand-alone section. In general, the GMP principles in the other sections of this 

document apply. Note that the principles of fermentation for “classical” processes for 

production of small molecules and for processes using recombinant and nonrecombinant organisms for production of proteins and/or polypeptides are the same, 

although the degree of control will differ. Where practical, this section will address 

these differences. In general, the degree of control for biotechnological processes used 

to produce proteins and polypeptides is greater than that for classical fermentation 

processes.

18.11 The term “biotechnological process” refers to the use of cells or organisms that have 

been generated or modified by recombinant DNA, hybridoma, or other why technology 

to produce APIs. The APIs produced by biotechnological processes normally consist of 

high molecular weight substances, such as proteins and polypeptides, for which specific 

guidance is given in this section. Certain APIs of low molecular weight, such as 

antibiotics, amino acids, vitamins, and carbohydrates, can also be produced by 

recombinant DNA technology. The level of control for these types of APIs is similar to 

that employed for classical fermentation.

18.12 The term “classical fermentation” refers to processes that use microorganisms existing 

in nature and/or modified by conventional methods (e.g., irradiation or chemical 

mutagenesis) to produce APIs. APIs produced by “classical fermentation” are normally 
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low molecular weight products such as antibiotics, amino acids, vitamins, and 

carbohydrates. 

18.13 Production of APIs or intermediates from cell culture or fermentation involves 

biological processes such as cultivation of cells or extraction and purification of 

material from living organisms. Note that there may be additional process steps, such 

as physicochemical modification, that are part of the manufacturing process. The raw 

materials used (media, buffer components) may provide the potential for growth of 

microbiological contaminants. Depending on the source, method of preparation, and 

the intended use of the API or intermediate, control of bioburden, viral contamination, 

and/or endotoxins during manufacturing and monitoring of the process at appropriate 

stages may be necessary.

18.14 Appropriate controls should be established at all stages of manufacturing to ensure 

intermediate and/or API quality. While this guidance starts at the cell

culture/fermentation step, prior steps (e.g., cell banking) should be performed under 

appropriate process controls. This guidance covers cell culture/fermentation from the 

point at which a vial of the cell bank is retrieved for use in manufacturing. 

18.15 Appropriate equipment and environmental controls should be used to minimize the risk 

of contamination. The acceptance criteria for quality of the environment and the 

frequency of monitoring should depend on the step in production and the production 

conditions (open, closed, or contained systems). 

18.16 In general, process controls should take into account: 

- Maintenance of the Working Cell Bank (where appropriate); 

- Proper inoculation and expansion of the culture; 

- Control of the critical operating parameters during fermentation/cell culture;

- Monitoring of the process for cell growth, viability (for most cell culture 

processes), and productivity where appropriate; 

- Harvest and purification procedures that remove cells, cellular debris, and 

media components while protecting the intermediate or API from contamination 

(particularly of a microbiological nature) and from loss of quality;

- Monitoring of bioburden and, where needed, endotoxin levels at appropriate 

stages of production; and 

- Viral safety concerns as described in draft ICH Guidance, “Q5A(R2), “Viral 

Safety Evaluation of Biotechnology Products Derived from Cell Lines of 

Human or Animal Origin.”3

3 https://www.fda.gov/media/163115/download (September 2022). When final, this guidance will represent FDA’s 

current thinking on this topic.
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18.17 Where appropriate, the removal of media components, host cell proteins, other processrelated impurities, product-related impurities, and contaminants should be 

demonstrated. 

18.2 Cell Bank Maintenance and Record Keeping

18.20 Access to cell banks should be limited to authorized personnel. 

18.21 Cell banks should be maintained under storage conditions designed to maintain 

viability and prevent contamination.

18.22 Records of the use of the vials from the cell banks and storage conditions should be 

maintained.

18.23 Where appropriate, cell banks should be periodically monitored to determine suitability 

for use. 

18.24 See ICH Guidance Q5D, “Quality of Biotechnological Products: Derivation and 

Characterization of Cell Substrates Used for Production of Biotechnological/Biological 

Products,”4

 for a more complete discussion of cell banking. 

18.3 Cell Culture/Fermentation

18.30 Where aseptic addition of cell substrates, media, buffers, and gases is needed, closed or 

contained systems should be used where possible. If the inoculation of the initial vessel 

or subsequent transfers or additions (media, buffers) are performed in open vessels, 

there should be controls and procedures in place to minimize the risk of contamination. 

18.31 Where the quality of the API can be affected by microbial contamination,

manipulations using open vessels should be performed in a biosafety cabinet or 

similarly controlled environment.

18.32 Personnel should be appropriately gowned and take special precautions handling the 

cultures.

18.33 Critical operating parameters (for example temperature, pH, agitation rates, addition of 

gases, pressure) should be monitored to ensure consistency with the established 

process. Cell growth, viability (for most cell culture processes), and, where 

appropriate, productivity should also be monitored. Critical parameters will vary from 

one process to another, and for classical fermentation, certain parameters (cell viability, 

for example) may not need to be monitored. 

18.34 Cell culture equipment should be cleaned and sterilized after use. As appropriate, 

fermentation equipment should be cleaned, and sanitized or sterilized. 

4 https://www.fda.gov/media/71463/download (September 1998)
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18.35 Culture media should be sterilized before use when appropriate to protect the quality of 

the API.

18.36 There should be appropriate procedures in place to detect contamination and determine 

the course of action to be taken. This should include procedures to determine the 

impact of the contamination on the product and those to decontaminate the equipment 

and return it to a condition to be used in subsequent batches. Foreign organisms 

observed during fermentation processes should be identified as appropriate and the 

effect of their presence on product quality should be assessed, if necessary. The results 

of such assessments should be taken into consideration in the disposition of the material 

produced. 

18.37 Records of contamination events should be maintained. 

18.38 Shared (multi-product) equipment may warrant additional testing after cleaning 

between product campaigns, as appropriate, to minimize the risk of crosscontamination. 

18.4 Harvesting, Isolation and Purification

18.40 Harvesting steps, either to remove cells or cellular components or to collect cellular 

components after disruption, should be performed in equipment and areas designed to 

minimize the risk of contamination.

18.41 Harvest and purification procedures that remove or inactivate the producing organism, 

cellular debris and media components (while minimizing degradation, contamination, 

and loss of quality) should be adequate to ensure that the intermediate or API is 

recovered with consistent quality. 

18.42 All equipment should be properly cleaned and, as appropriate, sanitized after use. 

Multiple successive batching without cleaning can be used if intermediate or API 

quality is not compromised.

18.43 If open systems are used, purification should be performed under environmental 

conditions appropriate for the preservation of product quality. 

18.44 Additional controls, such as the use of dedicated chromatography resins or additional 

testing, may be appropriate if equipment is to be used for multiple products. 

18.5 Viral Removal/Inactivation steps

18.50 See draft ICH Guidance Q5A(R2), “Viral Safety Evaluation of Biotechnology Products 

Derived from Cell Lines of Human or Animal Origin,” for more specific information. 

18.51 Viral removal and viral inactivation steps are critical processing steps for some 

processes and should be performed within their validated parameters. 
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18.52 Appropriate precautions should be taken to prevent potential viral contamination from 

pre-viral to post-viral removal/inactivation steps. Therefore, open processing should be 

performed in areas that are separate from other processing activities and have separate 

air handling units.

18.53 The same equipment is not normally used for different purification steps. However, if 

the same equipment is to be used, the equipment should be appropriately cleaned and 

sanitized before reuse. Appropriate precautions should be taken to prevent potential 

virus carry-over (e.g., through equipment or environment) from previous steps. 

19. APIs FOR USE IN CLINICAL TRIALS

19.1 General

19.10 Not all the controls in the previous sections of this guidance are appropriate for the 

manufacture of a new API for investigational use during its development. Section 19. 

APIs for Use in Clinical Trials provides specific guidance unique to these 

circumstances.

19.11 The controls used in the manufacture of APIs for use in clinical trials should be 

consistent with the stage of development of the drug product incorporating the API. 

Process and test procedures should be flexible to provide for changes as knowledge of 

the process increases and clinical testing of a drug product progresses from pre-clinical 

stages through clinical stages. Once drug development reaches the stage where the API 

is produced for use in drug products intended for clinical trials as specified in GFI #85 

(VICH GL9), “Good Clinical Practice, manufacturers should ensure that APIs are 

manufactured in suitable facilities using appropriate production and control procedures 

to ensure the quality of the API. 

19.2 Quality

19.20 Appropriate GMP concepts should be applied in the production of APIs for use in 

clinical trials with a suitable mechanism of approval of each batch.

19.21 A quality unit(s) independent from production should be established for the approval or 

rejection of each batch of API for use in clinical trials.

19.22 Some of the testing functions commonly performed by the quality unit(s) can be 

performed within other organizational units. 

19.23 Quality measures should include a system for testing of raw materials, packaging 

materials, intermediates, and APIs.

19.24 Process and quality problems should be evaluated. 

19.25 Labeling for APIs intended for use in clinical trials should be appropriately controlled 

and should identify the material as being for investigational use. 
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19.3 Equipment and Facilities

19.30 During all phases of clinical development, including the use of small-scale facilities or 

laboratories to manufacture batches of APIs for use in clinical trials, procedures should 

be in place to ensure that equipment is calibrated, clean, and suitable for its intended 

use.

19.31 Procedures for the use of facilities should ensure that materials are handled in a manner 

that minimizes the risk of contamination and cross-contamination.

19.4 Control of Raw Materials 

19.40 Raw materials used in production of APIs for use in clinical trials should be evaluated 

by testing or received with a supplier’s analysis and subjected to identity testing. When 

a material is considered hazardous, a supplier’s analysis should suffice.

19.41 In some instances, the suitability of a raw material can be determined before use based 

on acceptability in small-scale reactions (i.e., use testing) rather than on analytical 

testing alone. 

19.5 Production

19.50 The production of APIs for use in clinical trials should be documented in laboratory 

notebooks, batch records, or by other appropriate means. These documents should 

include information on the use of production materials, equipment, processing, and 

scientific observations.

19.51 Expected yields can be more variable and less defined than the expected yields used in 

commercial processes. Investigations into yield variations are not expected.

19.6 Validation

19.60 Process validation for the production of APIs for use in clinical trials is normally 

inappropriate, where a single API batch is produced or where process changes during 

API development make batch replication difficult or inexact. The combination of 

controls, calibration, and, where appropriate, equipment qualification ensures API 

quality during this development phase. 

19.61 Process validation should be conducted in accordance with section 12. Validation when 

batches are produced for commercial use, even when such batches are produced on a 

pilot or small scale.

19.7 Changes

19.70 Changes are expected during development, as knowledge is gained and the production 

is scaled up. Every change in the production, specifications, or test procedures should 

be adequately recorded.
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19.8 Laboratory Controls 

19.80 While analytical methods performed to evaluate a batch of API for clinical trials may 

not yet be validated, they should be scientifically sound. 

19.81 A system for retaining reserve samples of all batches should be in place. This system 

should ensure that a sufficient quantity of each reserve sample is retained for an 

appropriate length of time after approval, termination, or discontinuation of an 

application. 

19.82 Expiry and retest dating as defined in section 11.6 Expiry and Retest Dating applies to 

existing APIs used in clinical trials. For new APIs, section 11.6 does not normally 

apply in early stages of clinical trials.

19.9 Documentation

19.90 A system should be in place to ensure that information gained during the development 

and the manufacture of APIs for use in clinical trials is documented and available.

19.91 The development and implementation of the analytical methods used to support the 

release of a batch of API for use in clinical trials should be appropriately documented. 

19.92 A system for retaining production and control records and documents should be used. 

This system should ensure that records and documents are retained for an appropriate 

length of time after the approval, termination, or discontinuation of an application. 

20. GLOSSARY

Acceptance Criteria: Numerical limits, ranges, or other suitable measures for acceptance of test 

results.

Active Pharmaceutical Ingredient (API) (or Drug Substance): Any substance or mixture of 

substances intended to be used in the manufacture of a veterinary medicinal product and that, 

when used in the production of a drug, becomes an active ingredient of the drug product. 

API Starting Material: A raw material, intermediate, or an API that is used in the production 

of an API and that is incorporated as a significant structural fragment into the structure of the 

API. An API Starting Material can be an article of commerce, a material purchased from one or 

more suppliers under contract or commercial agreement, or produced in-house. API Starting 

Materials are normally of defined chemical properties and structure.

Batch (or Lot): A specific quantity of material produced in a process or series of processes so 

that it is expected to be homogeneous within specified limits. In the case of continuous 

production, a batch may correspond to a defined fraction of the production. The batch size can 

be defined either by a fixed quantity or by the amount produced in a fixed time interval.
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Batch Number (or Lot Number): A unique combination of numbers, letters, and/or symbols 

that identifies a batch (or lot) and from which the production and distribution history can be 

determined. 

Bioburden: The level and type (e.g., objectionable or not) of micro-organisms that can be 

present in raw materials, API starting materials, intermediates or APIs. Bioburden should not be 

considered contamination unless the levels have been exceeded or defined objectionable 

organisms have been detected.

Calibration: The demonstration that a particular instrument or device produces results within 

specified limits by comparison with those produced by a reference or traceable standard over an 

appropriate range of measurements.

Computer System: A group of hardware components and associated software, designed, and 

assembled to perform a specific function or group of functions. 

Computerized System: A process or operation integrated with a computer system. 

 

Contamination: The undesired introduction of impurities of a chemical or microbiological 

nature, or of foreign matter, into or onto a raw material, intermediate, or API during production, 

sampling, packaging, or repackaging, storage, or transport. 

Contract Manufacturer: A manufacturer performing some aspect of manufacturing on behalf 

of the original manufacturer.

Critical: Describes a process step, process condition, test requirement, or other relevant 

parameter or item that must be controlled within predetermined criteria to ensure that the API 

meets its specification.

Cross-Contamination: Contamination of a material or product with another material or 

product. 

Deviation: Departure from an approved instruction or established standard. 

Drug (Medicinal) Product: The dosage form in the final immediate packaging intended for 

marketing. (Reference GFI #73 (VICH GL3(R)), “Stability Testing of New Veterinary Drug 

Substances and Medicinal Products (Revision)”5

) 

Drug Substance: See Active Pharmaceutical Ingredient

Expiry Date (or Expiration Date): The date placed on the container/labels of an API 

designating the time during which the API is expected to remain within established shelf-life

specifications if stored under defined conditions, and after which it should not be used. 

5 https://www.fda.gov/media/70241/download (November 2007)
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Impurity: Any component present in the intermediate or API that is not the desired entity. 

Impurity Profile: A description of the identified and unidentified impurities present in an API.

In-Process Control (or Process Control): Checks performed during production in order to 

monitor and, if appropriate, to adjust the process and/or to ensure that the intermediate or API 

conforms to its specifications.

Intermediate: A material produced during steps of the processing of an API that undergoes 

further molecular change or purification before it becomes an API. Intermediates may or may 

not be isolated. (Note: this guidance only addresses those intermediates produced after the point 

that the company has defined as the point at which the production of the API begins.) 

Lot: See Batch

 

Lot Number: See Batch Number

Manufacture: All operations of receipt of materials, production, packaging, repackaging, 

labeling, relabeling, quality control, release, storage, and distribution of APIs and related 

controls.

Material: A general term used to denote raw materials (starting materials, reagents, solvents), 

process aids, intermediates, APIs, and packaging and labeling materials.

Mother Liquor: The residual liquid which remains after the crystallization or isolation 

processes. A mother liquor may contain unreacted materials, intermediates, levels of the API 

and/or impurities. It may be used for further processing.

Packaging Material: Any material intended to protect an intermediate or API during storage 

and transport. 

Procedure: A documented description of the operations to be performed, the precautions to be 

taken, and measures to be applied directly or indirectly related to the manufacture of an 

intermediate or API.

Process Aids: Materials, excluding solvents, used as an aid in the manufacture of an 

intermediate or API that do not themselves participate in a chemical or biological reaction (e.g., 

filter aid, activated carbon, etc.).

Process Control: See In-Process Control. 

Production: All operations involved in the preparation of an API from receipt of materials 

through processing and packaging of the API. 

Qualification: Action of proving and documenting that equipment or ancillary systems are 

properly installed, work correctly, and actually lead to the expected results. Qualification is part 
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of validation, but the individual qualification steps alone do not constitute process validation. 

Quality Assurance (QA): The sum total of the organized arrangements made with the object of 

ensuring that all APIs are of the quality required for their intended use and that quality systems 

are maintained.

Quality Control (QC): Checking or testing that specifications are met.

Quality Unit(s): An organizational unit independent of production which fulfills both Quality 

Assurance and Quality Control responsibilities. This can be in the form of separate QA and QC 

units or a single individual or group, depending upon the size and structure of the organization. 

Quarantine: The status of materials isolated physically or by other effective means pending a 

decision on their subsequent approval or rejection. 

Raw Material: A general term used to denote starting materials, reagents, and solvents intended 

for use in the production of intermediates or APIs.

Reference Standard, Primary: A substance that has been shown by an extensive set of 

analytical tests to be authentic material that should be of high purity. This standard can be: (1) 

obtained from an officially recognized source, (2) prepared by independent synthesis, (3) 

obtained from existing production material of high purity, or (4) prepared by further purification 

of existing production material. 

Reference Standard, Secondary: A substance of established quality and purity, as shown by 

comparison to a primary reference standard, used as a reference standard for routine laboratory 

analysis.

Reprocessing: Introducing an intermediate or API, including one that does not conform to 

standards or specifications, back into the process and repeating a crystallization step or other 

appropriate chemical or physical manipulation steps (e.g., distillation, filtration, chromatography, 

milling) that are part of the established manufacturing process. Continuation of a process step 

after an in-process control test has shown that the step is incomplete is considered to be part of 

the normal process, and not reprocessing. 

Retest Date: The date when a material should be re-examined to ensure that it is still suitable 

for use. 

Reworking: Subjecting an intermediate or API that does not conform to standards or 

specifications to one or more processing steps that are different from the established 

manufacturing process to obtain acceptable quality intermediate or API (e.g., recrystallizing with 

a different solvent).

Signature (signed): See Signed 
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Signed (signature): The record of the individual who performed a particular action or review. 

This record can be initials, full handwritten signature, personal seal, or authenticated and secure 

electronic signature.

Solvent: An inorganic or organic liquid used as a vehicle for the preparation of solutions or 

suspensions in the manufacture of an intermediate or API. 

Specification: A list of tests, references to analytical procedures, and appropriate acceptance 

criteria that are numerical limits, ranges, or other criteria for the test described. It establishes the 

set of criteria to which a material should conform to be considered acceptable for its intended 

use. “Conformance to specification” means that the material, when tested according to the listed 

analytical procedures, will meet the listed acceptance criteria.

Validation: A documented program that provides a high degree of assurance that a specific 

process, method, or system will consistently produce a result meeting pre-determined acceptance 

criteria.

Validation Protocol: A written plan stating how validation will be conducted and defining 

acceptance criteria. For example, the protocol for a manufacturing process identifies processing 

equipment, critical process parameters/operating ranges, product characteristics, sampling, test 

data to be collected, number of validation runs, and acceptable test results.

Yield, Expected: The quantity of material or the percentage of theoretical yield anticipated at 

any appropriate phase of production based on previous laboratory, pilot scale, or manufacturing 

data.

Yield, Theoretical: The quantity that would be produced at any appropriate phase of 

production, based upon the quantity of material to be used, in the absence of any loss or error in 

actual production. 

21. REFERENCES

GFI #73 (VICH GL3(R)), “Stability Testing of New Veterinary Drug Substances and Medicinal 

Products (Revision),” November 2007 

GFI #85 (VICH GL9), “Good Clinical Practice,” May 2001 

GFI #177 (VICH GL40), “Specifications: Test Procedures/Acceptance Criteria for New 

Biotechnological/Biological New Veterinary Medicinal Products,” June 2006