#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Draft Guidance 
 
This guidance document is being distributed for comment purposes only. 
 
Submit comments on this draft guidance by the dated provided in the Federal Register notice 
announcing the availability of the draft guidance.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Additional copies of this draft guidance document may be requested from the Policy and 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-fda-
guidance-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 
 
 
 
 
G M P
OOD  ANUFACTURING  RACTICE FOR 
ACTIVE PHARMACEUTICAL INGREDIENTS 
V M
USED IN  ETERINARY  EDICINAL 
P  
RODUCTS
 
 
 
 
 
 
 
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. 
 
 
 
    Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
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, FDAs guidance documents do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys 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 in-
house.  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  Application of this guidance to steps (shown in grey with an asterisk) used in 
Manufacturing  this type of manufacturing 
*Introduction 
Production of  *Physical 
of the API  *Isolation 
Chemical  the API  *Production of  processing 
Starting  and 
Manufacturing  Starting  Intermediate(s)  and 
Material into  purification 
Material  packaging 
process 
Cutting,  *Introduction 
*Physical 
API derived  Collection of  mixing,  of the API  *Isolation 
processing 
from animal  organ, fluid, or  and/or  Starting  and 
and 
sources  tissue  initial  Material into  purification 
packaging 
processing  process 
*Introduction 
*Physical 
API extracted  Cutting and  of the API  *Isolation 
Collection of  processing 
from plant  initial  Starting  and 
plants  and 
sources  extraction(s)  Material into  purification 
packaging 
process 
*Physical 
Cutting and 
Herbal extracts  Collection of  *Further  processing 
initial   
used as API  plants  extraction  and 
extraction 
packaging 
API consisting  Collection of  *Physical 
of comminuted  plants and/or  Cutting/  processing 
   
or powdered  cultivation and  comminuting  and 
herbs  harvesting  packaging 
Establishment 
*Physical 
Biotechnology:  of master cell  *Maintenance  *Cell culture  *Isolation 
processing 
fermentation/  bank and  of working  and/or  and 
and 
cell culture  working cell  cell bank  fermentation  purification 
packaging 
bank 
*Physical 
Classical  Maintenance  *Introduction  *Isolation 
Establishment  processing 
Fermentation to  of the cell  of the cells into  and 
of cell bank  and 
produce an API  bank  fermentation  purification 
packaging 
 
Increasing GMP requirements 
 
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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 cross- 
contamination 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 back-
up 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 cross- 
references 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 companys control do not need to be 
tested if the manufacturers 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 products 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 
manufacturers 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 companys 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 standards storage and use in 
accordance with the suppliers recommendations.  Primary reference standards obtained 
from an officially recognized source are normally used without testing if stored under 
conditions consistent with the suppliers 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 
manufacturers 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 
manufacturers 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 
methods 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 by-
products 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 acceptors 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 givers 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; 
-  Manufacturers 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 non-
recombinant 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 FDAs 
current thinking on this topic. 
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18.17  Where appropriate, the removal of media components, host cell proteins, other process-
related 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 cross- 
contamination. 
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 suppliers analysis and subjected to identity testing.  When 
a material is considered hazardous, a suppliers 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 
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