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WHO/DRAFT/18 February 2015 2

ENGLISH ONLY 3

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WHO GMP for Biological Products 5

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Proposed replacement of: TRS 822, Annex 1 7

(3rd Draft Version 2, 18FEB2015) 8

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NOTE: 10

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This document has been prepared for the purpose of inviting comments and suggestions on the 12

proposals contained therein, which will then be considered by the Expert Committee on Biological 13

Standardization (ECBS). Publication of this early draft is to provide information about the GMP 14

Guidelines for Biological Products to a broad audience and to improve transparency of the 15

consultation process. 16

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These Guidelines were developed based on the outcomes and consensus of the WHO informal 18

consultation convened in July 2014 with participants from national regulatory authorities, national 19

control laboratories, vaccine manufacturers and academia researchers. 20

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The text in its present form does not necessarily represent an agreed formulation of the 22

Expert Committee on Biological Standardization. Written comments proposing 23

modifications to this text MUST be received by 31 March 2015 in the Comment Form 24

available separately and should be addressed to the World Health Organization, 1211 Geneva 27, 25

Switzerland, attention: Department of Essential Medicines and Health Products (EMP). Comments 26

may also be submitted electronically to the Responsible Officer: Dr Dianliang Lei at email: 27

leid@who.int. 28

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The outcome of the deliberations of the Expert Committee on Biological Standardization will be 30

published in the WHO Technical Report Series. The final agreed formulation of the document will 31

be edited to be in conformity with the "WHO style guide" (WHO/IMD/PUB/04.1). 32

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© World Health Organization 2013 35

All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, 36 World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: 37

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+41 22 791 4857; e-mail: bookorders@who.int). Requests for permission to reproduce or translate WHO 1 publications – whether for sale or for non-commercial distribution – should be addressed to WHO Press, at 2 the above address (fax: +41 22 791 4806; e-mail: permissions@who.int). 3

The designations employed and the presentation of the material in this publication do not imply the 4 expression of any opinion whatsoever on the part of the World Health Organization concerning the legal 5 status of any country, territory, city or area or of its authorities, or concerning the delimitation of its 6 frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not 7 yet be full agreement. 8 9 The mention of specific companies or of certain manufacturers’ products does not imply that they are 10 endorsed or recommended by the World Health Organization in preference to others of a similar nature 11 that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished 12 by initial capital letters. 13 14 All reasonable precautions have been taken by the World Health Organization to verify the information 15 contained in this publication. However, the published material is being distributed without warranty of 16 any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies 17 with the reader. In no event shall the World Health Organization be liable for damages arising from its 18 use. 19

20 The named authors [or editors as appropriate] alone are responsible for the views expressed in this 21

publication. 22

23

Recommendations published by the WHO are intended to be scientific and advisory

in nature. Each of the following sections constitutes guidance for national regulatory

authorities (NRAs) and for manufacturers of biological products. If an NRA so

desires, these Recommendations may be adopted as definitive national requirements,

or modifications may be justified and made by the NRA. It is recommended that

modifications to these Recommendations be made only on condition that

modifications ensure that the product is at least as safe and efficacious as that

prepared in accordance with the recommendations set out below.

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Contents 1

CONTENTS ........................................................................................................................ 3 2

INTRODUCTION .................................................................................................................. 4 3

SCOPE .............................................................................................................................. 4 4

GLOSSARY ......................................................................................................................... 5 5

PRINCIPLES AND GENERAL CONSIDERATION .............................................................................. 9 6

PERSONNEL ..................................................................................................................... 10 7

STARTING AND RAW MATERIALS ......................................................................................... 11 8

SEED LOTS AND CELL BANKS ............................................................................................... 13 9

PREMISES AND EQUIPMENT ................................................................................................ 15 10

CONTAINMENT ................................................................................................................ 16 11

CLEAN ROOMS ................................................................................................................. 17 12

PRODUCTION ................................................................................................................... 18 13

CAMPAIGN PRODUCTION ................................................................................................... 20 14

LABELLING....................................................................................................................... 21 15

VALIDATION .................................................................................................................... 22 16

QUALITY CONTROL ........................................................................................................... 23 17

DOCUMENTATION (LOT PROCESSING RECORDS) ...................................................................... 25 18

USE OF ANIMALS .............................................................................................................. 25 19

PHARMACEUTICAL QUALITY SYSTEM (PQS) AND QUALITY RISK MANAGEMENT ............................ 27 20

REFERENCES .................................................................................................................... 27 21

AUTHORS AND ACKNOWLEDGEMENTS ................................................................................... 30 22

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Introduction 1

The source and methods employed in the manufacture of biological products for 2

human use represent critical factors in shaping the appropriate regulatory control. 3

Biological products can be defined therefore, largely by reference to their method of 4

manufacture and source. Biological products are derived from cells, tissues, or 5

microorganisms and reflect the inherent variability characteristic of living materials. 6

The drug substances in biological products are often too complex to be fully 7

characterized by utilizing physico-chemical testing methods and may show a marked 8

heterogeneity from one preparation to the next. Therefore, special considerations 9

should be taken in manufacturing biological products to maintain the consistency of 10

the quality of product. 11

12

The Good Manufacturing Practices (GMP) for biological products as an annex to 13

GMP for pharmaceutical products was adopted by the Expert Committee on 14

Biological Standardization (ECBS) and published in the WHO Technical Report 15

Series (TRS) in 1992. It has been recognized and used by regulators and industry. 16

This revision reflects the considerable developments and current perspectives of 17

GMP for the manufacture of biological products (1-12). 18

19

This document is intended to serve as a guide for establishing national guidelines for 20

GMP. The main principles and requirements for manufacturing biological products 21

are provided. If an NRA so desires, these guidelines may be adopted as definitive 22

national requirements. It is possible that modifications to this document may be 23

justified due to risk-benefit and legal considerations to each national regulatory 24

authority (NRA). In such case, it is recommended that modification to the principles 25

and technical specification of these guidelines be made only on the condition that the 26

modifications ensure product quality, safety and efficacy at least equivalent to that in 27

these guidelines. 28

29

Scope 30

This guidance document applies to the commercial manufacture and testing of 31

biological products from quality of starting materials and preparations, including 32

control over seed lots, cell banks and intermediates, through finished product and 33

testing. 34

35

Manufacturing procedures within the scope of these guidelines include: 36

growth of strains of microorganisms and eukaryotic cells; 37

extraction of substances from biological tissues, including human, animal, 38

plant tissues and fungi (allergens); 39

recombinant DNA (rDNA) techniques; 40

hybridoma techniques; 41

5

propagation of microorganisms in embryos or animals. 1

2

Biological products manufactured by these methods include allergens, antigens, 3

vaccines, hormones, cytokines, enzymes, human whole blood and plasma 4

derivatives(*)

, immune sera, immunoglobulins (including monoclonal antibodies), 5

products of fermentation (including products derived from rDNA), and diagnostic 6

agents for in vitro use, gene therapy, cell therapy, etc. 7

8

The present guidelines do not lay down detailed recommendations for specific classes 9

of biological products (e.g., vaccines) therefore, attention is directed to other specific 10

guidance documents issued by WHO and in particular, to the recommendations to 11

assure the quality, safety and efficacy of the specific product 12

(http://www.who.int/biologicals/en/). 13

14

Glossary 15

Besides the terms defined in WHO GMP for pharmaceutical products: main 16

principles (1), the definitions given below apply to the terms used in this document. 17

These terms may have different meanings in other contexts. 18

19

Adjuvant: Substances or combinations of substances that are used in conjunction 20

with a vaccine antigen to enhance (e.g., increase, accelerate, prolong and/or possibly 21

target) or modulate a specific immune response to the vaccine antigen in order to 22

enhance the clinical effectiveness of the vaccine. 23

24

Adventitious virus: Unintentionally introduced contaminant virus. 25

26

Allergen: An allergen is a molecule capable of inducing an IgE response and/or a 27

Type I allergic reaction, meaning, mild symptoms (sign/symptom clearly present, but 28

minimal awareness; easily tolerated). 29

30

Antibody: Proteins produced by the B-lymphocytes that bind to specific antigens. 31

Antibodies may be divided into two main types, monoclonal and polyclonal 32

antibodies, based on key differences in their method of manufacture. 33

34

Antigens: The active ingredient in a vaccine against which the immune response is 35

induced. Antigens may be live attenuated or inactivated preparations of bacteria, 36

viruses or parasites; crude cellular fractions or purified antigens, including 37

recombinant proteins (i.e. those derived from recombinant DNA expressed in a host 38

cell); polysaccharides and conjugates formed by covalent linkage of polysaccharides 39

to components such as mutated or inactivated proteins and/or toxoids; venoms; 40

41

(*) NOTE: Good Manufacturing Practices for blood and blood derived products is covered by WHO Technical Report Series, 42

No. 961, 2011. Annex 4, WHO Guidelines on Good Manufacturing Practices for Blood Establishments (11). 43

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synthetic antigens; polynucleotides (such as plasmid DNA vaccines); or living 2

vectored cells expressing specific heterologous antigens. 3

4

Bioburden: The level and type (i.e. objectionable or not) of micro-organisms present 5

in raw materials, media, biological substances, intermediates or finished products. 6

7

Bio-Hazard: Biological material considered to be hazardous to personnel, visitors 8

and/or the environment. 9

10

Biosafety level (BSL): The containment conditions required to safely handle 11

organisms of different hazards ranging from BSL1 (lowest risk, unlikely to cause 12

human disease) to BSL4 (highest risk, cause severe disease, likely to spread and no 13

effective prophylaxis or treatment available). 14

15

Biological starting materials: Raw materials from a biological source that mark the 16

beginning of the manufacturing process of a drug as described in a market 17

authorization (MA) or license application, from which the active ingredient is derived 18

either directly (e.g., plasma derivatives, ascitic fluid, bovine lung, etc.) or indirectly 19

( e.g. cell substrates, host/vector production cells, eggs, viral strains, etc.). 20

21

Campaign manufacture: The manufacture of a series of batches of the same product 22

in sequence in a given period of time followed by strict adherence to accepted control 23

measures before transfer to another product. The products are not run at the same 24

time but may be run on the same equipment. 25

26

Cell Bank: A collection of appropriate containers whose contents are of uniform 27

composition, stored under defined conditions. Each container represents an aliquot of 28

a single pool of cells. 29

30

Cell Culture: Maintenance or propagation of mammalian, human, or insect cells in 31

vitro (bioreactor). Cell cultures are operated and processed under axenic conditions to 32

ensure a pure culture absent of microbial contamination. 33

34

Cell stock: Cells expanded to a given number of cells to be aliquoted and used as 35

starting material for production of a limited number of lots of a cell based medicinal 36

product. 37

38

Clean area: An area maintained and controlled to prevent contamination of 39

pharmaceutical products with microorganisms or foreign substances, in compliance 40

with defined particle and microbiological cleanliness standards. 41

42

Cleaning Procedures Validation: A challenge study designed to prove that the 43

cleaning methods of product contact equipment/surfaces are effective based on 44

7

determining the most difficult to clean equipment/product (“worst case”), a certain 1

allowable level of a selected residue and the analytical methodology. 2

3

Containment: A process, equipment, system or facility to contain product, dust or 4

contaminants in one zone, preventing it from escaping but also entering to another 5

zone. 6

7

Continuous Culture: Process by which growth of cells is maintained by periodically 8

replacing a portion of the cells and medium such that there is no lag or saturation 9

phase. 10

11

Cross-Contamination: Contamination of a drug or biological starting material or 12

in-process intermediate with another drug or biological starting material or in-process 13

intermediate. In multi-product facilities, cross contamination can occur throughout 14

the manufacturing process, from generation of the Master Cell Bank (MCB) and 15

Working Cell Bank (WCB) through finishing. 16

17

Dedicated: Facility or piece of equipment used only in the manufacture of a 18

particular product or a closely related group of products. 19

20

Drug Product (dosage form, finished product, or final product): A pharmaceutical 21

product type that contains a biological drug substance, generally in association with 22

excipients. It corresponds to the dosage form in the immediate packaging intended for 23

marketing. 24

25

Drug Substance: A defined process intermediate containing the active ingredient, 26

which is subsequently formulated with excipients to produce the drug product. 27

28

Fermentation: Maintenance or propagation of microbial cells in vitro (fermenter). 29

Fermentation is operated and progressed under axenic conditions to ensure a pure 30

culture absent of contaminating microorganisms. 31

32

Harvesting: Procedure by which the cells, inclusion bodies or crude supernatants 33

containing the unpurified active ingredient are recovered. 34

35

Hybridoma. An immortalized cell line that secrete desired (monoclonal) antibodies 36

and are typically derived by fusing B-lymphocytes with tumour cells. 37

38

Inactivation: Removal or reduction to an acceptable limit of infectivity of 39

microorganisms or detoxification of toxins by chemical or physical modification. 40

41

Master Cell Bank (MCB): An aliquot of a single pool of cells which generally has 42

been prepared from the selected cell clone under defined conditions, dispensed into 43

multiple containers and stored under defined conditions. The MCB is used to derive a 44

8

Working Cell Bank (WCB). The testing performed on a new MCB (from a previous 1

initial clone, MCB or WCB) should be the same as for the MCB unless justified. 2

3

Monoclonal antibodies: Homogenous antibody population obtained from a single 4

clone of lymphocytes or by recombinant technology and which bind to a single 5

epitope. 6

7

Pharmaceutical Quality System: Management system to direct and control a 8

pharmaceutical company with regard to quality. 9

10

Polyclonal antibodies: Derived from a range of lymphocyte clones, produced in 11

human and animals in response to the epitopes on most ‘non-self’molecules. 12

13

Primary containment: A system of containment that prevents the escape of a 14

biological agent into the immediate working environment. It involves the use of 15

closed containers or safety biological cabinets along with secure operating 16

procedures. 17

18

Quality Risk Management: Quality risk management is a systematic process for the 19

identification, assessment and control of risks to the quality of pharmaceutical 20

products across the product lifecycle. 21

22

Raw materials: A general term used to denote starting materials, reagents and 23

solvents intended for use in the production of intermediates, Bulk Drug Substance, 24

APIs or final products. 25

26

Risk Group: The containment conditions required to safely handle organisms of 27

different hazards ranging from Risk Group 1 (lowest risk, no or low individual and 28

community risk) to Risk Group 4 (highest risk, high individual and community risk). 29

30

Seed lot: A quantity of live cells (prokaryotic or eukaryotic) or viruses which has 31

been derived from a single culture (although not necessarily clonal), has a uniform 32

composition and is aliquoted into appropriate storage containers from which all future 33

products will be derived, either directly or via a seed lot system. 34

35

Starting materials: Materials that mark the beginning of the manufacturing process, 36

as described in a market authorization or product license. Generally, starting material 37

refers to a substance of defined chemical properties and structure that contributes an 38

important and/or significant structural element(s) to the active substance (examples 39

for vaccines: synthetic peptides, synthetic glycans and starting materials for 40

adjuvants). The starting material for an antigen (drug substance) obtained from a 41

biological source is considered to consist of: 1) cells; 2) microorganisms; 3) plants, 42

plant parts, macroscopic fungi or algae; or 4) animal tissues, organs or body fluid 43

from which the antigen (drug substance) is derived. 44

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1

Vaccine: Preparation containing antigens capable of inducing an active immune 2

response for the prevention, amelioration or treatment of infectious diseases. 3

4

Working Cell Bank (WCB): Cell bank prepared from aliquots of a homogenous 5

suspension of cells obtained from culturing the fully characterized Master Cell Bank 6

under defined culture conditions. 7

8

Principles and general consideration 9

The manufacturing of biological products should be undertaken in accordance with 10

the basic principles of GMP. The points covered by these guidelines should therefore, 11

be considered complementary to the general recommendations set out in the current 12

WHO GMP for pharmaceutical products: main principles (1) and in other WHO 13

documents related specifically to the production and control of biological products 14

established by the WHO Expert Committee on Biological Standardization (ECBS) 15

(http://www.who.int/biologicals/en/). 16

17

The ways in which biological products are manufactured, controlled and administered 18

require particular precautions necessary. Potency of biological products can rarely be 19

expressed in units of mass, but determined through bioassays which are themselves 20

highly variable and often not predictive of the physiological or therapeutic effects on 21

humans. When bioassays can be replaced with immunological assays detecting very 22

discrete antigenic sites on representative components of the product, precision may 23

be increased. 24

25

Control of biological products nearly always involves biological techniques that have a 26

greater variability than physicochemical determinations. A robust and consistent 27

manufacturing process with adequate in-process controls is of greater importance in 28

the manufacture of biological products because certain deficiencies may not be 29

revealed by testing the finished product. The combination of variability in starting 30

materials and the potential for subtle changes during the manufacturing process of 31

biological products also calls for emphasis on production consistency which becomes 32

a special concern with the need to link the consistency to original clinical trials 33

documenting the product's safety and efficacy. 34

35

It is not possible for some biological active ingredients including live attenuated 36

bacteria and viruses, to be terminally sterilized by heat, gas, or radiation. In addition, 37

the efficiency of standard purification techniques or even sterile filtration may not be 38

possible due to the size and complexity of certain biological active ingredients (e.g., 39

whole cell pertussis, cholera), thus requiring a aseptic processing and mild 40

purification procedures throughout the manufacturing process. 41

42

10

Since starting materials and processing conditions used in cultivation processes are 1

designed to provide conditions for the growth of specific cells and microorganisms, 2

extraneous microbial contaminants have the opportunity to grow. Adventitious agents 3

arising from starting materials, from facility-derived microorganisms and from 4

contamination of product materials by operators, constitutes another critical aspect of 5

GMP for biological products aimed at preventing or reducing the risk of 6

contamination of starting materials, intermediate bulks, and finished products. The 7

design of the processes, equipment, facilities, utilities, sampling and training of the 8

operators are key considerations to prevent such contamination events. 9

10

Methods for inactivating viral and bacterial agents and their associated metabolites 11

from manufacturing areas and surfaces coming into contact with a product must be 12

shown to be efficacious, reliable, and consistent (i.e., validated). In addition, there is a 13

significant importance of cleaning procedures and hygiene as part of contamination 14

control. 15

16

Due to the risks inherent in producing and manipulating pathogenic and transmissible 17

microorganisms during production and testing of biological materials, GMP must 18

prioritize the safety of the recipient administered with the biological product, the 19

safety of the operators during operations and the protection of the environment. 20

As a result, quality risk management (QRM) principles are particularly important for 21

this class of products and should be used to develop the control strategy across all 22

stages of manufacture so as to achieve consistency, to minimize variability and to 23

reduce the opportunity for contamination and cross-contamination. Risk assessment 24

will also contribute to identifying the probable causes of unwanted or unanticipated 25

factors affecting the purity, potency, safety, efficacy and stability of the product, 26

assessing the effectiveness of measures to reduce or manage such risks and helping to 27

identify critical product attributes and process control parameters during development 28

and validation phases. 29

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Personnel 31

1. Personnel working in areas where biological active substances and products are 32

manufactured and tested should receive training and periodic retraining specific 33

to their duties and to the products being manufactured, including any specific 34

security measures to protect the product, personnel and the environment. 35

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2. Persons responsible for production and quality control should have an adequate 37

background in relevant scientific disciplines such as microbiology, biology, 38

biometry, chemistry, medicine, pharmacy, pharmacology, virology, immunology, 39

biotechnology and veterinary medicine, together with sufficient practical 40

experience to enable them to perform their duties. 41

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3. Training in cleaning and disinfection procedures, hygiene and microbiology is 1

particularly relevant to biological production because of the risk of microbial 2

contamination due to the handling of microorganisms, culture media and of 3

adventitious organisms. 4

5

4. During a working day, personnel and visitors should not pass from areas with 6

exposure to live micro-organisms, genetically modified microorganisms, animal 7

tissue, toxins, venoms or animals, to areas where other products (inactivated or 8

sterile) or different organisms are handled. If such passage is unavoidable, the 9

contamination control measures (e.g., clearly defined decontamination measures, 10

including a complete change of appropriate clothing and shoes and showering if 11

applicable) should be followed by all staff involved in any such production. 12

13

5. Personnel working in animal husbandry should be dedicated. 14

15

6. Where necessary, personnel engaged in production, maintenance, testing and 16

animal care (and inspections) should be vaccinated with appropriate specific 17

vaccines and have regular health checks. Apart from the obvious risk of exposure 18

of staff to infectious agents, potent toxins or allergens, it is necessary to avoid or 19

reduce the risk of contamination of a product with these agents. 20

21

7. Production of bacille Calmette-Guerin (BCG) vaccine and tuberculin products 22

should be restricted to staff who are carefully monitored by regular health checks 23

to include immunological status or chest X-ray. 24

25

8. Health monitoring of staff should be commensurate with the risk to the product 26

and personnel. Medical advice should be sought for personnel involved with or 27

exposed to hazardous organisms. 28

29

Starting and Raw Materials 30

1. The source, origin and suitability of starting and raw materials (e.g., 31

cryo-protectants, feeder cells, reagents, culture media, buffers, serum, enzymes, 32

cytokines, growth factors and amino acids) should be clearly defined. 33

Manufacturers should retain information describing the source and quality of the 34

biological materials used for at least two years after the expiry date of the 35

products produced from them. 36

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2. All starting and raw material suppliers should be initially qualified based on a 38

documented criteria and based on a risk based approach, including regular 39

assessments of their status. When materials are sourced from third parties (e.g., 40

brokers, who could increase the risk of contamination, especially if repackaging is 41

performed), both brokers and material manufacturers should be qualified and 42

audited as needed. 43

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1

3. Incoming starting and raw materials should be sampled under appropriate 2

conditions (e.g., Class A air supply) and based on justified criteria, tested using 3

Pharmacopoeial or validated approved methods and released by the Quality Unit 4

before use. The level of testing should be commensurate to the qualification level 5

of the supplier and its continuous performance, however, at least an identity test is 6

required on each container. Certificate of analysis could be used to replace some 7

testing, if appropriately justified. However, reduced testing may not be applicable 8

to some biological materials because of the inherent variability in range and 9

nature of biological starting materials. 10

11

4. Where the necessary tests for approving starting materials take a significantly 12

long time, it may be permissible to process starting materials before the test 13

results are available. The risk of using non approved material on the quality of the 14

product should be clearly justified in a documented manner, understood and 15

assessed under the principles of Quality Risk Management (QRM). In such cases, 16

release of a finished product is conditional on satisfactory results of these tests. It 17

must be assured that this is not a common practice and only occurs exceptionally. 18

The identification of all starting materials should be in compliance with the 19

requirements appropriate to its stage of manufacture. 20

21

5. Where sterilization of starting and raw materials is required, it should be carried 22

out where possible by heat. Where necessary, other appropriate validated methods 23

may also be used for this purpose (e.g., irradiation and filtration). 24

25

6. The risk of contamination of starting and raw materials during their passage along 26

the supply chain must be assessed, with particular emphasis on Transmissible 27

Spongiform Encephalopathy (TSE) (13). Other materials that come into direct 28

contact with manufacturing equipment or the product (such as growth media 29

during aseptic process simulations, and lubricants) must also be controlled. 30

31

7. The controls required for the quality of starting and raw materials and on the 32

aseptic manufacturing process (particularly for cell-based products, where final 33

sterilization is generally not possible and the ability to remove microbial 34

by-products is limited), assume greater importance and should be based on the 35

principles and guidance contained in the current WHO Good Manufacturing 36

Practices for Sterile Pharmaceutical Products (2) and on the section Clean Rooms 37

of this guideline, as applicable. 38

39

8. Where human or animal cells are used in the manufacturing process as feeder 40

cells, appropriate controls over the sourcing, testing, transport and storage should 41

be in place. 42

43

9. The transport of critical materials, reference materials, drug substances, human 44

13

tissues and cells to the manufacturing site must be controlled by a written 1

agreement between the responsible parties. The manufacturing sites should have 2

documentary evidence of adherence to the specified storage and transport 3

conditions including cold chain requirements and traceability. 4

5

10. Preparations extracted or purified from animal blood, bone, or tissues, such as 6

peptides and proteins, lipids, nucleic acids, enzyme preparations, virus or bacteria 7

should be purified in such a way as to prevent contamination; the removal process 8

should be demonstrated through validation studies. A risk assessment should be 9

determined to evaluate the potential for adventitious agents in biological starting 10

and raw materials. Labile biological starting and raw materials should be free of 11

adventitious agents (e.g., bacterial and fungal agents, cultivatable and 12

non-cultivatable mycoplasmas, mycobacteria and viruses) of the species from 13

which they are derived. WHO Guidelines on Good Manufacturing Practices for 14

Blood Establishments (11) and Requirements for the Collection, Processing and 15

Quality Control of Blood, Blood Components and Plasma Derivatives should be 16

considered for these products (14). 17

18

Seed Lots and Cell Banks 19

Guidance set out in WHO Good manufacturing practices for active pharmaceutical 20

ingredients, Section 18, Specific guidance for APIs manufactured by cell 21

culture/fermentation (3) should be followed. 22

23

1. In order to prevent the unwanted drift of genetic properties which might ensue 24

from repeated subcultures or multiple generations, the production of biological 25

products obtained by microbial culture, cell culture or propagation in embryos 26

and animals should be based on a system of master and working seed lots and/or 27

cell banks, which is actually the beginning of the manufacturing process of 28

certain biological products (e.g., vaccines). 29

30

2. The number of generations (e.g., passages) between the seed lot or cell bank and 31

the finished product should be consistent with the MA dossier and followed. 32

33

3. Cell based medicinal products are often generated from a cell stock obtained from 34

limited number of passages. In contrast with the two tiered system of master and 35

working cell banks, the number of production runs from a cell stock is limited by 36

the number of aliquots obtained after expansion and does not cover the entire life 37

cycle of the product. Cell stock changes should be covered by a validation 38

protocol and communicated to the NRA as applicable. 39

40

4. Establishment of seed lots and cell banks, including master and working 41

generations, should be performed under conditions which are demonstrably 42

appropriate. This should include an appropriately controlled environment to 43

14

protect the seed lot and the cell bank and the personnel handling them. To 1

establish the minimum requirements for air grade and environmental monitoring 2

see WHO Environmental Monitoring of Clean Rooms in Vaccine Manufacturing 3

Facilities - Points to consider for manufacturers of human vaccines, 2012 (15). 4

During the establishment of the seed lot and cell bank, no other living or 5

infectious material (e.g., virus, cell lines or microbial strains) should be handled 6

simultaneously in the same area or by the same persons, as defined in WHO 7

Recommendations for the evaluation of animal cell cultures as substrates for the 8

manufacture of biological medicinal products and for the characterization of cell 9

banks (16). 10

11

5. Quarantine and release procedures for master and working cell banks/seed lots 12

should be followed, including adequate characterization and testing for 13

contaminants. Initially, full characterization testing of the MCB shall be done 14

including genetic identification. Thereafter, the identity, viability and purity of 15

seed lots and cell banks should be regularly checked according to justified criteria. 16

In the case of anti-sera production, the potency of venoms is usually included as 17

part of the testing. Evidence of the stability and recovery of the seed lots and 18

banks should be documented and records should be kept in a manner permitting 19

trend evaluation. 20

21

6. Each storage container should be adequately sealed, clearly labelled and kept at 22

an appropriate temperature. A stock inventory must be kept. The storage 23

temperature should be recorded continuously using calibrated instruments and 24

where used, the liquid nitrogen level should be monitored. Any deviation from set 25

limits and any corrective and preventive action taken should be recorded. 26

Temperature deviations should be detected as early as possible (e.g., with the use 27

of an alarm system for temperature and Nitrogen level). 28

29

7. Seed lots and cell banks should be stored and used in such a way as to minimize 30

the risks of contamination or alteration (e.g., stored in qualified ultra-low 31

temperature freezers or liquid nitrogen storage containers). Control measures for 32

the storage of different seeds and/or cells in the same area or equipment should 33

prevent mix-up and take into account the infectious nature of the materials to 34

prevent cross contamination. 35

36

8. Both master and working seed lots and cell banks should be stored in two or more 37

controlled separate locations within the facility or at a separate site in order to 38

minimize the risks of total loss due to natural disaster, equipment malfunction or 39

human error. 40

41

9. The storage and handling conditions for the cell or seed banks should be defined. 42

Access should be restricted to authorized personnel and controlled; appropriate 43

records must be maintained. Record of location, identity and inventory of 44

15

individual containers should be kept. Once containers are removed from the seed 1

lot/cell bank management system, they should not be returned to stock. 2

3

Premises and Equipment 4

1. Products such as killed vaccines, including those made by rDNA techniques, 5

toxoids and bacterial extracts may, after inactivation, be manufactured on the 6

same premises as other sterile products provided that adequate decontamination 7

and cleaning measures are implemented based on quality risk management. 8

9

2. Cleaning and sanitization requires special attention to the fact that production of 10

biological products usually involves the handling of culture media and other 11

growth promoting agents. Consideration may be given to decontamination of 12

manufacturing areas with gaseous sterilants such as chlorine dioxide or hydrogen 13

peroxide. 14

15

3. Where processes are not closed (e.g., during additions of supplements, media, 16

buffers, gasses and manipulations during the manufacture of cell therapy 17

products) control measures should be put in place, including engineering and 18

environmental controls on the basis of QRM principles. 19

20

4. Equipment used during handling of live organisms and cells, including those for 21

sampling, should be designed to prevent any contamination during processing. 22

23

5. Wherever possible, the use of 'clean in place' and ‘sterilization in place’ systems, 24

steam sterilizable valves on fermentation vessels and sterile single use disposable 25

connectors should be used for aseptic connections to avoid exposure to the 26

environment and to human intervention, thus reducing the contamination risk. 27

28

6. Due to the variability of biological products and corresponding manufacturing 29

processes, approved starting materials that have to be measured or weighed for 30

the production process (e.g., culture media and buffers) may be kept in small 31

stocks in the production area for a specified period of time based on defined 32

criteria such as for the duration of manufacture of the lot or of the campaign, 33

provided that they are not returned to the general stock assuring proper inventory 34

traceability and control. Otherwise, materials used to formulate buffers, culture 35

media, etc., should be weighed and put into a solution in a contained area outside 36

the purification and aseptic areas in order to minimize particulate contamination 37

of the product. 38

39

7. In manufacturing facilities, separate changing rooms for entering and leaving 40

clean areas where live organisms are handled should be used. 41

42

16

Containment 1

1. Airborne dissemination of live microorganisms and viruses used for the 2

production process, including those from personnel, shall be avoided. 3

4

2. Adequate precautions shall be taken to avoid contamination of the drainage 5

system with dangerous effluents. Drainage systems must be designed so that 6

effluents can be effectively neutralized or decontaminated to minimize the risk of 7

cross-contamination. Local regulations must be complied with to minimize the 8

risk of contamination of the external environment according to the risk 9

associated with the biohazardous nature of waste materials. Specific 10

decontamination systems should be considered for effluents when infectious and 11

potentially infectious materials are used for production. 12

13

3. Dedicated production areas should be used for the handling of live cells capable 14

of persistence in the manufacturing environment and for pathogenic organisms 15

(i.e. Risk group 3 and 4 or Spore forming organisms) until the inactivation 16

process is accomplished and verified. For Bacillus anthracis, Clostridium tetani, 17

and Clostridium botulinum, strictly dedicated facilities should be utilized for 18

each individual product. 19

20

4. Production of BCG vaccine shall take place in a completely separated area and 21

by means of dedicated equipment and utilities. The hazard of 22

cross-contamination to other production/manufacturing areas should be reduced 23

to a minimum by use of a proper dedicated ventilation system. 24

25

5. Specific containment requirements may apply (e.g., Polio vaccine containment 26

requirements as per WHO global action plan to minimize poliovirus 27

facility-associated risk (GAP III) (17)) and WHO Guidelines for the safe 28

production and quality control of inactivated poliomyelitis vaccine manufactured 29

from wild polioviruses (18). The measures and procedures necessary for 30

containment (i.e. for the environment and safety of the operator) should not 31

conflict with those for product quality. 32

33

6. Air handling units should be designed, constructed and maintained to minimize 34

the risk of cross-contamination between different manufacturing areas as 35

required and may need to be dedicated for an area. Consideration, based on QRM 36

principles, should be given to the use of single pass air systems. In the case of 37

organisms in a group above Biosafety Risk Group 2, air should not be 38

recirculated and it shall be exhausted through HEPA filters that are regularly 39

checked for performance. 40

41

7. Primary containment equipment should be designed and initially qualified and 42

validated for integrity to ensure the prevention of the escape of biological agents 43

17

into the immediate working environment. Thereafter, based on relevant guidance 1

and QRM, periodic tests should be performed on the primary containment 2

equipment to ensure proper working conditions. 3

4

8. Activities in handling live biological agents must be performed in such a way to 5

prevent contamination of other products or egress of live agents into the work 6

environment or the outside environment. The viability of such organisms and 7

their biological classification should be taken into consideration as part of the 8

management of such risks. 9

10

9. Areas above Biosafety Risk Group 2 should always have a negative differential 11

pressure versus any adjacent non-biocontained areas. This will ensure that in the 12

unlikely event that both air lock doors are opened simultaneously, air will flow 13

from the non-biocotained area to the biocontained area. Differential pressure 14

alarms should be present. 15

16

10. Air vent filters should be hydrophobic and validated for their scheduled life span 17

with integrity testing at appropriate intervals where applicable and based on 18

appropriate QRM principles. 19

20

11. HEPA filters from air handling units should have a containment system to safely 21

remove the filter and thus, avoid exposure to operator and the environment in 22

non-controlled areas (i.e., a bag in bag out system). Once removed, these filters 23

should be decontaminated and properly destroyed. 24

25

Clean Rooms 26

1. The WHO GMP for Sterile Pharmaceutical Products (2) defines and establishes 27

the required level of air grade classification according to the operations performed 28

for injectable products including final aseptic fill. Additionally, in order to address 29

the specific manufacturing processes involved in the production of biological products, the 30

WHO guidance document, Environmental Monitoring of Clean Rooms in Vaccine 31

Manufacturing Facilities - Points to consider for manufacturers of human 32

vaccines (15), gives additional recommendations to be considered when defining 33

the environmental classification needed for typical biological manufacturing 34

processes. 35

36

2. With the exception of aseptic preparation, all processing of biological products 37

prior to the final fill of a drug product should be, at minimum, maintained in a 38

low bioburden environment. Additional controls should be taken as appropriate, 39

when open manipulation of the product is performed. 40

41

18

3. As part of the control strategy, the degree of environmental control of particulate 1

and microbial contamination of the production premises should be adapted to the 2

intermediate or finished product and also the production step, considering the 3

potential level of contamination of the starting materials and the risks to the 4

biological product. The environmental monitoring programme should be 5

supplemented by the inclusion of methods to detect the presence of specific host 6

microorganisms (i.e., yeast, moulds, anaerobes, etc.) where indicated by the QRM 7

principles. 8

9

Production 10

1. Since cultivation conditions, media and reagents are designed to promote the 11

growth of cells or microbial organisms, typically in an axenic state, particular 12

attention should be paid to the control strategy to ensure there are effective steps 13

toprevent or minimize the occurrence of unwanted bioburden, endotoxins, 14

viruses of animal and human origin and associated metabolites. 15

16

2. The principle of campaign manufacturing in the same facilities can be accepted 17

provided that specific precautions are taken and the necessary validations 18

(including cleaning validation) are made. Detailed recommendations on campaign 19

production are given in the section Campaign Production of this document. 20

21

3. The inoculum preparation area shall be designed such as to effectively control the 22

risk of contamination and should be equipped with a biosafety hood for local 23

containment. 24

25

4. If possible, growth media should be sterilized in situ by heat and in-line 26

sterilizing filters for routine addition of gases, media, acids or alkalis, etc., to 27

fermenters should be used, where possible. 28

29

5. Data from continuous monitoring of some production processes (e.g., 30

fermentation) should form part of the lot record. Where continuous culture is used, 31

special consideration to parameters such as temperature pH, pO2, CO2, and the 32

rate of feed or carbon source with respect to growth of cells should be given for 33

this type of production method. 34

35

6. Centrifugation and blending of products can lead to aerosol formation and 36

containment of such activities to minimize cross-contamination is necessary. 37

Accidental spillages, especially of live organisms, must be dealt with quickly and 38

safely. Validated decontamination measures should be available for each 39

organism or groups of related organisms. Where different strains of single 40

bacteria species or very similar viruses are involved, the decontamination process 41

may be validated with one representative strain, unless they vary significantly in 42

their resistance to the agent(s) involved. 43

19

1

7. Cross-contamination should be prevented by adoption of some or all of the 2

following measures: 3

processing and filling in segregated areas; 4

containing material transfer by means of airlocks, clothing change and 5

effective washing and decontamination of equipment; 6

avoid recirculation of untreated air, or re-entry of extracted air; 7

prevent aerosol formation (especially by centrifugation and blending); 8

aqcuire knowledge of key characteristics of all cells, organisms and any 9

adventitious agents (e.g., pathogenicity, detectability, persistence, 10

susceptibility to inactivation) within the same facility; 11

where production is characterized by multiple small lots from different 12

starting materials (e.g., cell-based products), factors such as the health 13

status of donors and the risk of total loss of a product from or for specific 14

patients should be taken into account when considering the acceptance of 15

concurrent work during development of the control strategy; 16

prevent live organisms and spores from entering non-related areas or 17

equipment by addressing all potential routes of cross-contamination, the 18

HVAC system, the use of single use components and closed systems; 19

conduct environmental monitoring specific for the micro-organism being 20

manufactured in adjacent areas. Attention should also be given to cross- 21

contamination risks arising from the use of certain monitoring equipment 22

(e.g., airborne particle monitoring) in areas handling live and/or spore 23

forming organisms; 24

use of campaign based production (see section on Campaign production 25

section). 26

27

8. To avoid contamination by spills or aerosols of potentially hazardous organisms, 28

production and control materials (including paper based documents) must be 29

adequately decontaminated. 30

31

9. In cases where a virus inactivation or removal process is performed, measures 32

should be taken to avoid the risk of recontamination of treated products by 33

non-treated products. 34

35

10. For products that are inactivated by the addition of a reagent, the process should 36

ensure the complete inactivation of the live organism (e.g., microorganisms 37

during vaccine manufacture). In addition to the adequate mixing of culture and 38

inactivant, consideration should be given to assure complete contact of all 39

20

product-contact surfaces exposed to live culture and where required, the transfer 1

to a second vessel. 2

3

11. A wide variety of equipment is used for chromatography. QRM principles should 4

be used to devise the control strategy on chromatographic columns, ultrafiltration 5

or diafiltration cassettes, housings and associated equipment when used in 6

campaign manufacture and in multi-product environments. The re-use of the same 7

column at different stages of processing of one product is discouraged and the 8

re-use of the same column for different products is not acceptable. Acceptance 9

criteria, operating conditions, regeneration methods, life span and sanitization or 10

sterilization methods of columns should be defined and validated. 11

12

12. Where donor (human or animal) health information becomes available after 13

procurement, which affects product quality, it should be taken into account in 14

recall procedures. 15

16

13. Reduction in bioburden associated with the procurement of living tissues and 17

cells may require the use of other measures such as antibiotics at early 18

manufacturing stages. In this case, their use should be justified and they should 19

be removed from the manufacturing process at the stage specified in the MA. 20

Acceptable residual levels should be defined and validated. Betalactam based 21

antibiotics should not be used during any stage of the process. 22

23

Campaign Production 24

1. For finishing (i.e., formulation, filling) operations, the need for dedicated 25

facilities or the use of campaigns in the same facility will depend on consideration 26

of the specific needs of the biological product; on the characteristics of other 27

products including any non-biological products; on fill technologies used; single 28

use-closed systems and on local NRA regulations. Packaging operations can be 29

done in a multiproduct facility. 30

31

2. The decision to use a facility or filling line on a campaign basis should be 32

justified in a documented manner and based on a systematic risk approach for 33

each product (or strain) considering the containment requirements and the 34

contamination risk and carry over to the next product. Campaign change 35

procedures, including sensitive techniques used for the determination of residues 36

shall be validated and proper acceptance criteria based on toxicity shall be 37

defined. Where equipment is assigned to continuous production or campaign 38

production of successive lots of the same intermediate, equipment should be 39

cleaned at appropriate intervals to prevent build-up and carry-over of 40

contaminants (e.g., degradants or objectionable levels of microorganisms). 41

42

21

3. Campaign changeover involves intensive cleaning and decontamination of the 1

manufacturing area. The decontamination and cleaning should include all 2

equipment and accessories used during production and the facility. It should 3

consider the following recommendations: 4

all waste is removed from the manufacturing area or sent to the 5

bio-waste system in a safe manner; 6

equipment is decontaminated and cleaned; 7

the area and processing equipment is effectively decontaminated, 8

cleaned, and sterilized (if applicable); 9

as required, product and materials should be transferred by a validated 10

transfer procedure; 11

a Quality Control and Quality Assurance unit shall review the 12

campaign changeover data (including monitoring results) and an area 13

inspection is executed prior to releasing the area for the next product. 14

15

4. When required, the corresponding diluent for the product can be filled in the same 16

facility based on the defined campaign production strategy. 17

18

5. To avoid cross-contamination and mix up, sufficient evidence should be provided 19

for bracketing different products in a multiproduct facility based on a documented 20

risk assessment. 21

22

6. When campaign-based manufacturing is considered, the facility layout and design 23

of the premises and equipment shall permit effective decontamination by 24

fumigation, where necessary, as well as cleaning and sanitizing after the 25

production campaign. Where campaign manufacture of spore-forming organisms 26

occurs in a facility or suite of facilities, only one product should be processed at 27

any one time. 28

29

Labelling 30

1. The information given on the inner label (on the container) and the outer label 31

(on the package) shall be approved by the NRA. 32

33

2. Special consideration should be taken on the following information for labels of 34

vaccines: 35

the nature and amount of any preservative present in the vaccine, if 36

applicable; 37

the nature and amount of the adsorbing agent, if applicable; 38

a warning that the vaccine should not be frozen, cold chain aspects and 39

Vaccine Vial Monitor (VVM) labelling, if applicable; 40

the warning that the vaccine should be shaken before use, if applicable. 41

42

22

3. Care should be taken in the preparation, printing, storage and application of 1

labels, including any specific text for patient-specific products, indicating the use 2

of genetically engineered contents on the immediate and outer packaging. In the 3

case of a cell therapy product used for autologous use, the unique patient 4

identifier and the statement “for autologous use only” should be indicated on the 5

outer packaging or, where there is no outer packaging, on the immediate 6

packaging. 7

8

4. The compatibility of labels for ultra-low storage temperatures, where such 9

temperatures are used, should be verified. 10

11

Validation 12

The nature of biological processes, handling of live materials and usual campaign 13

based production are the major aspects of biological products which require process 14

and cleaning validation. The validation of such processes considering the typical 15

existing variations of biological products, possible use of harmful and toxic materials 16

and inactivation processes, play an important role in demonstrating the production 17

consistency and in proving that the critical process parameters and product attributes 18

are controlled. A risk assessment approach should be used to determine the scope and 19

extent of validation. 20

21

1. All critical biological processes (i.e., inoculation, multiplication, fermentation, 22

cell disruption, inactivation, purification, virus removal, removal of toxic and 23

harmful additives etc.) are subject to process validation. Manufacturing control 24

parameters to be validated may include specific addition sequences, mixing 25

speeds, time and temperature controls, limits of light exposure, containment and 26

cleaning procedures. 27

28

2. After initial process validation studies have been finalized and routine production 29

begins, a Continued Process Verification (19) approach should be defined, taking 30

into consideration the inherent variability of biological products. A system or 31

systems for detecting unplanned departures from the process as designed should 32

be in place to assure that the process remains in a state of control. Collection and 33

evaluation of information and data on the performance of the process will allow 34

detection of undesired process variability. Evaluating the performance of the 35

process identifies problems and determines whether action should be taken to 36

correct, anticipate and prevent problems so that the process remains in control. 37

38

3. Cleaning validation should be performed in order to confirm the effectiveness of 39

cleaning procedures designed to remove biological substances and culture media. 40

Careful consideration should be given to the cleaning validation when campaign 41

base production is practiced. 42

43

23

4. Critical processes for inactivation or elimination of potentially harmful 1

microorganisms, including genetically modified microorganism with a biosafety 2

Risk group of 2 or above, are subject to validation. 3

4

5. Where they exist, WHO guidance documents should be consulted on the 5

validation of specific manufacturing methods (e.g., virus removal or 6

inactivation). 7

8

6. Due to the variability of processes, products and methods, process revalidation 9

should be triggered based on a detailed review of all changes, trends and 10

deviations occurred in a period of time (e.g., 1 year). 11

12

7. The integrity of containers used to store intermediate products and the hold times 13

must be validated. 14

15

Quality Control 16

1. Control of starting materials and intermediate, bulk and finished products 17

18

1.1. As part of Quality Control (QC) testing, sampling and sample handling 19

procedures for biological materials must take special consideration on the nature 20

of the materials being sampled to ensure testing carried out is representative of 21

the process. 22

23

1.2. Reference samples of each lot of a finished product should be stored in its final 24

packaging under the recommended conditions for at least one year after the 25

expiry date. Samples of active starting materials should be retained for at least 26

one year beyond the expiry date of the corresponding finished product. Samples 27

of other starting materials as well as intermediate of which critical parameters 28

cannot be tested in the final product, should be retained for at least two years after 29

the release of the product, if their stability allows this storage period. Certain 30

starting materials, e.g., components of culture media, need not necessarily be 31

retained. When a change of the vendor is needed and as appropriate, an impurity 32

profile comparison should be done as part of the risk analysis. 33

34

2. Test requirements 35

36

2.1. For cell-based products, microbiological tests (e.g., sterility test or purity check) 37

should be conducted on antibiotic free cultures of cells or cell banks to provide 38

evidence for absence of bacterial and fungal contamination and to be able to 39

detect fastidious organisms where appropriate. Where antibiotics are used, these 40

need to be neutralized at the time of testing. 41

42

2.2 The traceability of reference standards should be ensured. The use and storage of 43

24

reference standards for testing should be defined and recorded. The stability of 1

reference standards should be monitored and the performance of reference 2

standards should be trended andWHO Recommendations for the preparation, 3

characterization and establishment of international and other biological 4

reference standards (20) should be followed. 5

6

3. Stability Programme 7

8

3.1. All stability studies including real-time/real-condition stability, accelerated 9

stability and stress-testing, should be carried out according to the Guidelines on 10

stability evaluation of vaccines (21) and other relevant requirements. 11

Trend analysis should assure early detection of any process drift or assay drift, 12

and this information be part of the Product Quality Review of biological 13

products. 14

15

3.2. For products where on-going stability monitoring would normally require 16

testing using animals and no appropriate alternative or validated techniques are 17

available, the frequency of testing may take into account a risk-benefit approach. 18

The principle of bracketing and matrix designs may be applied if scientifically 19

justified in the protocol. 20

21

4. Analytical Method Validation 22

All the analytical methods used in the quality control of biological products should be 23

well characterized, fully validated and documented to a satisfactory standard in order 24

to yield reliable results. The fundamental parameters for this validation include 25

accuracy, precision, selectivity, sensitivity, reproducibility and stability, etc. (22-26). 26

27

In general, animal tests performed for quality control release are well described in the 28

relevant Pharmacopoeias and WHO guidance documents (22-26). Animal potency 29

tests are designed with multiple or single dilutions and replicates to take care of 30

variability and linearity and they are performed in comparison with 31

international/national reference standards and with appropriate assay controls. 32

Moreover, the respective tests are international standard methods. In the case of test 33

methods described in the relevant monographs, only a qualification of the laboratory, 34

laboratory equipment and personnel has to be performed. In addition to this, repeat 35

precision and comparability precision have to be shown in the case of animal tests. 36

However, repeatability and reproducibility can be demonstrated by reviewing 37

retrospective data over the years of the tests performed. In addition to the common 38

parameters typically used for validating assays (e.g., accuracy, precision, etc.) and 39

additional measurements should be considered during the validation of bioassays 40

based on the biological nature of the assay and reagents used. 41

42

25

Documentation (Lot processing records) 1

1. A separate vaccine lot processing record, summary protocol, should be prepared 2

for each lot, for the purpose of lot release by the NRA and the information 3

included should follow the WHO Guidelines for independent lot release of 4

vaccines by regulatory authorities (27). The summary protocol and all associated 5

records shall be of a type approved by the NRA and records shall be retained for 6

at least two years after the expiry date of the lot of the vaccine and be available at 7

all times for inspection by the NRA. 8

9

2. Starting and raw materials may need additional documentation on the source, 10

origin, distribution chain, method of manufacture and controls applied, to assure 11

an appropriate level of control including their microbiological quality. 12

13

3. Some product types may require specific definition of which materials constitute 14

a lot, particularly somatic cells treatment. For autologous and donor-matched 15

situations, the manufactured product should be viewed as a lot. 16

17

4. Where human cell or tissue donors are used, full traceability is required from 18

starting and raw materials, including all substances coming into contact with the 19

cells or tissues, through the confirmation of the receipt of the products at the 20

point of use, whilst maintaining the privacy of individuals and confidentiality of 21

health related information. 22

23

Use of Animals 24

Animals may be used for the manufacture or quality control of biological products. 25

Special considerations are required when animal facilities are present at a fabrication 26

site. Areas used for processing animal tissue materials and for performing tests 27

involving animals or microorganisms, including breeding, must be completely 28

separated from premises used for manufacturing biological products and should have 29

completely separate ventilation systems and separate staff. No animals shall be used 30

in the production area. Separation of different animals before (quarantine/test) and 31

under test should be considered, as well as the necessary animal acclimatization 32

process as part of the testing requirements. 33

34

For products manufactured from transgenic animals, traceability should be 35

maintained in the creation of such animals from the source animals. 36

37

1. A wide range of animal species are used in the manufacture of a number of 38

biological medicinal products. The use of animals may also be divided into: 39

- animals used for organ extraction (e.g., kidney); 40

26

- animals used for body fluids extraction (e.g., serum etc.); 1

- animals for breeding; 2

- animals for testing. 3

4

2. In addition to compliance with TSE regulations (13), other adventitious agents 5

that are of concern (zoonotic diseases, diseases of source animals) should be 6

monitored by an ongoing health programme and recorded and specialist advice 7

should be obtained in establishing such programmes. Instances of ill-health 8

occurring in the source/donor animals should be investigated with respect to 9

their suitability and the suitability of in-contact animals for continued use (in 10

manufacture, as sources of starting and raw materials, in quality control and 11

safety testing); the decisions must be documented. 12

3. A look-back procedure should be in place which informs the decision-making 13

process on the continued suitability of the biological active substance or 14

medicinal product in which the animal sourced starting or raw materials have 15

been used or incorporated. This decision-making process may include the 16

re-testing of retained samples from previous collections from the same donor 17

animal (where applicable) to establish the last negative donation. The 18

withdrawal period of therapeutic agents used to treat source/donor animals must 19

be documented and used to determine the removal of those animals from the 20

programme for defined periods. 21

4. Particular care should be taken to prevent and monitor infections in the 22

source/donor animals. Measures should include the sourcing, facilities, 23

husbandry, biosafety procedures, testing regimes, control of bedding and feed 24

materials, 100% fresh air supply, appropriate temperature and humidity 25

conditions considering the species being handled and water supply. This is of 26

special relevance to SpecificPpathogenFfree (SPF) animals where 27

Pharmacopoeial monograph requirements must be met. Housing and health 28

monitoring should be defined for other categories of animals (e.g., healthy 29

flocks or herds). 30

5. For products manufactured from transgenic animals, traceability should be 31

maintained in the creation of such animals from the source animals. Note should 32

be taken of national requirements for animal quarters, care and quarantine. 33

Housing for animals used in the production and control of biological products 34

should be separated from production and control areas. 35

6. For different animal species, key criteria should be defined, monitored and 36

recorded. These may include age, weight and health status of the animals. 37

7. Animals, biological agents and tests carried out should be appropriately 38

identified to prevent any risk of mix up and to control all identified hazards. 39

27

8. The facility layout should assure a unidirectional and segregated flow of healthy 1

and inoculated animals and waste decontamination areas. Personnel and visitors 2

should also follow a defined flow in order to avoid carryover and cross- 3

contamination. 4

Pharmaceutical Quality System (PQS) and Quality Risk Management 5

Biological products, as any pharmaceutical product, should be manufactured 6

considering the requirements of a Pharmaceutical Quality System (PQS) based on a 7

life-cycle approach, which should facilitate innovation and continual improvement, 8

and also strengthen the link between pharmaceutical development and manufacturing 9

activities, as defined in WHO Good manufacturing practices for pharmaceutical 10

products: Main Principles (1). Therefore, special attention should be paid to raw 11

material controls, change control, trend analysis and deviation management in order 12

to assure production consistency. 13

14

Operations in biological production and testing require specialized knowledge 15

considering the risks inherent in producing and manipulating pathogenic and 16

transmissible microorganisms. As a result, quality risk management (QRM) 17

principles are particularly important for this class of materials and should be used to 18

develop the control strategy across all stages among the supply chain, as described in 19

WHO Guidelines on quality risk management (28) and the Pharmaceutical Quality 20

System as described in ICH Q10 (29). 21

22

The QRM tools which may be used include Hazard Analysis and Critical Control 23

Point (HACCP) and Failure Mode Effect and Criticality Analysis (FMECA) for 24

preventive evaluation of the risks associated to a process in order to reduce the level 25

of uncertainty as required by WHO in Application of Hazard Analysis and Critical 26

Control Point (HACCP) methodology to pharmaceuticals (30). 27

28

References 29

1. WHO good manufacturing practices for pharmaceutical products: main 30

principles. In: WHO Expert Committee on Specifications for Pharmaceutical 31

Preparations: Forty-eighth report. Geneva: World Health Organization; 2013: 32

Annex 2 (WHO Technical Report Series, No. 986). 33

2. WHO GMP for sterile pharmaceutical products. In: WHO Expert Committee on 34

Specifications for Pharmaceutical Preparations: Forty-fifth report. Geneva: World 35

Health Organization; 2011: Annex 6 (WHO Technical Report Series, No. 961). 36

3. WHO good manufacturing practices for active pharmaceutical ingredients. In: 37

WHO Expert Committee on Specifications for Pharmaceutical Preparations: 38

Forty-fourth report. Geneva: World Health Organization; 2010: Annex 2 (WHO 39

Technical Report Series, No. 957). 40

28

4. Guide to good manufacturing practice for medicinal products. Annex 2. 1

Manufacture of biological medicinal products, Part I. PIC/S. 1 March 2014. 2

5. Guide to good manufacturing practice for medicinal products, Part II. PIC/S. 1 3

March 2014. 4

6. EU guidelines for Good Manufacturing Practice for Medicinal Products for 5

Human and Veterinary Use. Annex 2: Manufacture of Biological active 6

substances and Medicinal Products for Human Use. January 2013. 7

7. EU Guidelines to Good Manufacturing Practices for Medicinal Products for 8

Human and Veterinary Use. Part I: Chapter 6 Quality Control. 25 October 2005. 9

8. US FDA Current Good Manufacturing Practice for Finished Pharmaceuticals. 10

Title 21--Food and Drugs, Chapter I-Food and Drug Administration, Department 11

of Health and Human Services. Subchapter C--Drugs: General. CFR-Code of 12

Federal Regulations, Title 21, Volume 4, Revised as of April 1, 2014], 13

http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPar14

t=211&showFR=1. 15

9. WHO good practices for pharmaceutical quality control laboratories. In: WHO 16

Expert Committee on Specifications for Pharmaceutical Preparations: 17

Forty-fourth report. Geneva: World Health Organization; 2010: Annex 1 (WHO 18

Technical Report Series, No. 957). 19

10. Chinese Good Manufacturing Practice for Drugs (2010 revision). 20

(http://eng.sfda.gov.cn/WS03/CL0768/65113.html). 21

11. WHO Guidelines on Good Manufacturing Practices for Blood Establishments. In: 22

WHO Expert Committee on Specification for Pharmaceutical Products: 23

Forty-fifth report. Geneva: World Health Organization; 2011: Annex 4 (WHO 24

Technical Report Series, No. 961). 25

12. WHO good distribution practices for pharmaceutical products. In: WHO Expert 26

Committee on Specification for Pharmaceutical Products: Forty-fourth report. 27

Geneva: World Health Organization; 2010: Annex 5 (WHO Technical Report 28

Series, No. 957). 29

13. WHO guidelines on transmissible spongiform encephalopathies in relation to 30

biological and pharmaceutical products. Geneva, World Health Organization, 31

2003. (WHO/BCT/QSD/03.01) 32

(http://www.who.int/biologicals/publications/en/whotse2003.pdf). 33

14. Requirements for the collection, processing and quality control of blood, blood 34

components and plasma derivatives. In: WHO Expert Committee on Biological 35

Standardization: Forty-third report. Geneva: World Health Organization; 1992: 36

Annex 2 (WHO Technical Report Series, No. 840). 37

15. WHO Environmental Monitoring of Clean Rooms in Vaccine Manufacturing 38

Facilities - Points to consider for manufacturers of human vaccines, 2012 39

(http://www.who.int/immunization_standards/vaccine_quality/env_monitoring_c40

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12

13

Authors and acknowledgements 14

The scientific basis for the revision of these guidelines was discussed at the working 15

group meeting held in Thailand in 10-13 September 2007 with the following 16

participants: Dr Hikmat Alitamsar, Bio Farma Ltd, Bandung, Indonesia; Mr Praphon 17

Angtrakool, Ministry of Public Health, Nonthaburi, Thailand; Dr May Mahmoud 18

Farag Ahmed, Center for Control of Biologicals and Vaccines, Agousa, Egypt; Dr 19

David Buckley, Monash, ACT, Australia; Dr Maureen Dennehy, The Biovac Institute, 20

Cape Town, South Africa; Ms Xiaoman Dong, Beijing Tiantan Biological Products 21

Co., Ltd, Beijing, People's Republic of China; Dr Huib J. M. van de Donk, Den Haag, 22

Netherlands; Dr M. Gheisarzardeh, Ministry of Health and Medical Education, 23

Tehran, Iran; Dr Hoang Thi Hong, National Institute for Control of Vaccine and 24

Biologicals, Hanoi, Viet Nam; Mrs Wichuda Jariyapan, WHO Regional Office for 25

South-East Asia, New Delhi, India; Mr Milind Javadekar, Serum Institute of India Ltd, 26

Pune, India; Dr Diancai Jiang, State Food and Drug Administration, Beijing, People's 27

Republic of China; Mrs Teeranart Jivapaisarnpong, Ministry of Public Health, 28

Nonthaburi, Thailand; Dr Alireza Khadem, Pasteur Institute of Iran, Tehran, Iran; 29

Professor Sumana Khomvilai, Thai Red Cross Society, Bangkok, Thailand; Dr 30

Kwang-Ho Kim, Korean Food and Drug Administration, Seoul, Republic of Korea; 31

Dr Ivana Knezevic, WHO Headquarters, Geneva, Switzerland; Dr Kustantinah, 32

National Agency of Drug and Food Control, Jakarta Pusat, Indonesia; Dr Scott 33

Lambert, WHO Headquarters, Geneva, Switzerland; Professor Chung Keel Lee, 34

Advisor KFDA, Seoul, Republic of Korea; Mrs Jing Li, Sinovac Biotech Co., Ltd., 35

Beijing, People's Republic of China; Biologist Victor G. Maqueda, Argentina; Dr 36

Kyung-Il Min, Korean Food and Drug Administration, Seoul, Republic of Korea; Mr 37

Ian Rees, Medicines and Healthcare Products Regulatory Agency, London, United 38

Kingdom; Dr Chong Hock Sia, Health Sciences Authority, Singapore; Dr Mahendra 39

Suhardono, Bio Farma Ltd., Bandung, Indonesia; Ms Prapassorn Savaitnisagon 40

Thanaphollert, Ministry of Public Health, Nonthaburi, Thailand; Mr Sit 41

Thirapakpoomanunt, Ministry of Public Health, Bangkok, Thailand; Ms Jessica Teo, 42

Centre for Drug Administration, Singapore; Ms Antonia Retno Tyas Utami, National 43

31

Agency of Drug and Food Control, Jakarta, Indonesia; Dr Dang Thi Hong Van, 1

Institute for Vaccine and Biologicals, Nha Trang City, Viet Nam; Mr Bayu Wibisono, 2

National Agency of Drug and Food Control, Jakarta Pusat, Indonesia; Mr Jingsi Yang, 3

Kunming Institute of Medical Biology, Kunming, People's Republic of China; Mr 4

Yongting Yu, Kunming Institute of Medical Biology, Kunming, People's Republic of 5

China and a drafting group meeting held at WHO, Geneva, Switzerland from 30 to 31 6

October 2013 and attended by Mr Rao Acs, Central Drugs Standard Control 7

Organisation (CDSCO), Hyderabad, Andhra Pradesh, India, Dr Saeedeh Fakhrzadeh, 8

Biologic Department, Food and Drug Organization, Ministry of Health and Medical 9

Education, Islamic Republic of Iran, Biologist Victor G. Maqueda, Argentina, Mrs 10

Kakkanang Porkaew, Post-Marketing Control Division, Bureau of Drug 11

Administration, Food and Drug Administration, Ministry of Public Health, 12

Nonthaburi, Thailand, Dr Sandra O. Rumiano, Argentina, Juan Bautista Alberdi, 13

Argentina, Dr Youchun Wang, National Institutes for Food and Drug Control, Beijing, 14

China, Mr Bayu Wibisono, National Agency of Drug and Food Control, Jakarta, 15

Indonesia, Dr Martin Eisenhawer, Regional Office for South-East Asia, World Health 16

Organization, New Delhi, India, Dr Anil Chawla, Essential Medicines and Health 17

Products, Health System and Innovation, World Health Organization, Geneva, 18

Switzerland, Dr Alireza Broojerdi Khadem, Essential Medicines and Health Products, 19

World Health Organization, Geneva, Switzerland, Dr Ivana Knezevic, Essential 20

Medicines and Health Products, World Health Organization, Geneva, Switzerland, Dr 21

Sabine Kopp, Essential Medicines and Health Products, World Health Organization, 22

Geneva, Switzerland, Dr Dianliang Lei, Essential Medicines and Health Products, 23

World Health Organization, Geneva, Switzerland. 24

25

The first draft of these guidelines was prepared by Mr Rao Acs, Dr Biorkys Yáñez 26

Chamizo, Dr Saeedeh Fakhrzadeh, Mrs Kakkanang Porkaew, Dr Sandra O. Rumiano, 27

Dr Youchun Wang, Mr Bayu Wibisono, Dr Martin Eisenhawer, Dr Anil Chawla, Dr 28

Alireza Broojerdi Khadem, Biologist Victor G. Maqueda, Argentina, and Dr 29

Dianliang Lei, the drafting group for revision of WHO GMP for Biological Products 30

based on the principles defined in the aboved working group meeting and drafting 31

group meeting. 32

33

The second draft of the guidelines was prepared by Biologist Victor G. Maqueda, 34

Dr Biorkys Yáñez Chamizo, Dr Saeedeh Fakhrzadeh, Dr Sandra O. Rumiano, Dr 35

Youchun Wang, Mr Bayu Wibisono, Dr Martin Eisenhawer, Dr Anil Chawla, Dr 36

Alireza Broojerdi Khadem and Dr Dianliang Lei following the consultation held in 37

Tunisia from 22 to 24 July 2014 with the following participants: Dr Anil Chawla, 38

Greater Noida, Uttar Pradesh, India; Dr Saeedeh Fakhrzadeh, Biologic Department, 39

Food and Drug Organization, Ministry of Health and Medical Education, Islamic 40

Republic of Iran; Dr Elwyn Ggriffiths, Kingston upon Thames, United Kingdom; 41

Biologist Victor G. Maqueda, Argentina; Mrs Kakkanang Porkaew, Post-Marketing 42

Control Division, Bureau of Drug Administration, Food and Drug Administration, 43

Ministry of Public Health, Nonthaburi, Thailand; Dr Sandra O. Rumiano, Argentina; 44

32

Dr Youchun Wang, National Institutes for Food and Drug Control, Beijing, China; Mr 1

Bayu Wibisono, National Agency of Drug and Food Control, Jakarta, Indonesia; Dr 2

Helena Baiao, Inspection and Licensing Department, Infarmed, National Authority 3

for Medicines and Health Products Parque De Saude De Lisboa, Lisbon, Portugal; 4

Mrs Rubina Bose, CDSCO (HQ), Ministry of Health and Family Welfare, New Delhi, 5

India; Mr Madicke Diagne, Division du contrôle administratif des médicament 6

cumulativement au fonction de pharmacien inspecteu, Direction de la Pharmacie et 7

des Laboratoires, Dakar, Senegal; Mrs Rim Frikha, Directorate of Pharmacy 8

Inspection, Tunis, Tunisia; Ms Andrea Renata Cornelio Geyer, Agencia Nacional da 9

Vigilancia Sanitaria, Secretaria de Vigilancia Sanitaria, Ministerio da Saude 10

Esplanada dos Ministerios, Brasilia-DF, Brazil; Dr Nadir Harjee, Ontario, Canada; 11

Ms Dang Thi Minh Hang, Drug Administration of Vietnam, Ministry of Health, 12

Hanoi, Viet Nam; Dr Chung Keel Lee, Korea Food & Drug Administration, 13

Osongsaengmyeong Republic of Korea; Dr Henry Leng, Inspectorate and Law 14

Enforcement, Medicines Regulatory Affairs, Department of Health, Medicines 15

Regulatory Authority, Pretoria, South Africa; Dr Jenny Miteva, Bulgarian Drug 16

Agency, Sofia, Bulgaria; Dr Mohamed Refaat, Central Administration for 17

Pharmaceutical Affairs, Cairo, Egypt; Dr Maria Guadalupe Lopez Santos, Comisión 18

Federal para la Protección contra Riesgos Sanitarios (COFEPRIS), México D.F., 19

Mexico; Dr Anna Laura Salvati, Department of Evaluation and Registration, Agenzia 20

Italiana del Farmaco, Roma, Italy; Dr Willem Stevens, Center for Biological 21

Evaluation, Biologics and Genetic Therapies, Health Canada, Canada; Dr Salah 22

Uddin, Directorate General of Drug Administration, Dhaka, Bangladesh; Dr Anna 23

Mihaylova, Bulgarian Drug Agency, Sofia, Bulgaria; Mr Claudio Cabral, Butantan 24

Institute, Sao Paulo, Brazil; Dr Sonia Pagliusi, DCVMN International, Nyon, 25

Switzerland; Dr Vinicius Alves Pessanha, Oswaldo Cruz Foundation, Rio de Janeiro, 26

Brazil; Dr Dierk Rebeski, the Biovac Institute, Pinelands, South Africa; Dr Iin 27

Susanti, PT Biofarma, Bandung, Indonesia; Ms Celia Sayoko Takata, Butantan 28

Institute, Sao Paulo, Brazil; Dr Robert Chaplinsky, Global Quality Assurance, GSK 29

Vaccines, Belgium; Dr Michael Gershman, Pfizer, New York, United States of 30

America; Dr Pierre Lauer, Sanofi Pasteur, Lyon, France; Dr Sundar Ramanan, One 31

Amgen Center Drive, California, United States of America; Dr Philippe Rampignon, 32

GSK Vaccines, Belgium; Dr Martin Eisenhawer, World Health Organization, 33

Regional Office for South-East Asia, Bangkok, Thailand; Dr Houda Langar, World 34

Health Organization, Regional Office for the Eastern Mediterranean, Cairo, Egypt; Dr 35

Jinho Shin, World Health Organization, Regional Office for the Western Pacific, 36

Manila, Philippines; Dr Alireza Khadem Broojerdi, Essential Medicines and Health 37

Products Department, World Health Organization, Geneva, Switzerland; Dr Dianliang 38

Lei, Technologies Standards and Norms, Essential Medicines and Health Products 39

Department, World Health Organization, Geneva, Switzerland; Dr Iveta 40

Streipa-Nauman, Prequalification Team, Essential Medicines and Health Products 41

Department, World Health Organization, Geneva, Switzerland; Dr David Wood, 42

Technologies Standards and Norms, Essential Medicines and Health Products 43

Department, World Health Organization, Geneva, Switzerland. 44

33

1

The third draft was prepared by Biologist Victor G. Maqueda, Dr Biorkys Yáñez 2

Chamizo, Dr Saeedeh Fakhrzadeh, Dr Sandra O. Rumiano, Dr Youchun Wang, Dr 3

Anil Chawla, Dr Mohamed Refaat, Dr Alireza Broojerdi Khadem and Dr Dianliang 4

Lei by incorporating the comments from regulators and industry. 5