WHO GMP for Biological · PDF file1 1 2 WHO/DRAFT/18 February 2015 3 ENGLISH ONLY 4 5 WHO GMP...
Transcript of WHO GMP for Biological · PDF file1 1 2 WHO/DRAFT/18 February 2015 3 ENGLISH ONLY 4 5 WHO GMP...
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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
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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: [email protected]). 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: [email protected]). 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
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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
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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
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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
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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
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propagation of microorganisms in embryos or animals. 1
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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
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Adventitious virus: Unintentionally introduced contaminant virus. 25
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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
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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
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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
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(*) 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
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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
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Bio-Hazard: Biological material considered to be hazardous to personnel, visitors 8
and/or the environment. 9
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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
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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
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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
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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
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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
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Cleaning Procedures Validation: A challenge study designed to prove that the 43
cleaning methods of product contact equipment/surfaces are effective based on 44
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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
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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
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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
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Dedicated: Facility or piece of equipment used only in the manufacture of a 18
particular product or a closely related group of products. 19
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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
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Drug Substance: A defined process intermediate containing the active ingredient, 26
which is subsequently formulated with excipients to produce the drug product. 27
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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
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Harvesting: Procedure by which the cells, inclusion bodies or crude supernatants 33
containing the unpurified active ingredient are recovered. 34
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Hybridoma. An immortalized cell line that secrete desired (monoclonal) antibodies 36
and are typically derived by fusing B-lymphocytes with tumour cells. 37
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Inactivation: Removal or reduction to an acceptable limit of infectivity of 39
microorganisms or detoxification of toxins by chemical or physical modification. 40
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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
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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
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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
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Pharmaceutical Quality System: Management system to direct and control a 8
pharmaceutical company with regard to quality. 9
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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
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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
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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
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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
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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
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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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Vaccine: Preparation containing antigens capable of inducing an active immune 2
response for the prevention, amelioration or treatment of infectious diseases. 3
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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
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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
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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
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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
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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
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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
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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
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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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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
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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