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WHO/BS/2015.2253 2
ENGLISH ONLY 3
4
EXPERT COMMITTEE ON BIOLOGICAL STANDARDIZATION 5
Geneva, 12 to 16 October 2015 6
7
8
WHO GMP for Biological Products 9
10
Proposed replacement of: TRS 822, Annex 1 11
12
NOTE: 13
14
This document has been prepared for the purpose of inviting comments and 15
suggestions on the proposals contained therein, which will then be considered by the 16
Expert Committee on Biological Standardization (ECBS). Publication of this early 17
draft is to provide information about the GMP Guidelines for Biological Products to a 18
broad audience and to improve transparency of the consultation process. 19
20
These Guidelines were developed based on the outcomes and consensus of the WHO 21
informal consultation convened in July 2014 with participants from national 22
regulatory authorities, national control laboratories, manufacturers and academia 23
researchers and comments from the public consultation on WHO website in 2015. 24
25
The text in its present form does not necessarily represent an agreed 26
formulation of the Expert Committee on Biological Standardization. Written 27
comments proposing modifications to this text MUST be received by 28
14 September 2015 in the Comment Form available separately and should be 29
addressed to the World Health Organization, 1211 Geneva 27, Switzerland, attention: 30
Department of Essential Medicines and Health Products (EMP). Comments may also 31
be submitted electronically to the Responsible Officer: Dr Dianliang Lei at email: 32
34
The outcome of the deliberations of the Expert Committee on Biological 35
Standardization will be published in the WHO Technical Report Series. The final 36
agreed formulation of the document will be edited to be in conformity with the 37
"WHO style guide" (WHO/IMD/PUB/04.1). 38
39
WHO/BS/2015.2253
Page 2
© World Health Organization 2015 1
All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, 2 World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: 3 +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO 4 publications – whether for sale or for non-commercial distribution – should be addressed to WHO Press, 5 at the above address (fax: +41 22 791 4806; e-mail: [email protected]). 6
The designations employed and the presentation of the material in this publication do not imply the 7 expression of any opinion whatsoever on the part of the World Health Organization concerning the legal 8 status of any country, territory, city or area or of its authorities, or concerning the delimitation of its 9 frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may 10 not yet be full agreement. 11 12 The mention of specific companies or of certain manufacturers’ products does not imply that they are 13 endorsed or recommended by the World Health Organization in preference to others of a similar nature 14 that are not mentioned. Errors and omissions excepted, the names of proprietary products are 15 distinguished by initial capital letters. 16 17 All reasonable precautions have been taken by the World Health Organization to verify the information 18 contained in this publication. However, the published material is being distributed without warranty of 19 any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies 20 with the reader. In no event shall the World Health Organization be liable for damages arising from its 21 use. 22 23 The named authors [or editors as appropriate] alone are responsible for the views expressed in this 24 publication. 25
26
Recommendations published by 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.
27
28
29
30
WHO/BS/2015.2253
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Contents 1
1. INTRODUCTION ....................................................................................................... 4 2
2. SCOPE ..................................................................................................................... 4 3
3. GLOSSARY .............................................................................................................. 7 4
4. PRINCIPLES AND GENERAL CONSIDERATIONS ........................................................ 11 5
5. PHARMACEUTICAL QUALITY SYSTEM AND QUALITY RISK MANAGEMENT ............. 13 6
6. PERSONNEL ........................................................................................................... 14 7
7. STARTING MATERIALS .......................................................................................... 15 8
8. SEED LOTS AND CELL BANKS................................................................................. 17 9
9. PREMISES AND EQUIPMENT ................................................................................... 19 10
10. CONTAINMENT ...................................................................................................... 20 11
11. CLEAN ROOMS ...................................................................................................... 23 12
12. PRODUCTION ......................................................................................................... 23 13
13. CAMPAIGN PRODUCTION ....................................................................................... 25 14
14. LABELLING ........................................................................................................... 26 15
15. VALIDATION ......................................................................................................... 27 16
16. QUALITY CONTROL ............................................................................................... 29 17
17. DOCUMENTATION (BATCH PROCESSING RECORDS) ............................................... 31 18
18. USE OF ANIMALS ................................................................................................... 31 19
REFERENCES ................................................................................................................ 33 20
AUTHORS AND ACKNOWLEDGEMENTS ......................................................................... 36 21
22
23
WHO/BS/2015.2253
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1. Introduction 1
The source and methods employed in the manufacture of biological products for 2
human use represent critical factors in shaping appropriate regulatory control. 3
Biological products can be defined, therefore, largely by reference to their method of 4
manufacture and their source. Biological products are derived from cells, tissues or 5
microorganisms and reflect the inherent variability characteristics of living materials. 6
The active 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 and/or batch to the next. Consequently, special 9
considerations are needed when manufacturing biological products in order to 10
maintain the consistency of the quality of the product. 11
12
The Good Manufacturing Practices (GMP) for biological products, as an annex to 13
GMP for pharmaceutical products, were adopted by the Expert Committee on 14
Biological Standardization and were first published in the WHO Technical Report 15
Series in 1992. The GMP for biological products have been recognized and used by 16
regulators and industry since then. This revision reflects the considerable 17
developments since that time and current perspectives regarding GMP for the 18
manufacture of biological products (112). 19
20
This document is intended to serve as a basis for establishing national guidelines for 21
GMP. The main principles and recommendations for manufacturing biological 22
products are provided. If a national regulatory authority (NRA) so desires, these 23
guidelines may be adopted as definitive national requirements. It is possible that 24
modifications to this document may be justified due to the riskbenefit balance and 25
legal considerations in each authority. In such cases, it is recommended that any 26
modification to the principles and technical specifications of these guidelines should 27
be made only on the condition that the modifications ensure product quality, safety 28
and efficacy that are at least equivalent to what is recommended in these guidelines. 29
2. Scope 30
These guidelines apply to the commercial manufacture, control and testing of 31
biological products from starting materials and preparations, including seed lots, cell 32
banks and intermediates, through to the finished products. 33
34
Manufacturing procedures within the scope of these guidelines include: 35
growth of strains of microorganisms and eukaryotic cells; 36
WHO/BS/2015.2253
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extraction of substances from biological tissues, including human, animal and 1
plant tissues, and fungi; 2
recombinant DNA (rDNA) techniques; 3
hybridoma techniques; and 4
propagation of microorganisms in embryos or animals. 5
6
Biological products manufactured by these methods include allergens, antigens, 7
vaccines, hormones, cytokines, enzymes, human whole blood and plasma derivatives, 8
immune sera, immunoglobulins (including monoclonal antibodies), products of 9
fermentation (including products derived from rDNA), and diagnostic agents for in 10
vitro use, gene therapy, cell therapy, etc. The recommendations for manufacturing 11
blood and plasma-derived products are covered by WHO’s Guidelines on good 12
manufacturing practices for blood establishments (11) and Requirements for the 13
collection, processing and quality control of blood, blood components and plasma 14
derivatives (13). 15
16
Table 1 provides further guidance about the scope of application of the current 17
guidelines (6). It should be noted that this table is illustrative and is not intended to 18
describe the precise scope. 19
20
Table 1. Guidance on the scope of the current guidelines (illustrative) 21
Type and
source of
material
Example products Application of the guideline to steps in manufacture
1. Animal or
plant sources:
non-transgenic
Heparins, insulin,
enzymes, proteins,
allergen extract,
Advanced Therapy
Medicinal Products
(ATMPs), immunsera
Collection of
plant, organ,
tissue or fluid
Cutting, mixing,
and/or initial
processing
Isolation and
purification
Formulation,
filling
2. Virus or
bacteria/fermentat
ion/cell culture
Viral or bacterial
vaccines, enzymes,
proteins
Establishment and
maintenance of
MCB, WCB,
MVS, WVS
Cell culture and/or
fermentation
Inactivation when
applicable,
isolation and
purification
Formulation,
filling
3. Biotechnology
fermentation/cell
culture
Recombinant products,
mAbs, allergens,
vaccines,
gene therapy (viral and
nonviral vectors,
plasmids)
Establishment and
maintenance of
MCB, WCB,
MSL, WSL
Cell culture and/or
fermentation
Isolation,
purification,
modification
Formulation,
filling
4. Animal
sources:
Recombinant proteins,
ATMPs
Master and
working
Collection,
cutting, mixing,
Isolation,
purification and
Formulation,
filling
WHO/BS/2015.2253
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transgenic transgenic bank and/or initial
processing
modification
5. Plant sources:
transgenic
Recombinant proteins,
vaccines, allergen
Master and
working
transgenic bank
Growing and/or
harvesting1
Initial extraction,
isolation,
purification,
modification
Formulation,
filling
6. Human sources Urine-derived
enzymes, hormones
Collection of fluid Mixing, and/or
initial processing
Isolation and
purification
Formulation,
filling
7. Human and/or
animal sources
Gene therapy:
genetically modified
cells
Donation,
procurement and
testing of starting
tissue/cells1
Manufacture
vector, and cell
purification
and processing
Ex vivo genetic
modification of
cells, establish
MCB, WCB or
cell stock
Formulation,
filling
Somatic cell therapy Donation,
procurement and
testing of starting
tissue/cells1
Establish MCB,
WCB or cell stock
Cell isolation,
culture
purification,
combination with
noncellular
components
Formulation,
combination,
filling
Tissue engineered
Products
Donation,
procurement and
testing of starting
tissue/cells1
Initial processing,
isolation and
purification,
establish MCB,
WCB, primary cell
stock
Cell isolation,
culture,
purification,
combination with
noncellular
components
Formulation,
combination,
filling
1
The present guidelines do not lay down detailed recommendations for specific classes 2
of biological products (e.g. vaccines). Therefore attention is directed to other specific 3
guidance documents issued by WHO and, in particular, to recommendations to assure 4
the quality, safety and efficacy of the specific product.2 5
6
1 GMP guidelines, as described in this document, are not applied to this step. Other national
regulations, requirements, recommendations and/or guidelines may apply, as deemed necessary by the
NRA.
2 See: http://www.who.int/biologicals/en/ (accessed 3 July 2015).
WHO/BS/2015.2253
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3. Glossary 1
Besides the terms defined in WHO’s Good manufacturing practices for 2
pharmaceutical products: main principles (1), the definitions given below apply to 3
the terms as used in this document. These terms may have different meanings in other 4
contexts. 5
6
Active substance: A defined process intermediate containing the active ingredient, 7
which is subsequently formulated with excipients to produce the drug product. This 8
may also be referred to as a drug substance or active ingredient in other documents. 9
10
Adventitious agents: Contaminating microorganisms of the cell culture or source 11
materials, including bacteria, fungi, mycoplasmas/spiroplasmas, mycobacteria, 12
rickettsia, protozoa, parasites, transmissible spongiform encephalopathy (TSE) agents, 13
and viruses that have been unintentionally introduced into the manufacturing process 14
of a biological product. 15
16
The source of these contaminants may be from the legacy of the cell 17
line, the raw materials used in the culture medium to propagate the 18
cells (in banking, in production, or in their legacy), the environment, 19
personnel, equipment or elsewhere. 20
21
Allergen: An allergen is a molecule capable of inducing an Immunoglobulin E (IgE) 22
response and/or a Type I allergic reaction. 23
24
Antibodies: Proteins produced naturally by the B-lymphocytes that bind to specific 25
antigens. Using rDNA technology, antibodies are also produced in other (continuous) 26
cell lines. Antibodies may be divided into two main types – monoclonal and 27
polyclonal antibodies – on the basis of key differences in their methods of 28
manufacture. 29
30
Antigens: Substances (e.g. toxins, foreign proteins, bacteria, tissue cells) capable of 31
inducing specific immune responses. 32
33
Axenic: A single organism in culture which is not contaminated with any other 34
organism. 35
36
Bioburden: The level and type (i.e. objectionable or not) of micro-organisms present 37
in raw materials, media, biological substances, intermediates or finished products. 38
Regarded as contamination when the level and/or type exceed specifications. 39
40
WHO/BS/2015.2253
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Biohazard: Biological material considered to be hazardous to personnel, visitors 1
and/or the environment. 2
3
Biological starting materials: Starting materials derived from a biological source 4
that mark the beginning of the manufacturing process of a drug, as described in a 5
marketing authorization or licence application, from which the active ingredient is 6
derived either directly (e.g. plasma derivatives, ascitic fluid, bovine lung) or 7
indirectly (e.g. cell substrates, host/vector production cells, eggs, viral strains). 8
9
Biosafety risk group: The containment conditions required for safe handling of 10
organisms associated with different hazards, ranging from Risk roup 1 (lowest risk, 11
no or low individual and community risk, unlikely to cause disease) to Risk Group 4 12
(highest risk, high individual and community risk, cause severe disease, likely to 13
spread and no prophylaxis or treatment available). 14
15
Campaign manufacture: The manufacture of a series of batches of the same product 16
in sequence in a given period of time, followed by strict adherence to accepted 17
control measures before transfer to another product. The products are not run at the 18
same time but may be run on the same equipment. 19
20
Cell bank: A collection of appropriate containers whose contents are of uniform 21
composition and stored under defined conditions. Each container represents an 22
aliquot of a single pool of cells. 23
24
Cell culture: The process by which cells are grown in vitro under defined and 25
controlled conditions where the cells are no longer organized into tissues. Cell 26
cultures are operated and processed under axenic conditions to ensure a pure culture 27
absent of microbial contamination. 28
29
Cell stock: Primary cells expanded to a given number of cells to be aliquoted and 30
used as starting material for production of a limited number of lots of a cell-based 31
medicinal product. 32
33
Containment: The concept of using a process, equipment, personnel, utilities, 34
system or facility for containing product, dust or contaminants in one zone, 35
preventing them from escaping and also from entering into another zone. 36
37
Continuous culture: Process by which the growth of cells is maintained by 38
periodically replacing a portion of the cells and the medium so that there is no lag or 39
saturation phase. 40
41
WHO/BS/2015.2253
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Cross-contamination: Contamination of a starting material, intermediate product or 1
finished product with another starting material or product during production. In 2
multi-product facilities, cross-contamination can occur throughout the manufacturing 3
process, from generation of the master cell bank (MCB) and working cell bank 4
(WCB) through to finishing. 5
6
Dedicated: Facility, personnel, equipment or piece of equipment used only in the 7
manufacture of a particular product or a closely related group of products. 8
9
Feeder cells: Cells used in co-culture to maintain pluripotent stem cells. For human 10
embryonic stem cell culture, typical feeder layers include mouse embryonic 11
fibroblasts (MEFs) or human embryonic fibroblasts that have been treated to prevent 12
them from dividing. 13
14
Finished product: A finished dosage form that has undergone all stages of 15
manufacture, including packaging in its final container and labelling. This may also 16
be referred to as a finished dosage form, drug product, or final product in other 17
documents. 18
19
Fermentation: Maintenance or propagation of microbial cells in vitro (fermenter). 20
Fermentation is operated and progressed under axenic conditions to ensure a pure 21
culture absent of contaminating microorganisms. 22
23
Harvesting: Procedure by which the cells, inclusion bodies or crude supernatants 24
containing the unpurified active ingredient are recovered. 25
26
Hybridoma: An immortalized cell line that secrete desired (monoclonal) antibodies 27
and are typically derived by fusing B-lymphocytes with tumor cells. 28
29
Inactivation: Removal or reduction to an acceptable limit of infectivity of 30
microorganisms or detoxification of toxins by chemical or physical modification. 31
32
Master cell bank (MCB): A quantity of well-characterized cells of animal or other 33
origin, derived from a cell seed at a specific population doubling level (PDL) or 34
passage level, dispensed into multiple containers and stored under defined conditions. 35
The master cell bank is prepared from a single homogeneously mixed pool of cells. In 36
some cases, such as genetically engineered cells, the MCB may be prepared from a 37
selected cell clone established under defined conditions. However, the MCB may not 38
be clonal. The MCB is used to derive a working cell bank (WCB). 39
40
WHO/BS/2015.2253
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Monoclonal antibodies (mAbs): Homogenous antibody population obtained from a 1
single clone of lymphocytes or by recombinant technology and which bind to a single 2
epitope. 3
4
Pharmaceutical quality system (PQS): Management system for directing and 5
controlling a pharmaceutical company with regard to quality. 6
7
Polyclonal antibodies: Derived from a range of lymphocyte clones and produced in 8
humans and animals in response to the epitopes on most “non-self” molecules. 9
10
Primary containment: A system of containment that prevents the escape of a 11
biological agent into the immediate working environment. It involves the use of 12
closed containers or biological safety cabinets along with secure operating 13
procedures. 14
15
Quality risk management (QRM): A systematic process for the assessment, control, 16
communication and review of risks to the quality of pharmaceutical products across 17
the product life cycle. 18
19
Reference sample: A sample of a batch of starting material, packaging material or 20
finished product which is stored for the purpose of being analysed should the need 21
arise during the shelf-life of the batch concerned. 22
23
Retention sample: A sample of a fully packaged unit from a batch of finished 24
product. It is stored for identification purposes (e.g. presentation, packaging, labelling, 25
patient information leaflet, batch number, expiry date) should the need arise during 26
the shelf-life of the batch concerned. 27
28
Seed lot: A quantity of live cells (prokaryotic or eukaryotic) or viruses which has 29
been derived from a single culture (although not necessarily clonal), has a uniform 30
composition and is aliquoted into appropriate storage containers from which all future 31
products will be derived, either directly or via a seed lot system. 32
33
The following derived terms are used in these guidelines: 34
Master seed lot (MSL): a lot or bank of cells or viruses from which all future 35
vaccine production will be derived. The MSL represents a well-characterized 36
collection of cells or viruses of uniform composition. Also referred to as 37
“master virus seed” (MVS) for virus seeds, “master seed bank”, “master seed 38
antigen” or “master transgenic bank” in other documents. 39
Working seed lot (WSL): a cell or viral seed lot derived by propagation from 40
the MSL under defined conditions and used to initiate production of vaccines 41
on a lot-by-lot basis. Also referred to as “working virus seed” (WVS) for 42
WHO/BS/2015.2253
Page 11
virus seeds, “working seed bank”, “working seed antigen” or “working 1
transgenic bank” in other documents. 2
3
Specific pathogen free (SPF): Animal materials (e.g. chickens, embryos or cell 4
cultures) used for the production or quality control of biological products derived 5
from groups (e.g. flocks or herds) of animals free from specified pathogens. Such 6
flocks or herds are defined as animals sharing a common environment and having 7
their own caretakers who have no contact with non-SPF groups. 8
9
Starting materials: Any substances of a defined quality used in the production of a 10
pharmaceutical product, but excluding packaging materials. 11
12
Transgenic: An organism that contains a foreign gene in its normal genetic 13
component for the expression of biological pharmaceutical materials. 14
15
Vaccine: A preparation containing antigens capable of inducing an active immune 16
response for the prevention, amelioration or treatment of infectious diseases. 17
18
Working cell bank (WCB): A quantity of well-characterized cells of animal or other 19
origin, derived from an MCB at a specific PDL or passage level, dispensed into 20
multiple containers, and stored under defined conditions. The WCB is prepared from 21
a single homogeneously mixed pool of cells (often, this is the MCB). One or more of 22
the WCB containers is used for each production culture. 23
24
4. Principles and general considerations 25
The manufacture of biological products should be undertaken in accordance with the 26
basic principles of GMP. The points covered by these guidelines should, therefore, be 27
considered complementary to the general recommendations set out in the current 28
WHO Good manufacturing practices for pharmaceutical products: main principles 29
(1) and in other WHO documents related specifically to the production and control of 30
biological products established by the WHO Expert Committee on Biological 31
Standardization.1 32
33
The ways in which biological products are manufactured, controlled and administered 34
require particular necessary precautions. Control of biological products (e.g. potency 35
testing) can rarely be expressed in units of mass, but is determined through bioassays 36
1 See http://www.who.int/biologicals/en/, accessed 3 July 2015.
WHO/BS/2015.2253
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which are themselves highly variable in predicting the physiological or therapeutic 1
effects on humans, when compared to physico-chemical determinations. If bioassays 2
can be replaced with immunological assays detecting discrete antigenic sites on 3
representative components of the product, precision may be increased. 4
5
Therefore, a robust and consistent manufacturing process with adequate in-process 6
controls is of greater importance in the manufacture of biological products because 7
certain deficiencies may not be revealed by testing the finished product. The 8
combination of variability in starting materials and the potential for subtle changes 9
during the manufacturing process of biological products also requires emphasis on 10
production consistency which becomes a special concern because of the need to link 11
the consistency to original clinical trials documenting the product's safety and 12
efficacy. 13
14
It is not possible for most biological active ingredients, including live attenuated 15
bacteria and viruses, to be terminally sterilized by heat, gas or radiation. In addition, 16
some products, such as certain live vaccines (e.g. whole cell pertussis, cholera), must 17
maintain the viability and purity of the organisms, and this may prevent the use of 18
common purification techniques or sterile filtration processes. For these axenic 19
products, aseptic processing and mild purification procedures must be used 20
throughout the manufacturing process. 21
22
Since starting materials and processing conditions used in cultivation processes are 23
designed to provide conditions for the growth of specific cells and microorganisms, 24
extraneous microbial contaminants have the opportunity to grow. Adventitious agents 25
arising from starting materials, from facility-derived microorganisms and from 26
contamination of product materials by operators, constitute another critical aspect of 27
GMP for biological products which is aimed at preventing or reducing the risk of 28
contamination of starting materials, intermediate bulks and finished products. The 29
design of the processes, equipment, facilities and utilities, the sampling and the 30
training of the operators are key considerations in preventing such contamination 31
events. 32
33
Methods for inactivating viral and bacterial agents and their associated metabolites in 34
manufacturing areas and on surfaces coming into contact with a product must be 35
shown to be efficacious, reliable and consistent (i.e. validated). In addition, cleaning 36
procedures and hygiene are extremely important in contamination control. 37
38
Because of the risks inherent in producing and manipulating pathogenic and 39
transmissible microorganisms during production and testing of biological materials, 40
GMP must prioritize the safety of the recipient to whom the biological product is 41
administered, the safety of the operators during operations and the protection of the 42
WHO/BS/2015.2253
Page 13
environment. As a result, quality risk management (QRM) principles are particularly 1
important for this class of products and should be used to develop the control strategy 2
throughout all stages of manufacture so as to achieve consistency, minimize 3
variability and reduce the opportunity for contamination and cross-contamination. 4
5
Biosafety considerations, should follow national guidelines and (if applicable and 6
available) international guidelines. In most countries, regulation of GMPs and 7
biosafety are governed by different institutions. Especially in the context of 8
manufacturing of pathogenic biological products of Biosafety risk group 3 and 4, 9
close collaboration between those institutions is required to assure that both, product 10
contamination and environmental contamination levels are controlled within 11
acceptable limits. Specific recommendations regarding containment are outlined in 12
chapter 11. 13
5. Pharmaceutical quality system and quality risk 14
management 15
Biological products, like any pharmaceutical product, should be manufactured in 16
accordance with the requirements of a pharmaceutical quality system (PQS) based on 17
a life-cycle approach. This should facilitate innovation and continual improvement, 18
and should also strengthen the link between pharmaceutical development and 19
manufacturing activities, as defined in WHO’s Good manufacturing practices for 20
pharmaceutical products: main principles (1). Thus, special attention should be paid 21
to raw material controls, change control, trend analysis and deviation management in 22
order to ensure production consistency. 23
24
Operations in biological production and testing require specialized knowledge in 25
view of the risks inherent in producing and manipulating pathogenic and 26
transmissible microorganisms. As a result, QRM principles are particularly important 27
for this class of materials and should be used to develop the control strategy across all 28
manufacturing and control stages – including manufacture, quality control, quality 29
assurance, storage and distribution activities, as described in WHO guidelines on 30
quality risk management (14), and the pharmaceutical quality system as described in 31
Q10 guideline (15) of the International Conference on Harmonization (ICH). QRM 32
will also contribute to identifying the probable causes of unwanted or unanticipated 33
factors affecting the purity, potency, safety, efficacy and stability of the product, 34
assessing the effectiveness of measures to reduce or manage such risks, and helping 35
to identify critical product attributes and process control parameters during 36
development and validation phases. 37
38
WHO/BS/2015.2253
Page 14
Different tools may be used for QRM of the manufacture and control of biological 1
products, including – but not limited to – Hazard Analysis and Critical Control Point 2
(HACCP) (16) and Failure Mode Effects Analysis (FMEA). 3
4
6. Personnel 5
6.1 Personnel working in areas where biological active substances and products are 6
manufactured and tested should receive training and periodical retraining 7
specific to their duties and to the products being manufactured – including any 8
specific safety measures to protect the product, personnel and the environment. 9
The efficacy of training should be documented. 10
11
6.2 Persons responsible for production and quality control should have an adequate 12
background in relevant scientific disciplines such as microbiology, biology, 13
biometry, chemistry, medicine, pharmacy, pharmacology, virology, 14
immunology, biotechnology and veterinary medicine, together with sufficient 15
practical experience to enable them to perform their duties. 16
17
6.3 Training in cleaning and disinfection procedures, hygiene and microbiology is 18
particularly relevant to the production of biologicals because of the risk of 19
microbial contamination due to the handling of microorganisms, growth media 20
and adventitious organisms. 21
22
6.4 During a working day, personnel and visitors should not pass from areas with 23
exposure to live microorganisms, genetically modified microorganisms, animal 24
tissue, toxins, venoms or animals to areas where other products (inactivated or 25
sterile) or different organisms are handled. If such passage is unavoidable, the 26
contamination control measures (e.g. clearly defined decontamination measures, 27
including a complete change of appropriate clothing and shoes, and showering 28
if applicable) should be followed by all staff involved in any such production 29
unless otherwise justified on the basis of QRM. 30
31
6.5 Personnel working in animal husbandry should be dedicated to the animal 32
facility. 33
34
6.6 Where necessary, personnel engaged in production, maintenance, testing and 35
animal care (and inspections) should be vaccinated with appropriate vaccines 36
and should have regular health checks. Apart from the obvious risk of exposure 37
of staff to infectious agents, potent toxins or allergens, it is necessary to avoid 38
or reduce the risk of contaminating a product with these agents. 39
WHO/BS/2015.2253
Page 15
1
6.7 Staff assigned to production of bacille Calmette-Guerin (BCG) vaccine and 2
tuberculin products should not work with other infectious agents. In particular, 3
they should not work with virulent strains of M. tuberculosis, nor should they 4
be exposed to a known risk of tuberculosis infection. Additionally, they should 5
be carefully monitored, with regular health checks including validated 6
immunological blood assays and/or radiological examination. 7
8
6.8 Health monitoring of staff should be commensurate with the risk to the product 9
and the personnel. Medical advice should be sought for personnel involved with 10
or exposed to hazardous organisms. 11
12
7. Starting materials 13
7.1 The source, origin and suitability of starting materials (e.g. cryo-protectants, 14
feeder cells, reagents, growth media, buffers, serum, enzymes, cytokines, 15
growth factors, amino acids) should be clearly defined. Manufacturers should 16
retain information describing the source and quality of the biological materials 17
used for at least two years after the expiry date of the finished products 18
produced from them. 19
20
7.2 All starting material suppliers (i.e. manufacturers) should be initially qualified 21
on the basis of documented criteria and with a risk-based approach, and regular 22
assessments of their status should also be carried out. When starting materials 23
are sourced from brokers who could increase the risk of contamination by 24
performing repackaging operations, the brokers should be carefully qualified; 25
an audit may be a part of such qualification, as needed. 26
27
7.3 Incoming starting materials should be sampled – on the basis of justified criteria 28
– under appropriate conditions in order to prevent contamination. The samples 29
should be tested using pharmacopoeial or validated approved methods and 30
released by the Quality Unit before use. By no means should the sampling 31
process adversely affect the quality of the product, and particularly its sterility 32
when applicable. The level of testing should be commensurate with the 33
qualification level of the supplier and its continuous performance. However, at 34
least an identity test, or equivalent, is required on each container unless justified 35
on the basis of QRM principles and in agreement with all applicable guidelines. 36
37
7.4 Where the necessary tests for approving starting materials take a significantly 38
long time, it may be permissible to process starting materials before the test 39
WHO/BS/2015.2253
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results are available. The risk of using not-yet-approved material on the quality 1
of the product should be clearly justified in a documented manner, understood 2
and assessed under the principles of QRM. In such cases, release of a finished 3
product is conditional on satisfactory results of these tests. It must be ensured 4
that this is not common practice and occurs only exceptionally. The 5
identification of all starting materials should be in compliance with the 6
requirements appropriate to the stage of manufacture. 7
8
7.5 Where required, sterilization of starting materials should be carried out by heat 9
where possible. Where necessary, other appropriate validated methods may also 10
be used for this purpose (e.g. irradiation and filtration). 11
12
7.6 The risk of contamination of starting materials during their passage along the 13
supply chain must be assessed, with particular emphasis on transmissible 14
spongiform encephalopathy (TSE) (17). Other materials that come into direct 15
contact with manufacturing equipment and/or with potential product contact 16
surfaces (such as filter media, growth media during aseptic process simulations, 17
and lubricants) should also be controlled. A quality risk assessment should be 18
performed to evaluate the potential for adventitious agents in biological starting 19
materials. 20
21
7.7 The controls required for the quality of starting materials and on the aseptic 22
manufacturing process (particularly for cell-based products, where final 23
sterilization is generally not possible and the ability to remove microbial 24
by-products is limited) assume greater importance and should be based on the 25
principles and guidance contained in the current WHO good manufacturing 26
practices for sterile pharmaceutical products (2) and on the section “Clean 27
rooms” of the present document, as applicable. 28
29
7.8 The transport of critical materials, reference materials, drug substances, human 30
tissues and cells to the manufacturing site must be controlled by a written 31
quality agreement between the responsible parties. The manufacturing sites 32
should have documentary evidence of adherence to the specified storage and 33
transport conditions, including cold chain requirements. The continuation of 34
traceability requirements – starting at tissue establishments through to the 35
recipient(s), and vice versa, including materials in contact with the cells or 36
tissues – should be maintained. 37
38
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8. Seed lots and cell banks 1
Recommendations set out in WHO’s Good manufacturing practices for active 2
pharmaceutical ingredients, Section 18 on Specific guidance for APIs manufactured 3
by cell culture/fermentation (3) should be followed. 4
5
8.1 Where human or animal cells are used as feeder cells in the manufacturing 6
process, appropriate controls over the sourcing, testing, transport and storage 7
should be in place. 8
9
8.2 In order to prevent the unwanted drift of genetic properties which might result 10
from repeated subcultures or multiple generations, the production of biological 11
products obtained by microbial culture, cell culture or propagation in embryos 12
and animals should be based on a system of master and working seed lots 13
and/or cell banks, which is the beginning of the manufacturing process of 14
certain biological products (e.g. vaccines). 15
16
8.3 The number of generations (e.g. passages) between the seed lot or cell bank and 17
the finished product, defined as maximum, should be consistent with the 18
marketing auhorization dossier and should be followed. 19
20
8.4 Cell-based medicinal products are often generated from a cell stock obtained 21
from a limited number of passages. In contrast with the two-tier system of 22
MCBs and WCBs, the number of production runs from a cell stock is limited by 23
the number of aliquots obtained after expansion and does not cover the entire 24
life cycle of the product. Cell stock changes should be covered by a validation 25
protocol and communicated to the NRA, as applicable. 26
27
8.5 Establishment and handling of the MCBs and WCBs should be performed 28
under conditions which are demonstrably appropriate. These should include an 29
appropriately controlled environment to protect the seed lot and the cell bank 30
and the personnel handling them. To establish the minimum requirements for 31
clean room grade and environmental monitoring, see WHO’s Environmental 32
monitoring of clean rooms in vaccine manufacturing facilities: points to 33
consider for manufacturers of human vaccines, 2012 (18). During the 34
establishment of the seed lot and cell bank, no other living or infectious material 35
(e.g. virus, cell lines or microbial strains) should be handled simultaneously in 36
the same area or by the same persons, as defined in WHO’s Recommendations 37
for the evaluation of animal cell cultures as substrates for the manufacture of 38
biological medicinal products and for the characterization of cell banks (19). 39
40
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8.6 Quarantine and release procedures for master and working cell banks/seed lots 1
should be followed, including adequate characterization and testing for 2
contaminants. Initially, full characterization testing of the MCB should be done, 3
including genetic identification. A new MCB (from a previous initial clone, 4
MCB or WCB) should be subjected to the same established testing as the 5
original MCB, unless justified. Thereafter, the identity, viability and purity of 6
seed lots and cell banks should be checked regularly according to justified 7
criteria. In the case of anti-sera production, the potency of venoms is usually 8
included as part of the testing. Evidence of the stability and recovery of the seed 9
lots and banks should be documented and records should be kept in a manner 10
that permits trend evaluation. 11
12
8.7 Each storage container should be adequately sealed, clearly labelled and kept at 13
an appropriate temperature. A stock inventory must be kept. The storage 14
temperature should be recorded continuously and, where used, the liquid 15
nitrogen level should be monitored. Any deviation from the set limits, and any 16
corrective and preventive action taken, should be recorded. Temperature 17
deviations should be detected as early as possible (e.g. with the use of an alarm 18
system for temperature and nitrogen levels). 19
20
8.8 Seed lots and cell banks should be stored and used in such a way as to minimize 21
the risks of contamination or alteration (e.g. stored in qualified ultra-low 22
temperature freezers or liquid nitrogen storage containers). Control measures 23
for the storage of different seeds and/or cells in the same area or equipment 24
should prevent mix-up and should take into account the infectious nature of the 25
materials in order to prevent cross-contamination. 26
27
8.9 MSLs, MCBs, and preferably also WSLs and WCBs, should be stored in two or 28
more controlled separate sites in order to minimize the risks of total loss due to 29
natural disaster, equipment malfunction or human error. A contingency plan 30
should be in place. 31
32
8.10 The storage and handling conditions for the cell or seed banks should be defined. 33
Access should be restricted to authorized personnel and controlled; appropriate 34
records must be maintained. Records of location, identity and inventory of 35
individual containers should be kept. Once containers are removed from the 36
seed lot/cell bank management system, they should not be returned to stock. 37
38
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9. Premises and equipment 1
9.1 In general, preparations containing live microorganisms should not be 2
manufactured, and containers should not be filled in areas used for the 3
processing of other pharmaceutical products. However, if the manufacturer can 4
demonstrate and validate effective containment and decontamination of the live 5
microorganisms, the use of multi-product facilities may be justifiable. When 6
multi-product facilities involve live microorganisms, the manufacturer should 7
demonstrate and validate effective decontamination of the previously-used live 8
microorganisms. In addition, measures such as campaign production, closed 9
systems and/or disposable systems should be considered and should be based on 10
QRM (see sections on “Containment” and “Campaign production”). 11
12
9.2 Documented QRM should be carried out for every additional product in a 13
biological manufacturing multi-product facility, which may include a potency 14
and toxicological evaluation based on cross-contamination risks. Other factors 15
to be taken into account include facility/equipment design and use, personnel 16
and material flows, microbiological controls, physico-chemical characteristics 17
of the active substance, process characteristics, cleaning processes and 18
analytical capabilities relative to the relevant limits established from the 19
evaluation of the products. The outcome of the QRM process should be the 20
basis for determining the necessity for premises and equipment to be dedicated 21
to a particular product or product family and extent to which this should be the 22
case. This may include dedicating specific product contact parts. The NRA 23
should approve the use of a manufacturing facility for production of multiple 24
products on case-to-case basis. 25
26
9.3 Killed vaccines, antisera and other biological products – including those made 27
by rDNA techniques, toxoids and bacterial extracts – may, after inactivation, be 28
manufactured on the same premises provided that adequate decontamination 29
and cleaning measures are implemented on the basis of QRM. 30
31
9.4 Cleaning and sanitization require special attention since production of 32
biological products usually involves the handling of growth media and other 33
growth-promoting agents. Validation studies should be carried out for effective 34
cleaning, sanitization and disinfection, including elimination of residues of used 35
agents. Environmental and personnel safety precautions should be taken during 36
the cleaning and sanitization processes. Use of cleaning and sanitizing agents 37
should not pose any major risk to the performance of equipment; therefore 38
reasonable, but not excessive, use of cleaning, sanitization and disinfection 39
agents would be recommended. 40
WHO/BS/2015.2253
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1
Where open systems are utilized during processing (e.g. during addition of 2
growth supplements, media, buffers, gasses, sampling and aseptic 3
manipulations during the handling of live cells such as in cell therapy products), 4
control measures should be put in place to prevent contamination, mix-up and 5
cross-contamination. Logical and unidirectional flows of personnel, materials 6
and processes, use of clean-in-place (CIP) and sterilize-in-place (SIP) systems 7
should be considered wherever possible. Modern technologies such as the use 8
of sterile single-use disposable systems, connectors or components are 9
encouraged. 10
11
9.5 Because of the variability of biological products and the corresponding 12
manufacturing processes, approved starting materials that have to be measured 13
or weighed for the production process (e.g. growth media, solutions and 14
buffers) may be kept in small stocks in the production area for a specified 15
period of time according to defined criteria – such as for the duration of 16
manufacture of the batch or of the campaign. Appropriate storage conditions 17
and controls should be maintained during such temporary storage. These 18
materials should not be returned to the general stock. Materials used to 19
formulate buffers, growth media, etc. should be weighed and made into a 20
solution in a contained area using local protection (e.g. classified weighing 21
booth) outside the aseptic processing areas in order to minimize particulate 22
contamination of the latter areas. 23
24
9.6 In manufacturing facilities, logically designed change rooms should be used to 25
enter and exit clean areas where live organisms are handled. The mix-up of 26
entry and exit of personnel should be avoided (e.g. by separate entry/exit 27
change rooms). 28
29
10. Containment 30
10.1 Airborne dissemination of live microorganisms and viruses used for the 31
production process, including those from personnel, should be avoided. 32
33
10.2 Adequate precautions should be taken to avoid contamination of the drainage 34
system with dangerous effluents. Drainage systems should be designed in such 35
a way that effluents can be effectively neutralized or decontaminated to 36
minimize the risk of cross-contamination. Local regulations must be complied 37
with in order to minimize the risk of contamination of the external environment 38
according to the risk associated with the biohazardous nature of waste materials. 39
WHO/BS/2015.2253
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Specific decontamination systems should be considered for effluents when 1
infectious and/or potentially infectious materials are used for production. 2
3
19.3 Dedicated production areas should be used for the handling of live cells capable 4
of persistence in the manufacturing environment, for pathogenic organisms of 5
Biosafety Risk Group 3 or 4, and/or for spore-forming organisms until the 6
inactivation process is accomplished and verified. For Bacillus anthracis, 7
Clostridium tetani and Clostridium botulinum, strictly dedicated facilities 8
should be utilized for each individual product. Where campaign manufacture of 9
spore-forming organisms occurs in a facility or suite of facilities, only one 10
product should be processed at any one time. 11
12
Use of any pathogenic organism above Biosafety Risk Group 3 may be 13
permitted by the NRA according to the biohazard classification of the organism, 14
the riskbenefit analysis of the biological product and its emergency demand. 15
16
10.4 Production of BCG vaccine should take place in a completely separated area and 17
by means of dedicated equipment and utilities (e.g. ventilation systems) in order 18
to eliminate the hazard of cross-contamination to other production/ 19
manufacturing areas. 20
21
10.5 Specific containment requirements may apply for certain products (e.g. polio 22
vaccine) where containment requirements are defined in accordance with the 23
WHO global action plan to minimize poliovirus facility-associated risk (20) and 24
WHO’s Guidelines for the safe production and quality control of inactivated 25
poliomyelitis vaccine manufactured from wild polioviruses (21). The measures 26
and procedures necessary for containment (i.e. for the environment and safety 27
of the operator) should not conflict with those for product quality. 28
29
10.6 Air-handling systems should be designed, constructed and maintained to 30
minimize the risk of cross-contamination between different manufacturing 31
areas, as required. The need for dedicated air-handling units or single-pass 32
systems should be based on QRM principles, taking into account the relevant 33
organisms’ biohazard classification, containment requirements, process and 34
equipment risk. In the case of Biosafety Risk Group 3 organisms, air should not 35
be recirculated to any other area in the facility and should be exhausted through 36
high-efficiency particulate air (HEPA) filters that are regularly checked for 37
performance. A dedicated non-recirculating ventilation system and 38
HEPA-filtered exhaust air should be provided for handling Biosafety Risk 39
Group 4 organisms. 40
41
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10.7 Primary containment equipment should be designed and initially qualified for 1
integrity in order to ensure that the escape of biological agents and/or material 2
into the immediate working area and outside environment is prevented. 3
Thereafter, in line with relevant guidelines and QRM principles, periodical tests 4
should be performed to ensure that the equipment is in proper working 5
condition. 6
7
10.8 Activities associated with the handling of live biological agents (e.g. 8
centrifugation and blending of products which can lead to aerosol formation) 9
should be contained in such a way as to prevent contamination of other products 10
or egress of live agents into the working and/or outside environment. The 11
viability of such organisms and their biohazard classification should be taken 12
into consideration as part of the management of such risks. 13
14
Accidental spillages, especially of live organisms, must be dealt with quickly 15
and safely. Validated decontamination measures should be available for each 16
organism or groups of related organisms. Where different strains of single 17
bacteria species or very similar viruses are involved, the decontamination 18
process may be validated with one representative strain, unless the strains vary 19
significantly in their resistance to the agent(s) involved 20
21
10.9 Areas where Biosafety Risk Group 3 or 4 organisms are handled should always 22
have a negative air pressure relative to the environment. This will ensure the 23
containment of the organism in unlikely events such as failure of the door 24
interlock. Air-lock doors should be interlocked to avoid their being opened 25
simultaneously. Differential pressure alarms should be present wherever 26
required, and should be validated and monitored. 27
28
10.10 Equipment air-vent filters should be hydrophobic and validated for their 29
scheduled life span with integrity testing at well-justified appropriate intervals. 30
31
10.11 Where filtration of exhaust air is necessary, safe changing of filters or 32
bag-in-bag-out housings should be employed. Once removed, these filters 33
should be decontaminated and properly destroyed. Other inactivation 34
technologies such as heat inactivation and steam scavenging may be considered 35
for exhaust air, in addition to HEPA filtration, for effective inactivation of 36
pathogenic organisms of Biosafety Risk Groups 3 and/or 4. 37
38
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11. Clean rooms 1
11.1 The WHO good manufacturing practices for sterile pharmaceutical products (2) 2
defines and establishes the required class/grade of clean areas for the 3
manufacture of sterile products according to the operations performed, 4
including final aseptic fill. Additionally, in order to address the specific 5
manufacturing processes involved in the production of biological products, and 6
particularly vaccines, the WHO guidance document Environmental monitoring 7
of clean rooms in vaccine manufacturing facilities: points to consider for 8
manufacturers of human vaccines (18) gives additional recommendations for 9
consideration when defining the environmental classification needed for typical 10
biological manufacturing processes. 11
12
As part of the control strategy, the degree of environmental control of particulate 13
and microbial contamination of the production premises should be adapted to 14
the intermediate or finished product and also to the production step, taking into 15
account the potential level of contamination of the starting materials and the 16
risks to the biological product. 17
18
11.2 The environmental monitoring programme should be supplemented by the 19
inclusion of methods to detect the presence of specific microorganisms used for 20
production (e.g. recombinant yeast and toxin and polysaccharide producing 21
bacterium). The environmental monitoring programme may also include 22
detection of produced organisms (e.g. viruses or virus-like particles) and 23
adventitious agents of production organisms, especially when campaign 24
manufacture is applied on the basis of QRM principles. 25
26
12. Production 27
12.1 Since cultivation conditions, media and reagents are designed to promote the 28
growth of cells or microbial organisms, typically in an axenic state, particular 29
attention should be paid to the control strategy for ensuring that there are 30
effective steps for preventing or minimizing the occurrence of unwanted 31
bioburden, endotoxins, viruses of animal and human origin, and associated 32
metabolites. 33
34
12.2 The QRM process should be the basis for implementing the technical and 35
organizational measures required to control risks of cross-contamination. These 36
could include, though are not limited to, the following: 37
WHO/BS/2015.2253
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carrying out processing and filling in segregated areas; 1
containing material transfer by means of airlocks, clothing change and 2
effective washing and decontamination of equipment; 3
avoiding recirculation of untreated air; 4
acquiring knowledge of key characteristics of all cells, organisms and any 5
adventitious agents (e.g. pathogenicity, detectability, persistence, 6
susceptibility to inactivation) within the same facility; 7
when considering the acceptability of concurrent work in cases where 8
production is characterized by multiple small batches from different 9
starting materials (e.g. cell-based products), taking into account factors 10
such as the health status of donors and the risk of total loss of a product 11
from or for specific patients during development of the 12
cross-contamination control strategy; 13
preventing live organisms and spores from entering non-related areas or 14
equipment by addressing all potential routes of cross-contamination (e.g. 15
through the heating, ventilation and air conditioning (HVAC) system, the 16
use of single-use components and closed systems); 17
conducting environmental monitoring specific to the microorganism being 18
manufactured in adjacent areas while paying attention to 19
cross-contamination risks arising from the use of certain monitoring 20
equipment (e.g. airborne particle monitoring) in areas handling live and/or 21
spore-forming organisms; and 22
using campaign-based production (see section on “Campaign 23
production”). 24
25
12.3 When applicable, the inoculum preparation area should be designed such as to 26
control the risk of contamination effectively and should be equipped with a 27
biosafety hood for local containment. 28
29
12.4 If possible, growth media should be sterilized in situ by heat or in-line sterilizing 30
filters. Additionally, retentive in-line filters should be used for routine addition 31
of gases, media, acids or alkalis, etc., to fermenters or bioreactors. 32
33
12.5 Data from continuous monitoring of certain production processes (e.g. 34
fermentation) should form part of the batch record. Where continuous culture is 35
used, special consideration should be given to parameters such as temperature, 36
pH, pO2, CO2 and the rate of feed or carbon source with respect to growth of 37
cells. 38
39
12.6 In cases where a viral inactivation or removal process is performed, measures 40
(e.g. related to facility layout, unidirectional flow and equipment) should be 41
WHO/BS/2015.2253
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taken to avoid the risk of recontamination of treated products by non-treated 1
products. 2
3
12.7 For products that are inactivated by the addition of a reagent, the process should 4
ensure the complete inactivation of the live organism (e.g. during vaccine 5
manufacture). In addition to the adequate mixing of culture and inactivant, 6
consideration should be given to assuring complete contact of all product 7
contact surfaces exposed to live culture and, where required, the transfer to a 8
second vessel. 9
10
12.8 A wide variety of equipment and components (e.g. resins, matrices and cassettes) 11
are used for purification purposes. QRM principles should be applied to devise 12
the control strategy regarding these pieces of equipment and associated 13
components when used in campaign manufacture and in multi-product facilities. 14
While the reuse of components at different stages of processing of one product 15
is discouraged, the reuse of components for different products is not acceptable. 16
Acceptance criteria, operating conditions, regeneration methods, life span and 17
sanitization or sterilization methods of reused components should be defined 18
and validated. 19
20
12.9 Where donor (human or animal) health information becomes available after 21
procurement and/or processing, and this information relates to product quality, 22
appropriate measures should be taken – including product recall, if applicable. 23
24
12.10 Antibiotics may be used during the early stages of production to help prevent 25
inadvertent microbial contamination or to reduce the bioburden of living tissues 26
and cells. In this case, the use of antibiotics should be well justified and they 27
should be removed from the manufacturing process at the stage specified in the 28
marketing authorization. Acceptable residual levels should be defined and 29
validated. Beta-lactam antibiotics should not be used at any stage of the process. 30
31
13. Campaign production 32
13.1 The decision to use a facility or filling line for campaign manufacture should be 33
justified in a documented manner and should be based on a systematic risk 34
approach for each product (or strain), taking into account the containment 35
requirements and the risk of cross-contamination to the next product. Campaign 36
changeover procedures, including sensitive techniques used for the 37
determination of residues, should be validated and proper acceptance criteria 38
should be defined on the basis of toxicity residues of product from the last 39
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campaign, as applicable. Where equipment is assigned to continued production 1
or campaign production of successive batches of the same intermediate product, 2
equipment should be cleaned at appropriate intervals to prevent build-up and 3
carry-over of contaminants (e.g. product degradants or objectionable levels of 4
microorganisms). 5
6
13.2 For downstream operations of certain products, campaign production may be 7
acceptable if well justified (e.g. pertussis, diphtheria). For finishing operations 8
(i.e. formulation and filling), the need for dedicated facilities or the use of 9
campaigns in the same facility will depend on the specific needs of the 10
biological product, on the characteristics of the other products (including any 11
nonbiological products), on the filling technologies used (e.g. single-use closed 12
systems), and on local NRA regulations. Labelling and packaging operations 13
can be done in a multi-product facility. 14
15
13.3 Campaign changeover involves intensive cleaning and decontamination of the 16
equipment and manufacturing area. The decontamination and cleaning should 17
include all equipment and accessories used during production, as well as the 18
facility itself. The following recommendations should be considered: 19
Waste should be removed from the manufacturing area or sent to the 20
bio-waste system in a safe manner. 21
Materials should be transferred by a validated procedure. 22
The Quality Unit should confirm area clearance by inspection, along with 23
a review of the campaign changeover data (including monitoring results), 24
prior to releasing the area for the next product. 25
26
13.4 When required, the corresponding diluent for the product can be filled in the 27
same facility in line with the defined campaign production strategy. 28
29
13.5 When campaign-based manufacturing is considered, the facility layout and the 30
design of the premises and equipment should permit effective decontamination 31
by fumigation, where necessary, as well as cleaning and sanitizing after the 32
production campaign. 33
34
14. Labelling 35
14.1 The information provided on the inner label (on the container) and on the outer 36
label (on the package) should be readable, legible and approved by the NRA. 37
38
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14.2 Minimal key information should be printed on the inner label (also called the 1
container label), and additional information should be provided on the outer 2
label (e.g. carton) and/or product leaflet. 3
4
Special consideration should be given to the following information on labels of 5
vaccines, if applicable: 6
the nature and amount of any preservative present in the vaccine; 7
the nature and amount of the adsorbing agent; 8
a warning that the vaccine should not be frozen, cold chain requirements 9
and Vaccine Vial Monitor (VVM) labelling; and 10
a warning that the vaccine should be shaken before use. 11
12
14.3 Care should be taken and utmost security ensured in the preparation, printing, 13
storage and application of labels – including any specific text for 14
patient-specific products, indicating the use of genetically-engineered contents 15
on outer packaging. In the case of a cell therapy product used for autologous 16
use, the unique patient identifier and the statement “For autologous use only” 17
should be indicated on the outer packaging or, where there is no outer 18
packaging, on the immediate packaging. 19
20
14.4 The compatibility of labels for ultra-low storage temperatures, where such 21
temperatures are used, should be verified. The label should remain properly 22
attached to the container under different storage conditions and should have no 23
adverse effect on the quality of the product by leaching, migration and/or other 24
means. 25
26
15. Validation 27
Biological processes, handling of live materials and usual campaign-based 28
production, if applicable, are the major aspects of biological products which 29
require process and cleaning validation. The validation of such processes – in 30
view of the typical existing variability of biological products, possible use of 31
harmful and toxic materials and inactivation processes – plays an important role 32
in demonstrating production consistency and in proving that the critical process 33
parameters and product attributes are controlled. A QRM approach should be 34
used to determine the scope and extent of validation. 35
36
15.1 All critical biological processes (e.g. inoculation, multiplication, fermentation, 37
cell disruption, inactivation, purification, virus removal, removal of toxic and 38
harmful additives, filtration, formulation, aseptic filling, etc.), as applicable, are 39
WHO/BS/2015.2253
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subject to process validation. Manufacturing control parameters to be validated 1
may include specific addition sequences, mixing speeds, time and temperature 2
controls, limits of light exposure, containment and cleaning procedures. 3
4
15.2 After initial process validation studies have been finalized and routine 5
production has begun, a “continued process verification” (22) approach should 6
be defined, taking into consideration the inherent variability of biological 7
products. A system or systems for detecting unplanned departures from the 8
process as designed should be in place to ensure that the process remains in a 9
state of control. Collection and evaluation of information and data on the 10
performance of the process will allow for detection of undesired process 11
variability and will determine whether action should be taken to prevent, 12
anticipate and/or correct problems so that the process remains in control. 13
14
15.3 Cleaning validation should be performed in order to confirm the effectiveness of 15
cleaning procedures designed to remove biological substances, growth media, 16
process reagents, etc. Careful consideration should be given to cleaning 17
validation when campaign-based production is practised. 18
19
15.4 Critical processes for inactivation or elimination of potentially harmful 20
microorganisms of Biosafety Risk Group 2 or above, including genetically 21
modified ones, are subject to validation. 22
23
15.5 Where they exist, WHO guidance documents should be consulted on the 24
validation of specific manufacturing methods (e.g. virus removal or 25
inactivation). 26
27
15.6 Process revalidation may be triggered immediately by a process change, as part 28
of the change control system. In addition, because of the variability of processes, 29
products and methods, process revalidation may be conducted at predetermined 30
regular intervals according to risk considerations. A detailed review of all 31
changes, trends and deviations occurring within a defined time period (e.g. 1 32
year, based on the regular Product Quality Review) may require process 33
revalidation. 34
35
15.7 The integrity and specified hold times of containers used to store intermediate 36
products should be validated unless such intermediate products are freshly 37
prepared and used immediately, as appropriate. 38
39
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16. Quality control 1
16.1 As part of quality control sampling and testing procedures for biological 2
materials and products, special consideration should be given to the nature of 3
the materials being sampled in order to ensure that the testing carried out is 4
representative. 5
6
16.2 Samples may fall into two categories – reference samples and retention samples 7
– for the purposes of analytical testing and identification, respectively. For 8
finished products, in many instances the reference and retention samples will be 9
presented identically – i.e. as fully packaged units. In such circumstances, 10
reference and retention samples may be regarded as interchangeable. 11
12
16.3 Reference samples of biological starting materials should be retained for at least 13
one year beyond the expiry date of the corresponding finished product. 14
Reference samples of other starting materials (other than solvents, gases and 15
water), as well as intermediates of which critical parameters cannot be tested in 16
the final product, should be retained for at least two years after the release of the 17
product if their stability allows this storage period. Certain starting materials 18
such as components of growth media need not necessarily be retained. When a 19
change of vendor is needed, as appropriate, an impurity profile comparison 20
should be done as part of the relevant risk analysis. 21
22
16.4 Retention samples of a finished product should be stored in the final packaging 23
under the recommended storage conditions for at least one year after the expiry 24
date. 25
26
16.5 For cell-based products, microbiological tests (e.g. sterility test or purity check) 27
should be conducted on cultures of cells or cell banks free of antibiotics and 28
other inhibitory substances in order to provide evidence for absence of bacterial 29
and fungal contamination and to be able to detect fastidious organisms where 30
appropriate. Where antibiotics are used, they should be neutralized or removed 31
by filtration at the time of testing. 32
33
16.6 The traceability, proper use and storage of reference standards should be ensured, 34
defined and recorded. The stability of reference standards should be monitored, 35
and their performance trended. WHO’s Recommendations for the preparation, 36
characterization and establishment of international and other biological 37
reference standards (23) should be followed. 38
39
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16.7 All stability studies – including real-time/real-condition stability, accelerated 1
stability and stress-testing – should be carried out according to relevant 2
guidelines (e.g. WHO’s Guidelines on stability evaluation of vaccines (24), or 3
other recognized documents). Trend analysis of test results of the stability 4
monitoring programme should assure early detection of any process or assay 5
drift, and this information should be part of the product quality review (PQR) of 6
biological products. 7
8
16.8 For products where ongoing stability monitoring would normally require testing 9
using animals, and no appropriate alternative or validated techniques are 10
available, the frequency of testing may take into account a riskbenefit 11
approach. The principle of bracketing and matrix designs may be applied if 12
scientifically justified in the stability protocol. 13
14
16.9 Methods suitable for the quality control of biological starting materials, critical 15
intermediates and finished products should be used. In particular, for biological 16
products manufactured in multi-product facilities, methods should be in place to 17
address cross-contamination risks, if any. 18
19
16.10 All analytical methods used in the quality control of biological products should 20
be well characterized, fully validated and documented to a satisfactory standard 21
in order to yield reliable results. The fundamental parameters of this validation 22
include accuracy, precision, selectivity, sensitivity and reproducibility (2529). 23
24
16.11 In general, animal tests performed for quality control release are well described 25
in the relevant pharmacopoeias and in WHO guidance documents (2529). 26
Animal potency tests are designed with multiple or single dilutions and 27
replicates to address variability and linearity. These tests are performed in 28
comparison with international/national reference standards and with appropriate 29
assay controls. For test methods described in relevant monographs, only a 30
qualification of the laboratory test equipment and personnel has to be performed. 31
In addition to this, repeat precision and comparability precision have to be 32
shown in the case of animal tests. Repeatability and reproducibility can also be 33
demonstrated by reviewing retrospective test data. 34
35
In addition to the common parameters typically used for validating assays (e.g. 36
accuracy, precision, etc.), additional measurements should be considered during 37
the validation of bioassays based on the biological nature of the assay and 38
reagents used. 39
40
WHO/BS/2015.2253
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17. Documentation (batch processing records) 1
17.1 In general, the processing records of regular production batches must provide a 2
complete account of the manufacturing activities of each batch of biological 3
products, showing that it has been produced, tested and dispensed into 4
containers in accordance with the approved procedures. 5
6
In the case of vaccines, a batch processing record and a summary protocol 7
should be prepared for each batch for the purpose of lot release by the NRA. 8
The information included in the summary protocol should follow WHO’s 9
Guidelines for independent lot release of vaccines by regulatory authorities 10
(30). The summary protocol and all associated records should be of a type 11
approved by the NRA. 12
13
Records should be retained for at least two years after the expiry date of the 14
batch of the biological product and should be available at all times for 15
inspection by the NRA. 16
17
17.2 Starting materials and raw materials may require additional documentation on 18
source, origin, distribution chain, method of manufacture and controls applied 19
in order to ensure an appropriate level of control, including microbiological 20
quality, if applicable. 21
22
17.3 Some product types may require specific definition of what materials constitute 23
a batch – particularly somatic cells in the context of Advanced Therapy 24
Medicinal Products (ATMPs). For autologous and donor-matched situations, 25
the manufactured product should be viewed as a batch. 26
27
18. Use of animals 28
A wide range of animals may be used for the manufacture or quality control of 29
biological products. Special considerations are required when animal facilities 30
are present at a manufacturing site. Areas used for processing animal tissue 31
materials and for performing tests involving animals or microorganisms, 32
including breeding, must be completely separated from premises used for 33
manufacturing products and should have completely separate ventilation 34
systems and separate staff. No animals should be used in the production area. 35
Separation of different animal species before (quarantine/test) and under test 36
WHO/BS/2015.2253
Page 32
should be considered, as should the necessary animal acclimatization process as 1
part of the test requirements. 2
3
18.1 Animals may be used for different purposes. They may be categorized as: 4
animals used for organ extraction (e.g. kidney); 5
animals used for body fluids extraction (e.g. serum); 6
animals for breeding; and 7
animals for testing. 8
9
18.2 In addition to monitoring of compliance with TSE regulations (17), other 10
adventitious agents that are of concern (e.g. zoonotic diseases, diseases of 11
source animals) should also be monitored and recorded in line with specialist 12
advice on establishing such programmes. Instances of ill-health occurring in 13
the source/donor animals should be investigated with respect to their suitability, 14
and the suitability of in-contact animals, for continued use (e.g. in manufacture, 15
as sources of starting and raw materials, in quality control and safety testing). 16
Decisions should be documented. 17
18
18.3 A look-back procedure should be in place related to the decision-making 19
process on the continued suitability of the biological active substance or 20
medicinal product in which animal-sourced starting or raw materials have been 21
used or incorporated. This decision-making process may include the retesting 22
of retention samples from previous collections from the same donor animal 23
(where applicable) to establish the last negative donation. The withdrawal 24
period of therapeutic agents used to treat source/donor animals must be 25
documented and should be utilized in determining the removal of those animals 26
from the programme for defined periods. 27
28
18.4 Particular care should be taken to prevent and monitor infections in 29
source/donor animals. Measures should include, and be related to, the sourcing, 30
facilities, husbandry, biosafety procedures, testing regimes, control of bedding 31
and feed materials, 100% fresh air supply, appropriate temperature and 32
humidity conditions considering the species being handled, and water supply. 33
This is of special relevance to specific pathogen free (SPF) animals where 34
pharmacopoeial monograph requirements must be met. Housing and health 35
monitoring should also be defined for other categories of animals (e.g. healthy 36
flocks or herds). 37
38
18.5 For products manufactured from transgenic animals, traceability should be 39
maintained in the creation of such animals from the source animals. Note should 40
be taken of national requirements for animal quarters, care and quarantine. 41
42
WHO/BS/2015.2253
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18.6 For different animal species and lines, key criteria should be defined, 1
monitored and recorded. These may include age, weight and health status of the 2
animals. 3
4
18.7 Animals, biological agents and tests carried out should be appropriately 5
identified to prevent any risk of mix-up and to control all identified hazards. 6
7
18.8 The facility layout should ensure a unidirectional and segregated flow of healthy 8
animals, inoculated animals and waste decontamination areas. Personnel and 9
visitors should also follow a defined flow in order to avoid cross- 10
contamination. 11
12
References 13
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9
Authors and acknowledgements 10
The scientific basis for the revision of these guidelines was discussed at a working 11
group meeting held in Thailand in 10-13 September 2007 with the following 12
participants: Dr H. Alitamsar, Bio Farma Ltd., Bandung, Indonesia; Mr P. Angtrakool, 13
Ministry of Public Health, Nonthaburi, Thailand; Dr M.M.F. Ahmed, Center for 14
Control of Biologicals and Vaccines, Agousa, Egypt; Dr D. Buckley, Consultant, 15
Monash, Australia; Dr M. Dennehy, The Biovac Institute, Cape Town, South Africa; 16
Ms X. Dong, Beijing Tiantan Biological Products Co. Ltd., Beijing, China; Dr H.J.M. 17
van de Donk, Consultant, Den Haag, Netherlands; Dr M. Gheisarzardeh, Ministry of 18
Health and Medical Education, Tehran, Iran; Dr H.T. Hong, National Institute for 19
Control of Vaccine and Biologicals, Hanoi, Viet Nam; Mrs W. Jariyapan, WHO 20
Regional Office for South-East Asia, New Delhi, India; Mr M. Javadekar, Serum 21
Institute of India Ltd., Pune, India; Dr D. Jiang, State Food and Drug Administration, 22
Beijing, China; Mrs T. Jivapaisarnpong, Ministry of Public Health, Nonthaburi, 23
Thailand; Dr A. Khadem, Pasteur Institute of Iran, Tehran, Iran; Professor S. 24
Khomvilai, Thai Red Cross Society, Bangkok, Thailand; Dr K-H. Kim, Korean Food 25
and Drug Administration, Seoul, Republic of Korea; Dr I. Knezevic, World Health 26
Organization, Geneva, Switzerland; Dr Kustantinah, National Agency of Drug and 27
Food Control, Jakarta, Indonesia; Dr S. Lambert, World Health Organiation, Geneva, 28
Switzerland; Professor C.K. Lee, Advisor to the Korean Food and Drug 29
Administration, Seoul, Republic of Korea; Mrs J. Li, Sinovac Biotech Co. Ltd., 30
Beijing, China; Biologist V.G. Maqueda, Buenos Aires, Argentina; Dr K-I. Min, 31
Korean Food and Drug Administration, Seoul, Republic of Korea; Mr I. Rees, 32
Medicines and Healthcare Products Regulatory Agency, London, United Kingdom; 33
Dr C.H. Sia, Health Sciences Authority, Singapore; Dr M. Suhardono, Bio Farma 34
Ltd., Bandung, Indonesia; Ms P.S. Thanaphollert, Ministry of Public Health, 35
Nonthaburi, Thailand; Mr S. Thirapakpoomanunt, Ministry of Public Health, 36
Bangkok, Thailand; Ms J. Teo, Centre for Drug Administration, Singapore; Ms 37
A.R.T. Utami, National Agency of Drug and Food Control, Jakarta, Indonesia; Dr 38
D.T.H. Van, Institute for Vaccine and Biologicals, Nha Trang City, Viet Nam; Mr B. 39
WHO/BS/2015.2253
Page 37
Wibisono, National Agency of Drug and Food Control, Jakarta, Indonesia; Mr J. 1
Yang, Kunming Institute of Medical Biology, Kunming, People's Republic of China; 2
Mr Yongting Yu, Kunming Institute of Medical Biology, Kunming, China and a 3
drafting group meeting held at WHO, Geneva, Switzerland from 30 to 31 October 4
2013 and attended by Mr R. Acs, Central Drugs Standard Control Organisation, 5
Hyderabad, India; Dr S. Fakhrzadeh, Food and Drug Organization, Ministry of 6
Health and Medical Education, Islamic Republic of Iran; Dr V.G. Maqueda, Buenos 7
Aires, Argentina, Mrs K. Porkaew, Ministry of Public Health, Nonthaburi, Thailand; 8
Dr S.O. Rumiano, Consultant, Juan Bautista Alberdi, Argentina; Dr Y. Wang, 9
National Institutes for Food and Drug Control, Beijing, China; Mr B. Wibisono, 10
National Agency of Drug and Food Control, Jakarta, Indonesia, Dr M. Eisenhawer, 11
WHO Regional Office for South-East Asia, New Delhi, India; Dr A. Chawla, 12
Department of Essential Medicines and Health Products, World Health Organization, 13
Geneva, Switzerland; Dr A.R. Khadem, Department of Essential Medicines and 14
Health Products, World Health Organization, Geneva, Switzerland; Dr I. Knezevic, 15
Department of Essential Medicines and Health Products, World Health Organization, 16
Geneva, Switzerland, Dr S. Kopp, Department of Essential Medicines and Health 17
Products, World Health Organization, Geneva, Switzerland; Dr D. Lei, Department 18
of Essential Medicines and Health Products, World Health Organization, Geneva, 19
Switzerland. 20
21
The first draft of these guidelines was prepared by Mr R. Acs, Dr B.Yáñez Chamizo, 22
Dr S. Fakhrzadeh, Mrs K. Porkaew, Dr S.O. Rumiano, Dr Y. Wang, Mr B. Wibisono, 23
Dr M. Eisenhawer, Dr A. Chawla, Dr A.R. Khadem, Dr V.G. Maqueda and Dr D. Lei, 24
forming the drafting group for revision of WHO GMP for Biological Products based 25
on the principles defined in the above working group and drafting group meetings. 26
27
The second draft of the guidelines was prepared by Dr V.G. Maqueda, Dr B. Yáñez 28
Chamizo, Dr S. Fakhrzadeh, Dr S.O. Rumiano, Dr Y. Wang, Mr B. Wibisono, Dr M. 29
Eisenhawer, Dr A. Chawla, Dr A.R. Khadem and Dr D. Lei following the 30
consultation held in Tunisia from 22 to 24 July 2014 with the following participants: 31
Dr A. Chawla, Consultant,Greater Noida, Uttar Pradesh, India; Dr S. Fakhrzadeh, 32
Food and Drug Organization, Ministry of Health and Medical Education, Islamic 33
Republic of Iran; Dr E. Griffiths, Consultant, Kingston upon Thames, United 34
Kingdom; Biologist V.G. Maqueda, Buenos Aires, Argentina; Mrs K. Porkaew, 35
Ministry of Public Health, Nonthaburi, Thailand; Dr S.O. Rumiano, Consultant, 36
Argentina; Dr Y. Wang, National Institutes for Food and Drug Control, Beijing, 37
China; Mr B. Wibisono, National Agency of Drug and Food Control, Jakarta, 38
Indonesia; Dr H. Baiao, National Authority for Medicines and Health Products, 39
Lisbon, Portugal; Mrs R. Bose, Central Drugs Standard Control Organization, 40
Ministry of Health and Family Welfare, New Delhi, India; Mr M. Diagne, Direction 41
de la Pharmacie et des Laboratoires, Dakar, Senegal; Mrs R. Frikha, Directorate of 42
WHO/BS/2015.2253
Page 38
Pharmacy Inspection, Tunis, Tunisia; Ms A.R. Cornelio Geyer, Agencia Nacional da 1
Vigilancia Sanitaria, Brasilia, Brazil; Dr N. Harjee, Consultant, Ontario, Canada; Ms 2
D.T.M. Hang, Drug Administration of Vietnam, Ministry of Health, Hanoi, Viet Nam; 3
Dr C.K. Lee, Korea Food and Drug Administration, Osongsaengmyeong, Republic of 4
Korea; Dr H. Leng, Medicines Regulatory Authority, Pretoria, South Africa; Dr J. 5
Miteva, Bulgarian Drug Agency, Sofia, Bulgaria; Dr M. Refaat, Central 6
Administration for Pharmaceutical Affairs, Cairo, Egypt; Dr M.G. Lopez Santos, 7
Comisión Federal para la Protección contra Riesgos Sanitarios, México, Mexico; Dr 8
A.L. Salvati, Agenzia Italiana del Farmaco, Roma, Italy; Dr W. Stevens, Center for 9
Biological Evaluation, Biologics and Genetic Therapies, Health Canada, Canada; Dr 10
S. Uddin, Directorate General of Drug Administration, Dhaka, Bangladesh; Dr A. 11
Mihaylova, Bulgarian Drug Agency, Sofia, Bulgaria; Mr C. Cabral, Butantan 12
Institute, Sao Paulo, Brazil; Dr S. Pagliusi, DCVMN International, Nyon, 13
Switzerland; Dr V.A. Pessanha, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil; Dr 14
D. Rebeski, The Biovac Institute, Cape Town, South Africa; Dr I. Susanti, PT 15
Biofarma, Bandung, Indonesia; Ms C.S. Takata, Butantan Institute, Sao Paulo, Brazil; 16
Dr R. Chaplinsky, GSK Vaccines, Wavre, Belgium; Dr M. Gershman, Pfizer, New 17
York, USA; Dr P. Lauer, Sanofi Pasteur, Lyon, France; Dr S. Ramanan, Amgen, 18
California, USA; Dr P. Rampignon, GSK Vaccines, Wavra, Belgium; Dr M. 19
Eisenhawer, WHO Regional Office for South-East Asia, Bangkok, Thailand; Dr H. 20
Langar, WHO Regional Office for the Eastern Mediterranean, Cairo, Egypt; Dr J. 21
Shin, WHO Regional Office for the Western Pacific, Manila, Philippines; Dr A.K. 22
Broojerdi, Department of Essential Medicines and Health Products, World Health 23
Organization, Geneva, Switzerland; Dr D. Lei, Department of Essential Medicines 24
and Health Products, World Health Organization, Geneva, Switzerland; Dr I. 25
Streipa-Nauman, Department of Essential Medicines and Health Products, World 26
Health Organization, Geneva, Switzerland; Dr D. Wood, Department of Essential 27
Medicines and Health Products, World Health Organization, Geneva, Switzerland. 28
29
The third draft was prepared by Dr V.G. Maqueda, Dr B. Yáñez Chamizo, Dr S. 30
Fakhrzadeh, Dr S.O. Rumiano, Dr Y. Wang, Dr A. Chawla, Dr M. Refaat, Dr A.R. 31
Khadem and Dr D. Lei by incorporating the comments received from regulators and 32
industry through public consultation on the WHO website. 33
34
= = = 35
