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«Annex 5 WHO biosafety risk assessment and guidelines for the production and quality control of human influenza pandemic vaccines This document ...»

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© World Health Organization

WHO Technical Report Series No 941, 2007

Annex 5

WHO biosafety risk assessment and guidelines

for the production and quality control

of human influenza pandemic vaccines

This document provides guidance to national regulatory authorities and

vaccine manufacturers on the safe production and quality control of human

influenza vaccines produced in response to a threatened pandemic. The

document details international biosafety expectations for both pilot-scale and large-scale vaccine production and control and is thus relevant to both development and production activities. It should be read in conjunction with the WHO Laboratory Biosafety Manual (1) and replaces the earlier WHO guidance Production of pilot lots of inactivated influenza vaccines from reassortants derived from avian influenza viruses: Interim biosafety risk assessment (2). Tests required to evaluate the safety of candidate influenza vaccine reference viruses by WHO Reference Laboratories prior to release to vaccine manufacturers are also specified in this document.

The following text is written in the form of guidelines rather than recommendations. Guidelines allow greater flexibility than recommendations with respect to expected future developments in the field. These guidelines specify steps to minimize the risk of introducing influenza virus strains with pandemic potential from a vaccine manufacturing facility into the community. If a national regulatory authority so desires, these guidelines may be adopted as definitive national requirements, or modifications may be justified and made by a national regulatory authority. It is recommended that modifications to the principles and technical specifications of these guidelines be made only on condition that the modifications ensure that the risks of introducing influenza virus to the community are no greater than as outlined in the guidelines set out below.

Summary Introduction Glossary

1. Scope of the risk assessment

2. Hazard identification

2.1 Hazards associated with the type of pandemic vaccine viruses 2.1.1 Hazards associated with the recipient virus in a reassortant strain 2.1.2 Hazards arising from the inserted gene product in a reassortant vaccine strain 265 2.1.3 Hazards arising from reassortant viruses Direct hazards Indirect hazards 2.1.4 Hazards arising from the use of wild type viruses for pandemic strain vaccine production

2.2 Hazards arising from the type

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266 Summary International biosafety expectations for both the pilot-scale and large-scale production of human vaccines for a response to a pandemic influenza strain, and the quality control of these vaccines, are described in detail in these WHO Guidelines. Tests required to evaluate the safety of candidate influenza vaccine reference viruses prior to release to vaccine manufacturers are also specified in this document which is thus relevant to both development and production activities, and also to vaccine and biosafety regulators. A detailed risk assessment is presented that concludes that the likelihood of direct harm to human health would be high if non-reassortant H5 or H7 viruses with multiple basic amino acids at the haemagglutinin (HA) cleavage site and high in vivo pathogenicity are used for vaccine production. Such viruses could also pose a significant risk to animal health. Stringent vaccine biosafety control measures, defined as Biosafety Level (BSL)3 enhanced (pandemic influenza vaccine) are defined to manage the risk from vaccine production and quality control using such viruses in the pre-pandemic period. For all other vaccine strains, for example reassortants derived from H5 or H7 strains in which the multiple basic amino acid HA0 cleavage site has been removed, the direct risk to human health is very remote. Nevertheless, there is an indirect risk to human health due to a theoretical risk of secondary reassortment with normal human influenza viruses, resulting in a virus with avian-like coat proteins capable of replicating in humans. Although very unlikely, the secondary reassortant could become adapted to human infection and transmission which, if vaccine production was taking place in the pre-pandemic period, would have serious public health consequences.

The biosafety control measures that are proposed, defined as BSL2 enhanced (pandemic influenza vaccine), take this and also potential risks to animal health into account. Facility and personal protection specifications are provided for both BSL2 enhanced and BSL3 enhanced bioafety levels and guidance is provided on biosafety management and implementation within a vaccine production facility. Tests to be performed on candidate vaccine reference strains prior to release to vaccine developers depend on the type of virus but include, at a minimum, in vivo tests on ferrets or other susceptible mammals, and, where appropriate, chickens and egg embryos, plaque assays and sequencing.

Glossary The definitions given below apply to the terms used in these guidelines.

They may have different meanings in other contexts.

Aerosol A dispersion of solid or liquid particles of microscopic size in a gaseous medium.

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Biosafety committee An institutional committee of individuals versed in the subject of containment and handling of infectious materials.

Biosafety level 2 (or 3) (enhanced pandemic influenza) A specification for the containment of pandemic influenza during vaccine manufacture and quality control testing with specialized air handling systems, waste effluent treatment, immunization of staff, specialized training, and validation and documentation of physical and operational requirements.

Biosafety manual A comprehensive document describing the physical and operational practices of the laboratory facility with particular reference to infectious materials.

Biosafety officer A staff member of an institution who has expertise in microbiology and infectious materials, and has the responsibility for ensuring the physical and operational practices of various biosafety levels are carried out in accordance with the standard procedures of the institution.

Biological indicators The use of organisms to test the efficacy of sterilization processes.

Biological safety cabinet Primary and partial containment work enclosure used for manipulation of materials that may cause infections or sensitization to workers. They are equipped with high-efficiency particulate air (HEPA) filters and may or may not be open-fronted.

Certification Documentation that a system qualification, calibration, validation, or revalidation has been performed appropriately and the results are acceptable.

Decontamination A process by which an object or material is freed of contaminating agents.

268 Floor dams Purpose-built elevations to enclose liquid spills.

Fumigation The process whereby gaseous chemical is applied to an enclosed space for the purpose of sterilizing the area.

Good manufacturing practices That part of quality assurance which ensures that products are consistently produced as controlled to the quality standards appropriate to their intended use and as required by the marketing authorization.

HEPA filter A filter capable of removing at least 99.97% of all particles with a mean aerodynamic diameter of 0.3 micrometres.

Inactivation To render an organism incapable of replication by application of heat, or other means.

Seed lot A culture of microorganism distributed from a single bulk container in a single operation, in such a manner as to ensure uniformity and stability and to prevent contamination.

Positive pressure laminar flow hood An enclosure with unidirectional outflowing air, generally used for product protection.

Primary containment A system of containment, usually a biological safety cabinet or closed container, which prevents the escape of a biological agent into the immediate working environment.

Respirator A respiratory protective device with an integral perimeter seal, valves and specialized filtration, used to protect the wearer from toxic fumes or particulates.

Risk analysis A formalized documented process for analysing risks.

Secondary containment A system of containment, usually involving specialized air-handling, airlocks and secure operating procedures, which prevents the escape of a biological agent into the external environment or into other working areas.

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Validation The documented act of proving that any procedure, process, equipment, material, activity, or system actually leads to the expected results.

Introduction The earlier WHO guidance Production of pilot lots of inactivated influenza vaccines from reassortants derived from avian influenza viruses. An interim biosafety risk assessment (2) was prepared in response to the threat of a pandemic posed by the highly pathogenic H5N1 avian influenza viruses and the need to begin development of experimental vaccines. This threat persists and several countries are now planning large-scale production of H5N1 vaccine. The risk assessment that informed the WHO biosafety guidance for pilot-lot vaccine production (2) has therefore been reassessed in light of the intended greater scale of vaccine production and because production facilities are likely to be different from those used in developing small pilot lots, and also taking into account the experience gained from developing and testing vaccine reference viruses derived by reverse genetics from highly pathogenic avian influenza viruses.

This document follows the risk-assessment scheme used in the WHO biosafety guidance for pilot-lot vaccine production, but is extended to include considerations relating to the greater production-scale needed to supply large quantities of vaccines. The risks associated with large-scale production are likely to be different from pilot lots, e.g. the “open” aspect of some production processes and quantity of virus-containing waste. It also takes into account the considerable experience gained from highly pathogenic avian influenza viruses, and the hazards associated with such strains.

Furthermore, the range of options for vaccine development is broader than originally considered in the WHO risk assessment for pilot lot production and the present document has been expanded to encompass current vaccine development pathways.

Scope of the risk assessment 1.

Much effort has recently gone into the development of H5N1 vaccine and manufacture and the guidance presented is strongly influenced by the experience gained with this strain and our greater knowledge of H5 270 strains in general. It is, nevertheless, intended that the guidance will also be applicable to future threats from other potential pandemic strains, such as H2 or highly pathogenic H7.

There is a range of possible pathogenicities in the viruses used in candidate vaccine production not only for humans but also for other mammals and avian species. On the one hand, H5 viruses that can be highly pathogenic to both humans and chickens have been used to produce reassortant viruses genetically modified to be of low pathogenicity for chickens and mammals.

On the other hand, for strains inherently less pathogenic for humans, wildtype virus might be used directly for vaccine production. Thus reassortants derived by reverse genetics, empirically-derived reassortants, which may or may not be genetically modified, and native wild strains are within the scope of these guidelines.

Eggs have traditionally been used for the production of influenza vaccines, but cell culture techniques have been recently introduced and international expectations for production and quality control specifications defined (3).

For the development of pandemic vaccine, either method may be used; thus both egg and cell culture production methodologies are within the scope of this document.

Most effort to date with candidate pandemic vaccine development has been targeted towards inactivated vaccines. In one country however two live attenuated virus vaccines for potential pandemic strains are under development. This may raise important issues beyond the risks to humans, namely the potential for excreted viruses or their derivatives to infect and replicate in non-human species particularly in those raised for commercial purposes. As the detection of H5 and H7 influenza strains are notifiable strains to the Office International des Epizooties (OIE), widespread dissemination of such vaccine strains could have a significant economic impact as well as ramifications for international trade. Developers and regulators will need to assess both the human and the agricultural risk of live pandemic strain vaccines under development should shedding and replication be possible.

Both vaccine types (inactivated and live) are therefore covered in the scope of these guidelines.

Furthermore it is intended that the risk assessment and the guidelines on containment measures should apply to all facilities and laboratories that have a need to handle live vaccine virus. This includes not only the vaccine manufacturing facility but also to the quality control laboratories of the manufacturer and, if appropriate, to National Control Laboratories. The transport of live virus materials within and between sites should comply with international specifications (4).

Finally it should be noted that the risk assessment for vaccine manufacture will vary according to whether production is occurring in an interpandemic

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Hazard identification 2.

Hazards associated with pandemic vaccine manufacturing and laboratory testing are dependent on the type of pandemic vaccine strain (reassortant or wild type), method of production (egg-based or cell-based) and whether it is an inactivated or live attenuated virus vaccine. The type of vaccine strain, the proposed testing schedule and containment level are illustrated in Table 1.

Hazards associated with the type of pandemic vaccine virus2.1

2.1.1 Hazards associated with the recipient virus in a reassortant strain Pandemic vaccine reassortants have been produced on the human strain A/ PR/8/34 (PR8) as recipient virus. PR8 has had over 100 passages in each of mice, ferrets and embryonated chicken eggs. The result of such a passage history is complete attenuation of the virus and its inability to replicate in humans (5).

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