Because of their unique origin, biological products derived from normal or genetically-modified living organisms offer particular challenges concerning requirements for quality, safety and efficacy. Biological products are used in the diagnosis, treatment or prevention of disease, and include vaccines, blood, blood products, hormones, cytokines and a range of cellular technologies. To ensure the quality, safety and efficacy of these products, regulatory guidance, the provision of standards, and the design of appropriate tests must be provided which are in line with latest developments.

WHO, through its Expert Committee on Biological Standardization (ECBS), plays a key role in reviewing scientific progress and in establishing International Reference Preparations and Recommendations on production and control of biological products. The report of its Fifty-first meeting, held in November 2000, is summarized below.

* The Expert Committee included members from Belgium, Canada, China, the Netherlands, Mexico, the Russian Federation, United Kingdom, and the United States of America. Experts were invited from Austria, Canada, China, Denmark, Finland, France, Germany, Japan, Republic of Korea, the Netherlands, Switzerland, United Kingdom, and the United States of America. with representatives of the Council of Europe, European Plasma Fractionation Association, International Association for Biologicals, International Federation of Pharmaceutical Manufacturers Associations (IFPMA), International Society on Thrombosis and Haemostatis, and the Plasma Protein Therapeutics Association.

Oral polio vaccine

WHO Recommendations (formerly requirements) for Oral Polio Vaccine (OPV) were revised at the Fiftieth meeting of the ECBS in1999, and new quality control procedures introduced. These included the use of transgenic mice as an alternative to the neurovirulence test in primates for type 3 oral polio vaccine, as well as a test for the molecular consistency of production of the live virus vaccine (MAPREC assay).

At the Fifty-first ECBS meeting, data concerning the use of the transgenic mice model for testing the neurovirulence of types 1 and 2 were reviewed. The ECBS concluded that the mouse model provided an alternative neurovirulence assay also for types 1 and 2 oral polio vaccines and agreed to include this recommendation as an addendum to the updated Recommendations for Oral Polio Vaccine. However, it would be necessary for laboratories intending to use the alternative assay to follow standard training and implementation procedures. A programme of training and staged implementation has therefore been developed by WHO, with the collaboration of the Center for Biologics Evaluation and Research (CBER), Food and Drug Administration, USA, and the National Institute for Biological Standards and Control (NIBSC), United Kingdom, in order to facilitate the introduction of the new assays.

Inactivated polio vaccine

Updated Recommendations for Inactivated Polio Vaccine (IPV) were also adopted by the ECBS. The Recommendations (formerly requirements) for Inactivated Polio Vaccine were last revised in 1985 and there have been several advances in vaccine production technology and quality control since that time. Furthermore, as the goal of eradicating poliomyelitis due to wild-type polio viruses is in sight, laboratories that use wild polio viruses will become an important potential source of accidental reintroduction of wild virus into the community. To minimize this risk, WHO has developed a global action plan that requires increased biosafety containment of wild polio viruses (1). This applies to parts of the production process for IPV where wild polio viruses are used. For these reasons, it was essential for the IPV Recommendations to be urgently updated. The ECBS reviewed a draft which had already undergone considerable international consultation and, after making some comments, adopted the draft as the new Recommendations for Inactivated Polio Vaccine.

Production and control of Japanese encephalitis vaccine

Japanese encephalitis is a major cause of viral encephalitis in the Asia-Pacific region. A liveattenuated vaccine has been developed in China where it has also been licensed and used for a number of years as an alternative to existing inactivated vaccines. Several countries are interested in using the live attenuated vaccine.

Guidelines for the Production and Control of Japanese Encephalitis (JE) Vaccine (live) for Human Use were adopted by the ECBS. The document provides information and guidance concerning the history, characteristics, production and control of live attenuated Japanese encephalitis vaccine and is designed to facilitate progress towards the eventual international licensing of the vaccine. The text is written in the form of guidelines rather than Recommendations since further work is needed to develop and standardize appropriate methods and criteria for certain tests, such as the neurovirulence test.

Diphtheria, tetanus, pertussis and combined vaccines

A WHO Working Group recommended the development of a simple, robust and standardized assay to demonstrate consistency of immunological characteristics suitable for lot release of vaccines containing diphtheria and/or tetanus toxoid. The ECBS therefore discussed a proposal to amend the present requirements for diphtheria, tetanus, pertussis and combined vaccines to permit the use of a test procedure based on serological assay for this purpose. The ECBS endorsed the need to work towards a common model acceptable by all parties, provided that new problems were not created. The ECBS welcomed the steps already taken, but concluded that further work was necessary before any changes could be made to the present Recommendations. Further work on this issue is in progress.

A range of single component and combined acellular pertussis vaccines are now available. However, ethical considerations prevent clinical protection studies of new vaccines or vaccine combinations and so the need exists for a suitable animal model to evaluate vaccine potency. The immunogenicity of these vaccines does not necessarily reflect clinical efficacy. Studies of appropriate animal models to assess the protective activity of acellular pertussis vaccines are under way, and a respiratory challenge model appears to offer a good prospect for product characterization. Further studies of this model are planned as well as studies to assess the value of the modified intracerebral challenge assay of acellular pertussis vaccine as a discriminatory lot release assay.

Transmissible spongiform encephalopathies

The ECBS attaches considerable importance to measures undertaken to ensure the safety of vaccines and blood products with respect to transmissible spongiform encephalopathies (TSEs).

At its Fifty-first meeting, the ECBS discussed the current situation regarding measures taken to exclude materials possibly carrying bovine spongiform encephalopathy (BSE) from the production of vaccines and other biologicals, including issues related to the use of bovine serum and other bovine derived materials. Recent risk assessments, carried out in the USA and European Union, agree that any risk from vaccines and other biologicals is theoretical and negligible.

The safety of vaccines and other biologicals with respect to BSE is considered to be assured by a combination of sourcing of materials used in manufacture from safe sources with respect to country/herd/animal and by employing only tissues with no demonstrable infectivity. Furthermore, in relation to the safety of vaccines and other biologicals prepared from mammalian cells there is no evidence that the transmissible agent of BSE is capable of amplification in cultures of the non-neuronal cells that are currently used as substrates for production. Nevertheless, in view of rapid developments in this area the ECBS recommended that WHO should review the situation and update its report on Medical and Other Products in relation to Human and Animal Transmissible Spongiform Encephalopathies (2).

In addition, the ECBS noted that progress is being made by the Working Group on International Reference Materials for Diagnosis and Study of TSEs in the development and evaluation of essential human- derived reference materials. Efforts of the Working Group are aimed at the standardization of diagnostic procedures under development. The need for international reference reagents and panels to compare new diagnostic procedures for TSEs was considered to be a priority. Reports of these developments are published on the WHO Website at the following address: http://www.who.int/technology/biological.html.

International standards

The ECBS established 6 new or replacement International Standards and Reference Reagents covering a range of products (Table 1, page 220). Vaccines and Biomedicines Additionally, one International Reference Material is no longer needed and was discontinued following a public consultative process (3), (See Table 2, page 220). Also, due to a decrease in use or following a change in international requirements, the ECBS proposed to discontinue a number of reference materials at its next meeting subject to public comment to this notice. The materials proposed for discontinuation are listed in Table 3 (page 221). The WHO Catalogue has been updated appropriately (4).

Other activities

The ECBS was informed of discussions that had taken place at a WHO Consultation on International Biological Standards for in vitro Diagnostic Procedures held in September 2000. International biological standardization is becoming increasingly important for the regulation of clinical diagnostic procedures and the consultation was the first occasion when participants from the various disciplines had met together to discuss issues associated with the provision of international reference materials in this area.

Discussion centred on a standardization process, the Draft ISO document 17511, that involves the use of a reference system consisting of a reference material, a reference method and a reference laboratory. The ECBS considered that the draft ISO standard 17511 as presently written may not be entirely applicable to the measurement of complex biological substances in clinical samples, and it recommended WHO collaborate closely with the ISO and other scientific bodies involved in the in vitro diagnostics field. Issues should be resolved whereby the principles of ISO 17511 are maintained as far as possible, while the distinct characteristics and difficulties of biological substances are clearly recognized.

The ECBS endorsed Recommendations arising from a meeting on the standardization and control of serogroup B meningococcal vaccines and agreed that guidelines for outer membrane vesicles- based meningococcal vaccines should now be developed. The ECBS also recommended a review of evidence concerning immune responses to these vaccines and to consider how the assays could best be standardized and reliable immunological correlates of protection established. Finally, it agreed that it would be useful for WHO to set up a working group to consider all aspects of clinical management of meningococcal disease and possibly draft suitable guidance.

In October 1999 in the United Kingdom, a serogroup C conjugate vaccine became the first novel vaccine to be licensed for use in infants for which protective efficacy was not determined by a phase III study, but inferred from immunogenicity data. The ECBS was informed of an expert panel set up to assess current methodologies for measuring immune responses to meningococcal A/C conjugate vaccines and agreed with its recommendation that either human or rabbit serum could be used as the source of complement for the serum bactericidal assay. It also agreed with the criteria proposed to indicate protective human immune responses. However, the ECBS emphasized the need to review these criteria in the light of clinical protection data now emerging from the United Kingdom following the introduction of meningococcal C conjugate vaccine, especially in relation to the demonstration of immunological memory.

Draft Guidelines for the production and control of inactivated oral cholera vaccines were in the preliminary stages of development and were intended to reflect the needs for production and control of the new inactivated oral vaccines, even though further development work will be required. The ECBS recognized that this is a rapidly evolving field of great importance in developing countries. It welcomed and endorsed the action taken by the Secretariat.

A proposed Guidance Document on Viral Inactivation Procedures for Plasma and Plasma-derived Medicinal Products, intended to assure the viral safety of plasma-derived products, was discussed. The document will be circulated to national regulatory authorities less familiar with decontamination processes and will be widely reviewed at a WHO Consultation. A Guide for Good Manufacturing Practices for the Collection of Source Materials for the Production of Plasma Derivatives will be developed to complement the above guidance document, aiming to strengthen the technical capacity and expertise of the national regulatory authorities in the evaluation and control of blood plasmaderived medicinal products.

The ECBS also supported the initiative to develop guidelines on preclinical and clinical testing of vaccines - a project already in progress - and agreed that these Guidelines would be of considerable benefit in supporting national regulations and would serve as guidance for national regulatory authorities and industry, especially in developing countries, and for ethical committees.

References

1. World Health Organization. WHO Vaccine Assessment and monitoring. WHO global action plan for laboratory containment of wild polioviruses. Document WHO/V&B/99.32, Geneva, 1999. http://www.who.int/vaccinesdocuments/DocsPDF99/www9956.pdf

2. World Health Organization. Report of a WHO Consultation on medicinal and other products in relation to human and animal transmissible spongiform encephalopathies. WHO/BLG/97.2

3. WHO Drug Information, 13: 234 (1999).

4. World Health Organization. WHO Catalogue on International Biological Reference Preparations. http://www.who.int/technology/biological.html