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Copyright World Health Organization 1997 This document

Organization (WHO), and all rights are reserved by the

The document may, however, be freely reviewed,

whole, but not for sale or for use in conjunction with

3 Copyright World Health Organization 1997 This document is not a formal publication of the World Health Organization (WHO), and all rights are reserved by the Organization. The document may, however, be freely reviewed, abstracted, reproduced or translated, in part or in whole, but not for sale or for use in conjunction with commercial purposes. The views expressed in documents by named authors are solely the responsibility of those authors.

Please click inside the blue boxes below to access the chapters within What are biologicals? What is biological standardization?

challenge the conceptual and regulatory framework Developments that challenge the role of the International Reference Standard Methodology Summary and conclusions 11 15 18 19 19

Summary and conclusions 21 26 28 29 29 33 36 36 37 Remit Implications for organization and infrastructure Summary and conclusions 38 38 40 1 List of organizations and individuals who

4 Please click inside the blue boxes below to access the chapters within What are biologicals? What is biological standardization? Quality control and safety monitoring The public health importance of biologicals Reasons for the Review Summary and conclusions Growth prospects Developments that challenge the conceptual and regulatory framework Developments that challenge the role of the International Reference Standard Methodology Summary and conclusions Vaccines Blood and blood products Cytokines and growth factors Monoclonal and engineered antibodies Cell and tissue transplantation Genetics Spongiform encephalopathies Other areas Summary and conclusions Remit Implications for organization and infrastructure Summary and conclusions List of organizations and individuals who gave comments or advice 2 Questionnaire 3 Physico-chemical testing methods 4 US Food and Drug Administration: regulatory changes 5 Independent product testing at NIBSC 6 Cytokines and growth factors standardized or requiring standards

5 This RepOlt is the product of a Scientific Review commissioned by the UK's National Biological Standards Board (NBSB) in October The Review was conducted by an international committee under the chairmanship of Professor Sir Leslie Turnberg (President of the UK's Royal College of Physicians) over a 6-month period from January This Report was presented to the NBSB on 17 July 1996 when it was accepted and endorsed by the Board. A copy of this Report was received on behalf of the World Health Organization (WHO) by Or Fernando Antezana (Assistant Director General) on 8 October In presenting the Report to Or Antezana, Or John Evans (Chairman ofnbsb) thanked WHO for its collaboration and support for the Review, and also paid tribute to the European Agency for the Evaluation of Medicinal Products (EM EA), the European Pharmacopoeia (EP) and the European Department for the Quality of Medicines (EDQM) for their support and contributions. The Review examines the current and likely developments both in biological products and in the areas of science most relevant to this important field of human preventative and therapeutic medicine. The Review highlights the need for biological standardization and control to keep pace with scientific developments in the field, and stresses that this can only be achieved if the procedures and systems for biological standardization and control are founded on best scientific practice. The Review also concludes that there is a need for national and international organizations to collaborate closely and to discuss and agree priorities and respective roles in the field of biological standardization and control. NBSB will be pleased to help foster such collaboration. NBSB is a public body established by the UK Government in NBSB is responsible for the management of the National Institute for Biological Standards and Control (NIBSC). NIBSC operates as a WHO International Laboratory for Biological Standards, and within Europe as an Official Medicines Control Laboratory (OM CL).

6 Professor Sir Leslie Tumberg PresIdent Royal College qfphysiczctns United Kingdom Professor Pim van Aken Medical Director Central Laboratory qfthe Netherlands Red Cross Blood Tranifuslon Service (CLB) 17ze Netherlands Professor Jeffery Almond Department qf MICrobIology University qfreading Unzted Kingdom Or Femando Antezana 1 Assistant Director General World Health OrganizatIon Switzerland Or Roland Oobbelaer Head qfblologlcal StandardizatIon Instztut d'hygiene et d'epldemlologie Belgium Or Trevor Jones Director General Assodatlon qf the Bntish Phannaceutlcal Industry Unzted Kingdom Professor Jesus Kumate 1 Hospztal de Espedalzdades Centro Medlco NaClonal MexIco Or John Petricciani VIce PresIdent, Regulatory Ajfoirs GenetIcs InstItute USA Professor Giuseppe Vicari 3 Director Istltuto Supenore Di Sanzta Italy Or Kathryn Zoon Director Center for Blologks EvaluatIon and Research (CBER) Food and Drug AdmlrllJtratlon USA Mrs Norma Morris Umverslty College London Umted Kingdom I Nominated by the World Health Organization (WHO) 2 Nominated by the European Pharmacopoeia (EP) 3 Nominated by the European Medicines Evaluation Agency (EMEA)

Blood products, cytokines and hormones are other important and wellrecognised biological products.

7 1. Biological medicines are of central importance to public health. Vaccines are a striking example, where vaccination campaigns have succeeded in eradicating one major killer disease - smallpox - and are well on the way towards the elimination of polio. Blood products, cytokines and hormones are other important and wellrecognised biological products. Recent scientific and technological developments have opened the way to new kinds of product and new methods of manufacture, which makes a review of the standardization and control of these medicines timely. 2. Biologicals are products derived from biological sources, ie from living materials, and used in the prevention, treatment or diagnosis of disease, and in research. As for all performance-sensitive products that are nationally or internationally manufactured and used, standardization is of the utmost importance. The complexity and variability of both the biologicals and the bioassays used to test them led, at an early stage in the development of the field, to the use of the International Reference Standard, a sample of the product in question of defined purity and potency, against which all preparations of that product must be calibrated. The nature of biologicals also raises particular questions of quality control: the two distinctive features of quality control of bioi ogica Is are first the importance of in-process controls and testing, and second, in the case of certain especially sensitive biologicals, testing of each production batch (lot-by-iot testing) before its release on the market. Biologicals make an enormous contribution to the public health, but also require eternal vigilance against their considerable potential hazards. 3. The story across the wide field of bioi ogica Is is one of expansion and increasing diversity. There are many areas of very rapid growth, with the emergence of new products (eg cytokines, DNA vaccines), replacement of traditional products with recombinant equivalents (growth hormone, thrombolytic agents, coagulation factors) and new possibilities for treatment and diagnosis. Among the areas that seem likely to dominate the field of biologicals in the next 5 to 15 years vaccines and blood products are already well-established but are entering a phase of exciting new developments. Diagnostics, especially in relation to genetic disease, are of growing importance and will be of increasing concern for standardization and control. New therapies such as gene therapy, manipulation and reimplantation of cells and tissues, and animal to human transplants will all be based on biological materials needing the same care in regulation and monitoring as traditional products. It is of vital importance to all parties involved in these developments - regulators, manufacturers and the public - that regulatory guidance, provision of standards and design of appropriate tests keep pace with this growth.

9 Biological Standardization and Control vii pies and Xenotransplantation also are of growing significance and will need to be brought into the mainstream of standardization and control ofbiologicals; Effective management of regulation in this highly dynamic and productive field calls for application of priority-setting and risk assessment systems, further clarification and harmonization of roles of national and international agencies, and streamlining of process; Collaboration between scientists and scientific institutions is essential for efficiency, and should be strongly encouraged.

The first biological standard (Insulin) 'My

complete nonsense to try to define any unit of any

thing was to obtain the remedy in perfectly stable

quantity of such standard sample, internationally

determination to be the subject of indefinite

MacLeod replied that he had no doubt that such a

to believe that the preparation of such a standard

At that point, I was glad to be able to take from

10 The first biological standard (Insulin) 'My intervention took the form of insisting it was complete nonsense to try to define any unit of any remedy in absolute terms of reactions in a limited number of animals; and that, from the international point of view, the only sensible thing was to obtain the remedy in perfectly stable form and define the unit in terms of an absolute quantity of such standard sample, internationally accepted, leaving the laboratory methods of its determination to be the subject of indefinite possibilities of experimental improvement. MacLeod replied that he had no doubt that such a policy would be ideal, but that he had no reason to believe that the preparation of such a standard was a practical possibility. At that point, I was glad to be able to take from my waistcoat pocket a small tube of the preparation which was to be the first international standard and roll it across the table to MacLeod with the statement "Well, here it is!'" Sir Henry Dale, quoted injeffcoate et all

1.1 Setting up 1.1.1 In October 1995 the UK National Biological Standards Board (NBSB) commissioned a major scientific review of the field of biological standardization and control.

The Board manages the National Institute for Biological Standards and Control (NIBSq, through which it discharges its statutory function.

11 1.1 Setting up In October 1995 the UK National Biological Standards Board (NBSB) commissioned a major scientific review of the field of biological standardization and control. This Board was set up by the UK government in 1975 with a statutory responsibility to oversee the control testing of biological medicines and the development of biological standards. The Board manages the National Institute for Biological Standards and Control (NIBSq, through which it discharges its statutory function. During the 20 years of the Board's existence, there has been a rapid growth in biological products, emergence of new biotechnologies for their production, and development of new and more sophisticated techniques for their analysis through both biological and physico-chemical methods. In planning a strategy for the next 20 years, the Board wants to have the best possible independent assessment of present and future trends in products and technologies, and to relate these to public health, industrial, regulatory and consumer needs The nature of the field requires an international perspective, and the Board sets great store by having engaged the collaboration and support of the World Health Organization (WHO), the European Medicines Evaluation Agency (EMEA) and the European Pharmacopoeia (EP) in carrying out the Review. A distinguished international group, meeting under the chairmanship of Professor Sir Leslie Turnberg PRCP, were invited to carry out the Review. 11 Setting up 11 Membership and terms of reference HI! Mode of working

12 2 Biological Standardization and Control erence were: Taking into account the development of new products and medical tre::!tments based on biotechnology techniques; requiremenls Ihe protection health; developments scientific such as physico-chemical and alternatives to ziz vzvo testing; the need to make effective and efficient use of resources; and the international dimension of work in this field, 'ro consider control/salely monitoring report to NBSB on these matters. standardization and medicine, 1.3 Mode of working In carrying lask, the met three bctweenjanuarv June 1996 and consulted widely public health nizations and individuals. This circulation of tionnaire and application to individuals and organizations on specific issues (the names of organizations and individuals who gave their views are listed in Appendix 1; a copy of the questionnaire is at Appendix 2). The Committee concentrated throughout sui:nce: ie where science is leading' terms of both and improved and new lechnologies what are the quential needs Important arose about national and national structures may be required to meet the challenges of the future and, although these are largely outside the terms of reference of the present review, the Committee considered them worthy of some comment. The Committee's approach has been broad relevance. which are illustraled publications policies of a uf national and international With so many various organizations engaged in active and innovative work in this field, the Committee has not aimed for full coverage but has tended to draw examples predominantly from UK, European, and North American policy and practice. The Review also confines hiologicals 1 use, and has collsidered standardi;;ation and ofbiologicals in veterinary medicine, In accordance NBSB's wishes. Committee reached its conc1l1sicms independently of the Board, to whom it now presents its report.

Units and traceability in biological reference materials

Units and traceability in biological reference materials A. F. Bristow Division of Endocrinology National Institute for Biological Standards and Control Blanche Lane, South Mimms Potters Bar Herts EN6