WHOWHOWHO Technical Technical Technical Report Report Report Series Series Series 941941941 BIOLOGICAL BIOLOGICAL BIOLOGICAL ThisThisThis report report report presents presents presents the the recommendationsthe recommendations recommendations of ofa ofWHOa WHOa WHO Expert Expert Expert WHOWHOWHO EXPERT EXPERT EXPERT COMMITTEE COMMITTEE COMMITTEE CommitteeCommitteeCommittee commissioned commissioned commissioned to tocoordinate tocoordinate coordinate activities activities activities leading leading leading to tothe tothe adoptionthe adoption adoption of ofinternational ofinternational international recommendations recommendations recommendations for for the for the the ONONON BIOLOGICAL BIOLOGICAL BIOLOGICAL productionproductionproduction and and andcontrol control control of ofvaccines ofvaccines vaccines and and andother other other biologicals biologicals biologicals STANDARDIZATION STANDARDIZATION STANDARDIZATION andand andthe the establishmentthe establishment establishment of ofinternational ofinternational international biological biological biological reference reference reference STANDARDIZATIONSTANDARDIZATIONSTANDARDIZATION materials.materials.materials. TheThe Thereport report report starts starts starts with with with a discussiona discussiona discussion of ofgeneral ofgeneral general issues issues issues brought brought brought to tothe tothe attentionthe attention attention of ofthe ofthe Committeethe Committee Committee and and andprovides provides provides information information information onon theon the statusthe status status and and anddevelopment development development of ofreference ofreference reference materials materials materials for for for variousvariousvarious antibodies, antibodies, antibodies, antigens, antigens, antigens, blood blood blood products products products and and andrelated related related substances,substances,substances, cytokines, cytokines, cytokines, growth growth growth factors, factors, factors, and and andendocrinological endocrinological endocrinological substances.substances.substances. The The Thesecond second second part part partof ofthe ofthe report,the report, report, of ofparticular ofparticular particular relevancerelevancerelevance to tomanufacturers tomanufacturers manufacturers and and andnational national national regulatory regulatory regulatory authorities, authorities, authorities, Fifty-sixthFifty-sixthFifty-sixth Report Report Report containscontainscontains guidelines guidelines guidelines on on quality, on quality, quality, safety safety safety and and andeffi effi cacy effi cacy cacy of oflive oflive live attenuatedattenuatedattenuated rotavirus rotavirus rotavirus vaccines; vaccines; vaccines; DNA DNA DNA vaccines; vaccines; vaccines; a abiosafety abiosafety biosafety riskrisk riskassessment assessment assessment for for production for production production and and andquality quality quality control control control of ofhuman ofhuman human inflinfl uenzainfl uenza uenza pandemic pandemic pandemic vaccines; vaccines; vaccines; recommendations recommendations recommendations for for for inactivatedinactivatedinactivated rabies rabies rabies vaccines vaccines vaccines produced produced produced in incell incell substratescell substrates substrates and and and embryonatedembryonatedembryonated eggs; eggs; eggs; for for whole for whole whole cell cell pertussiscell pertussis pertussis vaccine; vaccine; vaccine; and and and forfor production,for production, production, control control control and and andregulation regulation regulation of ofhuman ofhuman human plasma plasma plasma forfor fractionation.for fractionation. fractionation. AlsoAlsoAlso included included included are are aare lista lista oflist ofrecommendations, ofrecommendations, recommendations, guidelines guidelines guidelines andand andother other other documents documents documents for for biological for biological biological substances substances substances used used used in in in WHO WHO WHO medicine,medicine,medicine, and and andof ofinternational ofinternational international standards standards standards and and andreference reference reference Technical Technical Technical reagentreagentreagent for for biological for biological biological substances. substances. substances. Report Report Report ISBNISBNISBN 978-92-4-120941-0 978-92-4-120941-0 978-92-4-120941-0 Series Series Series — — — 941 941 941 GenevaGenevaGeneva TRS941cover.inddTRS941cover.inddTRS941cover.indd 1 1 1 4.10.20074.10.20074.10.2007 15:49:13 15:49:13 15:49:13 The World Health Organization was established in 1948 as a specialized agency of the United Nations serving as the directing and coordinating authority SELECTED WHO PUBLICATIONS OF RELATED INTEREST for international health matters and public health. One of WHO’s constitutional functions is to provide objective and reliable information and advice in the fi eld of human health, a responsibility that it fulfi ls in part through its extensive programme WHO Expert Committee on Biological Standardization of publications. Fifty-fi fth report. The Organization seeks through its publications to support national health WHO Technical Report Series, No. 932, 2006 (137 pages) strategies and address the most pressing public health concerns of populations web site www.who.int/biologicals around the world. To respond to the needs of Member States at all levels of development, WHO publishes practical manuals, handbooks and training mate- WHO Expert Committee on Biological Standardization rial for specifi c categories of health workers; internationally applicable guide- Fifty-fourth report. lines and standards; reviews and analyses of health policies, programmes and WHO Technical Report Series, No. 927, 2005 (154 pages) research; and state-of-the-art consensus reports that offer technical advice and recommendations for decision-makers. These books are closely tied to the WHO Expert Committee on Biological Standardization Organization’s priority activities, encompassing disease prevention and control, Fifty-third report. the development of equitable health systems based on primary health care, WHO Technical Report Series, No. 926, 2004 (109 pages) and health promotion for individuals and communities. Progress towards better health for all also demands the global dissemination and exchange of informa-tion that draws on the knowledge and experience of all WHO’s Member coun-tries and WHO Expert Committee on Biological Standardization the collaboration of world leaders in public health and the biomedical sciences. Fifty-second report. WHO Technical Report Series, No. 924, 2004 (234 pages) To ensure the widest possible availability of authoritative information and guid- ance on health matters, WHO secures the broad international distribution of its publications and encourages their translation and adaptation. By helping to promote and protect health and prevent and control disease throughout the world, WHO’s books contribute to achieving the Organization’s principal objec-tive — the attainment by all people of the highest possible level of health The WHO Technical Report Series makes available the fi ndings of various international groups of experts that provide WHO with the latest scientifi c and technical advice on a broad range of medical and public health subjects. Members of such expert groups serve without remuneration in their personal capacities rather than as representatives of governments or other bodies; their views do not necessarily refl ect the decisions or the stated policy of WHO. An annual subscription to this series, comprising about six such reports, costs Sw. fr. 132.– or US$ 106.– (Sw. fr. 92.40 in developing countries). For further information, please contact Marketing and Dissemination, World Health Organization, 20 avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 2476; fax: +41 22 791 4857; e-mail: [email protected]). Further information on these or other WHO publications can be obtained from Marketing and Dissemination, World Health Organization, 1211 Geneva 27, Switzerland The production of rabies vaccine should be conducted by dedicated staffs who do not handle other infectious microorganisms, animals, or tissue cultures in the same working day. Steps should also be taken to minimize the risks of transmission of rabies virus from the production facility to the outside environment. A.3 Control of source materials A.3.1 Substrates for virus production Rabies vaccines may be produced in human diploid cells, in continuous cell lines, in primary hamster kidney cells or in primary chick embryo fi broblast cells. For human diploid and continuous cell lines section 3.1.1 should apply; for primary hamster kidney cells section 3.1.2 should apply; for primary chick embryo fi broblasts section 3.1.3 should apply; for embryonated duck eggs section 3.1.4 should apply. Section 3.1.5 applies to all types of cell substrates. A.3.1.1 Diploid cells and continuous cell lines The use of a diploid cell or continuous cell line for the manufacture of rabies vaccines should be based on the cell seed system. The cell seed should be approved by the national regulatory authority. The maximum number of passages (or population doublings) by which the working cell bank is derived from the cell seed should be approved by the national regulatory authority. WHO has established a cell bank of Vero cells characterized in accordance with the requirements in the report of the WHO Expert Committee on Biological Standardization (15), which is available as a well characterized starting material