Establishment of new and replacement World Health Organization International Biological Standards for human interferon alpha and omega

The complexity of the human interferon-alpha (IFN-alpha) family, with its m ultiple molecular forms and various biological activities, raises a number of scientific issues with regard to the biological standardisation of natur al and recombinant IFN-U products. To address such issues and to achieve an appropriate biological standardisation of human interferon-alpha (IFN-alph a) preparations, the National Institute for Biological Standards and Contro l (NIBSC) of the United Kingdom (UK), in association with the Centre for Bi ologics Evaluation and Research (CBER) of the United States of America (USA ), organised an international collaborative study, which was subsequently d ivided into two parts, Ninety-three participating laboratories from 29 coun tries worldwide participated in the first part of the study. They performed titrations on up to 15 different IFN-alpha preparations and one IFN-omega (omega) preparation in a variety of assays, including those based upon anti viral, antiproliferative, and other biological activities of IFN, and contr ibuted raw data from these assays to NIBSC for analysis and calculation of relative activities. Analysis of data from this part of the study showed a greater than expected assay-dependent disparity between the relative activi ties of different IFN-alpha preparations. This disparity was found when onl y antiviral assays were considered and even when there were only small mole cular dissimilarities between two otherwise closely related IFN-alpha prepa rations. The lack of assay independence and relative activity equivalence h as indicated that a single biological potency standard for all IFN-alpha su btypes and mixtures would be inappropriate. Hence, individual, homologous s tandards, each with a separate unitage, were required for biological standa rdisation and potency determinations of individual IFN-alpha subtypes. At t his stage, potency assignments to the IFN-alpha and -omega preparations inc luded in the study were made as far as possible on the basis of comparison of antiviral activity with that of the Ist International Reference Preparat ion (IRP) for IFN, human leukocyte. 69/19. However, it was recognised that other standards had been used in assays to estimate potencies of widely ava ilable. current, therapeutic IFN-alpha products. Thus, to ensure the contin uity of unitages already in use for IFN-alpha products, the second part of the study, which involved 12 members of the International Federation of Pha rmaceutical Manufacturers Association (IFPMA), was carried out using for ca libration of antiviral assays those IFN-alpha preparations that most closel y matched manufacturers' products or that had been previously used for assa y calibration by a manufacturer for a particular product. On the basis of d ata analysis from the second part of the study, potency assignments to the IFN-alpha preparations, as made in the first part of the study. were either left unchanged or changed to potency assignments that ensured as far as po ssible continuity with existing unitages. From among the IFN preparations e valuated. the following were recommended as the most suitable to continue o r replace existing WHO international standards (IS) and have subsequently b een formally established as WHO IS at the 51st meeting (October 1999) of th e WHO ECBS: 83/514. 1st WHO IS for human IFN-alpha1 8000 international unit s (IU): 95/650. 2nd WHO IS for human IFN-alpha 2a, 63,000 IU, 95/566. 2nd WHO IS for human IFN-alpha 2b, 70,000 IU; 95/580, 1st WHO IS for human IFN-alpha 2c, 40,000 IU; 95/572, 1st WHO IS for human IFN-alpha 1/8, 27,000 IU: 94/786, 1st WHO IS for human IFN-alpha Con1, 100,000 IU; 94/784, 2nd W HO IS for human IFN-alpha (leukocyte), 11,000 IU; 95/574, 1st WHO IS for hu man IFN-alpha (leukocyte n3), 60,000 IU; 95/568, 2nd WHO IS for human IFN-a lpha (lymphoblastoid n1), 38,000 IU; 94/754. 1st WHO IS for human IFN-omega , 20,000 IU. These WHO IS are available upon request to NIBSC. (C) 2001 Els evier Science B.V. All rights reserved.