Dr Agnes Artiges (director of the European Directorate for the Quality of Medicines, Strasbourg, France) explored the general "status of harmonised monographs "and then focused specifically on sterility testing and assessment of "bacterial endotoxins and microbial contamination”. She compared two distinct routes of harmonisation: (i) through the (inter)pharmacopoeial discussion group (PDG) — wherein the European (PhEur), United States and Japanese pharmacopoeias had met since 1990; and (ii) by observer participation in the relevant quality working-group, Q6A, of the ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use). She acknowledged that the ICH route was easier to follow with new products, in collaboration with innovative manufacturers, which led to similar guidelines for the three global regions. However, while the PDG was essentially a series of governmental organisations (thus, 44 adherents and observers for the PhEur), it indirectly recognised the interests of all manufacturers, generic and innovative.
She noted that the ICH guidelines generated by consensus in Q6A emphasised, in paragraph 2.8, the mandatory status of relevant pharmacopoeial methods, with commitment to seek harmonisation, or at least interchangeability, and transparency throughout the three regions.
Dr Artiges explained that the PDG studies followed seven stages, which she contrasted with the five steps of the ICH process. The first two stages involved the choice of which pharmacopoeia would co-ordinate the work, and which would then undertake the preparatory study of existing monographs and methods. In stage 3, the three compendia would publish simultaneously the initial proposals (in Pharmeuropa, USP Forum and JP Forum). Then at stage 4, the responses and comments would be correlated and published; and a consensus draft could be prepared and, at stage 5, signed off by the PDG. The remaining stages 6 and 7 covered publication of the agreed monograph in each house style and procedure, and then setting an implementation date. The current PDG work programme involved 50 excipients, 11 general methods and six methods especially applicable to biotechnology products. Dr Artiges admitted the difficulty of agreeing completely harmonised texts, given the marked differences in compendial style and practice, but she described a good compromise. Thereby, each compendium could list remaining differences in various parameters, such as test, reagent, method protocol, and test limits. Indicating progress for the alternative option of interchangeability, she noted that the PhEur had effectively harmonised its General Notices and an introductory statement that described the status of "harmonised "and "interchangeable "monographs. The USP had elaborated a "pending "chapter for user information; and all three compendia had formally undertaken not to make any unilateral changes to mutually agreed chapters.
Dr Artiges then turned to biological testing. She reported that a harmonised test for bacterial endotoxins had been adopted by the three compendia and should be implemented (stage 7) in USP XXIV, PhEur 2000 and JP 2001. PDG studies on sterility testing, after "many years of effort”, had reached stage 4, with a deadline for public comment by the end of 2000, although she suspected that there could be continuing disagreement about the period of testing. She said that a microbial contamination study was at an early stage; meetings in 1999-2000, co-ordinated by the PhEur, had involved triregional experts and input from ICH Q6A experts led by the US Food and Drug Administration. They had prepared texts for total viable counts and tests for specific micro-organisms, and consultation papers should appear in the three regional fora, seeking comments early in 2001.
She concluded by emphasising the achievements of the PDG collaboration: agreement on tests for bacterial endotoxins, extractable volume and PAG-electrophoresis, and common properties for a variety of excipients, while studies continued on sterility testing, microbial contamination, dissolution and disintegration, particulate contamination and uniformity of content.