The 1999 World Congress of Pharmacy and Pharmaceutical Sciences - the 59th international congress of the International Pharmaceutical Federation (FIP) - took place in Barcelona, Spain, from September 5 to 10. Our coverage continues with reports of two symposia on international aspects of regulatory affairs (Harmonising specifications for chemical and biological quality characteristics and Harmonising treatment of marketing authorisation variations), both held on September 7
The second symposium dealt with global differences in the way regulatory authorities treated post-approval changes and variations to marketing authorisations. Such treatment varied markedly between the three major regions and lack of harmonisation caused an additional burden for industry. This post-approval area was seen as a new priority for ICH.
Presenting a global overview of the different approaches to treating post-approval changes and variations in marketing applications, Dr GESA DEEG (Schering, Germany) said that Europe had a clear definition of "Type I" variations (for which an applicant could assume permission if not challenged within 30 days) and more severe "Type II" changes (which imposed a stay of 90 days and also required an amended expert report). But while the EU accepted 34 administrative and 28 chemistry/pharmacy changes as being of "Type I", there was no corresponding guidance on "Type II", which subsumed all other variations short of full reapplication, such as major changes in synthesis, sterilisation, excipients, dosage or therapeutic indication.
Dr Deeg compared this European approach with the three tiers in US Federal regulations, with requirements ranging from permitting immediate action (but which must be reported annually), through provision of a supplementary document for "changes being effected", up to "wait for prior approval". These regulations were intended to be replaced by the FDA 1997 guidance on "scale-up and post-approval changes", on which the FDA was currently awaiting comments. This guidance was backed by consultative drafts applicable to immediate release solid dose forms, semi-solid products and modified release oral preparations. This initiative, when coupled with current proposals for three clear "levels" - "unlikely", "could have" and "likely" to have significant impact on quality and performance - relating to minor, moderate and major changes, should be less demanding for industry.
In contrast, in Japan almost all changes had to be approved and in two categories - smaller changes, which warranted partial reapplication, and major changes, requiring full application. The problem for industry was the real differences between these systems, compounded by minor differences in national practices in the three regions.
Presenting a rationale for US controls on post-approval changes (PAC), Dr AJAZ HUSSAIN (Food and Drug Administration, Washington, US) acknowledged industry's need to make changes and the cost of redocumentation, but emphasised that regulators had to recognise public health concern that such changes had not compromised safety, quality and efficacy. In examining whether proposed changes affected product performance, regulators had three essential questions: What do we want to know? What assumptions are reasonable? How sure do we want to be?
Providing the European rationale, Dr PER HELBOE (Danish Medicines Agency) endorsed Dr Deeg's remarks on uncertainties arising from Type II variations and drew attention to the lack of a "Type zero", reflecting the FDA lowest tier.
The handling of variations depended on whether the original application went through centralised procedure (whereby EMEA rapporteurs, with considerable effort, had the revision "well-controlled"), mutual recognition (which had problems with co-ordinating start-times and exchanging information), or national licensing (which did not require, but increasingly used, the EU procedure). Whereas international harmonisation of dossier requirements was well advanced, there was little prospect, given the considerable resource implications, of harmonising control of post-approval variations, or of revising the ICH stability guideline. This meant that pre-marketing should be globally uniform but post-marketing could continue to vary widely.
However, there was still hope, according to Dr MICHAEL JAMES (Glaxo Wellcome, UK). He said that it was timely to build on the ICH (Q3 & Q7) common quality document, with current initiatives both sides of the Atlantic to review procedures and guidelines for post-approval variations; and he noted the encouraging series of mutual recognition agreements (MRAs) that the EU had variously negotiated with Australia, New Zealand, Canada, Switzerland and Japan.
Despite a series of obstacles and risks to harmonisation of processing variations, industry and regulators would gain many benefits from it. Examples were the facilitation of quality agreements, better implementation of good manufacturing practice in the MRAs, improved inter-regional communication and data exchange, use of sound scientific principles for appraising technical data (with data requirements globally harmonised), better industrial planning of process and product changes, more co-operation between companies, and more effective and efficient use of resources by agency and industry alike.
Drawing encouraging parallels of principle between FDA consultative drafts and European industry proposals, Dr James incorporated Dr Helboe's reference to a potential "Type zero" and added the category of "anticipated changes". From this amalgam he produced a prospective pan-Atlantic, five-tier structure, with reconcilable procedures and (largely US) definitions. But he warned that this dream would only become reality if the ICH took the concept under its umbrella. - reports contributed by Professor Geoffrey Phillips (a former secretary of FIP's laboratories and medicines control section).