According to article 4(1)(a) and 4(1)(b) of the new Directive (EC) No. 1234/2008, the new "Variations Regulation" published on 24 November 2008, the EMEA has created two guidelines, which describe the details of the various categories of variations on the one hand and the handling of the procedures laid down in the directive on the other hand. Both documents remain in the consultation phase until 18 May 2009.
In the guideline on the classification of variations, the categories of variations are defined as follows:
Type IA: a minor variation that has no or only a minimal impact on the quality, safety or efficacy of the medicinal product. The authority should be notified within 12 months after the variation ("do and tell").
Type IAiN: a minor variation that has no or only a minimal impact on the quality, safety or efficacy of the medicinal product, but that is relevant to the continuous supervision of the medicinal product. An immediate notification about the implemented variation has to be submitted to the authority. Within 30 days, the authority will either approve or disapprove of the variation ("do and tell").
Type II: a major variation that has a significat impact on the quality, safety or efficacy of the medicinal product and does not represent an extension of the marketing authorisation. The authority has to be notified. Within 60 days, the authority draws up an evaluation report and decides about the application ("tell, wait and do").
Type IB: a minor variation that can neither be classified as Type IA nor as Type IAiN, does not represent an extension of the marketing authorisation and has no or only a minimal impact on the quality, safety and efficacy of the medicinal product. Within 30 days, the authority will either approve or disapprove of the variation ("tell, wait and do").
Compared to the provisions of the "Guideline on dossier requirements for Type IA and IB notifications", which is currently in force, the requirements in the new "Guideline on the details of the various categories of variations" are much more differentiated. The new document defines e. g. a total of 32 IAiN cases for minor variations that have to be notified prior to implementation.
The draft guideline also includes cases in which variations fall in a new category. The change of an analytical test procedure for an active pharmaceutical ingredient (including the replacement or addition of a test procedure) has e. g. been a Type IB variation according to the regulations hitherto in force. According to the new guideline, this can be a type IA variation on the condition that the total impurity limits remain unchanged and no new, unqualified impurities are detected.
Another example: A new or updated Certificate of Suitability (CEP) is submitted. According to the new guideline this is - as before - a Type IA variation and, in case of a new CEP, a Type IAiN variation. However, the new condition is that the specifications for the impurities must not have changed.
As mentioned above, this draft guideline is still in the consultation phase. It remains to be seen in how far it will be revised due to comments from the industry.
Dr Gerhard Becker
On behalf of the European Compliance Academy (ECA)