Masterstudiengang "Drug Regulatory Affairs"


Quality related changes during the life-cycle of a medicinal product marketed in the EU and their impact on the pharmaceutical documentation (CTD module 3)

Dr. Beate Preuss (Abschlußjahr: 2004)

During the life-cycle of a medicinal product, a lot of quality-related changes will take place for different reasons, e.g.:

  • in the development phase of a product, focus is put on different aspects than in the post-approval phase
  • changes may be introduced for economic reasons
  • there are legal requirements to keep manufacture and control of a medicinal product in line with the current state of science and technology.

Changes will probably end up in variations according to the Commission Regulation 1084/2003/EC in the EU in order to fulfil regulatory compliance.

This thesis discusses frequent changes related to the quality of the drug substance and the drug product in the light of applicability of the variation regulation for type IA and IB notifications and arising problems thereof.

For the drug substance, change of manufacturer of the drug substance and change in the manufacturing process of the drug substance are chosen as examples. The respective requirements of the variation regulation in terms of documentation and the impact of the changes on dossier maintenance (module 3) are outlined. Focus is also put on internal GMP related actions for the chosen examples.

Characteristics of different types of documentation in the drug substance section of module 3, EDMF and CEP, are compared and their relative advantages and disadvantages are discussed. Decision trees are introduced as references for a brief overview.

Changes affecting the quality of a drug product are discussed in a site change scenario including various changes in manufacture as well as in analytical methods. Requirements for the variations are examined as well as dossier update, GMP aspects, transfer and validation of analytical methods.

The third aspect covered in this thesis is stability testing during the life-cycle of a medicinal product. This section explains differences between on-going and follow-up stability studies, identifies changes requiring stability testing and discusses consequences that might be drawn from out-of-specification results in stability testing.

It is concluded that use of the variation regulation does not seem to be applicable either for more complex changes nor for complete updates of module 3. Some ideas related to more intensive guidance for industry are given. Authorities and pharmaceutical manufacturers' associations have already started an improvement process in order to facilitate applications for variations.

A quite opposite approach would be strengthening of the reliability of the marketing authorisation holder by introducing new features such as Risk Management into the quality system. GMP inspections focussed on Change Management and the introduction of an Annual Report system could decrease the number of variations significantly.

Pages: 68, Appendices: 13