Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Impact of the new Variation Regulations 1084/2003 and 1085/2003 on the industrial practice of a multinationally operating pharmaceutical company with regard to the EU enlargement and the multinational procedure in performing variations ***

Britta Ginnow (Abschlußjahr: 2004)

The final versions of the Commission Regulations 1084/2003 and 1085/2003 entered into force on 17 July 2003 and applied from 1 October 2003. Especially industry requires a streamlined variation system in order to cope with the increased workload in performing variations and to facilitate the implementation of changes in the enlarged EU. This Master-Thesis discusses the impact of the new European Variation Regulations on the industrial practice of a multinationally operating pharmaceutical company and highlights the advantages and disadvantages in performing variations according to these Regulations in the enlarged EU and their suitability regarding the multinational procedure in performing variations with focus on a comparison of the three industry regions EU, USA and Japan.

The classification and procedures for minor changes of type IA and IB and the impact on industrial practice are examined by looking at administrative changes, manufacturing changes and changes affecting the quality control of the active substance and the medicinal product. For chemical-pharmaceutical changes, that occur in a manufacturing facility, the implementation of a change represents less logistic burden. It is an economic benefit, that the variation system offers the opportunity that production batches, manufactured to generate data to support the change, can be sold with the almost entire assigned shelf-life.

Major chemical-pharmaceutical changes can be implemented in a manufacturing facility for all concerned Member States of the enlarged EU at the same time. The classification as a type II variation of all changes to or addition of a therapeutic indication of a medicinal product means a significant reduction regarding the time line for implementation. Still having the possibility to file a new application to add a new indication allows for marketing options and increases business flexibility. The new procedure for type II variations is more flexible as it allows different time lines to be set depending on the change and the urgency of the matter. The expedited procedure, possible for type II changes related to safety issues, as well as the harmonised implementation of these changes are of importance to protect public health in the enlarged EU. The marketing authorisation holder is responsible for the implementation and should treat this task with carefulness in order to avoid any harm to patients for which the marketing authorisation holder could be liable. The same applies for urgent safety restrictions to be implemented with an agreed time frame, although the time line of 15 days seems quite short to prepare a documentation for the corresponding type II variation. For extensions, national and mutual recognition procedures are possible if the original authorisations are national. The applicant can choose to include the extension of a nationally authorised product into a MRP, which increases regulatory flexibility.

The Master-Thesis provides examples of more increased requirements regarding the documentation to support a change. The classification of changes is in many cases too schematic and restrictive. It does not offer any possibilities for a scientifically based consideration of a particular change, supported consequently by an appropriate documentation. The submission principles and national peculiarities still reflect an immense workload on industry, especially if more Member States of the enlarged EU participate in a variation procedure.

With regard to the multinational procedure in performing variations, the Master-Thesis compares time lines and data requirements of the revised EU variation system with the systems of post-approval changes in the USA and Japan. By means of a comparison of manufacturing transfers and changes in the manufacturing process of the active substance, it is concluded that the time line differences between the USA and the EU to implement a change are minimised. But the US classifies the changes more scientifically based, has more differentiated reporting categories and in many cases there is a different approach in the assessment of a change regarding its impact on quality, safety and efficacy of the medicinal product. For the time being, Japan assesses the changes completely differently from the USA and the EU. With the revision of the Japanese Pharmaceutical Affaires Law, Japan will introduce a system of minor changes as it is practiced in the EU and the USA. A common approach in performing minor changes in the three main industry regions is aspired, which will provide less time line differences and will mean less logistic burden to industry in future.

The Commission Regulations 1084/2003 and 1085/2003 provide simplified procedures to perform variations, but the target to reduce the workload in managing variations has not quite been achieved from industry's point of view. With regard to a multinational procedure in performing variations, the new Variation Regulations offer an improvement for the industrial practice. Nevertheless, the variation system should be optimised in the future and suggestions are made in the Master-Thesis. The revised legislative texts of 2004 offer an opportunity for improvements of the variation system and open the EU for a further harmonisation in per-forming multinational variations.

Pages: 71, Appendices 32