Masterstudiengang "Drug Regulatory Affairs"
Master-Thesis
Change Control Systems in Europe - How are they influenced by Regulation EC1234/2008 and Directive 2009/53? ***
Dr. Marko Kaulich (Abschlußjahr: 2010)
The pharmaceutical industry is undergoing immense change processes, either driven by the demand to adapt to the current state of scientific and technical knowledge or those changes resulting from acquisitions or mergers of companies and from outsourcing issues. While increasing flexibility or reducing the costs to remain competitive, product quality and regulatory compliance always need to be achieved.
Change control as a key element of a company´s quality management system is a formal cross-departmental process to achieve this aim. According to Annex 15 of GMP Guide all changes that may affect product quality or reproducibility of the process should be formally requested, documented and accepted. Impact analysis of each change control process should always include ga risk analysis and the decision on re-qualification and re-validation issues.
Assurance has to be taken, that intended changes are introduced in a controlled and coordinated manner, i.e. that they are accepted before implementation and release to the market. Even changes considered to be minor, might have a major impact on product quality or regulatory compliance, especially if not properly controlled. This process must be well-documented in a reproductive and traceable way to meet the rules of Good Documentation Practice and Archiving.
Time needed for implementation of any change control is increasing with the degree in complexity of change. Furthermore, it is increasing with the requirement of involvement of third parties with different regional requirements. In each change control procedure impact on the registration file of approved products needs to be assessed. Variations need to be submitted for any amendment to the approved registration file in order to keep up dossier compliance for batch release through the responsible Qualified Person.
For changes requiring regulatory submission activities (such as notifications or variations) the new Variation Regulation (1234/2008/EC) has a significant impact on a company´s change control system.
Innovations connected to this new Variation Regulation like the possibility of minor changes of type IA (annual notification or immediate notification), grouping of variations, the worksharing procedure, design space or the type IB by default system have provided a higher flexibility in the implementation of changes.
Minor variations of Type IA do not need to be notified to the competent authorities before implementation anymore. The MA holder only has to decide about the requirement of immediate notification after implementation or to submit it within the next 12 months after implementation by means of including it in an annual reporting. The challenge of this new system is the tracking of all changes not directly notified. This is only possible by using efficient tracking tools on the regulatory side, but also for the change control system. This is a clear disadvantage of the annual reporting system, since a related change can only be closed after regulatory notification, being one step of the implementation plan of a change control procedure, if applicable.
The possibility of grouping and worksharing of different variations has only delivered higher flexibility in submission activities. RA submissions can be combined for different products with the same topic or several strengths of one product. On one hand this combination reduces the administrative workload in RA department (e.g. lower amount of application forms, or avoiding redundant work), on the other hand though strategic planning within a department is getting more and more complex. It is recommended to contact the competent authority two or three months before submission of a grouped variation or worksharing procedure. This period of time needs to be included into the variation submission strategy as well as in the timelines of a change control procedure. Similar to the annual reporting system of type IA notifications, electronic tools for RA and responsible change control department are compulsory for thorough tracking of all planned activities.
Classification and Categorisation Guideline have delivered a list, what type of variation should be submitted for which kind of change. If not defined, the applicant has the possibility to submit a variation type IB by default, but the responsible authority can demand a type II variation in case of safety concerns. In case of unforeseen variation, the applicant has the possibility to request for recommendation of previously not classified changes. But this 45 days procedure is also a time barrier for each change control and variation procedure. Therefore, both systems do not seem to be well-accepted: companies tend to submit the type II variation directly, trying to avoid discussions with the competent authority.
The most important advancement of the Variation Regulation is the possibility of working in Design Space: Once a design space is approved by the competent authority, this leads to higher flexibility for RA and change control. Changes within an approved design space can be run on a minimum level, elimination the requirement of RA submission activities. The same scenario is applicable for generally-written dossiers: The more general a dossier is written, the lower the requirement to submit notifications or variations in case of changes.
The new Variation Regulation is currently only valid for registrations that were run through Centralised Procedure, MR- or DC- procedure. Directive 2009/03 intended to extend this new legislation also to medicinal products formerly achieved on a purely national level. The national competent authorities need to decide on this issue until 11 January 2011, especially for those MA´s granted before 01 January 1998. Otherwise, integration of these licences into Variation Regulation and implementation of Directive 2009/53 into national law needs to be conducted.
This decision on national levels is substantial, because different time lines for variations and therefore also for changes need to be taken into account. If a member state sticks to its former rules, the company also needs to run two different systems and/or is required to have such a flexible system that covers all demands. Different timelines and procedures for variations need to be taken into account in the implementation strategy of all change control processes.
Different opinions do exist: Manufacturers usually recommend to maintain the former rules (where applicable) to be more flexible than with the new system. Authorities are favouring the new system for all MAs resulting in a harmonised, uniform system. The latter will probably not be achieved, but the higher the degree of harmonisation, the lower the complexity in a change control system. The higher the complexity of work in a process, the higher the demand of well-trained personnel, especially in RA.
Pages: 34, Annexes: none