Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Parametric release of sterility of parenteral medicinal products

Timea Janosi (Abschlußjahr: 2005)

Language: English
 
Parametric release of sterility is a sterility release procedure based upon control, monitoring and documentation of a validated sterilisation process instead of release based upon end-product sterility testing.

The regulatory background that exists up to now for it are the PIC/S guidance on parametric release, which has the most international character, the Note for guidance on parametric release and the EU GMP annex 17 as EU documents and the Compliance policy guide to parametric release, issued by the FDA. The option for the implementation of parametric release is in addition mentioned in the pharmacopoeias of the ICH regions, EU, USA and Japan. Some of the guidance documents describe the possibility for parametric release instead of finished product testing in general, but the focus of guidance and recommendations lays on the replacement of the sterility test. The current regulatory frame lays a foundation for parametric release but the requirements need international harmonisation and mutual agreement.

The sterility test is considered as the last chance to detect a major sterilisation failure resp. non-sterility. It is the only analytical method available for products prepared under aseptic conditions and furthermore it is, in all cases, the only analytical method available to the authorities who have to examine a specimen of a product for sterility. The critical disadvantage of the sterility test is the statistical limitation and the low sensitivity to detect low levels of microbial contamination that can have an important impact on the product safety and quality. Once the sterilisation process is fully validated and operating consistently, parametric release of sterility of terminally heat sterilised products is the more accurate and reliable assessment of the probability of non-sterility of product lots. But to ensure the required sterility assurance level it is necessary to control a multitude of in-process parameters which must be specified on the basis of validations. The release of a batch with regard to the parameter sterility is then only justified if all results are within the specification. This fact has induced pharmaceutical manufacturers in Great Britain to change from the parametric release procedure back to finished product testing as they recognised: “It´s parametric rejection, not parametric release.”. Therefore the choice of critical parameters and their specification must be very well considered.

The key to parametric release of sterility is a compliance to GMP on a high level and a fully controlled and validated sterilisation process which can be achieved by the establishment of a sterility assurance system. The sterility assurance system is in the focus of the pre-authorisation inspection which is required prior to the approval of parametric release. An important part of the sterility assurance system is a suitable risk-analysis of each of its elements, including potential failure modes of equipment and procedures and the potential of human error, e.g. by applying the FMEA model. A consequent risk analysis programme identifying and preventing potential failure modes enables both, to improve quality and to reduce unnecessary costs and resources. Even if this additional requirement for parametric release is not explicitly specified for sterile products in general, it is rational, improve the sterility assurance system and thus could be wise to implement.

It should be taken into account that the implementation of parametric release of sterility might be a project for several years. The compensation of deficits to fulfil the requirements and the following authorisation procedure including the on-site inspection are probably the most time consuming stages of the entire project. If an approval is not achieved in each country of destination, an international oriented pharmaceutical manufacturer can get in difficulties. In this case, the only possible solution is to run both release procedures in parallel and to release batches by sterility testing for the country that has rejected parametric release and by parametric release for those that have approved it.

In most cases, parametric release will be introduced following a variation of an existing market authorisation when more experience has been gained with the manufacture of the product. It is a “major” variation within the EU and a prior approval supplement in the US. The parts of the CTD documentation concerned by an application for parametric release are the Quality overall summary and Module 3. In general, the documentation submitted for a new market authorisation or a variation should contain only those elements of the quality and sterility assurance that are specific for the medicinal product. The quality assurance of elements not specific to the product falls within the field of GMP. Therefore, the grade of detail presented in the registration documentation for application for parametric release of sterilisation must be very well considered.
 
Outlook
This Master thesis has demonstrated that there are still some hurdles that must be taken when parametric release is intended to be established. Right now, parametric release is an alternative to finished product testing. However, I could imagine, that it will be a requirement in the long term due to safety and quality reasons. The increasing requirements on the sterility test, e.g. on the conditions that allow a repeat of a failed sterility test, and the loss of confidence in its worth for the sterility assurance show the trend for a greater awareness of sterility safety. The important thing is that the industry as well as the regulatory authorities are prepared for this time and that a foundation is built by harmonising the international requirements and standards.

Pages:53, Annexes pages 7