Masterstudiengang "Drug Regulatory Affairs"


Background, evaluation, and impact of the new EMA-guideline: "Guideline on setting health base exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities" ***

Sabine Prohl (Abschlußjahr: 2017)

Language: English
Cross-contamination in shared production facilities is a concern. Early approaches in the European Union (EU) to control cross-contamination risks focused on certain types of actives (highly sensitising materials or biological preparations) for which segregated or self contained facilities were mandatory. Also certain product types should not be handled in the same facilities without clarifying this broad wording which led to much room for interpretation. Although cleaning validation studies were requested by the authorities, no clear guidance on how setting safe acceptance limits for such studies were provided. This led to further uncertainties and the use of arbitrary acceptance limits was very common.
On March 1, 2015 the revised chapters 3 Production and 5 Premises and Equipment of the EU Good Manufacturing Practice (GMP) guide came into force. They describe a paradigm change in dealing with cross-contamination issues in multi-production facilities. The revised chapters of the EU GMP guide are based on the principles of a quality risk management process as described in ICH Q9 guideline and require a scientific toxicological evaluation of possible cross-contamination risks in shared facilities for all substances, whereby beta lactam antibiotics are still exempted from these regulations.
That these new requirements can be met, the new guideline Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities was published by the European Medicines Agency (EMA) in November 2014. The effective date of this document was 1 June, 2015 for products newly introduced into multi-product facilities. For products already produced in shared facilities deadline for coming into operation was 1 December, 2015. Here the new guideline focuses on the Permitted Daily Exposure (PDE), whereby the method on deriving this health based approach is based on ICH Q3C Impurities: Guideline for Residual Solvents.
The overall scope of the new EMA-guideline is to ensure the safety of human patients. As cross-contamination poses a risk to public health, the guideline provides assistance on evaluating safe threshold limits for all classes of pharmaceutical substances based on a scientific evaluation of all available pharmacological and toxicological data including pre-clinical and clinical data. Exceptional cases, where a health based-approach is not applicable or only less data are available, are also covered and the EMA-guideline presents additional strategies in dealing with such specific cases.
Based on these calculated threshold limits possible risks can be identified and necessary safety measures established. As cleaning is a risk reducing measure, these acceptance criteria are also used to justify carry over limits used in cleaning validation studies.
The PDE provides increased quality and patient safety compared to the historically used default approaches (visually clean, 10 ppm, and 1/1000 dose criterion). Especially substances with cancerogenic, mutagenic and reprotoxic (CMR) properties were underestimated in the past, because the acceptance limits evaluated by the default approaches led to less strict limits.
Although the EMA-guideline provides recommendations on evaluation and implementation of the new approach, it leaves several areas ambiguous. To achieve the harmonisation requested by the EMA-guideline, further guidance from the authorities is required.
Pages: 70