21-23 September 2021
The British inspectorate MHRA has recently published an interpretation that goes into detail on the use of health based exposure limits and explains the cases where EMA's new concept can be applied. One essential element of that concept is EMA's Q&A Paper describing when a product should be classified as highly active.
After the revisions of Chapters 3 and 5 of the EU GMP Guide in 2015, more attention has been given to the topic cross contamination. At the same time, a guideline of the EMA was published introducing the concept of PDE values. Those health based exposure limits should be used to assess whether a product can be produced in a dedicated or in a multipurpose facitility. The background for that was the request of the pharmaceutical industry to be able to decide itself on a risk-based approach whether a product can be produced in a multipurpose facitility, or not. Previously, there was a rather inconclusive list requiring a dedicated facility e.g. for special products, special cytototix products or hormones. Because the 1/1,000 dose criterion used so far isn't really scientific and therefore not very suitable for a risk-based approach, the EMA introduced the PDE concept. This has led to some discussion as the calculation without toxicological/pharmocaological data and knowledge is not so clear-cut.
Now, the MHRA states that the full use of EMA's guide for the calculation of the PDE values is only necessary for so-called "highly hazardous" products. To answer the question whether a product is highly hazardous or not, one can refer to the new Q&A document of the EMA. Nevertheless, one should keep in mind that the assessment of hazard by means of EMA's paper, scientific data are also required which would also enable the calculation of the PDE limits.
However, Health Based Exposure Limits (HBELs) should be determined for all products. If a product is classified as not "highly hazardous", the 1/1,000 dose criterion can still be used. Now the question remains why the MHRA has published its interpretation before the final adoption of EMA's Q&A document. Generally, the cleaning limits calculated by means of the 1/1,000 dose criterion are more conservative than when using the PDE value as a basis.
EMA's Q&A document is currently at the draft stage. Comments can be submitted until the end of April to the EMA.
Faclilitating the understanding of the procedure of the development of the new values which should be used for the cleaning validation, for example, is the goal of an industrial guidance document - provided at the ECA Training Course Cross Contamination from 5-6 April in Heidelberg. There you will also train the calculation of ADE/PDE values in a workshop.