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EMA: Q&A-Draft on Exposure Limits

The EMA has released a Q&A draft document with its focus on setting health-based exposure limits for risk identification and the risk-based prevention of cross-contamination. The draft covers 14 questions and answers relating to the “Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities”, which was published in November 2014 and has been in force since June 2015.


The Q&A document provides detailed information on questions as:

  • Do companies have to establish Health Based Exposure Limits (HBELs) for all products?
  • What products/active substances are considered to be highly hazardous and why would they benefit from a full toxicological assessment?
  • Can calculation of HBELs be based on clinical data only?
  • Is the use of LD50 to determine health based limits acceptable?
  • How can limits for cleaning purposes be established?
  • What role do HBELs play in meeting the requirements of GMP Chapter 5 section 20?
  • Is it acceptable to simply segregate highly hazardous products in a dedicated area as a means of controlling risk of cross contamination?

The core message of the EMA is clear: HBELs should be established for all products. This is directly clarified in Question 1. A distinction is made between highly hazardous products (Question 2) and products that do not fall into this category (Question 4). Besides the definition five categories of highly hazardous products are listed. For those products, a complete toxicological profile according to the PDE-guideline should be established. The HBELs of all other products can be based on clinical data. If a product is well established and has a favourable therapeutic index, HBELs based on the 1/1000th minimum therapeutic dose approach would be considered as sufficiently conservative and could be utilised for risk assessment and cleaning purposes.

LD50 is not an adequate point of departure to determine an HBEL (Question 5).

Especially notable is Question 6 regarding cleaning validation, which brings traditional cleaning limits back into play. Originally, seen in connection with the new approach of Annex 15 and the PDE-guideline, those were regarded as obsolete. According to the answer to Question 6 cleaning limits should not only be established by means of PDE-values but also by a risk based approach and additional safety margins. Traditional cleaning limits used by industry such as 1/1000th of minimum therapeutic dose or 10 ppm of one product in another product, may accomplish this for non-highly hazardous products.

The Q&A draft is open for public consultation until 30 April 2017.


EMA: Questions and answers on implementation of risk based prevention of cross contamination in production



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