Whitepaper
27 Oct 2021

Implications of calculating the PDE as the exposure limit for the analysis of risks in shared installations

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In November 2014, the European Medicines Agency (EMA) published the Directive EMA/CHMP/ CVMP/SWP/169430/2012 on the establishment of exposure limits based on health criteria during the manufacture of different drugs in shared installations.In January 2015, the European Commission also revised Chapters 3 and 5 of the EU GMP Guidelines, updating the sections on the prevention of cross-contamination.
These updates entered into force in March of the same year.
Further, Annex 15 of the EU GMP Guidelines (item 10.6) stipulates that "The residual contamination limits of the product must be based on a toxicological assessment".
The dates for implementation of the new EMA Guidelines were June 2015 for new products and December 2015 for existing products (with deferral of these deadlines for a year for veterinary products).
Up until then, the limit values of 10 ppm or1/1000 of the lowest clinical dose were used for cleaning validations. The use of conventional limits translated, on the one hand into excessively restrictive limits for low toxicity products, far exceeding the limits necessary to guarantee patient safety. And on the other hand, the conventional limits did not offer enough protection for products considered to be highly toxic. Up until then, the categories with the highest risks concerned “certain hormones", "certain cytotoxic agents", etc., with no specific criteria.
Release of the EMA Directive implies determining exposure limits in accordance with toxicological criteria, and on the basis of characteristics inherent to each substance.The PDE (Permitted Daily Exposure) is calculated from pharmacological, toxicological and pharmacokinetic data and is similar to the ADE value (Acceptable Daily Exposure) described in the IPSE (International Society for Pharmaceutical Engineering) RiskMaPP.The two values represent the maximum daily dose of a substance that is not likely to cause adverse effects in an individual who is exposed to this dose or to a lower dose, every day throughout their life. In order to facilitate the implementation of these new GMP regulations in the pharmaceutical industry, the Socosur team of toxicology experts launched a project to calculate PDE values for Active Pharmaceutical Ingredients ("API"), as external service provider in January 2015.With an experience that is unique in Europe as a result of having performed the toxicological assessment and preparation of 1200 PDE monographs, we conducted an in-depth meta-analysis of the data obtained.A classification of PDE values was established, identifying 5 groups and allocating a danger level to each of them.
The results were analyzed against the ATC classification (anatomical, therapeutic, chemical) therapeutic groups.

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