News about GMP/cGMP


Finally: EMA’s Q&A on Health-Based Exposure Limits was published

On 30 April 2018, the EMA published the final, revised version of the Q&A document with its focus on setting health-based exposure limits for risk identification and the risk-based prevention of cross-contamination. The Q&A covers 13 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 has been in force since June 2015.

In January 2017, the EMA released a draft for public consultation (we reported). But this paper constituted a roll backwards!

It re-introduced the traditional criteria (such as 1/1000th of minimum therapeutic dose and 10 ppm) for establishing limits for cleaning validation. This contradicts the original scientific approach of establishing health based exposure limits. The need for a toxicological evaluation was introduced into the EU GMP Guide just because the traditional criteria are not scientifically based.

In June 2017, the EMA held a workshop with participants from industry and authorities. During the workshop it became clear that nobody is happy with the newly introduced differentiation between highly hazardous products and others as well as with the re-introduction oft he traditional criteria. The outcome was that the Q&A has to be finally revised.

What‘s in the new version?

  1. Health-Based-Exposure Limits (HBELs = PDEs) should be established for all medicinal products. The toxicological or pharmacological data, on which the HBEL calculation relies, requires periodical re-assessment throughout a product’s lifecycle.
  2. broad hypothetical model (Source: ISPE Baseline® Pharmaceutical Engineering Guide, Volume 7) could be considered to show the increasing level of hazard presented by products and there should be a commensurate increase in the level of control to prevent potential cross contamination in a shared facility. PDE values <10µg/day represent the highes risk and PDE values >10000µg/day the lowest. Actual PDE values should be used in QRM studies to determine the actual controls required.
  3. Once the health-based assessment has been completed and the PDE confirmed, these data should be used via a Quality Risk Management process to determine what controls need to be put in place and to assess if existing organisational and technical control measures are adequate or if they need to be supplemented.
  4. PDE reports should be determined by a person who has adequate expertise and experience in toxicology/pharmacology, familiarity with pharmaceuticals as well as experience in the determination of health-based exposure limits such as Occupational Exposure Levels (OEL) or PDE. Where experts are contracted to provide the HBEL, contractual agreements in compliance with Chapter 7 requirements should be in place prior to work being conducted.
  5. What responsibility do contract givers have to contract manufacturers in relation to data to support a HBEL assessment? Contract givers should either provide a full HBEL assessment to contract manufacturers or provide the data to allow the contract manufacturer to conduct the HBEL assessment. In either case the HBEL assessment, including data references and relevant experts should be available on request during inspection of the manufacturer.
  6. Limits for cleaning purposes can be established based on the PDE value, but should not be identical with it. For existing products, manufacturer’s historically used cleaning limits should be retained and can be considered alert limits provided that when taking cleaning process capability into account, they provide sufficient assurance that excursions above the PDE will be prevented.
  7. Analytical testing is expected at each changeover unless justified otherwise via a robust, documented Quality Risk Management (QRM) process.
  8. Visual inspection: Manufacturers should establish the threshold at which the product is readily visible as a residue. This should also take into account the ability to visually inspect the equipment, for example, under the lighting conditions and distances observed in the field. Visual inspection should include all product contact surfaces where contamination may be held. Non-product contact surfaces that may retain product that could be dislodged or transferred into future batches should be included in the visual inspection.
  9. Manufacturers cannot just segregate common products from other product types as a means of dealing with the risk to patient and animal safety. Although this may prevent contamination of other product classes it does not address the possibility for cross contamination within product classes.
  10. The LD50 is not an adequate point of departure to determine a HBEL for drug products.
  11. If a PDE cannot be determined or data cannot support manufacture in shared facilities then the Ectoparasiticides should be manufactured in dedicated facilities.
  12. Veterinary Medicinal Products: The guideline on setting health-based exposure limits indicates that the carry over limit should generally be derived using the human PDE. However, in cases where there is concern relating to known susceptibility of a particular species (e.g. monensin in horses) the HBEL approach should take into account knowledge of specific animal toxicity when evaluating products manufactured in shared facilities/equipment.
  13. PDE values should be established based on all available data, and particularly as the knowledge base for Investigational Medicinal Products (IMPs) is continually evolving the basis for establishing the PDE, should be regularly reviewed taking account of any new relevant data.


EMA – What’s New?