Archives: FAQs

Once the health based assessment has been completed and HBEL confirmed, these data should be used via a Quality Risk Management process to assess if current organisational and technical control measures are adequate, or in the case of new equipment/facility to determine what control measures are required. It is expected that the higher the hazard of products/active substances, the higher the inherent risk and the more significant organisational and technical control measures will be required. Health based exposure limits provide an accepted safe level of cross contamination and they should be used to justify cleaning limits.

Although the EMA guideline (EMA/CHMP/CVMP/SWP/169430/2012) may be used to justify cleaning limits (To recommend an approach to review and evaluate pharmacological and toxicological data of individual active substances and thus enable determination of threshold levels as referred to in the GMP guideline. These levels can be used as a risk identification tool and can also be used to justify carry over limits used in cleaning validation.), it is not intended to be used to set cleaning limits at the level of the calculated HBEL. 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 HBEL will be prevented. A similar process should be adopted when establishing cleaning alert levels for products introduced into a facility for the first-time. Results above the alert cleaning limit should trigger an investigation and, where appropriate, corrective action to bring the cleaning process performance within the alert cleaning limits. Repeated excursions above the alert cleaning limit will not be considered acceptable where these indicate that the cleaning method is not in control. Recognised appropriate statistical methods may be used to determine whether the cleaning process is in control or not.

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. This should include implementation of appropriate organisational and technical control measures to prevent contamination between such products within product specific HBELs.

Health-Based Exposure Limits should be established based on all available data, and particularly as the knowledge base for IMPs is continually evolving the basis for establishing the HBEL, should be regularly reviewed taking account of any new relevant data.

Health based exposure limits should be established based on all available data and as such assessments associated with IMPs should be regularly reviewed for presence of new data. Toxicology experts should also make judgments about the future potential of the material to demonstrate critical effects where key toxicological testing has not been completed (e.g. this may be based on comparison to other similar molecules where available) and any additional adjustment factors that may be appropriate. This would allow manufacturers to assume worst case and make sound judgments on the level of organisational and technical control measures required.

The aim of determining a health-based exposure limit is to ensure human safety, and consequently it is considered that good quality human clinical data is highly relevant. Unintended pharmacodynamic effects in patients caused by contaminating active substances may constitute a hazard thus clinical pharmacological data should be considered when identifying the critical effect. Consideration should be given to what extent the active substance in question has been associated with critical adverse effects in the clinical setting. If the most critical effect identified to determine a health-based exposure limit is based on pharmacological and/or toxicological effects observed in humans rather than animals, the use of the PDE formula may be inappropriate and a substance-specific assessment of the clinical data may be used for this purpose.

Toxicology being an inter-disciplinary science, an understanding of the physiology, biochemistry, pathology, endocrinology, pharmacology, clinical pharmacology, genetics, etc., is a must in order to make an integrated assessment of findings of toxicology studies and to identify potential signals from the clinical studies. Masters or PhD degree in the area of toxicology, veterinary medicine, human medicine, pharmacology etc. represents a relevant qualification that teaches these subjects. The depth and breadth of toxicology subjects covered in these courses vary. Certification by professional bodies in the field of toxicology is an endorsement of a person’s relevance of qualification and experience in the field of toxicology. Some of these certifications are based on successful completion of a written examination (ex: Diplomate of American Board of Toxicology), while others may be based on relevance of qualification and demonstration of actual practice of toxicology, and adequacy of experience in the toxicology field (ex: European Registered Toxicologist). In summary, the most critical attribute that a person should process in order to be able to derive a PDE is combination of relevant educational qualification, understanding of basic science of toxicology, and adequate experience in the field of toxicological risk assessment.

Health-Based Exposure Limits 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 Permitted Daily Exposure (PDE).

No, LD50 is not an adequate point of departure to determine an HBEL.

Yes, HBELs should be established for all products. HBELs for highly hazardous products are expected to be completed in full as per the EMA guideline (EMA/CHMP/CVMP/SWP/169430/2012) or equivalent.