Yes. Extrapolation of an OEL or OEB (lower end of the range) to a preliminary Permitted Daily Exposure (PDE) can be simply done by using the following formula: PDE (µg/day) = OEL (µg/m3) x 10 m3 (the volume air breathed by a worker in 8 hours). Additional adjustment factors may be needed due to potential differences in target population (worker vs patient), route of exposure etc. If the resulting PDE value is 10 µg/day or lower the product should be considered as highly hazardous.
Yes, except in the case of highly sensitising active substances and products.
In such facilities the standard body weight value for adults of 50 kg used for calculating the HBEL should be replaced by a lower body weight value (e.g., children: 10 kg, new-borns: 3.5 kg, prematurely born new-borns: 0.5 kg) and used for HBEL determination for all relevant products in order to reflect the worst case situation.
Inspectors should evaluate the company’s assessment of the competence of their expert in the field by reviewing justification of experience and qualification.
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.