EMA Releases Q&A on Exposure Limits and Hazardous Compounds

The European Medicines Agency (EMA) on Monday released for public consultation a new question and answer document focused on the risk-based prevention of cross contamination in pharmaceutical manufacturing and setting health-based exposure limits for risk identification.

The 14 questions and answers hone in on specifics such as “Do companies have to establish Health Based Exposure Limits (HBELs) for all products?” (yes), which products or active substances are highly hazardous, how the HBEL model can be applied to early phase Investigational Medicinal Products (IMPs) where limited data is available and whether HBELs need adjustment if pediatric drugs are manufactured in shared facilities with adult and animal drugs.

At the Q&A’s outset, EMA makes clear: “HBELs should be established for all products.”

Evidence that a drug product or active substance falls within any of the following five categories should result in a product being considered highly hazardous, EMA says:

• “Genotoxic (specifically mutagenic) compounds that are known to be, or highly likely to be, carcinogenic to humans. Compounds of this group are easily identifiable, since genotoxicity would be related to the pharmacology, e.g. as DNA alkylating cytostatics, and their use is usually restricted to oncology indications with respective warning statements in the Summary of Product Characteristics.
• Compounds that can produce reproductive and/or developmental effects at low dosages, for example where evidence exists of such effects being caused by a clinical dose of <10 mg/day (veterinary dose equivalent 0.2 mg/kg/day) or dosages in animal studies of ≤1 mg/kg/day.
• Compounds that can produce serious target organ toxicity or other significant adverse effects at low doses, for example where evidence exists of such effects being caused by a clinical dose of <10 mg/day (veterinary dose equivalent 0.2 mg/kg/day) or dosages in animal studies of ≤1 mg/kg/day.
• Compounds with a high pharmacological potency i.e. recommended daily dose of <1 mg (veterinary dose equivalent 0.02 mg/kg).
• Compounds with a high sensitising potential.”

In terms of establishing limits for cleaning purposes, EMA also notes that such limits should continue to be based on risk assessments and additional safety margins to help account for uncertainty in the cleaning processes and analytical variability.

“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 nonhighly hazardous products. For products classed as highly hazardous, where a thorough risk assessment can justify manufacture in shared facilities, cleaning limits should include safety factors beyond the HBEL and should not be higher than the traditional cleaning limits approach,” the Q&A says.

Questions and answers on implementation of risk based prevention of cross contamination in production and ‘Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities’ (EMA/CHMP/CVMP/SWP/169430/2012)