EMA Clarifies Exposure Limits, Risk-Based Models for the Prevention of Contamination in Drug Manufacturing

The EMA is clarifying agency expectations on the implementation of risk-based models and exposure limits to prevent cross-contamination during manufacturing in a Q&A guideline, telling manufacturers that all products should have health-based exposure limits (HBEL).

The Q&A guideline supplements a draft document from 2013 on setting health-based exposure limits to identify manufacturing risks — clearing up what products and active substances the EMA deems highly hazardous and how the HBEL model applies to investigational medicines with limited data and facilities manufacturing both pediatric and adult therapies (DID, Jan. 8, 2013). Furthermore, it spells out the connection between HBEL and GMP requirements and the establishment of cleaning limits.

The EMA identified the following compounds as highly hazardous: genotoxic compounds, such as mutagenic, that are highly likely or known to be carcinogenic to humans; compounds that can produce reproductive or developmental effects at low dosages; compounds that can produce serious target organ toxicity or other significant adverse effects at low doses; compounds with a high pharmacological potency; and compounds a high sensitizing potential.

Exposure limits for investigational medicines should be based on available data and regularly reviewed in case new findings become available, the agency said. Adjustments must be made for pediatric medicines to determine the HBEL. Specifically, the standard body weight for calculating HBEL should be lowered to a value representing pediatric weights, such as 3.5 kg for a newborn or 10 kg for a child.

HBEL can be used to assess a quality risk management process and determine if current organizational and technical control measures meet GMP standards. In the case of new equipment, the model can be used to determine the necessary control measures. The EMA explains that highly hazardous compounds heighten the inherent risk of cross-contamination and more significant organizational and technical control measures will be required.

EMA guidelines on HBEL are not designed to set cleaning limits, but the model can be used to justify those limits, the document said, advising manufacturers to continue relying on the standard approaches, which use risk assessments and safety margins to justify these limits.

Traditional approaches for determining cleaning limits — such as 1/1000th of minimum therapeutic dose or 10 ppm of one product in another product — can be used for non-highly hazardous products, the EMA said. Highly hazardous compounds require safety factor evaluations beyond the HBEL to set cleaning limits, and those limits, should not be higher than a traditional approach.

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