Establishing Health-Based Exposure Limits for APIs in the EU

The  evaluation of risks related to the  carryover contamination of one or more drugs into another during manufacturing is the focus of the European Medicines Agency (EMA) guideline “Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities ”.  In effect since June 1, 2015, the recommendations in this guideline have impact on the manufacture of multiple medicinal products in shared facilities.  This guideline outlines requirements and methods for establishing health-based exposure limits that are to be used when evaluating risks related to the possibility of carryover contamination, with the aim of addressing the safety of human, and animal, patients potentially exposed to residual active substances via medicinal products.  Manufacturers and drug companies need to adhere to the guideline to address  potential cross-contamination of active pharmaceutical ingredients (APIs, or drug substances) for products to be marketed in Europe.  Similar guidelines specific to other regulatory jurisdictions have not been released to date.

The health-based exposure limit for a given API is the permitted daily exposure (PDE) value (also known as the allowable daily exposure, or ADE).  Derivation of a PDE value requires  examination and interpretation of toxicology/safety data, pharmacology (efficacy) data, information on the route of administration, and other considerations.  The PDE value is used to help establish cleaning validation requirements in manufacturing facilities (e.g., maximum allowable carryover values, or MACO values) and to assist with decisions regarding the use of dedicated equipment or facilities for certain APIs.

Drug companies and contract development and manufacturing organizations (CDMOs) need to be aware of the guideline’s expectations regarding data collection and assessment, methods used to derive PDE values, and reporting requirements.