Specifications and Acceptance Criteria for Impurities: new FDA Principles!

The Office of Pharmaceutical Quality within the FDA's Center for Drug Evaluation and Research (CDER) has published the MAPP (Manual of Policies and Procedures) document "MAPP 5017.2 - Establishing Impurity Acceptance Criteria As Part of Specifications for NDAs, ANDAs, and BLAs Based on Clinical Relevance". This came into force on 18 January, 2018.

The new FDA document provides principles on the determination of specifications and acceptance criteria for non-mutagenic impurities in authorisation applications (NDAs, ANDAs, und BLAs), based on clinical relevance.

Clinically relevant acceptance criteria are defined as a set of acceptance ranges to which an impurity should conform so that the product is save and effective when used as labelled.

While the ICH guidelines Q3A(R2) and Q3B(R2) are to be applied to new molecular entities manufactured by chemical synthesis, the requirements in this FDA document are directed at other active substances and drug products, such as semi-synthetic and fermentation products or synthetic peptides for which the ICH requirements are not directly applicable.

The principles described in this new FDA document may be applied to investigational medicinal products (IMPs) or enantiomeric impurities, for example.

The FDA lists precise requirements on what information a specification must include in case of "specified impurities". The terminology used should be comparable to the ICH guidelines Q3A(R2), Q3B(R2) and Q6A.

Residual solvents and elemental impurities are explicitly excluded since both are sufficiently described in the ICH guidelines Q3C and Q3D and since the limits and specifications in these ICH guidelines are sufficient from the FDA's point of view.

Please also see the complete FDA document "MAPP 5017.2 - Establishing Impurity Acceptance Criteria As Part of Specifications for NDAs, ANDAs, and BLAs Based on Clinical Relevance".