Final Guidance on Listing Drug-Substance Impurities in ANDAs

The US Food and Drug Administration last week posted the final version of its Guidance for Industry, ANDAs: Impurities in Drug Substances. The document provides agency recommendations for establishing acceptance criteria for impurities in drug substances. It also provides recommendations on the chemistry, manufacturing, and controls (CMC) information to include the reporting, identification, and qualification of impurities in drug substances produced by chemical synthesis in abbreviated new drug applications (ANDAs), drug master files, and ANDA supplements.

According to the guidance, FDA recommends a list of impurities (i.e., organic, inorganic, and residual solvents) be included in the specifications for a drug substance. The submission should also include a rationale (including an impurity profile) for the inclusion or exclusion of impurities in the drug-substance specification. The guidance also provides guidance on the information regarding specified impurities; that is, individual impurities (identified and unidentified) for which a specific acceptance criteria has been established and included in the drug-substance specification.

When establishing acceptance criteria for an impurity, FDA recommends companies should first determine whether the US Pharmacopeia includes a limit for a specified impurity. If the level of a specified impurity is above the level provided in USP, “appropriate qualification” should be conducted. Qualification is also recommended when the specified impurity is not listed in USP.

As stated in the guidance, an impurity is considered qualified when it meets one or more of the following conditions:

• The observed level and proposed acceptance criterion for the impurity do not exceed the level observed in the reference listed drug product

• The impurity is a significant metabolite of the drug substance

• The observed level and the proposed acceptance criterion for the impurity are adequately justified by the scientific literature

• The observed level and proposed acceptance criterion for the impurity do not exceed the level that has been adequately evaluated in toxicity studies.

Further information regarding qualification thresholds and procedures are provided in the guidance.