New FDA Guidance on Impurities in APIs for Generics

In June 2009, FDA's Office of Generic Drugs published the first revision of the "Guidance for Industry ANDAs: Impurities in Drug Substances", which replaces the first version of this guideline of November 1999. The change became necessary mainly due to the revision of the ICH Guideline Q3A in 2003. The FDA starts from the fact that a great part of the contents of Q3A(R) also applies to the registration of generic medicinal products in the USA (ANDAs).

The guideline includes revised recommendations on the CMC (Chemistry, Manufacturing, and Controls) information that has to be submitted in the listing, identification and qualification of impurities in active pharmaceutical ingredients (APIs) manufactured by chemical synthesis. This applies to:

  • ANDAs (Abbreviated New Drug Applications)
  • Drug Master Files (DMFs) including Type II DMFs
  • Supplements to ANDAs if changes have been made to the synthesis or processing of an API

The guideline also includes recommendations for defining acceptance criteria for impurities in APIs.

The FDA recommends that the specifications of an API should include a list of impurities. Stability studies, chemical development studies and the analytical results of routine batches can be used for predicting these impurities, which will probably occur in the final product. In this context, it is important that these impurities were found in batches produced by exactly the same manufacturing procedure as the products that will later be marketed.

The specifications of an API should include a list with the following types of impurities:

Organic impurities:

  • each specified and identified impurity
  • each specified and unidentified impurity
  • each unspecified impurity with an acceptance criterion "less than" that does not exceed a certain limit
  • the sum of all impurities

Residual solvents
Inorganic impurities

Further topics of this guidance for industry are the questions of how to define the acceptance criteria for impurities and how to qualify impurities. Here the text mentions that toxicity testing is the least preferred method for the qualification of impurities.

The complete document can be found here:

Dr Günter Brendelberger
On behalf of the European Compliance Academy (ECA)

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