The New FDA Guideline on Impurities in Generics

In the middle of July, the FDA published a revised guideline with the title "ANDAs: Impurities in Drug Substances". This guideline takes the place of the corresponding document issued in November 1999. Due to the revision of the ICH Guideline "Impurities in New Drug Substances" (Q3A(R)) in 2003, the FDA deemed it necessary to revise the corresponding guidance for generics, too, since the Agency takes the view that the principal contents of Q3A(R) can equally be applied to generics.

The guideline includes provisions regarding the question which pieces of information have to be submitted on impurities of chemically synthesised active pharmaceutical ingredients (APIs) in

  • applications for a marketing authorisation for a generic drug (ANDAs)
  • Drug Master Files (DMFS) including Type II DMFs and
  • supplements to an ANDA due to changes in the manufacturing process of the API

The main requirements of the revised guidance are as follows:

Listing all impurities
This list is meant to be created on the basis of impurities found in the batches manufactured by the commercial process indicated in the dossier. Specified as well as unspecified impurities, residual solvents and inorganic impurities have to be listed together with a critical discussion of the impurity profile.

Setting acceptance criteria for impurities
For any occurring impurity, it has to be checked whether the impurity has already been specified in the USP. If this is the case, the acceptance criterion should not be set higher than the one mentioned in the official monograph. If no limit exists for a specified impurity in the USP, the impurity has to be qualified.

Qualification of impurities
An impurity is considered qualified if

  • its level and the indicated acceptance criterion do not exceed that of the reference medicinal product
  • it can unmistakeably be traced back to the API
  • its level and the indicated acceptance criterion are adequately justified by scientific literature
  • its level and the indicated acceptance criterion do not exceed the limit determined by means of toxicological studies

The guidance includes a well-structured decision tree illustrating the different scenarios and the consequences resulting from them, e.g. the necessity to qualify an impurity.

The original new guidance document can be found here.

Author:
Dr Gerhard Becker
On behalf of the European Compliance Academy (ECA)

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