Equivalence Criteria of Impurities for API Process Validation

Recommendations and Rationales
For validation of a process to prepare a new API, the impurity profile should be comparable
to or better than the profile determined during process development, or for batches used for
clinical or toxicological studies. For evaluation of a newly developed or modified process to
prepare an API that is already commercially distributed, the comparison provides assurance that
the process produces material that is equivalent to (or better than) acceptable material prepared in
the past by an existing process, with respect to impurities.
The need to evaluate equivalence for isolated process intermediates should be considered on
a case-by-case basis.
For some validations, insufficient reference batches are available for a meaningful comparison.
Meeting established limits is considered adequate for the equivalence comparison in these
situations. For other validations, the availability of adequate reference batch data makes the use
of statistical acceptance criteria more desirable because it enables comparison of the validation
batches to established process capability data.
A. Selection of appropriate reference batches:
1. New Products (new API or intermediate process at first manufacturing site)
Batches prepared during process development should be selected. These may include
batches prepared in Production equipment, and those prepared at laboratory and pilot
scale. They should be batches made by the same process and may include pivotal
clinical batches, and those used for toxicological and/or stability studies. In many
cases, the number of acceptable development batches may be relatively small.
2. Existing APIs
a) Major changes undergoing revalidation, or first-time validation 􀂱 Reference
batches should be selected from plant batches prepared prior to the validation to
be performed.