The cited NDA–ANDA guidance focuses on the potential effect of process changes on the drug product. The following excerpt
provides insight into FDA's general expectations but, unfortunately, does not offer quantitative criteria to be satisfied:
When testing is performed, the applicant should usually assess the extent to which the manufacturing change has affected the
identity, strength, quality, purity, and potency of the drug product. Typically this is accomplished by comparing test results
from pre- and post-change material and determining if the test results are equivalent. Simply stated: Is the drug product
made after the change equivalent to the drug product made before the change? An exception to this general approach is that
when bioequivalence is re-documented for certain ANDA post-approval changes, FDA recommends that the comparator be the reference
listed drug. Equivalence comparisons frequently have a criterion for comparison with calculation of confidence intervals relative
to a predetermined equivalence interval. For this, as well as for other reasons, equivalent does not necessarily mean identical. Equivalence may also relate to maintenance of a quality characteristic (e.g., stability) rather than a single performance
of a test (3).
Elsewhere in the NDA guidance, equipment elements are discussed in terms of their influence on bioequivalence. The following
passage appears later in the same NDA guidance:
Minor Changes (Annual Report)—The following are examples of changes considered to have a minimal potential to have an adverse
effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety
or effectiveness of the drug product.
1. For drug products, changes to equipment of the same design and operating principle and/or changes in scale except as otherwise
provided for in this guidance (3).*
This reference is actually more flexible, in that it does not use the word "identical," but only mentions shared design and
operating principles. Thus, equivalence in equipment may be more accepted than is ordinarily recognized. It may embrace different
vendors, and sometimes encompasses different sizes of equipment.
Additional statements about equipment equivalence appear in various sterilization documents from the International Organization
for Standardization. These statements are relevant for medical devices, but pharmaceutical and biotechnology firms seem rarely
to consider them (5, 6). Nevertheless, the clear consensus is that demonstrating equivalence as it relates to process equipment
is acceptable to regulatory authorities. But current guidances or standards that discuss equivalence lack a clear set of expectations
for the demonstration of equivalence between multiple equipment units. The NDA and ANDA guidance document cites bioequivalence,
but usually in terms of testing product that is many steps removed from where equivalence is being sought. The effect of essential
unit operations such as sterilization, cleaning, and early process steps on bioequivalence is difficult, if not impossible,
to discern. For these applications, one must consider how equivalence might be demonstrated independently of bioequivalence.
Moreover, as stated consistently in the NDA–ANDA guidance document, bioequivalence is unlikely to be influenced meaningfully
by equivalent, if not actually identical, equipment.
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