21 CFR 211 Section 211.84 of the US-American GMP regulations for
manufacturers of drug products lays down requirements for testing and
approval or rejection of components for drug manufacturing.
In the Human
Drug CGMP Notes of the first Quarter of 2001 (which the FDA will mail you if
you request them with reference to the Freedom of Information Act) the
question was asked whether a drug product manufacturer is obliged to conduct
a GMP Compliance Audit on the site of each component supplier.
In the following you will find a summary of the answer given by Brian J.
Hasselbalch from FDA's CDER (Center for Drug Evaluation and Research). Brian
J. Hasselbalch also referred to an earlier statement by the FDA in the Human Drug CGMP Notes
of December 1998.
From the FDA's point of view, it is not mandatory for a drug
product manufacturer to conduct an on-site audit of the manufacturing of a
component supplier. Under 21 CFR 211.84, all lots of all components (API and
excipient) must be tested before use for compliance with the predetermined
On condition that the drug product manufacturer has qualified the supplier,
it is possible to reduce the full testing of each lot of a component
provided that the manufacturer establishes the reliability of the supplier's
analytical test results by means of appropriate validation at appropriate
intervals (21 CFR 211.84(d)(2)). Brian Hasselbalch stresses that validation
of the supplier's test results is achieved through testing and/or
examination - not through audits!
In order to check the reliability of the supplier's test results, the
drug product manufacturer usually performs full testing on the first
lots from a new supplier or of a new component and compares them with the results
recorded in the supplier's Certificate of Analysis. At a later stage, the
CFR requires testing at regular intervals. Within the framework of FDA
inspections, some FDA Inspectors noted a 483 observation when a drug product
manufacturer did not perform this comparison once a year. However, from the
FDA's point of view, this is too narrow an interpretation!
The CFR permits that, once having validated a supplier, the drug product
manufacturer may rely on the supplier's Certificate of Analysis provided
that, in addition, one specific identity test is performed on each lot. In
this way, a supplier validation makes it possible to reduce the scope of the
tests. Alternatively, a drug product manufacturer can waive this
possibility for supplier qualification and instead perform full testing on
each lot of components received.
In general, the FDA welcomes the additional conduct of supplier audits.
An on-site inspection can help to build up greater confidence in the
supplier, which could not be achieved by the mere accuracy of laboratory results. However,
the conduct of audits does not release the drug product manufacturer from
the duty to verify the quality of the components before their use by means
of testing or examination. Notwithstanding this, a validation programme
including audits of the manufacturing of a component supplier can justify a
longer interval until a required revalidation.