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20 October 2003

FDA Requirements on the Qualification of Component Suppliers

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 specifications.
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.

Note: On this point, there is a difference between the GMP requirements in the US and in Europe! Chapter 5 item 30 of the EC GMP Guide requires that "There should be appropriate procedures or measures to assure the identity of the contents of each container of starting material." So the European requirements are much stricter than the American CFR requirements. According to Annex 8 to the EC GMP Guide, for the sampling of starting and packaging materials, in Europe exceptions to these strict rules are possible in case the drug product manufacturer takes the following points into account:

  • The supplier's understanding of the GMP requirements
  • The conditions under which the starting material is produced and controlled

In practice, this means that here it is possible to reduce full identity testing only if an audit has actually been conducted on the site of the manufacturer of the starting material.

Dr Gnter Brendelberger


PS From the FDA's point of view, supplier audits can still help to reinforce the confidence in a supplier. This proof can also be furnished by means of inexpensive third-party audits, i.e. by audits that are conducted by a third person, who has often been engaged by several companies. This opportunity is offered by the APIC Audit Programme at Apart from pharmaceutical companies that can initiate an audit, API manufacturers, too, can order a GMP audit.

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