FDA Requirements on the Qualification of Component Suppliers

GMP News No. 355

GMP News
20 October 2003

FDA Requirements on the Qualification of ComponentSuppliers

21 CFR 211 Section 211.84 of the US-American GMP regulations formanufacturers of drug products lays down requirements for testing andapproval or rejection of components for drug manufacturing.

In the HumanDrug CGMP Notes of the first Quarter of 2001 (which the FDA will mail you ifyou request them with reference to the Freedom of Information Act) thequestion was asked whether a drug product manufacturer is obliged to conducta 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). BrianJ. Hasselbalch also referred to an earlier statement by the FDA in the Human Drug CGMP Notesof December 1998.

From the FDA's point of view, it is not mandatory for a drugproduct manufacturer to conduct an on-site audit of the manufacturing of acomponent supplier. Under 21 CFR 211.84, all lots of all components (API andexcipient) must be tested before use for compliance with the predeterminedspecifications.
On condition that the drug product manufacturer has qualified the supplier,it is possible to reduce the full testing of each lot of a componentprovided that the manufacturer establishes the reliability of the supplier'sanalytical test results by means of appropriate validation at appropriateintervals (21 CFR 211.84(d)(2)). Brian Hasselbalch stresses that validationof the supplier's test results is achieved through testing and/orexamination - not through audits!

In order to check the reliability of the supplier's test results, thedrug product manufacturer usually performs full testing on the firstlots from a new supplier or of a new component and compares them with the resultsrecorded in the supplier's Certificate of Analysis. At a later stage, theCFR requires testing at regular intervals. Within the framework of FDAinspections, some FDA Inspectors noted a 483 observation when a drug productmanufacturer did not perform this comparison once a year. However, from theFDA's point of view, this is too narrow an interpretation!

The CFR permits that, once having validated a supplier, the drug productmanufacturer may rely on the supplier's Certificate of Analysis providedthat, in addition, one specific identity test is performed on each lot. Inthis way, a supplier validation makes it possible to reduce the scope of thetests. Alternatively, a drug product manufacturer can waive thispossibility for supplier qualification and instead perform full testing oneach 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 thesupplier, which could not be achieved by the mere accuracy of laboratory results. However,the conduct of audits does not release the drug product manufacturer fromthe duty to verify the quality of the components before their use by meansof testing or examination. Notwithstanding this, a validation programmeincluding audits of the manufacturing of a component supplier can justify alonger interval until a required revalidation.

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

  • The supplier's understanding of the GMPrequirements
  • The conditions under which the startingmaterial is produced and controlled

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

Dr Günter Brendelberger


PSFrom the FDA's point of view, supplier auditscan still help to reinforce the confidence in a supplier. This proof canalso be furnished by means of inexpensive third-party audits, i.e. by auditsthat are conducted by a third person, who has often been engaged by severalcompanies. This opportunity is offered by the APIC AuditProgramme at www.api-compliance.org. Apart from pharmaceutical companies that can initiate an audit, APImanufacturers, too, can order a GMP audit.

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