A common observation during FDA inspections is a failure of the drug company to perform incoming testing of raw materials and relying solely upon the suppliers CofA. A common misconception is that I can simply accept the CofA from my supplier with no testing or qualification of the supplier.
This is not acceptable per the cGMPs – as stated in 21 CFR 211.84.d (1-6):
(d) Samples shall be examined and tested as follows:
(1) At least one test shall be conducted to verify the identity of each component of a drug product. Specific identity tests, if they exist, shall be used.
(2) Each component shall be tested for conformity with all appropriate written specifications for purity, strength, and quality. In lieu of such testing by the manufacturer, a report of analysis may be accepted from the supplier of a component, provided that at least one specific identity test is conducted on such component by the manufacturer, and provided that the manufacturer establishes the reliability of the supplier’s analyses through appropriate validation of the supplier’s test results at appropriate intervals.
(3) Containers and closures shall be tested for conformity with all appropriate written specifications. In lieu of such testing by the manufacturer, a certificate of testing may be accepted from the supplier, provided that at least a visual identification is conducted on such containers/closures by the manufacturer and provided that the manufacturer establishes the reliability of the supplier’s test results through appropriate validation of the supplier’s test results at appropriate intervals.
(4) When appropriate, components shall be microscopically examined.
(5) Each lot of a component, drug product container, or closure that is liable to contamination with filth, insect infestation, or other extraneous adulterant shall be examined against established specifications for such contamination.
(6) Each lot of a component, drug product container, or closure with potential for microbiological contamination that is objectionable in view of its intended use shall be subjected to microbiological tests before use.
How common is this? A review of the FY 2018 Turbo data from FDA identified 85 total citations broken down as follows:
During the period of June 8-July 8, there were 3 warning letters published with 21 CFR 211.84(d) cited (The warning letters are linked via the hyper links below):
Firm 1: You purchased components such as bulk homeopathic drug [redacted tablets, and containers and closures from outside suppliers, but you did not test these incoming materials for identity and other quality attributes upon receipt nor had you verified the accuracy of certificates of analysis (COA).
Firm 2: You failed to test incoming active pharmaceutical ingredients (API) and other components you use to manufacture your drug products to determine their identity, purity, strength, and other appropriate quality attributes. Instead, your firm relied solely on the component supplier’s analysis report without establishing the reliability of your suppliers’ analyses through appropriate validation.
Firm 3: Your firm failed to adequately test incoming active pharmaceutical ingredients (API) and other raw materials you use in manufacturing your drug products to determine the conformance to identity, purity, strength, and other specifications. Instead, your firm released API and other materials based on the certificate of analysis (COA) from your supplier without establishing the reliability of the supplier’s analysis through appropriate validation and ensuring at least one specific identity test is conducted for each lot.
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