In earlier blogs, we have written about specific technical items related to identity testing.  However, a review of Warning Letters published on the US FDA website for the months of December 2019 and January 2020, revealed three Warning Letters citing instances of failures to perform identity testing of active pharmaceutical ingredients prior to the manufacturing of pharmaceutical drug products. As a result, it seemed to be a good time to re-visit this issue and some previous clear and concise FDA Guidance on the topic of Identity Testing.

The FDA Q&A type guidance we will be briefly summarizing  can be found here.  The specific guidance and references applicable to Identity Testing appear in Items #4 and #15 of the guidance document and should be reviewed in their entirety.

Item #4 of the guidance notes the following, “§ 211.84(b) establishes the principles to be followed in designing a sampling program for components.  The requirements of this section can be summarized as follows:

  • Samples are to be representative of the shipment received.
  • The number of containers sampled as well as the amount of material sampled from each container is to be based on statistical criteria for component variability, confidence levels, and the degree of precision required.
  • The sample program takes into account the past quality history of the supplier.
  • The sample amount is to be sufficient for the necessary analysis and reserve samples.”

Other sections of Item #4 of the guidance discuss the following important elements of an effective identity testing program:

  • The number of containers of each component from each shipment that a firm must sample and test to comply with the CGMP requirements for identity testing.
  • And the question of whether the CGMPs permit identity testing on a pooled (also known as composite) sample of multiple containers

In Item #15 of the guidance, FDA describes the finished drug product manufacturer responsibilities in the CGMP regulations related to another important and often misunderstood aspect of identity testing as follows:

“21 CFR 211.84(d)(2) states that “[E]ach 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.”  Therefore, if the finished drug product manufacturer accepts the test results from an API supplier’s COA rather than performing the tests itself (other than for identity, which the manufacturer is required to perform), the manufacturer must validate the API supplier’s reliability. This validation procedure is established by the finished drug product manufacturer and should be consistent with the principles of CGMP and risk management.”

The absolute most critical concern is that the component/material to be used in any drug product manufacturing process is what it is purported to be.  With the ever-increasing complexity of the pharmaceutical supply chain, the potential for mix-ups of the material at the original manufacturer or at subsequent re-packagers or distributors prior to the component’s arrival at the drug product manufacturing location needs to always be a consideration and should be a key element to the design of an effective Identity Testing process.  The importance of an effective identity testing process is critical to the most important responsibility of the global pharmaceutical industry, the effectiveness and safety of all drug products.