ICH Q7 refers to the need to establish the impurity profile for an active pharmaceutical ingredient (API). It says:

“An impurity profile describing the identified and unidentified impurities present in a typical batch produced by a specific controlled production process should normally be established for each API. The impurity profile should include the identity or some qualitative analytical designation (e.g., retention time), the range of each impurity observed, and classification of each identified impurity (e.g., inorganic, organic, solvent).”

This also applies to the impurity profile of a drug product, where the firm needs to demonstrate an understanding of what impurities are sourced from the API versus those that are drug product degradants arising from manufacturing and/or on stability. ICH Q3B(R2) states:

“The impurity profiles of the batches representative of the proposed commercial process should be compared with the profiles of batches used in development and any differences discussed.”

ICH Q3B goes onto state that any degradation product observed in stability studies should be identified when present at a level greater than the identification threshold. A drug product’s impurity profile is integral to the Quality Target Product Profile (QTPP) and would naturally be identified as a Critical Quality Attribute, where there needs to be an understanding of the expected impurity profile that is afforded from the validated manufacturing process where impurities are known to originate from the API (as related substances) or degradation products. As such, it is critical to know how process parameters and material impact the impurity profile and then accordingly what control strategy is being employed to ensure that the impurity profile meets the established QTPP requirements.

A natural question to ask would be, how do I know whether my control strategy is proving to be effective towards the materials impurity profile requirements? Naturally, one would state that, if my material meets specification requirements, then all is good. However, it is recommended that one considers the capability of the analytical procedure and, as such, an impurity that is observed above the method’s Quantitation Limit (QL) that is not expected (based upon the known impurity profile that was established as part of process validation), be it as part of release or stability, should not be ignored, even if it below the specification. An investigation should be initiated to identify said impurity and determine the source and, thus, the cause for the presence and the associated product quality/patient risk. Therefore, it is imperative that, when evaluating manufacturing process changes (including the sourcing of new incoming material/component suppliers), the impact to the qualified impurity profile is a key element that must be assessed as part of change management.

One of the critical lines of defense to ensure that unexpected impurity profile results are being self-identified by the firm (and not being pointed out during an Agency inspection!) is to ensure that analysts are aware of the qualified, expected impurity profile for that commercial product. This is where some firms will attach the expected impurity profile at the time of release and on stability with respective impurity labels to the test procedures and have profile templates within LIMS. Such approaches should also be considered for in-process testing. The goal is to have the analysts familiar with the expected impurity profile for the manufacturing process from incoming release through product release and stability such that there is a confidence that anything “unexpected” will be known and addressed with an investigation. 

If you have any questions relating to tracking/monitoring impurity profiles and developing associated controls, Lachman Consultants can help you! Please contact Paul Mason at p.mason@lachmanconsultants.com for support with this critical undertaking.

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Paul Mason, Ph.D., is a Senior Director at Lachman Consultants who has 20+ years of experience in the pharmaceutical industry. He is a Quality Control chemist experienced in sterile parenteral, API, and solid oral dosage forms. His experience spans finished dosage form, CMOs, and API (intermediates) manufacture support in both a Quality Control and Analytical Development setting. Dr. Mason possesses a deep understanding of business strategy relating to drug research, development, quality assurance, quality control, CMC submissions, laboratory design, clinical and pre-clinical quality/analytical development support. In addition, he has provided expert scientific support for the timely resolution of complicated scientific issues raised by FDA application reviewers.