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FDA Warning Letters and Form 483s can offer a path to better compliance, says Siegfried Schmitt, vice president, Technical, at Parexel.
Q: FDA publishes redacted Warning Letters and Form 483s with inspection observations on their website. What can we learn from these, and where do we need to be cautious?
A: Such information can be considered compliance intelligence (i.e., it forms part of the pool of information a company relies on to build an appropriate quality management system, design its systems and operations in such a way that they adhere to the regulations and deliver a product that meets its predetermined quality attributes, and to build and staff their organization adequately). Regulations and laws are limited in their comprehensiveness, which means that there are many possible ways for companies to achieve compliance. Sometimes, the appropriateness is challenged or found defective in inspections by regulators, and this will lead to observations on FDA’s Form 483. In cases where FDA finds that the shortcomings are not addressed sufficiently and completely, the agency may issue a Warning Letter (WL). These are meant to be a last warning (1,2).
Clearly, any company can learn from mistakes made by others, helping them to prevent making the same mistakes. To understand the benefits and limitations of the learnings from WLs and form 483s, we need to look at what information they contain, or not. An observation on Form 483 may read like this: “Your media fills failed to accurately simulate commercial operations. Our inspection found the aseptic operations simulated during your media fills were not sufficiently representative of commercial aseptic manufacturing operations for (b)(4). For example, the type and frequency of manual interventions was not representative.” What we can learn from this is that media fills must be as similar as possible to normal aseptic operations.
However, there are many things that we do not know, such as:
It is very unlikely that a reader of the FDA observation will have the answers to these questions. Yet, this is not necessary. It is important to understand the context of the observation and appreciate its seriousness. Then you need to ask the above questions about your operations, about your media fills. That is the real value that you will gain from these regulatory observations.
Vol. 36, No. 7
When referring to this article, please cite it as Schmitt, S. The Inspection Result: Warning Letters and Form 483s. BioPharm International 2023 36 (7).