The Inspection Result: Warning Letters and Form 483s

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:

• The reason for that behavior:
  • Did the company apply a risk-based approach that was not acceptable to the inspectors, or was it simply that the company decided to do less during the media fills?
  • Were the operators following the protocol or did they deviate?
  • Did the protocol provide sufficient clarity and detail or did the company rely on the experience of the operators?
  • Is there an appropriate quality culture in that company?
• Level of competency:
  • Were operators and managers insufficiently trained or aware of the regulations, or were they knowingly ignorant?
  • Was there adequate quality oversight or not?
  • Was this the first time, the company performed media fills?
• Complexity of the operation:
  • Does the operation require many different manual interventions or only a few?
  • Did this happen throughout the media fill or perhaps only during start-up, or perhaps only one of the shifts, or perhaps only with some of the media fills?

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.

References

1. FDA. ORA FOIA Electronic Reading Room. FDA.gov (accessed June 7, 2023).
2. FDA. Warning Letters. FDA.gov (accessed June 7, 2023).

Article details

BioPharm International
Vol. 36, No. 7
July 2023
Page: 42

Citation

When referring to this article, please cite it as Schmitt, S. The Inspection Result: Warning Letters and Form 483s. BioPharm International 2023 36 (7).