Uncertainty & Assumptions
Failure to perform adequate investigations into "unknown discrepancies" continues to be the #1 cited GMP regulatory observation, year after year, often leading to unfortunate regulatory action (e.g., Warning Letters & recalls). The regulation requires discrepancies to be “thoroughly investigated”, but how thorough is thorough enough? To answer this question, we must reflect through the lens of the modern CGMP. To do this, we need a clean break with the past. Past pitfalls that have led to regulatory problems can generally be attributed to the failure to address and rationalize uncertainty and assumptions that were included in the investigation (scope, root cause, product impact), causing the end result (conclusion & CAPA) to fall short of regulatory and patient expectations.
The modern CGMP Quality System, especially considering the tools outlined in ICH Q9 (R1), does not allow one to:
1. Leave uncertainty unacknowledged, and
2. Include assumptions without acknowledging them as such.
It is perfectly acceptable to be uncertain (in fact it is required in most investigations). It is also perfectly acceptable to include assumptions within an investigation. What is not acceptable, from a regulatory and patient safety standpoint, however, is to pretend that these inclusions are as good as true (or scientifically justified in the same category as fact)! Nope. These are in separate categories, each carrying different weight when it comes time for the final decision to be made. This is a critical fault that we see regularly cited in FDA Form 483s, with wording such as failure to provide “scientific rationale” for the ultimate conclusion & CAPA. Modern QRM tools take all the subjectivity encountered during the course of the investigation and force us to acknowledge what we don’t know. As a result, brilliantly, we can take the subjectivity out of the final conclusion & CAPA. That is how we can deal with uncertainty and assumptions while still ensuring patient safety. Very cool.
ICH Q9 (R1) states that “While subjectivity cannot be completely eliminated from quality risk management activities, it may be controlled by addressing bias and assumptions, the proper use of quality risk management tools and maximizing the use of relevant data and sources of knowledge (see ICH Q10, Section 1.6.1).”
“All participants involved with quality risk management activities should acknowledge, anticipate, and address the potential for subjectivity.”
In conclusion, and as a friendly reminder, transparency is always rewarded in the end. It takes practice and the right tools, but lucky for us, the roadmap for success has already been drawn through harmonized guidance.
Join us this May as we discuss, debate, and work through real-life case studies with the central theme of conducting thorough & scientific investigations that will pass any regulatory scrutiny, and ultimately ensure safety of our patients despite the inevitable: unexpected events.
Let’s go!
Pete
