The second law of CAPAdynamics
Many warning letters (if not all of them), mention an inadequate response to the FDA Form 483 as the rationale for issuing the letter. The firm’s proposed CAPA is inadequate, as it did not address some concern the agency had following the inspection with regard to patient safety. PIC/s defines a “critical” deficiency as [a 483 observation] that points to “significant risk of producing either a product which is harmful to the human or veterinary patient”. Failing to address this “significant risk” properly leads to the issuance of the letter.
Many of these firm’s to whom these letters are issued have failed to grasp the “laws of CAPAdynamics”. These laws have stood the test of time, and y’all already know, but let’s do a quick refresher! The “1st law of CAPA dynamics” states: ‘responding to the regulator requires CAPA(s), but not all CAPA(s) lead to reduction of risk’. This law is as solid as the First Law of Thermodynamics (my personal favorite), and the failure to address risk is a no-brainer choice for FDA’s Office of Compliance = regulatory action.
The “2nd law of CAPA dynamics” now steps in to address how to objectively reduce risk at the granular level. The second law states: ‘meaningful reduction in the second dimension of risk requires a change in how the work is done’. Clarification of work instructions (or SOPs), or “group awareness training” violates the second law, and should only be used when addressing minor or lower criticality risks. In this blog, we have discussed the two dimensions of risk at length (R = S * V/P), and we know that the severity of any hazard is carved into stone, the only way to reduce it is to eliminate the hazard entirely through major process change. These are generally difficult and may even require regulatory submission (and definitely $$), therefore not always feasible. So we are generally stuck with vulnerability (manual) or probability (automated) as the risk dimensions available for inclusion in the CAPA. Let’s discuss a recent FDA Warning Letter issued on May 27 to the firm Pharmathen International S.A., located in Greece, and involving manual workflows that require an evaluation of the vulnerability dimension (probability is unknown and cannot be used here). The first citation cites failure to adequate manage risk of microbial contamination in sterile products. The FDA lays out the deficiencies in juicy detail, then responds to the firm’s response:
For those of us viewing risk from the regulatory perspective, the gap is obvious. How do any of these proposals objectively address the current risk of microbial contamination? They don’t: they are subjective and require good luck to be effective. The firm was likely calculating the risk using the wrong dimension… probability. A clear violation of the laws of CAPAdynamics!
Remember the 2nd law: ‘meaningful reduction in second dimension of risk requires a change in how the work is done’ – in this case through the lens of “vulnerability”.
Hope you can join us at an upcoming workshop where we dig deeper into the regulatory perspective or risk and how to demonstrate you are on the same page during inspection or within your 483 response!
Pete
