I retired from the FDA about one year ago this summer. I have mixed feelings about my twenty-one years with the Agency, but I mostly reflect back on the good memories and the great people I had the pleasure to learn from and work alongside. I find myself pivoting to my second curve, as popularized in the recent Arthur Brooks book “From Strength to Strength: Finding Success, Happiness, and Deep Purpose in the Second Half of Life.” That’s quite an introduction to this short blog regarding parametric release, and I offer it here as both a book recommendation and an attempt to meet the book’s call for my jump from fluid to crystallized intelligence (i.e., wisdom).
The wisdom I have to impart here is targeted to those sterile drug product manufacturers that are terminally sterilizing drug products and releasing lots by USP <71> Sterility Tests. Specifically, I want to remind you (or bring to your attention) that there is an alternate pathway for drug product release without performing a USP <71> sterility test. This alternate pathway is parametric release, and it applies to the FDA’s NDA, ANDA, BLA, and ANADA applications for drug products sterilized by terminal sterilization. The benefits of releasing drug product immediately versus after the USP <71> fourteen-day incubation period include economic and process efficiency. More importantly, the strategy offers greater assurance that a batch meets sterility requirements versus a lot released by USP <71>.
What is parametric release exactly? The short answer is that the “parametric” in parametric release represents the critical process “parameters” and corresponding acceptance criteria for a validated terminal sterilization cycle that are defined and must be met to release the drug product in place of the USP <71> sterility test. The longer answer is that the FDA has a 2010 guidance that explicitly describes parametric release and the strategy needed to implement it. This guidance, titled Submission of Documentation in Applications for Parametric Release of Human and Veterinary Drug Products Terminally Sterilized by Moist Heat Processes, defines parametric release as a “sterility assurance release program where demonstrated control of the sterilization process enables a firm to use defined critical process parameters, in lieu of the sterility test, to fulfill the intent of 21 CFR 211.165(a), and 211.167(a). Under this strategy, market release of terminally sterilized products can be based upon meeting the defined sterilization parameters and not on performing an approved sterility test.” The guidance can be found here.
As in all things related to perceived free lunches, some may read this and think “it’s too good to be true!” I assure you that many firms have successfully implemented this parametric release strategy and that the steps to FDA approval are not inherently difficult. In my mind, the benefits of this strategy far outweigh the risks. One common perceived risk is the cited guidance statement that batches of drug product that fail any critical process parameter are rejected (unless a reprocessing provision applies), which means that a product batch that fails for parametric release cannot be retested by USP <71>, pass, and be subsequently released. My assessment of this risk is that the sterilization process understanding of a terminal sterilization cycle for parametric release affords greater control and measurable metrics for batch release versus release by a USP <71> sterility test method fraught with known limitations.
My message of “wisdom” is that in the high-stakes world of sterile drug product manufacturing, where patient safety is paramount, many manufacturers already have the terminal sterilization process understanding in place to support a parametric release program. The regulatory expectation in the industry is clearly one of continuous improvement (updated ICH Q9(R1) and EU Annex 1 are recent examples). I would gently offer here that your next Quality Unit meeting considers how to respond to a future auditor who asks, “Why aren’t you releasing terminally sterilized drug products by parametric release?”
If you have read this content and would like to hear more, consider reaching out for an LCS assessment of the practicality of product released by parametric release. We can help with questions regarding submission strategy for parametric release (i.e., a new submission or a prior approval supplement), selection of load monitors, release specification and Certificate of Authenticity (COA) recommendations, and interpretation of the cited FDA guidance narrative. Reach out to us at LCS@LachmanConsultants.com for a consultation.
