FDA to USP: Sterility is top concern with extended BUDs

Tomorrow, September 15, 2020, the USP will be having a call for comments regarding the appeals related to extending Beyond Use Dates in USP Chapter <795> & <797>.

The primary concerns of the FDA have to do with sterility assurance as related to environmental monitoring, media fills, cleaning procedures and final product testing procedures. I have to agree that for the higher risk compounds (i.e. starting with non-sterile ingredients), <797> doesn’t go far enough for these particular quality assurance controls.  

In conjunction with USP <1116> (Microbiological control and monitoring of aseptic environments) and an additional chapter specifically on what exactly a stability study is I think we’re on the right path to mitigating some of these concerns from the FDA. A chapter designed to outline the exact parameters of what a stability study I believe would be rather simple to create given USP has criteria that they already use for their own USP monographs. I assume they have an internal document that outlines the process and procedures for stability studies on their own monograph compounds. Even the contract laboratory that USP uses for performing their stability studies is one that many compounders already use for their sterility, endotoxin, fungal and potency testing.  

However, USP <797>, as previously stated doesn’t go into detail for specific controls for “high” risk compounds. Another chapter should be created separating out compounding from non-sterile ingredients. A new chapter specific for compounds starting from non-sterile ingredients would heavily concentrate on the sterility assurance aspects of compounding high risk formulations. This new chapter would mimic some of the FDAs guidances for setting up and having the proper quality systems in place to ensure sterility. 

The concerns specifically stated by the FDA in their letter to USP, “the same microbiological controls (e.g., cleaning/disinfecting, personnel qualification, environmental monitoring and media fill frequencies) and microbiological testing procedures (e.g., sterility and bacterial endotoxins) will be used at a given pharmacy to prepare its CSPs,” points to having quality systems (Production, facilities and equipment, laboratory controls, materials, packaging and labeling and quality) in place to ensure the sterility of the compound. While some may say this is pushing us further toward GMP, I wouldn’t disagree, but I think we (compounders) could benefit from learning more about the sterility assurance aspects of compounding. 

There have been several chapters added to the USP compounding compendium (<1228.x>, <1229.x>) that cater to getting compounders on the right track for putting in place some of the controls necessary for depyrogenation, sterilization and the use of biological indicators. USP Chapter <1163> (quality assurance in pharmaceutical compounding) sets some of the standards for what tests need/should be performed based on the dosage forms – an extension of this chapter could perhaps contain the criteria for exactly what a standardized stability study would look like.  

Lastly, there are several internationally (and FDA) recognized guidances and documents that when put together outline the components of a stability study including:  

• FDA Guidance: Expiration Dating and Stability Testing for Human Drug Products
• Guidance for Industry Q1A(R2) Stability Testing of New Drug Substances and Products
• FDA Guidance Container Closure 
• FDA Guidance: Drug Stability Guidelines
• FDA Guidance Q1D Bracketing and Matrixing
• USP <51>Antimicrobial Effectiveness Testing
• USP <1112> Application of Water Activity Determination to Nonsterile Pharmaceutical Products
• USP <71> Sterility Tests
• USP <85> Bacterial Endotoxins Test

Unfortunately, there needs to be quite a bit more discussion and definitely additional chapters written for mitigating all of the FDAs concerns. This should be a priority for the CEC for the 20-25 cycle. In the interim, the current revision of USP <797> could be written to reference the aforementioned guidances in order to allow a path for being able to use stability studies to extend BUDs.

About the author:

Seth DePasquale is a pharmacist and co-founder of LyceumCE.com, a website dedicated to providing innovative training in sterile compounding through a video-based format. Seth is a 2002 graduate of Albany College of Pharmacy in Albany, NY and is a Registered Pharmacist in New York, Kentucky, Michigan, Oklahoma, Texas, West Virginia, Virginia, Alabama, Tennessee, Mississippi, Arkansas, Nebraska, Louisiana and Oregon.