Can we share Stability Studies?

I received this question this week:

What do you think about sharing a stability study with another pharmacy? Would that be acceptable?

I tried to answer this delicately because I’m not a state inspector, nor do I work for or have an inside track into what the FDA is thinking. In all honesty, my opinion doesn’t really mean a whole lot. However, I was involved in the discussion that was held online with representatives from USP and the FDA. I’ll be sharing some of what was discussed during this meeting in regards to shared stability studies.

There was a letter shared during that meeting from the FDA addressed to USP (the highlighting is my own, not on original letter) regarding the extension of beyond use dates (BUDs). Throughout the letter the FDA cautions the USP from allowing compounders to extend BUDs based on stability studies for a number of reasons including inconsistencies between stability studies (no standard stability study definition), the concern for lack of environmental monitoring and quality assurance pertaining to the sterility of a preparation.

The idea of sharing stability studies, either via a database or just sharing amongst two pharmacies was actually brought up at this USP public discussion forum. While it may seem like a viable option at first in order to make it more feasible for pharmacies to extend BUDs, there are several arguments against sharing stability studies in this manner.

First, all things must be equal. When a stability study is performed it’s done using a particular ingredients, vial, stopper, seal, etc. The container closure part of the study is of utmost importance as this is what separates the inside, sterile, preparation from the outside environment.

Aside from all of the ingredients being the same which has to do with the physical and chemical stability of the product, there’s actually 5 different types of stability we’re concerned with (from USP Chapter <1191> Stability Considerations in Dispensing Practice):

• Chemical: Each active ingredient retains its chemical integrity and labeled potency, within the specified limits.
• Physical: The original physical properties, including appearance, palatability, uniformity, dissolution, and suspendability, are retained.
• Microbiological: Sterility or resistance to microbial growth is retained according to the specified requirements. Antimicrobial agents that are present retain effectiveness within the specified limits.
• Therapeutic: The therapeutic effect remains unchanged
• Toxicological: No significant increase in toxicity occurs

The biggest concern of the FDA in sharing stability studies would be the microbiological stability of products between different pharmacies. This is truly a valid point and concern that the FDA has. Just because all of the ingredients (assuming all are USP grade) and even materials used may be the same, the process controls (i.e. environmental monitoring, personnel monitoring, other in-process controls) may be very different between pharmacies. So the question is, how do we go about getting the sterility assurance we need to perform consistently between locations.

Quality Systems

Throughout the world, there are several manufacturers at any given time making the same product (think generic manufacturers). How is it they’re able to maintain control over their environment equal to or above that of their competitors to the point that the FDA doesn’t have this concern?

Having a more robust environmental monitoring plan and more quality programs in place to ensure that the sterility of the preparation will be the only way to mitigate some of the concerns of the FDA regarding sterility. All of these quality programs I’m referring to:

• Facility and equipment controls
• Laboratory controls
• Materials
• Labeling and Packaging
• Production
• Quality

This is how the FDA inspects all facilities, based on this model of quality systems. What 503A pharmacies really lack is in an overall quality system, materials, facilities and equipment and production systems. But let’s stay on track with trying to mitigate the main concern of the FDA: sterility. A shared environmental monitoring plan with the collection of data and acceptable criteria and limits would NEED to be set by both pharmacies in order to share a stability study. Check out this FDA guidance document to get an idea of what an environmental monitoring plan would look like.

Just to be clear, by having a stability study, that does NOT allow you to bypass end product testing. Sterility, endotoxin, fungal and possibly potency would still need to be done on every batch.

503A vs 503B

One other point that was brought up by John Metcalfe from the FDA, at the USP open forum, was that he sees the ability to extend BUDs as one of the dividing lines between 503A and 503B pharmacies. I actually have a ton of respect for John Metcalfe, he’s extremely pragmatic and he’s up there as being one of my favorite microbiologists (yes, I do have a list of a few – nerd alert); he truly knows what he’s talking about. I’ve had the pleasure of speaking with him on a couple of occasions; he’s professional and very knowledgeable. That being said, I respectfully disagree.

I think there’s a need for 503A pharmacies to be able to extend BUDs and there’s a way to do this safely with the end patient in mind. Not all formulations can be frozen and/or terminally sterilized to get the max beyond use dating (going by the 2019 revision of USP <797>). But in order for costs to make sense and for a pharmacy to operate with efficiency, batch compounding must be done.

Stability Study Guidance

In a previous post I outlined what a stability study looks like and the criteria are publicly available but here’s a few important documents you should take a look at:

• ICH Q1A (R2) – Stability Testing of New Drug Substances and Products
• FDA Drug Stability Guidelines
• FDA Guidance: Container Closure Systems for Packaging Human Drugs and Biologics
• FDA Guidance: Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice

The last guidance in this list gives some direction on what an environmental monitoring program would look like for an operation performing aseptic processing (without terminal sterilization). If you are at all interested in trying to share a stability study with another pharmacy it will be of utmost importance that you read that last document to understand what the expectations of the FDA would be for an environmental monitoring program.

I don’t think this conversation of having shared stability studies is over. I think there’s more to this that’s worth exploring. If we do increase the assurance of sterility by having more robust environmental controls and monitoring, this would only improve the quality of our compounding and at the same time extend our BUDs for the safety of our patients. If the necessary standards were put in place and they were being followed I see a path forward for sharing stability studies between pharmacies.

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