With increased enforcement of <797> standards by State Boards of Pharmacy (SBOP), pharmacies may have to adjust their BUDs. While the current version of <797> makes reference to using <795> to establish BUDs if there are no references or data available, this will soon change in the next revision slated for release/enforcement December 2019 (may depend on your State).
In my own experience in trying to learn exactly what a stability study was I’ve found a little bit of conflicting information. However, there are some good resources out there that point out exactly what criteria is necessary for a valid stability study (see references). After all, if you’re going to put up the money for one of these it’d be nice to only have to do it once. Let’s focus on what exactly a stability study entails and why they’re so expensive.
The key to what a stability study is and isn’t has much to do with whether a stability indicating assay is being used. A stability indicating assay in simple terms uses forced degradation (usually heat) of your product to determine if any excipients or by-products will alter the way the assay is able to detect the drug. If you’ve had any chemistry classes you may remember chromatography (if you’re like me, nope!). If not, check out this video from Kahn academy or this post (also from Kahn academy). The basic “need-to-know” is that you need to figure out if anything in the product will affect the assay for detecting your main ingredient (the API). And again, just to repeat the main point: you need to force the degradation of your product. This is the key difference between a true stability study and what’s called a potency over time study. Potency over time is literally just that: you’re detecting the potency of the product over time. This unfortunately is NOT stability indicating and does not pass muster for extending beyond use dates.
If you’re looking to extend your BUD to 180 days you would want to pick time points that would allow you to see if the product is going to degrade at any points in between zero and 180. Typically you’d perform testing at 0, 14, 30, 60, 90, 120, 180. Using 30 day intervals (after day 30) would ensure that if you start to lose potency at day 90 and don’t make it to 120 you can stop the study at that point and you’d still be able to claim your dating for 90 days. It’s recommended to do a minimum of 5 time points in any study to determine linearity.
Some other components of a stability study may include: pH, potency, container closure integrity, particulate matter, sterility and endotoxin. Do these all need to be done at every time point? Maybe not. You may be able to do an initial and final for some of these. However, keep in mind if any of the key factors fall out of spec (sterility, endotoxin, potency) you will not be able to claim the dating. The point here is that you should think carefully about which tests to include at each time point while trying to minimize costs; unfortunately that’s a fine line to walk. Be conservative, but smart about what may affect the stability of the product (pH would be one that you may consider doing at each time point).
If you have multiple vial sizes for your product (10 and 30 mL vials) you may consider cutting that down to one; each of these would need to have it’s own stability study done because the containers are different and may affect the stability of the compound.
If you have multiple strengths of the same product consider bracketing. This simply involves doing a stability study of the highest concentration and lowest concentration; with all other factors being equal (the vial, closure, excipients must all be the same). Again, with all things being equal you can claim stability of all of the strengths in between your two extreme concentrations.
One last recommendation is to consider using 3 lots of product for your stability study. This will show that your stability study wasn’t just a one time fluke and was able to be repeated not once but on two additional occasions, hopefully with similar results.
Why do they cost so much? (Ice Cube sit tight)
There’s actually quite a bit of work involved in validating each of these methodologies. First, if you’ve been doing sterility testing and claiming USP <71> compliance you more than likely have method suitabilities on file for those products. If not, you’ll have to have this done; this typically costs between $400-600 (depending on the lab, check out THIS POST to learn about method suitability). In addition, the lab will need to validate methodologies for testing endotoxin, potency and antimicrobial effectiveness (USP <51>). Just like I stated above the reasoning for testing 3 lots; to validate each of these methodologies they need to be repeated multiple times in order to design a validated method.
If you’re looking to perform a stability study on a single ingredient product for 6 month to 1 year dating the cost will more than likely be over $10,000. This is highly dependent on the lab you choose and which tests you select to perform at each time point. I’ve tried to lay out in simple terms the absolute minimum that’s required to claim and defend your beyond use dates against any board of pharmacy that may inspect your pharmacy. More importantly you can assure your patients that the product has the stability that’s claimed on the label with scientifically backed data. The quicker we adopt this kind of mindset, the more legitimate we look.
If you’re really looking to get this done here’s how I would assess my operation, there are a couple of options:
- 80/20 rule: this is key and I truly believe this holds true in almost any business: 80% of your revenue is generated by 20% of your products. I encourage you to do the math, you’ll be surprised! For my own business this comes down to 4 compounds, we could literally stop making everything but these 4 products and we’d maintain 84% of our revenue. I was baffled when I realized this.
- Keep in mind that if you have multiple vial sizes you need to perform stability studies on each vial size. Are each of these necessary to have for your business? Cut the fat if possible.
- Start sooner rather than later: these studies can take quite a while to develop and perform; start with your most profitable products. Depending on your SBOP, their enforcement may be gentle at first but I’m guessing will get more strict the closer we get to December 2019 (<797> revision). While there’s most likely a grace period for enforcement of the revision most of this we should’ve been following for quite some time. If you’re not doing sterility testing at all and extending BUDs: I STRONGLY caution against this. Boards are starting to take this VERY seriously (arguably they should’ve been doing all along!) Check this article from Drug Topics about a VT pharmacist and pharmacy that lost their licenses. Here’s what the State of VT wrote up. If you’re claiming not having to do sterility testing because you’re doing batches of less than 25: read this.
- If all of this seems crazy and just doesn’t make good business sense: follow the BUDs in <797>. The worst case scenario is claiming 24 hour BUD which seems like a really bitter pill to swallow but honestly it’s what should’ve been followed since the inception of <797>.
Gary Ritchie, a GMP consultant and director of an analytical lab, pointed out that some testing labs will offer stability data for similar formulations from another manufacturer (or pharmacy). Do not go down this road. Stability studies MUST be formulation specific, compounded by YOUR company in order to be considered valid.
FOR THOSE WONDERING ABOUT THE PODCAST…
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About the author:
Seth DePasquale is a pharmacist and co-owner of BET Pharm, LLC in Lexington, KY; a compounding pharmacy specializing in long-acting injectable hormone formulations for equine reproduction. 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.