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Going Back to Cali…hmm, I don’t think so.

Going Back to Cali…hmm, I don’t think so.
December 13, 2017 Seth DePasquale
In BUDs, Sterile Compounding, USP 797

There’s so many changes to compounding pharmacy rules these days it’s hard to keep everything straight. It’d be great if we could agree on a single quality standard considering ones zip code shouldn’t dictate the level of safety built into a compounded product. Nonetheless, let’s discuss some of the changes California is considering.

California’s BUDs

The California Pharmacists Association (CPhA) has put forth a proposal to change some of the California Code of Regulations (CCR) pertaining to compounding. Largely, I tend to strongly disagree with what they’re looking to change when it comes to Beyond Use Dating (BUD). In their proposed changes rather than using a stability study to extend BUDs (which was what California was originally considering) CPhA suggests:

(3) Extension of a beyond use date is only allowable when supported by the following:

(A) Sterility testing that incorporates method suitability testing in accordance with USP Chapter <71>, Method Suitability Test (strike through “method suitability test”)

(B) Container Closure Integrity Test, and

(C) Stability Studies (strike through “studies”) Research and Analysis

(D) A pharmacist, using his or her professional judgment may establish an extended date as provided in (A), (B), and (C), if the pharmacist researches by consulting and applying drug specific and general stability documentation and literature; analyzes such documentation and literature as well as the other factors set forth in this subdivision, and maintains documentation and research, analysis and conclusion. The factors the pharmacist must analyze include: (i) the nature of the drug and its degradation mechanism, (ii) the dosage form and its components, (iii) the container in which it is packaged, (iv) the expected storage conditions, and (v) the intended duration of therapy. Documentation of the pharmacist’s research and analysis supporting an extension must be maintained in a readily retrievable format as part of the master formula

I have to admit, I wasn’t at the meeting and I’m basing most of what I’m about to write on what I’ve been able to piece together. It seems as though the CPhA wants to “mirror” the current <797> standard (or at least pieces of it) that makes reference to using BUDs based on <795>:

BUDs for CSPs that lack justification from either appropriate literature sources or by direct testing evidence shall be assigned as described in Stability Criteria and Beyond-Use Dating under Pharmaceutical Compounding—Non-sterile Preparations 〈795〉.

The committee has tabled the discussion until the next meeting in March to further debate this issue. What I find particularly interesting in CPhAs proposed language is that a pharmacist would be able to extend a sterile injection’s beyond use date based on their “research and analysis,” however I’m unclear as to what that means. Proper analysis to truly assign a BUD seemingly would be a stability indicating study; as referenced in a paragraph just a few down the above sentence taken from <797>:

It should be recognized that the truly valid evidence of stability for predicting beyond-use dating can be obtained only through product-specific experimental studies. Semi-quantitative procedures such as thin-layer chromatography (TLC) may be acceptable for many CSPs. However, quantitative stability-indicating assays such as high-performance liquid chromatographic (HPLC) assays would be more appropriate for certain CSPs.

There is certainly a real case against extending beyond use dates without any actual data. If we’re referring to a single dose compound that will be administered within hours of being prepared that’s one thing but it’s entirely different when it’s a multi-dose container that is compounded and dispensed months later. I honestly don’t know which situation is more prevalent but my guess would be the latter given the push back present; and if that is the case stability indicating studies are certainly warranted. How can we honestly say that the compound hasn’t lost any potency without actual evidence? While some references may give an indication as to what a drug may do under certain conditions this offers no data that we can scientifically justify using on each compound being made in every pharmacy. If a reference isn’t using the same lots of the chemicals being used and isn’t being performed under the same conditions (in the exact environment, compounded by the same person), how valid would that reference be for knowing the stability of a compound?

Definition of “Batch”

One section of <797> that will be rectified in the next revision of <797> is the definition of a batch in terms of end product testing requirements. California has unfortunately taken cue from the current version of <797> and has added language stating that only a “batch” requires end product testing. CPhA would like to define a “batch” as greater than 25 units. Here’s what <797> says:

All high-risk level CSPs that are prepared in groups of more than 25 identical individual single-dose packages (e.g., ampuls, bags, syringes, vials) or in multiple-dose vials (MDVs) for administration to multiple patients or that are exposed longer than 12 hours at 2° to 8° and longer than 6 hours at warmer than 8° before they are sterilized shall meet the sterility test (see Sterility Tests 〈71〉) before they are dispensed or administered.

Admittedly, this was a major faux pas on the part of USP when they wrote it like this. This has been interpreted to mean that if you don’t compound batches of greater than 25, you never have to perform end product testing; and has led to a scary gap. I strongly caution California NOT to make this same mistake!

For those that may be following this particular part of <797> to the letter, I have one question: does that actually make sense? Forget for a second that we have a standard with the above wording. Think about the fact that we’re making a compound that’s supposed to be sterile and will be injected into the muscle, vein…spine of a person or animal. Why would it matter if we’re making 5 or 26; or for that matter 2000? The compound is made much the same way whether you’re making 1 or 100. The only inherent risk that goes up is the number of people affected by a contaminated product. The value of someone’s life in these terms only becomes extremely valuable when it’s your own or someone you know.

I’d be remiss if I didn’t bring up a few other points to this discussion: we could talk about if it’s a single dose injection, how quickly it’s going to be administered (from the time it’s made) and whether we’re compounding from non-sterile ingredients. Of course these are all good points to think about when determining a beyond use date, however USP has already put forth some fairly decent standards when it comes to this.

The argument could be made that testing a portion of a batch doesn’t ensure sterility (the only way to do that is to test 100% of the batch, leaving none for the patient). While this is absolutely correct you can make statistical inferences based on the number of units being made and those that are tested.

Final Thought

I have to admit that <797> is by no means perfect and I’ve been outspoken on some much needed revisions; however there’s a good portion that is NOT destined for the trash heap! The proposed changes from CPhA alter what happens to be some parts of <797> that actually make sense (when correctly interpreted); adopting their version would be a mistake that would potentially be to the detriment of the patients of California and beyond. While debating the “shoulds” and “shalls” of <797> may seem like a fun way to pass the time for some; what about the question of what we “should” do based on what’s best for the safety of the patient?

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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.

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  1. […] 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. […]

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