Compounding Pharmacies and the Need for Rapid Methods

Or how to avoid getting nipped in the BUD

“They’re cutting our BUDs!” I heard this from an exasperated compounding pharmacist looking for any way to make the most out of his product’s shelf life. BUDs, or the Beyond-Use Dates assigned to compounded products, determine when a product must be destroyed if it has not yet been used.  Wasted products are not good for business or patients.  

The draft chapter for USP <797> “Pharmaceutical Compounding – Sterile Preparations” has been available for almost a year. The massive overhaul of the parameters used to assign Beyond-Use Dates should no longer be a surprise. In most cases, compounded products will have shorter shelf lives. This heavily impacts batch planning and availability to patients.  

There are some ways to extend the BUDs that are outlined in the new revision. Most notably, performing a sterility test on each lot can often double the BUD window. But waiting for a sterility test takes at least two weeks, which significantly cuts into that window.  

There’s another seemingly minor change that could help alleviate this issue. In the current version of USP <797>, there’s a single line buried in the sterility test section that briefly mentions alternative methods:

“A method not described in the USP may be used if verification results demonstrate that the alternative is at least as effective and reliable as the USP Membrane Filtration method or the USP Direct Inoculation of the Culture Medium method where the Membrane Filtration method is not feasible”

Unfortunately, the current reference offers no direction for demonstrating method effectiveness.  Without direction as to what will be accepted by relevant regulatory bodies, the reference is nearly useless.  It’s difficult to invest in a project without a clear road map for approval.

Rapid Acceptance of Alternative Methods

The simple change in the USP <797> revision is the addition of three cross-references to another USP chapter, <1223> “Validation of Alternative Microbiological Methods”. One reference is in the new introduction section, which signals alternative methods are front of mind for the standard setters. The other two references are in the Sterility test section, highlighting the test with such a pressing need for faster results. USP <1223> is the roadmap hopeful rapid method users were looking for. Using a rapid sterility test boosts the BUD timeline while minimizing the impacts of the traditional incubation period.  

I’ve written about <1223> on this Eureka blog before. I am proud of what my team at Charles River did, putting together a package that could be used by Celsis® rapid method users to validate their system and gain regulatory approval. Prominent service laboratories that work with compounding labs, including ARL Bio Pharma and Pharmetric Laboratory, have also completed their own independent Celsis validation per <1223>. There’s not much time left before <797> becomes official, but rapid methods in good regulatory standing are available to you today.

Personal Reflections on Shelf-life

It’s difficult to make this post without acknowledging the importance of the compounding industry for meeting unique patient needs. The shift in regulatory standards around BUDs undoubtedly makes it more difficult to meet those needs. I also understand how regulators, who are acting on behalf of patients, want these products to be safe.  

In 2009 I was working in a QC department for a large CMO. We received a warning letter. Included in it was a minor observation related to reagent expiration dates in the QC labs. Most of these test reagents were in multi-use containers. Analysts opened a container, weighed out the material they needed, then returned the container to storage. All material was removed from storage and disposed once it exceeded the manufacturer-assigned expiration date.

But the date assigned by the manufacturer is based on unopened material held in ideal storage conditions. Repeatedly opening the container may or may not impact the material’s effectiveness over time. How could we justify using the material for as long as we did?

That’s a similar question USP <797> writers asked themselves when materials with defined expiration dates are compounded into a new product. Unless proven otherwise, it’s safer to assume a mixture of these materials will lose effectiveness prior to any of the individual material expiration dates.

USP <797> writers took an approach like our observation response. We assigned shorter expiration dates to all open material, similar to how <797> set maximum BUDs based on product category. There’s room for pushback because the dates seem arbitrary, which is why they allow for extensions of BUDs with appropriate stability data. It’s a difficult position to be in when you must standardize a broad market, but I can appreciate the work that was done.

With that in mind, let’s remember this industry challenge with BUDs exists for a good reason – patient safety.  With rapid methods, we have a way to minimize the impact of this challenge.