Right as the Compounding Expert Committee of the US Pharmacopeial Convention made some revisions and changes to the USP general chapter 797 for sterile compounding, they also made equally extensive revisions to the USP General Chapter 795 Pharmaceutical Compounding – Nonsterile Preparations.
The revised document has closed for public comments, and the changes are to become official and thus implemented on December 1, 2019, the same day as the revisions to 797 are to be made official.
There are plenty of significant changes and revisions that have been made, but we will only speak to some of the major ones who have the most significant impact on all of you.
These changes include:
- Changes to BUDs (allowable beyond-use dates) in the case of the absence of stability information on preserved aqueous dosage forms and non-aqueous dosage forms.
- Further expansion of requirements for BUDs in the absence of stability information.
- Addition of specified guidelines that deal with the handling of complaints and reporting of adverse events.
- Addition of specified guidelines that are related to personnel and staff requirements for qualification, training, evaluation, garbing, and hygiene.
- Addition of minimal frequencies for sanitizing and cleaning of nonsterile compounding equipment and areas.
- Removal of nonsterile preparations categories that were based on the complexity of the compounding process.
- Removal of information that’s specific to dealing with hazardous drugs. Compounders are instructed to take a better look at the USP Chapter 800, that deals with dangerous drugs and the handling of such substances in a healthcare setting, where this information already exists in greater detail.
All in all, the changes mostly deal with the same subjects that were revised and altered in USP Chapter 797. You should also take a look at these changes as well to get all the necessary information you need.
Changes to the Requirements for Assigning Allowable Beyond-Use Dates (BUDs)
These significant changes and expansions to existing requirements for assigning BUDs are the essential part of all the changes made in these new documents. They have the immense potential to affect how the compounders perform in general practice pharmacy. We are focusing on these parts most precisely because of the impact these changes will have.
Now, the existing USP General Chapter 795 states that compounders, when assigning BUDs, need to consult and apply all general stability and drug-specific documentation and literature only when it is available. For that reason, many compounding pharmacies have used, for example, peer-reviewed articles and other similar references to deliver on these requirements and provide scientific justification when they need to extend existing BUDs.
With the changes now made, this practice will be much harder going forward. That’s because the changes say that the BUDs can be extended past their maximums, only in the case of the absence of CNSP-specific stability information (Compounded Non-Sterile Preparation.) If a stability study exists, be it published or unpublished, that uses stability indicating assays for specific API, CNSP and container-closure will be used.
These changes need a review in greater detail in the original proposed changes as they are not possible to summarize in a way that doesn’t omit relevant information.
All in all, the revisions made here will significantly hinder the finding of reviewed journal articles and other literature previously mentioned, mostly because much of this literature is not container-closure or formulation specific.
Changes in Stability-Indicating Methods
In continuing our focus on summarizing the most significant changes – it’s worth noting that the proposed changes now require the use of a stability-indicating assay and stability studies.
The existing practice is that compounding pharmacies collect data to support the extended BUDs they want to make, by using a contract analytical laboratory to test the potency of these preparations. They do this at particular time intervals for the proposed BUD.
Unfortunately, this practice won’t be possible anymore because of the proposed changes in the chapter itself, but also because these practices do not meet the requirements of stability studies. To be more precise – potency testing is not conducted using stability-indicating assays which measure the potency of active ingredients. What’s more, all stability-indicating assays do, in fact, measure potency of active ingredients, but only a handful of potency testing methods indicate stability, making them unusable when these changes take effect at the end of 2019.
All the main differences between stability studies and potency tests boil down to the analytical testing methods which are used.
A stability study is a method that’s specially developed for differentiating between active ingredients and the possible presence of other substances (like degradation products, impurities, and excipients.) A stability-indicating assay for these stability studies is created by degrading the compounded preparations by force and through exposure to decomposition-inducing conditions (light, acids, bases, oxidation, heat, etc.). In the end, a stability-indicating assay can only be validated if these degradation products that were made as a result are present. That makes increases or decreases in active ingredients that signify changes in the drug concentration assured.
On the other hand, a potency test is only reliable for quantitatively determining the drug concentration only during the time of compounding. Only a handful of potency methods can also separate an intact drug from degradation products, a process that’s entirely possible using stability studies. Because potency tests cannot accomplish this, these other substances have the potential to mask or stimulate the behavior of the drug, which can also result in an inaccurate concentration of active ingredients. That, in essence, means that you cannot interpret these results as something that determines the product’s stability through time, as there are many degrading ingredients or changes in the drug concentration which weren’t detected.
Everything we just discussed signifies that, as of December 1, 2019, the requirements for assigning and extending BUDs are becoming stricter and harder to create.
We advise all compounding pharmacies to start developing new strategies for the creation of extended BUDs for their preparations if they want to continue allowing unrestricted access to compounding medications to their patients.