Last Call to Comment on the Proposed USP 797 Changes
Since the 2019 proposed changes to USP 797 were remanded in 2020, a new proposal was released in September of 2021 for stakeholder review and comment.
Proposed Changes Overview
Several minor changes were made throughout all of the sections in the proposed 2021 version of USP 797. If the 2021 revision is implemented, administration, hazardous compounding, and radiopharmaceutical compounding will all be considered out of the scope of the chapter. There are several implications with this fact, one of which is that USP <800>, Hazardous Drugs — Handling in Healthcare Settings, will become officially enforceable in many states. Another of which is that healthcare settings would be able to bypass USP <797> requirements when mixing or reconstituting a single dose of sterile medication for an individual patient in accordance with directions contained in FDA approved labeling provided by a product’s manufacturer consistent with that labeling.
Aside from the changes described above, the most notable changes to the 2021 proposed USP 797 revision are focused on BUD assignments. This makes sense since the 2019 proposal was largely scrutinized for not providing a pathway to extend the beyond use dates of compounds. While the current 2008 version of <797> categorizes low, medium and high risk CSPs, the 2021 proposal distinguishes three categories of CSPs for BUD assignment — Category 1, Category 2, and Category 3. Category 1 and 2 CSPs were first announced in the 2019 proposal and their default BUD limits have not changed in the 2021 proposal. Category 3 CSPs were introduced in the 2021 proposal, which enjoy extended beyond use dating. The three categories described in the 2021 USP 797 proposal are primarily based on a risk assessment that accounts for the state of environmental control under which they are compounded, the probability for microbial growth during the time they will be stored, and the time period within which they must be used.
Risk Assessment for Establishing BUDs
When establishing a BUD for a CSP, compounders must consider parameters that may affect stability, including but not limited to:
Chemical and physical stability properties of the formulation
Compatibility of the container closure system with the finished preparation (e.g., leachables, interactions, adsorption, storage conditions, etc.)
The achievement and maintenance of sterility is also a factor in beyond-use date assignments for CSPs. As such, compounders must assess the following as part of the CSP BUD justification:
Conditions of the environment in which the CSP is prepared (e.g., cleanroom suite or SCA)
Aseptic processing and sterilization method
Starting components (e.g., sterile or non-sterile starting materials)
Whether or not sterility testing is performed
Storage conditions (e.g., packaging and temperature)
Additional Requirements for Extended BUD Compounds (e.g., Category 3)
Compounders that want to assign longer BUDs than those established for Category 1 and Category 2 CSPs, additional requirements must be met at all times, even on days category 3 CSPs aren’t being made. For assigning longer BUDs that are up to double as those assigned for Category 2 and up to 180 days, category 3 CSPs must:
Undergo sterility testing
Test endotoxins if applicable
Perform personnel qualification more frequently – every 3 months
Use all low-lint sterile garb, no exposed skin is allowed in the buffer room, garb must be changed upon each entry
Use sporicides for cleaning weekly
Execute a more extensive and frequent environmental monitoring program
Confirm stability through a validated stability indicating study
The proposed revisions to do not prohibit dispensing a CSP prior to getting the results of testing as long as the ability to recall the preparation is established.
New Limit on Batch Size
The 2021 proposal also clarifies that some category 2 and all category 3 CSPs require sterility testing according to USP 71 requirements. Also, if the proposed changes are approved, the maximum batch size for all CSPs requiring sterility testing will be limited to 250 final yield units. As per the USP Expert Committee explanation, the rationale is based on the low threshold for test samples as part of the testing process. Contamination is often not uniform across an entire batch. So it is reasoned that the limit of 250 final yield units reduces the risk of contamination going undetected.
Real World Implications
It is obvious that pharmacies wanting to apply extended beyond use dates to their CSPs will be particularly impacted by the 2021 proposed changes to USP 797. Stakeholders have argued that many of the additional requirements for extended beyond-use dating closely resemble some of the GMP processes and heightened controls that 503B outsourcing facilities have to abide by. Others have debated that the 250-unit cap on batch compounding is arbitrary, has weak scientific basis, is cost-prohibitive, and will cause compounders to avoid preparing such compounds (thereby decreasing patient access).
Restore Health Consulting predicts that if these changes are implemented as is:
Some pharmacies will shy away from assigning extended BUDs to CSPs altogether to avoid the additional requirements imposed on category 3 compounds.
Other pharmacies that assign extended BUDs to several CSPs may consider becoming a 503B since there would be several additional hoops to jump through.
Certain healthcare facilities may decide to downsize their compounding department and perform more administration per FDA labeling, which could decrease the confidence in sterility of the products administered.
All practice sites will have to align their SOPs and master formulas with the changes.
The Deadline Approaches
The changes outlined in this article are just proposals, they are not yet official and are not intended to be enforceable at this time. You can find the proposed revisions on the USP website. USP has scheduled a virtual open forum for January 19, 2022 so that you can ask questions regarding USP 797 changes to the Expert Committee. If you are concerned that one or more of the proposed revisions could affect your practice or patient access to sterile compounds, you can submit comments through the USP online portal. You have until January 31, 2022 to submit comments. The committee may take several weeks to months to review all comments and consider amending the proposed changes. If the Committee moves to implement the proposed changes, there will be a six-month period before the changes become official (and enforceable in most states).