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The release of USP chapter <800> and the revisions to USP <795> and USP <797>, official as of November 1st 2023, indicate a changing regulatory climate and a trend towards increasingly high standards for the extension of beyond use dates (BUDs) beyond the default recommended by the guidelines. Prior to guideline changes official in November 2023, USP <795> offered limited information regarding what qualified as sufficient data to support BUD extension. Former USP <795> guidelines did not specifically address strength or formulation extrapolation or the specific use of stability indicating methods, stating instead “the compounder shall refer to the manufacturer for stability information and to the literature for applicable information on stability, compatibility, and degradation of ingredients; shall consider stability factors in 〈1191〉; and shall use his or her compounding education and experience. All stability data shall be carefully interpreted in relation to the actual compounded formulation”.1 Antimicrobial effectiveness testing (AET) per USP <51> was also not required and with regards to container closure the guideline specified only that the container in which a formulation is packaged “should be considered”.1 USP <797> suffered from similar lack of concrete requirements for BUD extension. Previous USP <797> guidelines, official until November 2023, stated that compounders must “consult and apply drug-specific and general stability documentation and literature where available” and though the guideline stated “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” theoretically predicted BUD extension was not prohibited and specific tests and requirements for BUD extension other than sterility tests were not noted.2 This lack of clarity on acceptable criteria for the extension of beyond use dates lead to clarification in USP <795> and <797> guideline updates.
USP <795> BUD Extension
To qualify for BUD extension under these more stringent guidelines a compounder must perform the below testing once for each concentration, or once at a high and low concentration bracketing a range of strengths:
1. Evaluate active pharmaceutical ingredient (API) stability using a stability-indicating analytical method
2. Perform testing in a container closure of the same composition that will be used to dispense the final product
3. Perform AET per USP <51> for any aqueous compounded preparation3
Many studies used for BUD extension before these guideline updates only evaluated for stability using a stability indicating analytical method, without testing in a bracketed fashion or testing individual and various combination products. AET per USP <51> for aqueous nonsterile compounded preparations was also infrequently performed as a part of these previous studies. As a result, many studies completed and compliant with previous USP <795> guidelines are no longer relevant under these new USP <795> guideline changes. Though Fagron has an existing USP <795> guideline update compliant study with several hormones bracketed in our Phytobase vehicle, studies in HRT Heavy are in the process of being updated and the Phytobase study is being expanded.
USP <797> BUD Extension
Significant changes to beyond use date extension per USP <797> have also been implemented. The guideline has done away with BUD distinctions based on low, medium, and high risk, and instead limits BUD depending on procedures and environment of the compounding pharmacy as well as sterilization method and sterility testing.2,4 Only pharmacies that meet qualifications as a Category 3 pharmacy may perform or cite study information to extend the BUD of CSPs beyond what is offered to Category 2 pharmacies. A full review of differences between Category 1, 2, and 3 pharmacies is beyond the scope of this blog. We have provided a resource document USP <797> Category Breakdown, that covers some of the major differences. In short, the differences include things like more frequent air quality monitoring, surface sampling, and employee competencies for Category 3 pharmacies. If a qualifying Category 3 pharmacy wishes to extend the BUD of a preparation to the limits specified in Table 14: BUD Limits for Category 3 CSPs, they must complete the below testing:
• Documented stability indicating analytical testing on an exact formulation (API grade, excipient grade, and procedures are identical) in a container closure of a specific composition
• Particular Matter in Ophthalmic Solutions per <789> or Particular Matter in Injections per <788> performed once per formulation where relevant
• Once for each formulation and container closure system, package integrity evaluation for sterile products per <1207> is performed
• AET per USP <51> for any multi-dose vials
In addition to that testing per formulation, each time a Category 3 CSP Is prepared USP <71> sterility testing and bacterial endotoxin testing must be performed in addition to the standard visual inspection outlined in section 12.1. As with USP <795> guideline changes, many studies previously cited for BUD extension for sterile formulations will no longer qualify under guideline changes official in November.
Summary
Changes to USP <795> and <797> requirements for BUD extension reflect a growing concern in industry for more robust information to justify sterility and stability of CSPs. Among other changes, both guidelines now specify the need for stability indicating testing specifically (as opposed to potency overtime) as well as antimicrobial effectiveness testing for verification of efficacy of the chosen preservative system. Please reach out to the FACTS team at facts.support@fagronacademy.us with further questions regarding updates to BUD requirements for <795> and <797> guidelines!
References:
1. United States Pharmacopeia and National Formulary (USP 43-NF 38). Pharmacopeial Forum Vol No 47(6). Accessed September 25, 2023. https://online.uspnf.com/uspnf/document/1_GUID-98DCB48D-DC23-4A63-AD2E-01CA8979FB7E_5_en-US?source=Search%20Results&highlight=795
2. United States Pharmacopeia and National Formulary (USP 43-NF 38-7037). Pharmacopeial Forum Vol No 47(6). Accessed November 14th, 2023. https://online.uspnf.com/uspnf/document/1_GUID-A4CAAA8B-6F02-4AB8-8628-09E102CBD703_6_en-US?source=Search%20Results&highlight=797
3. United States Pharmacopeia and National Formulary (USP 43-NF 38). Pharmacopeial Forum Vol No 47(6). Accessed September 25, 2023. https://online.uspnf.com/uspnf/document/1_GUID-98DCB48D-DC23-4A63-AD2E-01CA8979FB7E_6_en-US?source=Search%20Results&highlight=795
4. United States Pharmacopeia and National Formulary (USP 43-NF 38-7037). Pharmacopeial Forum Vol No 47(6). Accessed November 27th, 2023. https://online.uspnf.com/uspnf/document/1_GUID-A4CAAA8B-6F02-4AB8-8628-09E102CBD703_7_en-US?source=Search%20Results&highlight=797
