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By Dylan Herr, Eagle RA/QA Development Manager
The content below was based on an earlier proposed version of USP General Chapter 797. However, USP has since released a newer version of the chapter. To see our most current content about the new version of the chapter, please read our blog post Proposed Changes to USP 797.
On June 1, 2019, a revised version of USP General Chapter <797> was published. The revised chapter will become official in the United States Pharmacopeia on December 1, 2019, along with a revised version of General Chapter <795>, which addresses nonsterile compounding, and the new General Chapter <800>, which addresses hazardous drugs.
The revised USP <797> differs significantly from the current version. Many of the changes in the revised chapter will be relatively simple for pharmacies to address through small procedural updates and personnel training, such as the requirement for different incubation times and temperatures for growth media, or the requirement that incubators are not stored in classified areas. Other changes, however, will be significantly more challenging for some pharmacies to implement. The most significant changes, which I will focus on in this article, are changes in how beyond-use dates (BUDs) are assigned and in testing requirements.
Beyond-Use Dating Requirements The new USP <797> defines three different classifications of compounded sterile preparations (CSPs): immediate use, Category 1 and Category 2. The differences between each CSP classification are largely related to the environment in which the CSP was prepared, the resulting level of risk of microbial contamination and the BUD that can be assigned.
Immediate use CSPs are not subject to the requirements outlined in USP <797>, as this classification addresses the preparation of sterile compounds for direct and immediate administration to a patient within four hours. They must be prepared in accordance with written procedures to ensure good aseptic practice, must require no more than three different sterile starting components, and must be discarded if administration does not begin within four hours of preparation.
All CSPs that are not immediate use fall into the classification of Category 1 or Category 2 based on the environment in which they are prepared. Category 1 CSPs are compounded in an ISO 5 primary engineering control (such as a laminar-airflow workstation) that is located in a segregated compounding area. Category 2 CSPs are compounded in an ISO 5 primary engineering control that is located in an ISO 7 buffer area. While the facility design and control requirements for Category 1 CSPs are not as stringent as those for Category 2 CSPs, the chapter states that “the requirements that are not specifically described as applicable to Category 1 or Category 2, such as training, competency testing, and personal hygiene for personnel, are applicable to the compounding of all CSPs.”1 It is therefore important for pharmacies only compounding Category 1 CSPs to employ quality systems that are nearly as robust as those in pharmacies compounding Category 2 CSPs.
“It is therefore important for pharmacies only compounding Category 1 CSPs to employ quality systems that are nearly as robust as those in pharmacies compounding Category 2 CSPs.”
Besides compounding environment, the primary difference between Category 1 and Category 2 CSPs is the maximum allowable BUD that can be assigned to these preparations. The maximum permitted BUD for a Category 1 CSP is 12 hours when the preparation is stored at a controlled room temperature (20–25° C), or 24 hours when it is stored under refrigerated conditions (2–8° C).
The maximum permitted BUD for a Category 2 CSP, as outlined in Table 11 of the chapter, is dependent on whether:
The revised chapter allows longer BUDs for CSPs that are terminally sterilized, have passed sterility testing, are prepared from sterile starting components and are stored under colder conditions, as these factors help to minimize the risk of microbial contamination or proliferation in finished CSPs.
As an example of how the processing and storage conditions affect the allowable BUD, consider a CSP that is prepared from nonsterile starting components and is stored under refrigerated conditions. If this CSP is sterilized via filtration and is not tested for sterility, the maximum allowable BUD is four days. If sterility testing is performed and passed, the maximum permitted BUD increases to 45 days. If this same CSP was terminally sterilized instead of filter sterilized, it would be allowed a 28 day BUD without sterility testing, or a 60 day BUD if it passes a sterility test.
Another significant change with respect to assigning BUDs is the removal of language that discusses methods of extending BUDs for sterile preparations compounded in an ISO 5 primary engineering control located in an ISO 7 buffer area. While the current USP Chapter <797> allows compounders to use stability studies or relevant scientific literature to extend BUDs for these preparations, the revised chapter does not provide any means of extending BUDs beyond those outlined in Table 11. This is also contrary to the revised Chapter <795>, which allows for extended BUDs on nonsterile preparations if appropriate stability studies are conducted. USP addresses this with question 69 on their Chapter <797> frequently asked questions webpage. The question is, “Can the BUD of Category 2 CSPs be extended beyond those in Table 11. BUDs for Category 2 CSPs?” The answer USP provides is, “The chapter states that BUDs for Category 2 CSPs must be established in accordance with Table 11. However, if there is a compounded preparation monograph for a particular CSP formulation, that BUD may be assigned if the CSP is prepared according to the monograph and all monograph requirements are met.”2
“While the current USP Chapter <797> allows compounders to use stability studies or relevant scientific literature to extend BUDs for [Category 2 CSPs], the revised chapter does not provide any means of extending BUDs beyond those outlined in Table 11.”
Shorter BUDs may result in increased patient costs and operational challenges, so many compounders may try to maximize the allowable BUD by terminally sterilizing or freezing all of the CSPs they prepare. However, they should exercise caution when taking this approach. The revised chapter advises compounders to take into account the physical and chemical stability of CSPs and their components prior to freezing or refrigerating them, as not all CSPs will be compatible with colder conditions. The chapter also requires the compounder to ensure that the container-closure system used to package frozen CSPs is able to withstand the stress of being frozen and thawed. Finally, CSPs that have been thawed are not permitted to be re-frozen. The chapter also points out that while CSPs may be kept under multiple storage conditions prior to use, the BUD is not cumulative. To illustrate this, the chapter provides the following example: “An aseptically processed CSP prepared from one or more nonsterile starting component(s) cannot be stored for 45 days in a freezer, then 4 days refrigerated, and then 1 day at controlled temperature for a total of 50 days.”1
Additionally, while CSPs that are terminally sterilized are permitted a longer BUD, compounders must define and validate their terminal sterilization cycles. The revised chapter requires that pharmacies prepare detailed standard operating procedures that address sterilization cycle factors such as temperature, pressure, allowable loading conditions, and the use of biological indicators or endotoxin challenge vials. Prior to terminally sterilizing a CSP, the compounder must first demonstrate the effectiveness of the sterilization cycle through use of biological indicators, temperature sensing devices and other physiochemical confirmation methods. The compounder must ensure that the contents of the sterilizer — and not just the equipment itself — reaches the required temperature for sterilization for the duration of time required to achieve an appropriate level of sterility assurance. Lastly, temperature-sensing devices, such as calibrated data or chart recorders, must be used along with appropriate biological indicators to verify that the cycle performs within specification.
“The revised chapter requires that pharmacies prepare detailed standard operating procedures that address sterilization cycle factors such as temperature, pressure, allowable loading conditions, and the use of biological indicators or endotoxin challenge vials.”
Testing Requirements The revised USP <797> removes the current chapter’s requirement that all batches of CSPs in quantity of 25 units or more must be tested for sterility. Instead, Category 2 CSPs must be tested for sterility if they are assigned a BUD that requires sterility testing per Table 11. The chapter requires that CSPs are tested for sterility using either the compendial method outlined in USP Chapter <71> or a validated alternative method. The chapter also requires that a method suitability test, also described in USP <71>, is conducted to demonstrate that the sterility test is capable of detecting microbial contamination. One of the challenges of the USP Chapter <71> sterility testing method is the 14–18 day incubation time that the method requires. For a Category 2 CSP stored at controlled room temperature, the product will lose up to half of its shelf-life before the sterility test results are available. Fortunately, Eagle is able to offer compounders sterility test results within two business days using our ScanRDI® rapid sterility testing, a method that has been validated as a suitable alternative according to USP Chapter <1223>.
A helpful change in the new chapter is the addition of provisions for small batches of CSPs with regards to required sample sizes for sterility testing. Under the current chapter, the number of units to be tested for sterility is based on Table 3 of USP <71>. For batches smaller than 40 units, four containers must be tested for sterility. The new chapter, however, allows compounders to test 10% of the batch size — rounded up to the next whole number — for batches that are under 40 units. As an example, for a batch size of 15 containers, the compounder must only test two units for sterility, as opposed to the four that would be required under USP <71>.
“The new chapter, however, allows compounders to test 10% of the batch size — rounded up to the next whole number — for batches that are under 40 units.”
The revised chapter also recommends that nearly all injectable Category 2 CSPs are tested for bacterial endotoxins. However, the chapter states that Category 2 injectable CSPs that are assigned a BUD based on sterility testing must be tested for bacterial endotoxins. It also states that Category 2 injectable CSPs that are prepared from nonsterile components should be tested for bacterial endotoxins, even if they are assigned a BUD that does not require sterility testing. (Keep in mind that a “must” is a requirement, but a “should” is a recommendation.)
Lastly, the revised chapter addresses the testing of multiple-dose CSPs. All multiple-dose CSPs are required to be prepared as Category 2 CSPs, and therefore may not be prepared in a segregated compounding area. Additionally, the chapter requires that compounders conduct USP General Chapter <51> antimicrobial effectiveness testing at least once for each formulation in the container-closure system in which it will be dispensed. For formulations with a range of different strengths, compounders may apply a bracketing approach by testing the highest and lowest strength of the formulation so long as the concentration of inactive ingredients, including the preservative, does not change. It does allow compounders to rely on antimicrobial effectiveness testing documented in peer-reviewed literature sources as long as the formulation, preservative and container-closure system are identical to those used in the peer-reviewed study.
“All multiple-dose CSPs are required to be prepared as Category 2 CSPs, and therefore may not be prepared in a segregated compounding area.”
This article is not intended to be an exhaustive examination of the changes to USP <797>. We at Eagle recommend that all compounding pharmacies read and re-read the revised chapter well in advance of December 1, 2019, when it becomes official, in order to become familiar with all changes that may affect their practices. The revised chapter is available for free on USP's website. Additionally, Eagle’s expert consultants can assist pharmacies by performing a comprehensive assessment of their existing practices and procedures to identify gaps between current operations and the requirements of the new chapter, and to help identify appropriate actions to take. If you have any questions about the revised chapter, please contact Eagle Client Care at 800.745.8916 for further assistance.
Dylan Herr joined the Eagle team in 2017. Before that, she worked for five years as the practice manager and compliance officer of a 503A compounding pharmacy. In this role, Dylan led the development and implementation of quality systems and standard operating procedures in addition to managing daily operations of the home infusion practice. Dylan also led the pharmacy through NABP, BOP and FDA inspections, and helped it achieve ACHC and PCAB® accreditation. Her formal education includes a bachelor’s degree in anthropology from Dartmouth College.
References
1. United States Pharmacopeial Convention. (2019). General chapter <797> pharmaceutical compounding — Sterile preparations. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc. 2. United States Pharmacopeial Convention. (2019). FAQs: <797> pharmaceutical compounding — Sterile preparations. Retrieved from https://www.usp.org/frequently-asked-questions/pharmaceutical-compounding-sterile-preparations