THE PCCA BLOG

A Summary of Proposed Changes to USP <797>

Thu, 29 Nov 2018 19:35:00 GMT

A Summary of Proposed Changes to USP <797>

By Dylan Herr

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 However, USP has since released a newer version of the chapter.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 July 27, 2018, the Compounding Expert Committee of the United States Pharmacopeial Convention published proposed revisions to USP chapter <797> Pharmaceutical Compounding – Sterile Preparations. The proposed chapter is open to public comments until November 30, 2018, and is expected to become official on December 1, 2019. The proposed revision differs from the current chapter in both its structure and content. Some of the changes are significant and will require major adjustments in pharmacy systems and processes, while other changes will be easier to accommodate. Here is a summary of some of the changes.

Classifying CSPs

The current chapter classifies compounded sterile preparations (CSPs) as low-, medium-, or high-risk level CSPs based on the sterility of the starting components and the number and types of compounding manipulations. The proposed chapter, however, eliminates this system of classifications and instead classifies sterile preparations as either a category 1 or category 2 CSP based on the conditions under which the product was prepared. Category 1 CSPs are preparations that are compounded in a segregated compounding area, which consists of an ISO 5 primary engineering control—such as a laminar-airflow workbench—that is located outside of an ISO 7 clean room. All CSPs that are prepared in an ISO 5 primary engineering control located in a classified clean room environment are considered category 2 CSPs.

Beyond-Use Dating Requirements

The proposed chapter also changes the system for assigning beyond-use dates to CSPs. Instead of assigning a maximum allowable beyond-use date (BUD) based on the risk level of the preparation, the proposed chapter follows a new system for assigning BUDs based on several different factors related to achieving and maintaining sterility.

Category 1 CSPs

Category 1 CSPs are only allowed a BUD of 12 hours at controlled room temperature or 24 hours if refrigerated.

Category 2 CSPs

The proposed guidelines allow a longer BUD for category 2 CSPs, especially those that are terminally sterilized, prepared using only sterile components, tested for sterility, or stored in refrigerated or frozen storage conditions. Table 12 from the proposed chapter summarizes these requirements.

Table 12: BUDs for Category 2 CSPs¹
Preparation Characteristics		Storage Conditions
Sterilization Method	Sterility Testing Performed & Passed	Controlled Room Temp (20–25° C)	Refrigerator (2–8° C)	Freezer (-25 to -10° C)
Aseptically prepared CSPs	No	Prepared from one or more nonsterile starting components: 1 day	Prepared from one or more nonsterile starting components: 4 days	Prepared from one or more nonsterile starting components: 45 days
	No	Prepared from only sterile starting components: 4 days	Prepared from only sterile starting components: 9 days	Prepared from only sterile starting components: 45 days
	Yes	30 days	45 days	60 days
Terminally sterilized CSPs	No	14 days	28 days	45 days
Terminally sterilized CSPs	Yes	45 days	60 days	90 days

Terminal Sterilization

As indicated in the table above, CSPs that are sterilized in their final container-closure systems (terminal sterilization) are permitted longer BUDs than CSPs that are sterilized via filtration. The proposed chapter explicitly states that “terminal sterilization (e.g. dry heat, steam, or irradiation) is the preferred method unless the specific CSP or container-closure system cannot tolerate terminal sterilization.”¹ This differs from the current chapter, which only requires that “the selected sterilization method both sterilizes and maintains the strength, purity, quality, and packaging integrity of CSPs.”²

Investigations and Corrective Actions

The proposed chapter places a greater emphasis on the requirement for conducting investigations and implementing corrective actions. The current chapter only explicitly calls for an investigation to be conducted in the event of a sterility test failure or the recovery of colony-forming units during environmental monitoring if the facility’s action level is exceeded.

The proposed chapter, however, identifies a number of specific scenarios that require that a designated person conduct investigations, implement corrective actions and document such activities, including:
•   Media fill failure
•   Personnel qualification failure
•   Facility certification failure
•   Out-of-specification results on laboratory tests
•   Quality-control check failures
•   Complaints that indicate a quality issue with CSPs
•   Adverse events

Calibration, Certification, and Qualifications

The proposed chapter also places a larger emphasis on routine calibrations, certifications and qualifications of equipment and classified areas. For example, the proposed chapter explicitly requires the certification or calibration of temperature and pressure monitoring devices, dry heat ovens, and incubators on an ongoing basis. Additionally, the proposed chapter requires that calibrated chart recorders are used to monitor each cycle for sterilization and depyrogenation in autoclaves and dry heat ovens.

The proposed chapter also provides additional clarifications on requirements for the certification of classified clean room areas, such as:
•   Airflow testing to determine air velocity and volume, air exchange rate, and room pressure cascade. The facility certification report must document the air changes per hour (ACPH) supplied by the HVAC, the ACPH supplied by the primary engineering control(s) and the total ACPH
•   HEPA-filter integrity-leak testing
•   Total particle count
•   Smoke visualization studies to demonstrate unidirectional airflow

Lastly, the proposed chapter emphasizes that all testing performed as part of the facility certification must be conducted under dynamic operating conditions (i.e., normal operating conditions with personnel present in the clean room).

Conclusion

This is not an exhaustive list of changes in the proposed revision of USP chapter <797>. We at Eagle strongly recommend that compounding pharmacies review the revised chapter in order to determine how the potential changes could affect their practices. If you have questions about any testing or compliance concerns, please contact us at 800.745.8916.

Dylan Herr is a Business Development Specialist at Eagle.

Want to learn more about testing and compliance? Listen to The Mortar & Pestle: A PCCA Podcast. In episodes four and five, Ross Caputo, PhD, President of Eagle Analytical Services, discusses the world of analytical testing.

A version of this article was originally published the Fall 2018 issue of the Apothagram, PCCA’s quarterly, members-only magazine.

References
1. United States Pharmacopeial Convention. (2018). <797> pharmaceutical compounding –Sterile preparations [In-process revision: General chapters]. Pharmacopeial Forum, 44(5). Retrieved from http://www.usppf.com/pf/pub/
2. United States Pharmacopeial Convention. (2018). <797> pharmaceutical compounding –Sterile preparations. In United States pharmacopeia and national formulary (USP 41st ed. & NF 36th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.

What the Proposed USP <795> Revisions Mean for BUDs

Mon, 12 Nov 2018 16:45:00 GMT

By Dylan Herr, Eagle Business Development Specialist

The content below was based on an earlier proposed version of USP General Chapter 795. 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 795. "

On March 30, 2018, the Compounding Expert Committee of the United States Pharmacopeial Convention published proposed revisions to USP chapter <795> Pharmaceutical Compounding – Nonsterile Preparations. The revised chapter was open to public comments until July 31, 2018, and is expected to become official on December 1, 2019. Major revisions to the chapter include, but are not limited to, the following:

Removal of information specific to the handling of hazardous drugs; compounders were instructed to refer to USP chapter <800> Hazardous Drugs – Handling in Healthcare Settings
Addition of specific guidelines related to requirements for personnel training, evaluation, qualification, hygiene and garbing
Addition of minimum frequencies for cleaning and sanitizing nonsterile compounding areas and equipment
Removal of categories for nonsterile preparations based on the complexity of compounding processes
Addition of specific guidelines on complaint handling and adverse event reporting
Changes to the allowable beyond-use date (BUD) in the absence of stability information for nonaqueous dosage forms and for preserved aqueous dosage forms
Expansion of requirements for assigning BUDs for compounded preparations in the absence of stability information¹

Assigning BUDs

Of the proposed revisions, the expansion of requirements for assigning BUDs in the absence of stability information has the most potential to affect the way that compounders practice pharmacy. The current USP chapter <795> only requires that “when assigning a BUD, compounders shall consult and apply drug-specific and general stability documentation and literature when available.”² To meet this requirement, many compounding pharmacies use peer-reviewed journal articles and other literature references in order to provide a scientific justification for extended BUDs.

The revised chapter, however, states that BUDs may be extended past the maximum BUD by type of preparation in the absence of CNSP-specific stability information (as outlined in Table 3) “if there is a stability study (published or unpublished) using a stability-indicating assay for the specific API, CNSP (compounded nonsterile preparation), and container-closure that will be used.”¹ The inclusion of these requirements will make finding peer-reviewed journal articles and other literature references more challenging, as many of them are not formulation or container-closure specific.

Stability-Indicating Methods
Additionally, the revised chapter requires the use of a stability-indicating assay for stability studies. Historically, many compounding pharmacies have collected data to support extended BUDs for their formulations by having a contract analytical laboratory test the potency of the preparation at certain time-point intervals over the proposed BUD. This type of potency-over-time testing, however, does not meet the requirements of a stability study and of the revised USP <795> chapter, as it is not conducted using a stability-indicating assay to measure the potency of the active ingredient(s). While all stability-indicating assays measure the potency of an active ingredient, not all potency testing methods are stability-indicating.

One of the primary differences between a potency test and a stability study comes down to the analytical testing method used. While a potency testing method is reliable at quantitatively determining the concentration of a drug in a preparation at the time of compounding, not all potency testing methods are capable of separating the intact drug from its degradation products. As a result, these other substances could potentially mask or simulate the analytical behavior of the intact drug, resulting in an inaccurate concentration of the active ingredient. Results from this type of testing cannot be interpreted to determine that the product is stable over time, as there may have been degradant products or changes in the concentration of the active drug that were present, but not detected.

As a comparison, a stability-indicating assay is a potency testing method that is specifically developed and validated to differentiate between the active ingredient and the presence of other substances, such as impurities, degradation products and excipients. A stability-indicating assay is typically developed by forcibly degrading the compounded preparation through exposure to conditions known to produce decomposition, such as light, heat, oxidation, acids and bases. The stability-indicating assay is then validated in the presence of the resulting degradation products, which provides assurance that any increases or decreases in the active ingredient represent actual changes in the concentration of the drug.

Conclusion
All of this means that the requirements for extending the BUDs of nonsterile compounded preparations will likely become more stringent on December 1, 2019. We recommend that compounding pharmacies start developing strategies for establishing extended BUDs for their preparations now so as not to interrupt patient access to compounded medications.

PCCA has already invested the resources in their FormulaPlus™ program to provide members access to formulations with extended BUDs that have undergone testing using stability-indicating assays. PCCA members can access the complete list of FormulaPlus formulations here.

Furthermore, at Eagle, not only can we develop, validate and execute stability-indicating assays for most sterile and nonsterile compounded preparations, but we also offer consulting services on all aspects of testing and regulatory compliance. If you have questions about any of these matters, please contact us at 800.745.8916.

A version of this article was originally published the Summer 2018 issue of the Apothagram, PCCA’s quarterly, members-only magazine.

References
1. United States Pharmacopeial Convention. (2018). <795> pharmaceutical compounding –Nonsterile preparations [In-process revision: General chapters]. Pharmacopeial Forum, 44(3). Retrieved from http://www.usppf.com/pf/pub/
2. United States Pharmacopeial Convention. (2017). <795> pharmaceutical compounding –Nonsterile preparations. In United States pharmacopeia and national formulary (USP 41st ed. & NF 36th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.