By Matt Martin, PharmD, BCSCP, PCCA Director of Clinical Services

This article was updated on January 19, 2022.

On September 1, 2021, the United States Pharmacopeia (USP) prepublished their latest proposed revisions to General Chapter 797, Pharmaceutical Compounding — Sterile Preparations. These proposed changes are not in effect now and have several steps to go through before they will become official. The most important next step is the comment deadline for this chapter, which is March 17, 2022. If pharmacies and other stakeholders would like to submit comments about improvements to the proposed changes, they will need to do so by that date.

USP has held two open forums on the proposed revisions, which were opportunities for them to present information about the proposed revisions and their process along with allowing the attendees to ask questions about the proposed revisions. Now is the time for compounding pharmacies to consider how changes to the chapter may affect their practices, patients and procedures to prepare for submitting their comments on anything that they feel should be improved in the proposed revisions.

The most significant proposed revision to USP 797 is the inclusion of Category 3 compounded sterile preparations (CSPs) in addition to the Category 1 and 2 CSPs that were in the previously proposed revision to Chapter 797 in 2019. The addition of the third category involves many other changes in how pharmacies compounding CSPs must operate as well, which I have outlined below.

Beyond-Use Dates

When USP released the previous version of the revised Chapter 797 in 2019, there were two categories of CSPs. In the proposed version released in 2021, these two categories are still present with the same BUDs from the 2019 version. Category 1 CSPs are compounded under the least controlled environmental conditions and therefore are assigned a BUD of 12 hours or less at controlled room temperature or 24 hours or less when refrigerated and meeting the additional requirements for Category 1 CSPs. Category 2 CSPs require more environmental controls and testing than Category 1 CSPs and may be assigned a BUD of greater than 12 hours at controlled room temperature or more than 24 hours if refrigerated, but not exceeding the limits established in Table 11 of the proposed revisions. Please see Table 11 in the proposed revisions to review these BUDs.

In 2019, compounders took notice of the fact that there was not a way to extend the BUDs of Category 1 or 2 compounds. The 2021 proposed version of USP 797, however, has added Category 3 sterile preparations, which can have longer BUDs compared to those for Category 1 and Category 2 sterile preparations that were described originally in the 2019 proposed revisions. Category 3 BUDs are found in Table 12 of the proposed Chapter 797 (below).

In order to use these BUDs, the Category 3 sterile preparations have a number of additional requirements beyond Category 2 preparations. The BUD of a Category 3 sterile preparation must be supported by a stability-indicating assay that is validated according to USP 1225, Validation of Compendial Procedures. The sterile preparation relying on this stability study for its extended BUD must be made using the same ingredients and procedures as the study. In addition, the Category 3 sterile preparation must be packaged in a container closure that is composed of the same materials as that used in the study.

Category 3 sterile preparations that are injections or ophthalmic solutions must pass the appropriate particulate matter test once for each formulation. Injections have to pass testing according to USP 788, Particulate Matter in Injections, while ophthalmic solutions have to pass testing according to USP 789, Particulate Matter in Ophthalmic Solutions. Additionally, the container closure systems used for injections and ophthalmic solutions must pass testing according to USP 1207, Package Integrity Evaluation — Sterile Products, for each formulation.

Endotoxin Testing

Category 1 sterile preparations do not require endotoxin testing. Category 2 sterile injectable preparations compounded from one or more nonsterile components and assigned a BUD that requires sterility testing must also be tested for endotoxin content complying with USP 85, Bacterial Endotoxins. If a Category 2 sterile preparation is compounded from one or more nonsterile components but is assigned a BUD that does not require sterility testing, it is not required to have endotoxin testing, although the proposed revisions suggest that it should be tested. Category 3 sterile injectable preparations compounded from one or more nonsterile components must be tested for endotoxin content in accordance with USP 85.

Garbing Practices

Beyond the data and testing supporting the formulation, there are additional requirements for the compounder and others who enter the classified area where Category 3 sterile preparations are compounded. Anyone entering the classified areas used for compounding Category 3 sterile preparations must adhere to stricter garbing practices:

• Compounders are not allowed any exposed skin in the buffer room (e.g., face and neck must be covered).
• All low-lint garb must be sterile.
• Once a compounder leaves a classified area, disposable garbing items must be discarded, and laundered garb must not be reused without being laundered and resterilized with a validated cycle.

Environmental Monitoring

Personnel compounding Category 3 sterile preparations are required to perform media fills with glove fingertip sampling and surface sampling of the direct compounding area at least every three months, compared to at least every six months for those compounding Category 1 or 2 sterile preparations.

Pharmacies compounding Category 3 sterile preparations have more frequent monitoring requirements. Viable air sampling using an impaction device must be completed for each classified area monthly for facilities preparing Category 3 sterile preparations, compared to every six months for facilities preparing Category 1 or 2 preparations. This is a notable change because the 2019 proposed revisions to Chapter 797 required monthly viable air sampling for facilities compounding Category 2 sterile preparations.

Surface sampling is required weekly for Category 3 sterile preparations and also must be performed with each batch of a Category 3 sterile preparation. By contrast, when preparing Category 1 or Category 2 preparations, surface sampling is required on a monthly basis. Surface sampling must be done in all classified areas and pass-throughs. The sampling has to include:

• The interior of the primary engineering control (PEC), which is typically a laminar airflow workstation, as well as the equipment contained in it
• Staging or work area(s) near the PEC
• Frequently touched surfaces

Pharmacies must also conduct viable air sampling and surface sampling:

• When new facilities and equipment are certified
• After any facilities or equipment are serviced (see Section 4, Facilities and Engineering Controls)
• When any problems are identified (e.g., microbial growth in sterility tests of preparations)
• When problematic trends are identified (e.g., failed fingertip and thumb sampling results, failed media fill testing, or repeated air or surface contamination)
• When changes are made to the facility or processes that could impact the compounding environment (e.g., change in cleaning agents)

Pharmacies must conduct total airborne particle count testing in all classified areas during dynamic operating conditions at least every six months for all categories of sterile preparations as well.

Cleaning and Sanitizing

Cleaning in the proposed Chapter 797 has received some additional considerations. Pharmacies must clean surfaces prior to disinfecting them, unless they use EPA-registered (or equivalent) one-step disinfectant cleaners that clean and disinfect at the same time. However, the disinfectant must have sporicidal properties, so it’s important to confirm that the disinfectant or one-step disinfectant cleaner is sporicidal. After cleaning and disinfecting, pharmacies must apply sterile 70% isopropyl alcohol to remove any residues.

One significant difference exists in the frequency of sporicidal application between Category 1 and 2 preparations and Category 3 preparations. When pharmacies prepare Category 3 sterile preparations, they must apply a sporicidal agent to the PEC, the equipment in the PEC, work surfaces outside the PEC, equipment outside the PEC, pass-throughs and floors at least weekly. Compounding Category 1 and 2 preparations, on the other hand, require application of a sporicidal agent to all of these areas on a monthly basis.

Along with these changes, the process for cleaning the PEC has received more detailed directions. Compounders must:

• Remove visible particles or residue from the equipment and interior surfaces of the PEC with an appropriate solution using sterile, low-lint wipes
• Apply a sterile cleaning agent followed by a sterile disinfecting agent (or an appropriate one-step disinfectant cleaner as described above) to equipment and interior surfaces of the PEC using sterile, low-lint wipes
• Ensure the cleaning and disinfecting agents are in contact with surfaces for the time specified by the manufacturer
• Apply sterile 70% isopropyl alcohol to equipment and all interior surfaces in the PEC using sterile, low-lint wipes
• Allow the surfaces and equipment to dry before beginning compounding processes

Next Steps in the Process

After the March 17, 2022, comment deadline, the USP Compounding Expert Committee will to review all submitted comments and determine if they will need to make further changes to the proposed chapter. The committee does not have a defined time period for reviewing the comments submitted, so it’s no possible to accurately predict a future implementation date for the chapter. If the USP Compounding Expert Committee moves to implement the revisions to USP 797, they will provide a six-month implementation window before the chapter becomes official, which would also be when it would become enforceable in most states. The new USP Chapter 797 will also be significant for USP Chapter 800, Hazardous Drugs — Handling in Healthcare Settings, because when the new Chapter 797 becomes official, it will also make Chapter 800 “compendially applicable.” In USP terms, this means that it will also become enforceable in many states. For more information about this chapter, visit the PCCA USP 800 webpage.

Pharmacies and other stakeholders can find the proposed changes to USP 797 on USP’s website along with a link to submit comments on the proposed revisions . PCCA has a wide variety of resources available to help pharmacies navigate the changing compounding standards and regulatory environment. PCCA members can reach out to us today if they would like to see how we can help them move forward in their practices.

Matt Martin, PharmD, BCSCP, is the Director of Clinical Services at PCCA. He joined the PCCA Clinical Services department in September 2014. Matt graduated from Morehead State University with a BS in Chemistry in 2002 and received his PharmD from the University of Kentucky College of Pharmacy in 2006. Prior to joining the PCCA team, Matt worked in pharmacy compounding for more than eight years and has experience with both sterile and nonsterile preparations.