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

This article ws updated on January 14,2022.

On September 1, 2021, the United States Pharmacopeia (USP) prepublished their latest proposed revisions to General Chapter 795, Pharmaceutical Compounding — Nonsterile Preparations. These proposed changes are not in effect now and have several steps to go before they will become official. The most important next step in the process is the comment deadline for this chapter, which is March 17, 2022. Pharmacies and other stakeholders that wish to submit comments about improvements to the proposed changes will need to do so by that date.

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

Training

In the proposed changes to USP 795, there are some themes that stand out when compared to the current version of the chapter. There is a significant expansion and emphasis on training, including knowledge in and demonstration of core competencies. It is important to highlight that training includes not only the ability to read and understand the concepts, but also for the trainee to demonstrate both their knowledge and their ability to perform the tasks. The training and demonstration of knowledge and ability must also be documented. The core competencies listed in the proposed revisions are:

• Hand hygiene
• Garbing
• Cleaning and sanitizing
• Handling and transporting components and compounded nonsterile preparations (CNSPs)
• Measuring and mixing
• Proper use of equipment and devices selected to compound CNSPs
• Documentation of the compounding process (described in Section 7 of the chapter, Master Formulation and Compounding Records)

In addition, training must include:

• Reading and understanding the chapter as well as other applicable standards and relevant literature (such as USP Chapters 7, 51, 659, 800, 1112, 1163, 1178 and 1231, all of which are referenced in USP 795)
• Understanding and interpreting safety data sheets (SDSs) and, if applicable, certificates of analysis (COA)
• Reading and understanding procedures related to the staff member’s compounding duties

It is significant that hand hygiene, garbing, cleaning and sanitizing are cited as core competencies for nonsterile compounding. While some may consider garbing and personal protective equipment (PPE) as items there to protect the compounder from drugs and chemicals they work with, the garbing process and PPE are also significant tools in reducing the potential contamination that people can produce through shedding of skin and bacteria throughout the workday. In other words, properly donned PPE protects the compounder from chemicals and protects the chemicals (and CNSPs) from the compounder.

Cleaning and Sanitizing

Table 1 of the proposed changes to USP 795 also defines minimum schedules for cleaning and sanitizing nonsterile compounding areas. While this chapter is addressing nonsterile compounding, it is also important to consider that USP has multiple chapters on microbial limits for nonsterile preparations, including USP 61 and USP 62. These chapters look at total microbial contamination limits and specific objectionable microorganisms that should not be in nonsterile compounds. The FDA has also been focused on the quality of the environment in which nonsterile preparations are compounded through their guidance document Insanitary Conditions at Compounding Facilities and has been explicit in stating that insanitary conditions are a focus for their inspections of compounding facilities. I’ve written more about the FDA Insanitary Conditions guidance on The PCCA Blog as well.

Beyond-Use Dates

Beyond-use dates (BUDs) are always of significant interest to compounders because they affect patient care opportunities. In considering BUDs, it is common to consider the chemical and physical properties of the active pharmaceutical ingredient (API) in the formulation. However, the proposed chapter increases focus on the container closure system that will be used for the final formulation. Compounders are expected to consider the potential of the container closure to interact with the CNSP, visually inspect the integrity of the container closure prior to releasing the CNSP and consider the possibility of the container closure degrading over the BUD of the preparation. The integrity of the container closure is important because an improperly sealed, cracked or degraded container closure can potentially lead to microbial contamination or a loss of potency for the compounded preparation.

The concept of water activity was introduced in the last proposed revisions to Chapter 795 and has been further highlighted in these latest proposed revisions. Water activity is the water that is unbound and freely available to participate in chemical, biochemical or physicochemical reactions or provide an environment that can support microbial growth. Compounded preparations with a water activity less than 0.6 are considered anhydrous and are provided longer default BUDs because they are less likely to allow degradation of the active ingredient or allow microbial growth. The discussion on water activity has been expanded in the proposed revisions, and examples of the water activity of various dosage forms have been added to the chapter as opposed to only referencing USP 1112, which is the chapter on water activity.

Also on The PCCA Blog: Why Water Activity Matters in Pharmacy Compounding

The maximum BUDs that can be assigned to compounded nonsterile preparations without additional stability data remain fairly similar to the former proposed revisions, but with a few key updates. Nonaqueous topicals, suppositories and troches are now preparations that can have up to a 180-day default BUD. Nonaqueous oral preparations still have a 90-day maximum default BUD. Aqueous dosage forms remain separated based on whether or not they have a preservative: Non-preserved aqueous dosage forms can have up to a 14-day BUD when stored at refrigerated temperature, and preserved aqueous dosage forms can have up to a 35-day BUD at room temperature or under refrigeration.

BUDs of preparations can be extended up to 180 days with a stability study (published or unpublished) using a stability-indicating analytical method for the API(s), CNSP and type of container closure that will be used. If the BUD of an aqueous preparation is being extended beyond the default BUD offered by the proposed revisions, the formulation must also be tested for the performance of the preservative, known as antimicrobial effectiveness testing, according to USP Chapter 51.

The proposed revisions to Chapter 795 also permit the use of bracketing for both stability studies and antimicrobial effectiveness testing. Bracketing is performing the tests on a low concentration and a high concentration of the active ingredient(s) in the formulation. If the formulation passes the tests at both concentrations, then the data can be applied to all strengths of the formulations between the two that were tested.

As a side note, PCCA has developed over 175 FormulaPlus^™ formulations that have been tested with stability-indicating assays and USP 51 antimicrobial effectiveness testing when appropriate to provide extended BUDs. Some of these are bracketed formulations to help PCCA members address the variety of strengths that are prescribed by practitioners. These formulations therefore meet all of the current and proposed guidelines in USP 795.

The Designated Person(s)

Responsibility for the performance of the compounding operation is another new theme in the proposed revisions to Chapter 795. A new role within USP chapters is called the “designated person(s).” The designated person(s) is one or more individuals assigned to be responsible and accountable for the performance and operation of the facility and personnel for the preparation of CNSPs. Specifically, the designated person(s) is tasked with over 20 areas of responsibility in the proposed revisions. It is important to note that a pharmacy can have one designated person or several, hence the “(s)” at the end of “person(s).” These responsibilities can therefore be divided among members of the team who are appropriate for each responsibility. A few of the key responsibilities of the designated person(s) are training, documentation, and quality control and quality assurance. While I discussed training above, it is imperative to highlight the need for documentation. The proposed revisions call out a variety of areas for documentation, including:

• Personnel training, competency assessments and qualification records, including corrective actions for any failures
• Equipment records (e.g., calibration, verification and maintenance reports)
• Certificates of analysis and all documentation required for components not conventionally manufactured
• Receipt of components
• Standard operating procedures, master formulation records and compounding records
• Release-inspection and testing records
• Information related to complaints and adverse events, including corrective actions taken
• Results of investigations and corrective actions
• Records of cleaning and sanitizing the designated compounding area
• Temperature logs
• Accommodations to personnel compounding CNSPs
• Any required routine review (e.g., yearly review of quality assurance and quality control programs, yearly review of chemical hazard and disposal information)

The proposed revisions make reference to USP 1163 on quality assurance, which can be a helpful resource in developing the required formal written quality assurance and quality control program. This program should establish a system of:

• Adherence to procedures
• Prevention and detection of errors and other quality problems
• Evaluation of complaints and adverse events
• Appropriate investigations and corrective actions, such as:
  • Determining when recalls must be initiated, which should include procedures to immediately notify the prescriber of a failure of specifications with the potential to cause patient harm (e.g., strength, purity or other quality attributes)
  • Determining the distribution of any affected CNSP, including other affected lots, and the date and quantity of distribution
  • Identifying patients who have received the CNSP
  • Recalling any unused dispensed stock and quarantining any stock remaining
  • Disposing of the recalled CNSP and documentation thereof

What Comes Next

After the March 17, 2022, comment deadline, the USP Compounding Expert Committee will have to review the comments and determine if further changes to the proposed chapter will be made. The USP Expert Committee does not have a defined time period for reviewing the comments submitted, which is one reason that a future implementation date cannot be precisely predicted. If the USP Compounding Expert Committee moves to implement the revisions to USP 795, they would provide a six-month implementation window before the chapter becomes official, which is also when it would become enforceable in most states. The new USP Chapter 795 will also be significant for USP Chapter 800, Hazardous Drugs — Handling in Healthcare Settings. When the new USP Chapter 795 becomes official, it will also make USP Chapter 800 “compendially applicable” in USP terms, meaning that it will also become enforceable in many states. For more information on this chapter, visit the PCCA USP 800 webpage.

Pharmacies and other stakeholders can find the proposed changes to USP 795 on USP’s website as well as a link to submit comments on the proposed changes . PCCA also 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.