Revision Process

On September 1, 2021, the United States Pharmacopeia (USP) released proposed revisions to <797> and <795> (available at: go.usp.org/Proposed_2021_Revisions_795_797).4,5 These proposed revisions were drafted by the USP Compounding Expert Committee (CEC) and reflect public health considerations, scientifically robust approaches, and numerous stakeholder engagement activities. The chapters are open for an extended public comment period and will remain so through January 31, 2022. At the close of the public comment period, the USP CEC will review and address the comments. Should significant revisions be required, further drafts will be created followed by an additional public comment period; otherwise, the chapters will be approved and published with an official date, which must be at least 6 months after the publication date. This period is purposely designed to allow time for compounders to prepare and make practice changes prior to the official date.

Resource Impact

While not yet official, a thorough review of the changes in the proposed revised chapters can aid organizations in determining if an additional allocation of resources (eg, capital, personnel) should be planned. The resource impact from the proposed chapters on multihospital health systems is quantified herein via a grading system (low, medium, and high) based on the impact to both personnel and finances (see TABLE 1). Further, an ‘impact multiplier’ serves to demonstrate the proportional rate of increased demands in the newly proposed chapters versus the minimum requirements in the current chapters. The multipliers assume the performance of sterile-to-sterile compounding only, excluding the specific requirements for nonsterile-to-sterile compounding (ie, high-risk). The full resource impact may vary depending on the structure of a given pharmacy’s staffing levels, sourcing strategies (insourcing vs. outsourcing), implementation of best practices, specific state requirements, etc.For the purposes of this evaluation, the personnel impact assumes these activities are insourced.

Click here to view a larger version of this table.

Resource Impact: <797> Category 1 and 2

Several of the proposed revisions to USP <797> are likely to impact pharmacy resources. Key revisions to review include increased frequencies of compounding personnel competency evaluation, environmental monitoring, and cleaning and disinfecting practices; beyond-use date (BUD) determinations; batch size limitations; and documentation requirements. These notable revisions are focused on promoting patient safety by improving quality control and sterility assurance.

Within the hospital setting, it is not feasible to perform sterility and other quality tests on each CSP; therefore, risk-based BUDs are applied based on revised determinations that start with the CSP’s site of preparation (ie, segregated compounding area or cleanroom suite). A heightened focus on sterility assurance measures must be established to prevent CSP contamination and subsequent patient harm.

The revised chapter provides significant detail for competency evaluations of compounding personnel and increases the frequency of each evaluation. Further, additional new work activities have been added to the competency evaluation, including a post-media fill surface sample within the direct compounding area (DCA) to demonstrate whether the compounder maintained the cleanliness of the surfaces during a simulated compounding process (ie, media fill). Each sampling activity (eg, gloved fingertip and thumb sampling, media fill testing, surface samples, etc) has specific incubation temperature and incubation times, and requires sufficient incubator space, documentation, and re-testing for out of specification results (see Table 2).

Click here to view a larger version of this table.

 CASE STUDY 1 

Impact of Surface Sampling Requirements

The proposed revisions to USP <797> outline the specific locations and frequency of surface sampling throughout the cleanroom suite. All classified areas must be sampled including the primary engineering controls (PEC) and all equipment contained within it, all staging or work areas near the PEC, and all frequently touched areas. Samples from each location must be incubated at both 30-35°C and 20-25°C to ensure proper growth environments for all potential contaminants. This may require compounders to purchase new incubation equipment to allow for multiple temperature ranges and sufficient space to incubate required samples within a given period of time.

Applying this revised surface sampling requirement to a single 925 square foot cleanroom suite located at a community teaching hospital would equate to a minimum of 40 samples that would need to be taken at least monthly (see FIGURE 1). This increase in the frequency and quantity of surface samples will require significant personnel time to complete the sampling procedures, incubate the samples, monitor for microbial growth, and document each sample. With expanded sampling frequency and locations, there may be an increase in the discovery of out-of-specification (ie, failed) tests that then require careful investigation, remediation, and additional sampling.

Click here to view a larger version of this figure.

 CASE STUDY 2 

Outsourcing vs Insourcing New Sampling Requirements

Under the currently official chapter, personnel compounding low- and/or medium-risk CSPs must successfully complete the initial testing and evaluation, followed by garbing and gloved fingertip and thumb sampling (GFS) competency and media fill testing once every 12 months. The proposed revisions to USP <797> state that compounding personnel are required to successfully complete a competency evaluation consisting of media-fill testing, followed by gloved fingertip and thumb sampling on both hands and surface sampling of the direct compounding area. The evaluation should be completed at least one time every 6 months for personnel compounding Category 1 and 2 CSPs, and at least one time every 3 months for personnel working with Category 3 CSPs. It is important for sites to weigh both the financial and administrative impacts of the proposed revised USP <797> standards on the ongoing competency evaluation processes.

To quantify this impact, consider the implementation of additional observations and testing at an academic medical center with 3 primary cleanroom suites that are staffed by approximately 50 pharmacy technicians. Local third-party vendors provided the following quotes:

• $60-$100 per GFS (including media, lab analysis, and report)
• $130-$195 per media-fill testing kit
• $200-$275 per hour for an onsite technician to complete testing
• GFS observation is 15 minutes per staff member
• Media-fill competency is 45 minutes per assessment (from garbing and hood cleaning to media fill sampling and processing)
• Vendors may also charge a travel fee

Under the proposed revised USP <797>, outsourcing biannual GFS will cost at least $11,000-$16,800. For the proposed bi-annual media-fill evaluation for Category 1 and Category 2, it will cost at least $28,000-$40,100 (not including the additional direct compounding area plate requirement).

Conversely, the competencies could be completed in-house overseen by a pharmacist or technician using incubators in the pharmacy department or the microbiology lab. In this case, the cost of 2 agar plates can be as low as $5, and ordering supplies to create a media fill competency kit may average around $25 per kit.

While the financial impact is significantly lower for hospitals that insource GFS and media-fill testing, the personnel impact of these changes must be considered. Oversight and maintenance of the program is time consuming. In addition, a variety of tasks must be accounted for including ordering supplies, preparing media fill kits and supplies, maintaining expiration dates, monitoring incubator temperatures and logs, scheduling staff for competency, following up with staff, conducting competencies, labeling and incubating media, transferring media to second incubator, tracking incubations and temperatures, reading media, logging lot and expiration of media, documentation, and report generation. The time required for administrative and quality oversight of the program varies depending on the team and tools utilized.

Resource Impact for <797> Category 3

Compounders may elect to prepare Category 3 CSPs to achieve longer BUDs than those assigned for Category 1 or Category 2 CSPs. Since Category 3 CSPs will be held for longer periods, the potential risk of patient harm is elevated due to the increased risks for chemical degradation, physical incompatibilities, compromising of the container closure system, and microbial proliferation. Therefore, additional requirements have been established for Category 3 CSPs in relation to sterility, stability, environmental monitoring, and personnel monitoring.

Category 3 supports BUDs up to a maximum of 180 days if all conditions are met. To apply these extended BUDs, any Category 3 CSP produced by a site must be supported by a validated stability-indicating assay (see USP <1225> for additional guidance). All injectable or ophthalmic solutions must pass USP <788> or USP <789> particulate-matter testing at least once for each formulation. Furthermore, any CSP relying on these studies for validation must be made using the same ingredients, procedures, and stored in the same container closure system as the CSP studied. Note that this testing requires a sizeable financial commitment.

Under the proposed revised <USP> 797, Category 3 CSPs require more frequent personnel and environmental monitoring than are required for Category 1 and Category 2 CSPs. Meeting these new expectations will require additional resources to perform, monitor, and document this new work (see TABLE 3).

Click here to view a larger version of this table.

For CSPs requiring a sterility test (eg, Category 3 CSPs), the maximum batch size is 250 final yield units. For compounders that currently produce batch sizes in excess of 250 final yield units, this will require operational changes that could include preparing smaller batch sizes more frequently or preparing several smaller batches at a time. For either method, it is important to weigh the financial impact from the additional sterility tests as well as the additional wasted samples (due to destructive testing).

Resource Impact from <795> Revisions

The proposed revisions in USP <795> for compounded nonsterile preparations (CNSPs) provide specifications for the environment of nonsterile compounding, cleaning frequency of the nonsterile compounding space, and specific requirements for establishing BUDs (See TABLE 4). The revisions introduce defined minimum frequencies for both cleaning and sanitizing certain surfaces (eg, walls, ceiling) within the nonsterile compounding space. Additional clarity is provided on the ‘designated area’ that includes various physical constraints (eg, no carpet, limit other concurrent activities, minimize cross contamination from noncompounding areas). To meet these new specifications, some organizations may require facility upgrades.

Click here to view a larger version of this table.

Default BUD limits are provided based on water activity level (aqueous or nonaqueous), type of preparation, and storage temperature. Additionally, there is an option to extend BUDs for CNSPs by either conforming to a USP-NF compounded preparation monograph or using appropriate stability information. Due to the high costs of stability-indicating assays, organizations may choose to reduce the BUD to meet the default limits or conform to available USP compounded preparation monographs. Note that the latter approach may require concentration or ingredient changes. If the BUD of the CNSP is extended beyond the default limits, a USP <51> antimicrobial effectiveness test must be performed for the aqueous formulation. The resource impact of these additional studies will be variable by organization depending on the volume of products needing extended BUDs. Organizations can choose to perform or outsource these studies, or they can modify their CNSP BUDs to be within the default limits, and thus avoid additional costly testing.

 CASE STUDY 3 

BUD Analysis of the Nonsterile Formulary

To determine the resource implications of additional testing (eg, USP <51> antimicrobial effectiveness testing) in support of BUDs, the CNSP formulary was analyzed to determine which would require additional testing per the proposed revised chapter. A total of 69 distinct CNSP master formulation records (MFRs) were analyzed for water activity based on:

• Formulation
• Use of preservatives
• Stability data referenced
• Conformation to a USP compounded monograph
• Current BUD

The analysis revealed that 23% of the compounds held a BUD that met the limits of the proposed revisions; 23% required no modifications as the BUD was supported by a USP compounded monograph; but 54% would require antimicrobial effectiveness testing to support the current BUD without modification. Evaluation of each stability study will require a significant investment of personnel time to ensure they meet the definition of ‘stability-indicating’.

Conclusion

As a result of continued pharmaceutical compounding tragedies, compounding misadventures, and patient harm and death, there is a growing need to improve the state of compounding. The proposed revised versions of USP <797> and <795> provide heightened personnel and environmental monitoring and controls, which will aid in meeting this demand. Many of the proposed changes will require personnel and financial investments for new or increased frequency of certain activities (compared to the current standards).

As the proposed revisions are not yet official, organizations have an opportunity to determine how best to plan for personnel and capital resource requests and analyze any impacts on the operational finance budgets. We strongly encourage organizations to provide public comments to USP CEC regarding the proposed revisions to ensure patient safety is addressed while also accounting for the resulting personnel and financial impacts on individual compounding operations.

References

1. Institute of Medicine (IOM) Committee on Quality of Health Care in America. Crossing the Quality Chasm: A New Health System for the 21st Century. Washington (DC): National Academies Press (US); 2001.
2. Pharmaceutical compounding—sterile preparations (general information chapter 797). In: The United States Pharmacopeia, 43rd rev., and the National Formulary, 38 ed. Rockville, MD: The United States Pharmacopeial Convention. 2008.
3. Pharmaceutical compounding—nonsterile preparations (general information chapter 795). In: The United States Pharmacopeia, 43rd rev., and the National Formulary, 38 ed. Rockville, MD: The United States Pharmacopeial Convention. 2014.
4. Proposed Revisions to <797> Pharmaceutical Compounding – Sterile Preparations. Sept 1, 2021. Accessed December 1, 2021. https://go.usp.org/Proposed_2021_Revisions_795_797.
5. Proposed Revisions to <795> Pharmaceutical Compounding – Nonsterile Preparations. Sept 1, 2021. Accessed December 1, 2021. https://go.usp.org/Proposed_2021_Revisions_795_797.

Austin S. Price, PharmD, MBA, is a PGY-1 health system pharmacy administration and leadership resident at Moses Cone Memorial Hospital in Greensboro, North Carolina. He received his doctor of pharmacy degree and MBA from Campbell University and is currently pursuing a MS in pharmaceutical sciences.

Laura Meleis, PharmD, MS, BCPS, is the assistant director of pharmacy quality, compliance, and regulatory affairs at Massachusetts General Hospital in Boston, Massachusetts. She completed her undergraduate degree at the University of Central Florida, followed by her doctorate of pharmacy at the UNC Eshelman School of Pharmacy.

Caroline Childs, PharmD Student, is a PY4 at the University of North Carolina Eshelman School of Pharmacy. She received her bachelor’s degree in biology at Appalachian State University. Caroline plans to pursue an acute care pharmacy residency after graduation.

Kevin N. Hansen, PharmD, MS, BCPS, BCSCP, is the assistant director of pharmacy at Moses H. Cone Memorial Hospital. He received a doctor of pharmacy degree from the Lake Erie College of Osteopathic Medicine and an MS in pharmaceutical sciences from the UNC Eshelman School of Pharmacy.