USP Compliance Presents Unique Challenges for Outpatient Oncology

Compliance with United States Pharmacopeia (USP) Chapter Standards is vital to maintaining patient and employee safety within all health care settings. As a brief review, USP Chapter <797> provides standards for sterile compounding and focuses on patient safety through the reduction of microbial contamination, while USP Chapter <800> outlines standards for the handling of hazardous drugs, concentrating on the safety of both employees and patients through the reduction of hazardous drug contamination.^1,2These chapters finally became enforceable by regulatory agencies in November of 2023 after many delays.

Pharmacists in a compounding lab | Image credit: Nisit | stock.adobe.com

USP compliance has a tremendous number of moving parts, and navigating these elements can quickly become overwhelming. This is especially true for outpatient oncology practices, as many do not have a licensed pharmacy as part of their business model and therefore are not licensed under their state Board of Pharmacy. This creates a challenging situation that is arguably unique to practices operating in the outpatient oncology space.

Although much has been written about how pharmacies can achieve USP compliance, there has been very little focus from the position of outpatient oncology practices, some of which may not have access to the expertise a licensed pharmacy and personnel provides. Compliance, however, is achievable for these practices with careful planning and execution. Many of them—both large and small—are making great strides in advancing compliance. Examining key changes within these chapters that affect outpatient oncology, along with proven strategies for ensuring compliance, can help outpatient oncology practices integrate USP standards into their daily operations and meet regulatory requirements.

Ambiguity Around Compliance

A significant percentage of hazardous drugs with antineoplastic properties are prepared and administered within the outpatient oncology setting. Practices should understand who their regulators are and what requirements need to be followed, as requirements vary by state. For physician-licensed outpatient oncology practices, regulators are state Medical Boards or Societies, the Occupational Safety and Health Administration, accreditation organizations, the Centers for Medicare and Medicaid Services, and the FDA. Many organizations, such as the American Society of Clinical Oncology and the American Urological Association, have released their interpretation of USP standards,but these entities hold no enforcement authority. The bottom line is that practices must perform their own analysis and interpretation for their specific setting.

Practices often ask what the consequences are of non-compliance, and unfortunately, there is no simple answer, as it depends on the state, how the practice is licensed, and which regulatory bodies the practice falls under. Thankfully, great progress is being made in most practices – despite the ambiguity – by incorporating ISO 5 biological safety cabinets, negative pressure environments, appropriate waste management, personal protective equipment (PPE), closed system drug-transfer devices, and aseptic technique, as well as extensive training to ensure competency is achieved.

USP Changes Affecting Outpatient Oncology

Practices can begin implementing changes to better comply with USP Chapter Standards by familiarizing themselves with recent updates. Although the current Chapter <800> is nearly identical to the 2016 original draft version, several significant modifications were made to Chapter <797> from its original 2008 version. Some of the most notable changes impacting outpatient oncology include the following:^1,3,4

• A switch to Category 1, 2, and 3 along with immediate-use beyond-use dating (BUD) for compounded sterile preparations: This is a significant shift from low, medium, and high-risk categories for BUDs. Most practices will utilize immediate-use (up to 4-hour BUD) or Category 1 dating (up to 12-hour room temperature or 24-hour refrigeration) for assigning BUDs. For Category 1 dating, the biological safety cabinet needs to be placed in an unclassified containment segregated compounding area (C-SCA) which has requirements for negative pressure, external ventilation, and air changes per hour. For practices with a fully compliant cleanroom suite, Category 2 BUDs can be leveraged. However, the real value would mainly apply to batched quantities of pre-medications since most immunotherapies are not stable in solution beyond 24 hours and chemotherapy doses are often not rounded, limiting the possibility of reusing a preparation in the event of cancellation.
• Training and competency validation for personnel preparing immediate use compounded sterile preparations (CSPs): Initial and ongoing training and competency validation must include aseptic technique, hand hygiene, PPE use, and cleaning procedures. This also applies to nursing staff since they often prepare pre-medication or select non-hazardous drug preparations such as injectable irons for immediate use on a designated countertop.
• Practice standard operating procedures (SOPs) to address disinfection of re-useable PPE:This is especially important given the many provisions established during the COVID-19 pandemic, when PPE was in severe shortage. Fortunately, the supply chain has stabilized, but practices may still be reusing some PPE. SOPs must include what is considered reusable, how it will be labeled and stored, when it must be replaced, and how it will be disinfected and maintained during extended use.
• Expansion of the requirement for maintaining master formulation and compounding records to include any immediate-use preparations:For consistency and compliance, all practices must have master formulation recordsfor how all CSPs will be prepared (concentrations, compatibility, labeling, storage, BUDs, and special instructions including filtering or light protection requirements). Compounding records must also be maintained, especially when CSPs are batched or made in advance of a patient order.
• More frequent surface, media-fill and gloved-fingertip sampling (GFTS) during personnel competency testing:Personnel validation is now much more frequent for both media-fill testing and GFTS. Frequency of testing is based on BUDs butwill typically be every 6 months. GFTS presents a unique challenge within the outpatient setting due to barriers regarding using sterile gloves and the need for incubation to accurately perform the testing. There are now also requirements for surface sampling to validate cleaning of the work area. Most health systems are performing all of this in-house within their lab department, which may be beyond the capabilities of most outpatient infusion practices. This creates an opportunity to partner with nearby labs to assist with incubation of these samples.
• Requirements for viable particulate testing within all classified spaces, such as the primary engineering control (PEC) or hood and classified rooms (buffer and ante rooms):C-SCAs are not classified, and only the PEC requires sampling within that environment. Additionally, it is important that practices have an SOP in place describing how positive samples exceeding allowable limits will be addressed.
• Having a designated person with direct oversight responsible and accountable for employee training, facility operation, and preparation of CSPs:Chapter <800> created the position of a designated individual responsible for overseeing all hazardous drug handling, and now, Chapter <797> creates a similar position focused on sterile compounding, facility operations, training, validation, and maintaining SOPs and competencies. The preference is for a dual role for a single designated person in a practice.
• Addition of the following definition: “Sterile compounding is defined as combining, admixing, diluting, pooling, reconstituting, repackaging, or otherwise altering a drug bulk substance to create a sterile preparation.”Based on this definition, the vast majority of outpatient oncology infusion centers are compounding sterile preparations.

Addressing the Misconceptions

There are many misguided assumptions and misinterpretations of applicability of USP Standards for health care entities. Hopefully, the additional wording defining what USP considers to be compounding helps clarify this for those in the outpatient setting. It is indisputable that outpatient oncology practices are performing duties such as admixing, dilutions, reconstitution, and combining drugs within a preparation. For instance, consider the example of combining multiple pre-medications, electrolytes, or chemotherapy drugs into the same infusion bag for administration.

Additionally, it is important to research practice workflows and the preparations being prepared and administered to see how theycompare with definitions and directives provided by the FDA, USP, your state Medical Board, and even your state Board of Pharmacy. Specifically, the FDA offers a definition for compounding, which may be helpful:⁵ “Compounding is generally a practice in which a licensed pharmacist, a licensed physician, or, in the case of an outsourcing facility, a person under the supervision of a licensed pharmacist, combines, mixes, or alters ingredients of a drug to create a medication tailored to the needs of an individual patient.”Further, microbial contamination knows no bounds and is not prejudiced to only inpatient or licensed pharmacy environments.

Lastly, although Chapter <800> further defined antineoplastic drugs as those included in Table 1 of the most current National Institute for Occupational Safety and Health (NIOSH) List, the last official NIOSH list was published in 2016, leaving the 2020 list in draft format.^2,6,7 This creates additional work for a practice to determine whether newer drugs should be considered hazardous. A multitude of both injectable and oral drug therapies have been approved and launched since these NIOSH lists were last published, including novel antibody drug conjugates. This signals the importance of conducting a thorough review of all drugs handled in your practice to determine what precautions are necessary for maintaining employee and patient safety.

Practices should follow Chapter <800> provisions for conducting risk assessments for all hazardous drugs handled by employees.² Several notable examples would be the preparation of zoledronic acid infusions and administration of leuprolide packaged within a prefilled syringe or kit. Practices need to decide specific handling procedures for these drugs if they do not plan to utilize full precautions such as those required for preparations of cisplatin or 5-fluorouracil. Factors that go into these decisions include whether the preparation takes place within a negative-pressure biological safety cabinet, whether or not the drug can be stored within an automated dispensing cabinet, what the required level of PPE is, and how waste will be handled. While these steps are somewhat labor intensive, they offer a baseline expectation and help create consistency throughout the process. It is important to remember a hazardous drug is dangerous, regardless of the setting where it is being used. But the level of hazardous risk may be different based on how an entity handles a particular drug.

Practices Must Be Proactive About Compliance

Practices must proactively ensure compliance with USP Chapter Standards, recognizing them as minimum standards of practice rather than suggestions. It is not advisable to assume exemption from requirements or rely on interpretation from non-regulatory entities. Being proactive involves creating a path to full compliance, and neglecting compliance poses a risk to patients and employees. Patients deserve the highest level of care and safety regardless of the setting where they receive treatment, and employees deserve no less.

REFERENCES

1. United States Pharmacopeia and National Formulary (USP 41-NF 36). United States Pharmacopeial Convention; 2022; Chap 797. Accessed December 1, 2023. https://www.usp.org/compounding/general-chapter-797

2. United States Pharmacopeia and National Formulary (USP 41-NF 36). United States Pharmacopeial Convention; 2022; Chap 800. Accessed December 1, 2023. https://www.usp.org/compounding/general-chapter-hazardous-drugs-handling-healthcare

3. Hansen K, Campbell R, et al. Compounding updates: NIOSH and USP chapter updates 2022. Presented at: ASHP Midyear Clinical Meeting & Exhibition. 2022.

4. USP Compounding Standards and Beyond-Use Dates. US Pharmacopeia. Accessed January 2, 2025. https://go.usp.org/USP_Compounding_BUD_Fact_Sheet.pdf

5. Human Drug Compounding. FDA. Updates December 18, 2024. Accessed January 1, 2025. https://www.fda.gov/drugs/guidance-compliance-regulatory-information/human-drug-compounding

6. NIOSH List of Hazardous Drugs in Healthcare Settings, 2020. CDC. 2020. Accessed January 2, 2025. https://www.cdc.gov/niosh/docket/review/docket233c/pdfs/DRAFT-NIOSH-Hazardous-Drugs-List-2020.pdf

7. NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2016. CDC. 2016. Accessed January 2, 2025. https://www.cdc.gov/niosh/docs/2016-161/pdfs/2016-161.pdf