Over the past 3 years, numerous articles have addressed the requirements of the recently finalized United States Pharmacopeia (USP) General Chapter <800>, which becomes official on July 1, 2018. Once official, state boards of pharmacy may codify and require compliance. Most of this discussion has focused on sterile hazardous drug (HD) preparation; nevertheless, there is a significant, oftentimes unrealized risk in manipulating and preparing non-sterile HDs. Both USP <800> and the National Institute for Occupational Safety and Health (NIOSH) provide specific guidance, requirements and recommendations for receiving, storing, compounding, and handling non-sterile HDs within the pharmacy.

Considerations for Non-Sterile HD Compounding

An HD is defined as having carcinogenicity, teratogenicity or developmental toxicity, reproductive toxicity in humans, organ toxicity at low doses, or genotoxicity; in addition, a new drug that has a similar structure to an existing HD may be defined as an HD.1 These drugs must be prepared and handled with the goal of protecting health care workers and hospital employees, primarily through containment strategies.

While there is some flexibility in how health systems approach protecting employees from hazardous substances, certain requirements are mandatory; for example, requirements for primary and secondary engineering controls are described at length in USP <800> and all facilities are required to establish a site-specific list of HDs. To begin, organizations should set standardized definitions of hazardous medications and categorize them appropriately. USP <800> allows for two approaches: either all HDs are handled under USP <800> requirements, including bulk powders or active pharmaceutical ingredients (APIs); or an Assessment of Risk is performed for select dosage forms of HDs that are not antineoplastic, but do require manipulation. As part of this undertaking, consider the drug, risk of exposure, and the type of manipulations that may or may not occur throughout the medication-use process. For example, a medication that is manipulated (eg, crushing a tablet or preparing an injection for dispensing) may require hazardous categorization; conversely, if it is received in a final dispensable form—wherein its risk is mitigated—it may not require such categorization.2

Choosing a C-PEC

Containment primary engineering controls (C-PECs) may be required when manipulating non-sterile HD dosage forms, as exposure to particles or dust is possible. The C-PEC must provide protection to the compounder and to the environment during HD compounding or manipulation. A containment ventilated enclosure (CVE), Class I biological safety cabinet (BSC), or a Class II BSC may be used; each has its attendant advantages and disadvantages.

• A Class I BSC does not protect the product being handled; however, it does protect the environment and personnel from exposure to the product being manipulated. Class I BSCs may be ductless (ie, not externally vented), which requires a redundant (double) HEPA filter prior to returning exhaust into the room or must be exhausted outside of the building. Certain Class I BSC models can be converted from non-vented to vented, which may be an important consideration when choosing a cabinet.
• Class II BSCs, which are commonly used during sterile compounding, offer environmental, personnel, and product protection. If a Class II BSC is utilized to compound sterile and non-sterile products at a facility, the BSC must be thoroughly disinfected and decontaminated prior to compounding in order to ensure the sterility of the direct compounding area. Bringing non-sterile products/ingredients into a sterile environment increases the risk of further contaminating a sterile PEC. Ideally, a Class II BSC should be designated solely for non-sterile compounding.

Regardless of the C-PEC chosen, USP <800> states that a Class I CVE and Class II BSC or compounding aseptic containment isolator (CACI) must be externally ventilated (out of the building) or a Class I CVE must use a redundant HEPA filter. C-PECs must be placed within a separate room, referred to as the containment secondary engineering control (C-SEC). Unlike in sterile compounding, the area does not require ISO Class 5 or 7 air quality. However, the C-SEC must be physically separated, operate under negative pressure (0.01”-0.03” w.c.), and have less than 12 air changes per hour.2

Developing Policies and Procedures

Organizations must consider the risk of exposure and create appropriate policies and procedures (P&Ps) for the manipulation of non-sterile HDs. NIOSH and USP Chapter <800> require the use of two pairs (ie, double gloves) of American Society for Testing and Materials (ASTM)-approved chemotherapy gloves and a protective gown for any type of HD preparation.³ Gloves must be powder free and inspected for physical defects before use. Sterile gloves are required when performing sterile compounding. To provide increased protection, USP recommends that disposable gowns be coated in a laminate material. These gowns must be long sleeved, have elastic or knit closed cuffs, and close in the back. All personal protective equipment (PPE) must be disposed of in an appropriate waste container and cannot be reused.2

Cleaning and Maintaining Quality

Equipment and areas where HDs are handled should be cleaned regularly; in addition, the compounding area must be decontaminated after any spill occurs, when contamination is suspected, at the beginning and end of each shift, in 30-minute intervals when drug handling is ongoing, and before and after certification.

USP <800> describes four steps to cleaning HD areas: deactivation, decontamination, cleaning, and disinfection (see Table 1). While in-depth cleaning is typically associated with sterile preparations, it is just as important for non-sterile areas. When cleaning HD handling areas, clean from the cleanest area to the dirtiest and from top to bottom to reduce the possibility of contamination. Agents used for cleaning should be assessed to ensure they are appropriate for the specific HDs used and for the specific surface being cleaned.

Prior to USP <800>, pharmacies typically developed competencies or learning modules focused primarily on sterile product preparation. With the implementation of USP <800>, pharmacy staff that usually works outside of a sterile preparation area must receive appropriate HD training, demonstrate competency, and thereafter be reevaluated at least every 12 months.

Conclusion

Non-sterile HDs are frequently encountered in various health care settings. Risks when preparing and manipulating non-sterile HDs should be carefully considered. Risk mitigation requires the ability to identify which drugs belong in this category, establishing an appropriate, designated area for the preparation and manipulation of these drugs, the proper use of PPE, and a mastery of the proper cleaning techniques. In addition, developing a P&P and properly training all personnel reinforces the importance of safety in non-sterile HD preparation and manipulation.

References

1. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990;47(5):1033-1049.
2. USP <800> Hazardous Drugs—Handling in Healthcare Settings. United States Pharmacopoeia Web Site. www.usp.org/sites/default/files/usp_pdf/EN/m7808.pdf. Accessed August 9, 2016.
3. National Institute for Occupational Safety and Health. NIOSH Pocket Guide to Chemical Hazards. Dept. of Health and Human Services, Center for Disease Control and Prevention, National Institute for Occupational Safety and Health, 2014.
4. Department of Health and Human Services. Centers for Disease Control and Prevention. NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2014. http://www.cdc.gov/niosh/docs/2014-138/pdfs/2014-138.pdf. Accessed October 7, 2016.