Marina Reed

	In response to the numerous concerns regarding antineoplastic drugs and other medications that may threaten the health of patients and health care workers, the National Institute for Occupational Safety and Health (NIOSH) developed a list, updated biennially, of hazardous drugs. Cancer chemotherapy, antivirals, and hormone therapies are only some of drugs listed in the 2016 NIOSH list.

	NIOSH classifies hazardous drugs as those that exhibit any of the following 6 characteristics in humans or animals: 

	A key takeaway is that because NIOSH classifies hazardous drugs based on the 1990 definition provided by the American Society of Hospital Pharmacists (ASHP, now known as the American Society of Health-System Pharmacists), the institute may not accurately classify newer pharmaceuticals, such as bioengineered drugs that are target specific. Moreover, NIOSH has not attempted to perform risk assessments on each drug or determine exposure limits.

	NIOSH groups hazardous drugs into 3 categories (

) that are primarily focused on classifying the potential for reproductive and developmental toxicity, based on the needed dose to produce toxicity in animals and/or whether adverse effects are observed in animals at or near the maximum recommended human dose.

	Three tables in the 2016 list outline the hazardous drugs and their properties, compiled from the updated 2014 NIOSH list of hazardous drugs and the 2016 update, which included 34 new drugs (

). There were no deletions from the 2014 list.

	 The NIOSH tables include a Supplemental Information column, which describes potential black box warnings and/or the FDA pregnancy category. Although the FDA removed the pregnancy letter categories for prescription labeling in 2015, the 2016 NIOSH list continues to use the that lettering system.

 Most of the drugs categorized as X and D meet the ASHP criteria for hazardous drugs and are recorded in the 2016 NIOSH list.

	The FDA definitions of the 2 most prevalent categories are as follows in 

	NIOSH recommends that in addition to using the information provided in the 2016 list of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, organizations create their own list based on their formulary.

 The third section of the NIOSH alert provides detailed information on how to create a hazardous drug list.

	Health care personnel must be aware of the risk of altering formulations. Coated tablets or capsules that are administered without modification may not pose a hazard, but if they are crushed or placed in an automated counting machine, the dust that results may pose a risk via inhalation or skin contact.

	Overall, approximately 8 million US health care workers are potentially subjected to the risks of hazardous drugs; moreover, the use of antineoplastic agents and drugs is increasing quickly. It is imperative that organizations identify the hazardous drugs on their formulary, as well as implement procedures and policies that protect their patients and workers.

		The National Institute for Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings, 2016. Centers for Disease Control and Prevention website. cdc.gov/niosh/docket/review/docket233a/pdfs/2016-161finalpublication.pdf. Published September 2016. Accessed June 22, 2017.

		US Food and Drug Administration. Content and Format of Labeling for Human Prescription Drug and Biological Products; Requirements for Pregnancy and Lactation Labeling, 73 Fed. Reg. 30831-68 (May 29, 2008).

		The National Institute for Occupational Safety and Health. Hazardous drug exposures in health care. Centers for Disease Control and Prevention website. cdc.gov/niosh/topics/hazdrug/default.html. Updated August 25, 2017. Accessed July 6, 2017.

Articles

Chemotherapy, antivirals, and hormone therapies are among the drugs addressed in the 2016 National Institute for Occupational Safety and Health list.

Key Points From the 2016 NIOSH List of Antineoplastic and Hazardous Drugs in Health Care Settings

	The new United States Pharmacopeial Convention (USP) chapter, effective January 1, 2018, focuses on specific guidelines and standards for each step in the process of handling hazardous drugs. USP <800> outlines key requirements and steps that protect both patients and health care workers from the adverse effects of hazardous drugs (HDs). These 18 pages describe the responsibilities of health care personnel, facilSity requirements—including those related to proper receipt, storage, and compounding of HDs&mdash;correct usage of personal protective equipment (PPE), and the required standard operating protocols, of which there are many. For these new USP standards to be effective, executive leaders and pharmacy departments must work together to implement these changes.

	When approaching a plan for handling HDs, leaders of each organization need to be proactive in developing their compliance with USP <800>. Leaders must recognize that not all changes can, or need to be, implemented at once. To eliminate unpredictable barriers, entities should have a defined strategy that focuses first on changes that are easy to implement. The modifications must be made in a way that minimizes interruptions to ongoing pharmacy operations; this allows the provision of continuous care to patients. 

	Determining which changes are easily implemented and which are not—or even which changes need to be made at all&mdash;can be a huge task by itself. Therefore, organizations should, according to Sahadeo and Weber (2015), compile a team of “pharmacy experts in supply chain management, compounding, hazardous drugs (oncology pharmacists), and pharmacy administration” to perform a gap analysis and identify key areas that need attention.

	Areas to include in the gap analysis are the current hazardous drug list and how it compares with the 2016 National Institute for Occupational Safety and Health (NIOSH) list of antineoplastic and other hazardous drugs in health care settings; the existing policies and procedures for handling HDs, including PPE; and the training received by personnel who are potentially exposed to HDs. Seeking input from workers who have handled or currently handle HDs can provide a different perspective and additional information on how effective the existing training and policies are.

	Section 2 in USP <800> requires organizations to maintain a list of hazardous drugs that is reviewed and updated annually. The 2016 NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings can be used, as can Material Safety Data Sheets, FDA approved package inserts, and special health warnings from manufacturers. Reports and case studies published in medical and other health care professional journals, along with evidence-based recommendations, can be used if they meet the criteria for defining hazardous drugs.  

	A key acknowledgment is that some dosage forms that do not pose a risk in their current formulation (eg, tablets and capsules) may be hazardous when exposed to skin or inhaled due to residual dust. USP suggests performing a risk assessment for these formulations to determine “alternative containment and work practice strategies.” 

	Overall, when assessing a drug and its potential risk, USP <800> encourages entities to take a “more conservative approach when there is uncertainty.” 

Policies, Procedures, and Standard Operating Protocols 

	Multiple sections in USP <800> require entities to establish policies and procedures at each step of the HD handling process to ensure safety. One policy is the minimum required training for all potentially exposed health care personnel. The training must encompass the entire HD handling cycle. 

	The training should include an overview of the list of HDs and the HDs’ accompanying risks, a review of standard operating procedures (SOPs) associated with HD handling, proper use of PPEs, proper use of equipment and devices, response to known or suspected HD exposure, and proper disposal of HDs and trace-contaminated materials.

	In addition to the required training, USP mandates that personnel who handle HDs demonstrate competency in proper handling. This assessment must be documented, and each employee is subjected to annual reassessment. Moreover, personnel who are of reproductive age must confirm in writing that they understand the risk associated with handling HDs. Similar to the reassessment of competency in proper HD handling for personnel, the compounding supervisor must maintain and reassess SOPs for the safe handling of HDs every 12 months. 

		Designation of HD areas for receipt, storage, compounding

		Use and maintenance of proper engineering controls

		Deactivation/decontamination/cleaning/disinfection

	The USP Convention’s new chapter on handling hazardous drugs in health care settings will require hospital-based pharmacies to spend millions of dollars on upgrades of facilities and equipment; however, proactive and efficient preparations will hopefully mean well-spent money that leads to higher-quality practices and safer patients and employees.

		Beans BE. USP <800> adds significant safety standards: facility upgrades needed to protect employees from hazardous drugs. 

		Sahadeo P, Weber RJ. USP <800>: key considerations and changes for health systems. 

. 2015;50(10):941-949. doi: 10.1310/hpj5010-941.

		NIOSH [National Institute for Occupational Safety and Health] alert: preventing occupational exposures to antineoplastic and other hazardous drugs in health care settings. CDC/NIOSH website. 

https://www.cdc.gov/niosh/docs/2004-165/pdfs/2004-165.pdf#page=37

. Published September 2004. Accessed June 23, 2017.

		The United States Pharmacopeial Convention. General Chapter <800> Hazardous Drugs - Handling in HealthCare. 

http://www.usp.org/frequently-asked-questions/hazardous-drugs-handling-healthcare-settings

When approaching a plan for handling hazardous drugs, leaders of each organization need to be proactive in complying with USP  regulations.

Developing a Plan for Hazardous Drug Handling

EACH YEAR, MORE THAN 8 MILLION US health care personnel are potentially exposed to hazardous medications. Since the 1970s, the literature has indicated the possible harmful effects on health care workers from low-level work-related exposure to any of more than 200 medications that are considered hazardous drugs (HDs). Acute and chronic health effects have been reported, including headaches, ocular problems, rashes, hair loss, adverse reproductive health, and increased cancer risk.

Prior to USP <800>, the main guidance related to the handling of HDs was USP <797>. This regulation described the proper guidelines for sterile compounding of both hazardous and nonhazardous drugs, with a main goal of preventing harm to patients that could result from microbial or other contamination of sterile products; however, USP <797> lacked standards for the handling of HDs.

USP <800> outlines new quality-of-practice standards for handling HDs that not only promote patient safety, but also the safety of health care personnel who are exposed daily to HDs. The chapter, effective July 1, 2018, includes the entire drug handling process, from receipt to the proper disposal of both sterile and nonsterile products:

Compounding supervisor: section 4 contains a unique requirement for organizations to designate a “compounding supervisor” who is qualified and trained in every aspect of the HD handling process. The United States Pharmacopeial Convention (USP) does not go into detail about specific credentials or even if the position needs to be in the pharmacy department. As a result, pharmacy leaders have flexibility when either creating a new position within the pharmacy department or assigning more responsibility to an existing position. USP stresses that the person designated with this responsibility understands the reasoning for HD risk-prevention policies, the risk HDs pose to everyone, and the risk of noncompliance. The compounding supervisor is responsible for the “oversight of monitoring the facility and maintaining reports of testing/sampling performed in facilities.” 

Facility requirement: section 5 is broken into 4 subsections: receipt, storage, compounding, and containment supplemental engineering controls. In general, Section 5 states that HDs must be handled at each stage in a manner that promotes patient safety, employee safety, and environmental protection. For example, every entrance to HD handling areas must display a noticeable sign regarding the hazard. One key requirement is the designation of HD-specific areas for receipt and unpacking, storage, nonsterile compounding, and sterile compounding. This requirement can present challenges to organizations because it requires multiple spaces designated to specific steps in the HD handling process, most of which must have negative pressure from surrounding areas.

Receipt: USP <800> requires unpacking of HDs and HD active pharmaceutical ingredients (APIs) from the original container to be done in a neutral-pressure or negative-pressure room, reducing the risk of HD contamination outside of the pharmacy area through airborne spread. Moreover, it is imperative that unpacking is not done in sterile compounding areas or positive pressure areas.

Storage: USP <797> placed HDs in a separate space to prevent contamination and personal exposure. However, USP <800> takes the 2014 National Institute for Occupational Safety and Health (NIOSH) HD stratification into consideration, stating that nonantineoplastic HDs, reproductive risk-only HDs, and final dosage forms of antineoplastic HDs can be stored with nonhazardous drugs in inventory. Antineoplastic drugs or HD APIs requiring manipulation other than counting the final dosage must be stored separately from nonhazardous drugs in a negative pressure room with at least 12 air changes per hour (ACPH). In addition, refrigerated antineoplastic HDs must be stored separately from nonhazardous drugs in a dedicated refrigerator in a negative-pressure area with at least 12 ACPH.

Compounding: USP <800> mandates engineering controls to be used in all stages of the compounding process to protect from cross-contamination and microbial contamination2,3 and classifies these controls as primary, secondary, and supplemental, as shown in the Table 13. Sterile and nonsterile compounding facilities should also be considered, as shown in Table 2.

One key point is the use of a containment segregated compounding area (C-SCA), an ISO unclassified containment secondary engineering control (C-SEC) with minimal requirements for airflow and room pressure. Still, C-SCAs are segregated, maintain negative pressure, and have appropriate air exchange. A C-SCA can replace a C-SEC during sterile compounding only for low- and medium-risk drugs with beyond-use dating limited to 12 hours. Overall, a C-SCA is a less expensive option, providing a benefit to clinics that do not have the required infrastructure.

Closed-system transfer devices: closed-system transfer devices (CSTDs) are C-SECs. In 2004, NIOSH cited a US investigation that demonstrated that the use of CTSDs for 6 months helped reduce the concentrations of drugs previously detected in the urine of health care personnel. When dosage form allows, CSTDs should be used when compounding HDs; they are required when administering antineoplastic HDs. However, USP states there is no certainty that all CSTDs will perform adequately. Entities should carefully assess the performance claims about available CSTDs based on “independent, peer-reviewed studies and demonstrated containment reduction.”

Environmental quality and control: environmental wipe sampling for HD surface residue should be performed initially and every 6 months thereafter. The sampling should expand from the interior and equipment of containment primary engineering controls to the patient administration areas. USP acknowledges the lack of studies on the effectiveness of wipe sampling kits, addressing the ambiguity on the correct number and size of wipe samples. It states that wipe sampling kits should be verified before use.

Personal protective equipment (PPE): although USP <800> outlines guidelines for the use of PPE, it requires that entities address all activities not listed in section 7 by developing appropriate standard operating protocols (SOPs) for PPE use. Specifics of this section include the use of gloves, gowns, and head, hair, and shoe covers when compounding sterile and nonsterile HDs. Additionally, gloves, which must meet the American Society for Testing and Materials standard D6978, should be worn for all HD handling (antineoplastic, nonantineoplastic, and reproductive risk only). USP requires all personnel administering chemotherapy to use 2 pairs of gloves and requires the use of HD permeability-resistant gowns when administering any injectable HD.

Spill prevention: SOPs must be developed for spill prevention and containment; moreover, all personnel required to clean up an HD spill must receive proper training in spill management, use of PPE, and NIOSH-certified CTSDs. The SOPs must address the size and scope of a spill, who is responsible, and the type of PPE required.

Medical surveillance program: in section 18, USP addresses the medical surveillance program as part of a “comprehensive exposure control program” that complements the engineering control systems described earlier. This secondary prevention tool is a proactive approach to minimize adverse health effects in those who were potentially exposed. It encompasses early detection of health problems as it progresses and compares trends in the health care personnel population. Key elements of the program are outlined in this section, including the development of an approach to recognize personnel who were potentially exposed to HDs, as well as a follow-up plan if changes are found related to drug toxicity. USP stresses the importance of consistency with the entity’s human resource policies and confidentiality when handling employee medical records.

USP <800> is intended to provide a standardized guideline because tight control of each step in the HD lifecycle is necessary. Overall, properly educating pharmacy workers and physicians—as well as risk management, legal, and drug delivery personnel&mdash;is crucial in providing quality protection to patients and their health care team.

1. Beans BE. USP <800> adds significant safety standards: facility upgrades needed to protect employees from hazardous Drugs. P T. 2017;42(5):336-339.

2. Sahadeo P, Weber RJ. USP <800>: key considerations and changes for health systems. Hosp Pharm. 2015;50(10):941-949. doi: 10.1310/hpj5010-941.

3. The United States Pharmacopeia Convention. General chapter <800> Hazardous Drugs - Handling in HealthCare. http://www.uspnf.com/uspnf/pdf/download?usp=40&nf=35&s=0&q=usp40nf35s0_c800.pdf&officialOn=May1,2017&target=oldwindow&time=1498237873336. Accessed June 23, 2017.

4. National Institute for Occupational Safety and Health. NIOSH alert preventing occupational exposures to antineoplastic and other hazardous drugs in health care settings. cdc.gov/niosh/docs/2004-165/pdfs/2004-165.pdf#page=37. Accessed June 23, 2017.&ensp;

The chapter, effective July 1, 2018, includes the entire drug handling process, from receipt to the proper disposal of both sterile and nonsterile products:

Quality-of-practice Standards for Handling Hazardous Drugs: What You Should Know

 US health care personnel are potentially exposed to hazardous medications. Since the 1970s, the literature has indicated the possible harmful effects on health care workers from low-level work-related exposure to any of more than 200 medications that are considered hazardous drugs (HDs). Acute and chronic health effects have been reported, including headaches, ocular problems, rashes, hair loss, adverse reproductive health, and increased cancer risk.

USP <800> outlines new quality-of-practice standards for handling HDs that not only promote patient safety, but also the safety of health care personnel who are exposed daily to HDs. The chapter, effective July 1, 2018, includes the entire drug handling process, from receipt to the proper disposal of both sterile and nonsterile products

 section 4 contains a unique requirement for organizations to designate a “compounding supervisor” who is qualified and trained in every aspect of the HD handling process. The United States Pharmacopeial Convention (USP) does not go into detail about specific credentials or even if the position needs to be in the pharmacy department. As a result, pharmacy leaders have flexibility when either creating a new position within the pharmacy department or assigning more responsibility to an existing position. USP stresses that the person designated with this responsibility understands the reasoning for HD risk-prevention policies, the risk HDs pose to everyone, and the risk of noncompliance. The compounding supervisor is responsible for the “oversight of monitoring the facility and maintaining reports of testing/sampling performed in facilities.” 

 section 5 is broken into 4 subsections: receipt, storage, compounding, and containment supplemental engineering controls. In general, Section 5 states that HDs must be handled at each stage in a manner that promotes patient safety, employee safety, and environmental protection. For example, every entrance to HD handling areas must display a noticeable sign regarding the hazard. One key requirement is the designation of HD-specific areas for receipt and unpacking, storage, nonsterile compounding, and sterile compounding. This requirement can present challenges to organizations because it requires multiple spaces designated to specific steps in the HD handling process, most of which must have negative pressure from surrounding areas.

USP <800> requires unpacking of HDs and HD active pharmaceutical ingredients (APIs) from the original container to be done in a neutral-pressure or negative-pressure room, reducing the risk of HD contamination outside of the pharmacy area through airborne spread. Moreover, it is imperative that unpacking is not done in sterile compounding areas or positive pressure areas.

 USP <797> placed HDs in a separate space to prevent contamination and personal exposure. However, USP <800> takes the 2014 National Institute for Occupational Safety and Health (NIOSH) HD stratification into consideration, stating that nonantineoplastic HDs, reproductive risk-only HDs, and final dosage forms of antineoplastic HDs can be stored with nonhazardous drugs in inventory. Antineoplastic drugs or HD APIs requiring manipulation other than counting the final dosage must be stored separately from nonhazardous drugs in a negative pressure room with at least 12 air changes per hour (ACPH). In addition, refrigerated antineoplastic HDs must be stored separately from nonhazardous drugs in a dedicated refrigerator in a negative-pressure area with at least 12 ACPH.

USP <800> mandates engineering controls to be used in all stages of the compounding process to protect from cross-contamination and microbial contamination

 and classifies these controls as primary, secondary, and supplemental, as shown in the Table 1

. Sterile and nonsterile compounding facilities should also be considered, as shown in Table 2

closed-system transfer devices (CSTDs) are C-SECs. In 2004, NIOSH cited a US investigation that demonstrated that the use of CTSDs for 6 months helped reduce the concentrations of drugs previously detected in the urine of health care personnel. When dosage form allows, CSTDs should be used when compounding HDs; they are required when administering antineoplastic HDs. However, USP states there is no certainty that all CSTDs will perform adequately. Entities should carefully assess the performance claims about available CSTDs based on “independent, peer-reviewed studies and demonstrated containment reduction.”

 environmental wipe sampling for HD surface residue should be performed initially and every 6 months thereafter. The sampling should expand from the interior and equipment of containment primary engineering controls to the patient administration areas. USP acknowledges the lack of studies on the effectiveness of wipe sampling kits, addressing the ambiguity on the correct number and size of wipe samples. It states that wipe sampling kits should be verified before use.

: although USP <800> outlines guidelines for the use of PPE, it requires that entities address all activities not listed in section 7 by developing appropriate standard operating protocols (SOPs) for PPE use. Specifics of this section include the use of gloves, gowns, and head, hair, and shoe covers when compounding sterile and nonsterile HDs. Additionally, gloves, which must meet the American Society for Testing and Materials standard D6978, should be worn for all HD handling (antineoplastic, nonantineoplastic, and reproductive risk only). USP requires all personnel administering chemotherapy to use 2 pairs of gloves and requires the use of HD permeability-resistant gowns when administering any injectable HD.

 SOPs must be developed for spill prevention and containment; moreover, all personnel required to clean up an HD spill must receive proper training in spill management, use of PPE, and NIOSH-certified CTSDs. The SOPs must address the size and scope of a spill, who is responsible, and the type of PPE required.

 in section 18, USP addresses the medical surveillance program as part of a “comprehensive exposure control program” that complements the engineering control systems described earlier. This secondary prevention tool is a proactive approach to minimize adverse health effects in those who were potentially exposed. It encompasses early detection of health problems as it progresses and compares trends in the health care personnel population. Key elements of the program are outlined in this section, including the development of an approach to recognize personnel who were potentially exposed to HDs, as well as a follow-up plan if changes are found related to drug toxicity. USP stresses the importance of consistency with the entity’s human resource policies and confidentiality when handling employee medical records.

USP  outlines new quality-of-practice standards for handling hazardous drugs that promote the safety of patients and health 