USP : Key Changes and Additions to USP

Hazardous drug contamination is an issue of vital importance for specialty pharmacists. Abundant evidence has shown links between the handling of hazardous drugs (HDs) and increased risks for cancer, teratogenicity, and reproductive problems.

The risks surrounding the handling and manipulation of HDs have been recognized since the late 1970s, with more than 17 guidelines for HDs published over more than 30 years by 6 organizations and government agencies. However, despite the meticulous attention focused on drug safety, HD handling regulations continue to change.^1-7

Although the US Pharmacopeial Convention (USP) addressed HDs in a 2008 update to USP <797> for the issue of compounding sterile parenteral HDs, the update fell short due to a lack of guidance for nonparenteral products. As a result, in March 2014, USP published a proposed set of guidance known as USP <800> that dealt with HD handling in health care settings.

In the nearly 2 years since its initial publication in draft form, USP <800> has undergone periods of public comment and revision. As of February 1, 2016, USP <800> is approved and final.^3,7-9

Enforceability and Key Changes

Due to provisions of USP numbered below 1000 being legally enforceable, following the adoption of these rules by individual state boards, USP <800> may subject pharmacies to both state board and FDA inspections.

Like USP <797> and USP <795>, the provisions of proposed USP <800> deal with product transport, product storage, compounding, preparation, and administration of parenteral products. However, USP <800> builds on earlier regulations by focusing on HDs and occupational safety.

The regulations require HD storage and preparation in areas separate from non-HDs and will eliminate the practice of compounding small volumes of HDs in areas where non-HDs are routinely prepared, which is allowed under USP <797>.

In another important change, USP <800> requires the administration of HDs with the use of closed-system transfer devices (CSTDs) to minimize HD exposure to nurses who administer these drugs to patients.^5,7-9

The new requirements in USP <800> may pose major implementation challenges for pharmacists and pharmacy managers, as certain provisions may require pharmacies to change workflow patterns and make major purchasing decisions. In addition, limited financial resources may pose an important challenge to implementation of USP <800> regulations.

It is important to be familiar with the provisions of these proposed regulations and to take early steps to reduce implementation difficulties later on.⁸

USP <797>: Adoption of and Compliance With Existing Regulations

Although compliance with USP <797> has improved over time, current legislation governing sterile product compounding is a patchwork of state-specific regulations with wide variations between jurisdictions.

Despite the fact that USP <797> is a legally enforceable standard irrespective of state-specific legislation, only about half of state regulations specifically reference USP <797> in sterile compounding rules.^4,8

In a nationwide survey conducted in 2014, two-thirds of respondents from 719 pharmacies throughout the United States and Canada reported handling HDs. Several reasons were cited by respondents for a lack of full USP <797> compliance (Figure 1).

State pharmacy boards, including the state boards of California, Florida, Minnesota, and Texas, have conducted inspections ensuring compliance with USP <797> standards in hospitals. Partially as a result of this increased regulatory oversight, between 2011 and 2014, self-reported compliance rates with USP <797> increased from 73.9% to 81.3% for sterile products and from 71.3% to 75.4% for hazardous drugs (Figure 2).⁸

Primary Engineering Controls for HDs

Of the primary engineering controls used to protect health care workers from HDs, the 2014 survey found that Class II biological safety cabinets (BSCs) were the most common equipment used for HD compounding, followed by compounding aseptic containment isolators (CACIs).

Under USP <800>, Class II BSCs or CACIs remain the standard primary engineering controls for preparation of sterile HDs.⁸ For nonsterile HD compounding, primary engineering controls include externally vented Class I BSCs and containment-ventilated enclosures (CVEs).

Because Class I BSCs and CVEs prevent the escape of HDs but do not guarantee product sterility, these cannot be used for preparation of sterile HDs. USP <800> continues to allow Class II BSCs and CACIs to be used for nonsterile compounding.

However, a BSC or CACI that is used for nonsterile HD compounding must be dedicated for that purpose only. Switching back and forth from nonsterile to sterile HD compounding in a CACI or BSC without thorough cleaning and disinfection is not permissible.^7,10

Negative-Pressure Environments: A New Requirement

Regardless of the type of primary engineering control used, under USP <800>, HD preparation must always occur in a negative-pressure environment. Currently, many BSCs and CACIs reside in positive-pressure or neutral-pressure environments.

Building a clean room is one way to meet the negative-pressure environment requirement. However, this is prohibitively expensive for many organizations. Some organizations may opt for a less expensive alternative: building a negative-pressure containment segregated compounding area (C-SCA) that is vented to the outside, with at least 12 air changes per hour.

Unlike clean rooms, these negative-pressure environments do not need to meet the standards of the International Organization for Standardization. However, sterile products prepared in C-SCAs may have a shorter beyond-use date (12 hours) than sterile products prepared in clean rooms.^7,8

In addition to the costs for building a negative-pressure environment, pharmacies may need to purchase additional primary engineering controls (eg, BSCs, CACIs, and CVEs) to use in negative-pressure rooms dedicated to HD preparation.

Under USP <797>, pharmacies could prepare HDs using the same BSCs or CACIs used for non-HDs (provided the volume of HD prescriptions was not very high). This provision is often referred to as the, “low-volume exception.”

With the implementation of USP <800>, however, this exception will be eliminated.^7,8

Because negative-pressure rooms intended for HD compounding cannot be used for non-HD compounding, USP <800> regulations will require pharmacies to furnish a separate negative-pressure room with an additional primary engineering control system used exclusively for HD compounding.

It is unlikely that pharmacies will simply discontinue compounding HDs, as the scope and range of products considered HDs has expanded considerably beyond antineoplastic drugs through HD definitions set by the National Institute for Occupational Safety and Health (NIOSH).^7,8,11

HDs as Defined by NIOSH

USP <800> uses a broad definition of HDs set by NIOSH that include drugs in any of 6 categories: carcinogenic drugs, teratogenic drugs, reproductive toxins, drugs with organ toxicity at low doses, genotoxic drugs, or new drugs that mimic existing HDs.

This list may be useful as a starting place in distinguishing between HDs and non-HDs. However, each institution will need to develop its own individual list.

The NIOSH list, which was last updated in 2014, is available at cdc.gov/niosh/docs/2014-138/pdfs/2014-138.pdf.

As the list is updated every 2 years, a revised list is expected later this year. Sample products from the list are listed in the Table.¹¹

Reviewing the current list and demarcating HDs from non-HDs is a useful first step in preparing for USP <800>. Importantly, USP <800> regulations mandate reviewing the HD list (and documenting the review process) at least once each year.^7,11

Receiving and Storage of HDs

USP <800> requires the receipt and unpacking of antineoplastic HDs in a negative-pressure or neutral-pressure area. It also requires storage of most HDs in a negative-pressure room with at least 12 air changes per hour (some HDs, such as capsules or film-coated tablets, may be kept with non-HDs if certain precautions are in place).

Additionally, USP <800> requires storage of all HDs in a separate refrigerator from non-HDs, with the HD refrigerator kept in a negative-pressure room with at least 12 air changes per hour. These regulations may require pharmacies to build additional storage areas and purchase additional refrigerators.^7,8

Handling HDs and Supplemental Engineering Controls

For many HDs, exposure can occur not only during the receipt, transport, storage, compounding, and dispensing of medications (typically handled by pharmacy staff), but also via activities managed by nurses.

These nursing activities include exposure during the administration of hazardous parenteral medications and contact with the bodily fluids of patients taking HDs in the course of patient care activities.^7,8

Supplemental engineering controls, such as CSTDs, have an important role in protecting health care workers from occupational exposure to HDs. Once connected to the reservoir, such as a drug vial, CSTD devices equalize the pressure gradient between the vessel containing the drug and the syringe.

Without a pressure equalization system, differences in pressure can generate fine aerosols. These aerosols may escape into the air and expose the environment, patients, and health care professionals to HDs.

Whereas some CSTDs equalize pressure using a pressure equalization chamber, other CSTDs use an integrated filter to cleanse escaping air contaminated with hazardous drug vapors or aerosols.^12,13

Although the use of CSTDs in the pharmacy is recommended during preparation of HDs but not required under USP <800>, the regulations require nurses to use a CSTD when administering HDs to patients. Although CSTDs can be used by nurses in most cases, some highly reactive alkylating agents (eg, bendamustine) may not be compatible with CSTD materials.

In these rare cases, the USP <800> regulations recognize that a CSTD cannot be used.^12-14

CSTD Selection

USP <800> introduces many new provisions that will eventually require hospital pharmacies to build additional storage rooms and compounding areas, and to purchase additional primary engineering controls (eg, BSCs, CACIs, and CVEs) to ensure that HDs are prepared separately from non-HDs.

Additionally, because hospitals will eventually gain access to CSTDs in nursing units, they may also extend CSTD use to hospital pharmacies.^12,13

The CSTD selection process should include several considerations^12,13:

• Adherence with the closed system definition set by NIOSH, the Oncology Nursing Society (ONS), and International Society of Oncology Pharmacy Practitioners (ISOPP) as a device that is mechanically closed, prevents anything from entering the system, and does not allow drug or drug vapor to exit the system
• Consideration of published literature on maintenance of dry connections (membrane litmus testing, fluorescence dye testing, or smell tests)
• Consideration of ease-of-use and ergonomic concerns
• Collaboration with nursing stakeholders to coordinate acquisition of CSTDs suitable for use in both pharmacy and nursing settings

Three key design considerations include:

• Whether or not the CSTD is needle-free or has a hidden needle
• Whether or not the pressure equalization system of the CSTD is filter-based or mechanically closed to contain aerosols
• Whether the connection mechanism is based on Luer connection or a double-membrane connection to maintain a dry connection site

Available CSTDs include the BD PhaSeal System, Spiros, Texium/SmartSite, Tevadaptor, ChemoClave, ChemoLock, VialShield, and Equashield/Equashield II.^12,13

In 2015, NIOSH published a draft containment protocol for testing which CSTD systems are effective in preventing vapors and liquids from escaping into the surrounding environment.

Although this protocol excludes CSTDs that use air-cleansing systems, it allows vapor containment testing under the NIOSH protocol for most commonly used products on the market, including the BD Phaseal System, Spiros, ChemoLock, VialShield, and Equashield/Equashield II.

Of these, only the BD Phaseal System and Equashield/Equashield II have the preferential characteristic of a double-membrane connector. Other differences between products should be discussed with company representatives.¹³

In terms of efficacy data, published evidence supports the protective efficacy of both the BD PhaSeal System and Equashield/Equashield II.

For example:

• More than 25 published studies support the performance and efficacy of the BD PhaSeal System in protecting health care workers from hazardous drugs (see bd.com/pharmacy/phaseal/evidence/studies.asp).
• Sessink et al (2011) reported levels of surface contamination of antineoplastic drugs in 22 US hospitals before and several months after adoption of the BD PhaSeal CSTD system. Levels of surface contamination with all 3 antineoplastic drugs sampled were significantly lower: cyclophosphamide (95% reduction; P <.0001), ifosfamide (90% reduction; P <.001), and 5-fluorouracil (65% reduction; P <.01).15
• Wick and colleagues (2003) determined that the BD PhaSeal system led to real-world reductions in personnel exposure. Before and 6 months after implementation of the BD PhaSeal CSTD in a hospital pharmacy, all personnel were evaluated using 24-hour urine samples. Of 8 employees, 6 showed evidence of cyclophosphamide exposure and 2 showed evidence of ifosfamide exposure prior to the use of the BD PhaSeal System. After implementation, none of the 8 employees had evidence of cyclophosphamide or ifosfamide in their urine samples.¹⁶
• Clark and colleagues (2013) reported the efficacy of the EquaShield CSTD in reducing surface contamination at a single cancer center before and after the system’s adoption. Researchers used a kit to collect samples from 5 areas of the pharmacy, 5 areas of the infusion suite, and 2 areas in offices. Whereas approximately half of the samples showed contamination before adoption of the system, no contamination with cyclophosphamide or 5-fluorouracil was identified in the final sample collection (for other evidence see equashield.com/).¹⁷

Final Thoughts

Although USP <800> introduces multiple new requirements for pharmacies, this legislation is intended to protect pharmacists, nurses, pharmacy technicians, and others from the potential carcinogenic and teratogenic effects of HDs.

By taking early, proactive steps to implement key areas of USP <800>, pharmacists can minimize the disruptive effects of these new guidelines and make decisions now that will reduce costs later when specialized pharmacy building contractors are inundated with remodeling projects and hospitals are scrambling to choose appropriate supplemental engineering controls.

Michael Page, PharmD, RPh, has worked as a community pharmacist at CVS Pharmacy and is currently clinical editor in clinical and scientific affairs at Pharmacy Times.

References

• Falck K, Gröhn P, Sorsa M, Vainio H, Heinonen E, Holsti LR. Mutagenicity in urine of nurses handling cytostatic drugs. Lancet. 1979;1(8128):1250-1251.
• Massoomi F. Safe handling of hazardous drugs: an evolving legislative and regulatory landscape. ProCE Inc website. s3.proce.com/res/pdf/PharMEDium2015Aug.pdf. Accessed January 2016.
• Bui S. USP chapter <800> proposal and revisions. Texas Society of Health-System Pharmacists website. tshp.org/uploads/2/9/1/1/2911890/bui_handout.pdf. Accessed January 2016.
• Jenkins MT. USP chapter <800>: handling hazardous medications in healthcare settings. Virginia Society of Health-System Pharmacists website. www.vshp.org/uploads/6/3/6/0/6360223/jenkins_slides.pdf. Accessed January 2016.
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• An update on protecting health care practitioners and patients from hazardous drugs. American Society of Health Systems Pharmacists website. ashpadvantagemedia.com/downloads/2015-USP800-discussion-guide.pdf. Accessed January 2016.
• United States Pharmacopeial Convention (USP). USP-NF general chapter <797>: pharmaceutical compounding—sterile preparations.
• Introduction to biological safety cabinets. Baker Company website. bakerco.com/introduction-biological-safety-cabinets. Accessed January 2016.
• NIOSH list of antineoplastic and other hazardous drugs in healthcare settings, 2014. Centers for Disease Control and Prevention website. cdc.gov/niosh/docs/2014-138/pdfs/2014-138.pdf. Accessed January 2016.
• Preventing occupational exposures to antineoplastic drugs. cdc.gov/niosh/docs/2004-165/pdfs/2004-165.pdf. Centers for Disease Control and Prevention website. Accessed January 2016.
• Page MR. Closed-system transfer devices: design characteristics and evolving performance standards. Specialty Pharmacy Times website. specialtypharmacytimes.com/publications/specialty-pharmacy-times/2015/december-2015/closed-system-transfer-devices-design-characteristics-and-evolving-performance-standards. Published December 10, 2015. Accessed January 2016.
• Treanda (bendamustine hydrochloride) Solution by Teva: FDA statement - not compatible with closed system transfer devices, adapters, and syringes containing polycarbonate or acrylonitrile-butadiene-styrene. US Food and Drug Administration website. www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm437626.htm. Accessed January 2016.
• Sessink PJ, Connor TH, Jorgenson JA, Tyler TG. Reduction in surface contamination with antineoplastic drugs in 22 hospital pharmacies in the US following implementation of a closed-system drug transfer device. J Oncol Pharm Pract. 2011;17(1):39-48. doi: 10.1177/1078155210361431.
• Wick C, Slawson MH, Jorgenson JA, Tyler LS. Using a closed-system protective device to reduce personnel exposure to antineoplastic agents. Am J Health Syst Pharm. 2003;60(22):2314-2120.
• Clark BA, Sessink PJ. Use of a closed system drug-transfer device eliminates surface contamination with antineoplastic agents. J Oncol Pharm Pract. 2013;19(2):99-104. doi: 10.1177/1078155212468367. &emsp;