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INTRODUCTION

Note to users: At the time this monograph was posted, the USP-NF had delayed the effective dates of General Chapter <797> indefinitely. The chapter was to have become official on December 1, 2019, but USP-NF announced on September 23, 2019, that appeals were pending on provisions of the chapter regarding beyond-use dating, use of alternative technologies proven equivalent to those described in the chapter, and applicability of the chapter to veterinary practitioners. This notice and content of this program will be updated as events occur.

Compounding has been a fundamental aspect of providing medicines to patients for centuries. Physicians, chemists, and pharmacists manipulated naturally derived products (including those of plant, mineral, and animal origin) into medicines. They did this through mixing, grinding, filtering, percolating, heating, and distilling, which led to preparations of vinegars, extracts, infusions, elixirs, syrups, tinctures, ointments, and pills. The rise of manufactured medicines in the late 1800s and early 1900s decreased the need for compounded preparations on a large scale, but compounding continued to be part of the “art” of pharmacy and addressed the specific needs of the patient. Today, compounding has made a resurgence because of many drug shortages in recent years; the need for customized drug formulations as a result of allergies; special dosage forms for pediatric patients, geriatric patients, and special needs populations; and the movement toward specialty and personalized medicines.

Today’s compounding pharmacy practice includes sterile preparations and nonsterile preparations. Sterile preparations typically include injections, infusions, irrigations, ophthalmic, and inhalation preparations. Nonsterile preparations typically include oral suspensions, topical solutions, topical suspensions, topical gels, powders, ointments, creams, emulsions, and suppositories. The U.S. Food and Drug Administration (FDA) defines compounding as “…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.”¹

This continuing pharmacy education program focuses on compounded sterile preparations (CSPs) as related to the 2019 revised General Chapter <797> Pharmaceutical Compounding—Sterile Preparations.

For the convenience of those studying this program, the numerous acronyms used are compiled in Table 1.

BRIEF HISTORY OF STERILE COMPOUNDING

Sterile compounding evolved primarily in hospitals in the 1960s and 1970s. It involves preparations that are made in sterile environments (aseptically) by mixing, diluting, repackaging, or manipulating injectable products. The injections and infusions compounded in hospitals and other health systems include large-volume parenterals (LVPs) and small-volume parenterals (SVPs).² Intravenous (IV) admixtures are those LVPs or SVPs to which sterile drug products or components have been added; sterile compounded products also include ophthalmic solutions and irrigation solutions.

Beginning with pharmacist-prepared, centralized IV admixtures in the 1960s, hospitals have provided aseptic environments within which to compound sterile products and prevent microbial contamination, including the use of laminar airflow hoods and rooms with high-efficiency particulate air (HEPA) filters and work practices to support aseptic compounding. Even with these precautions, however, there have been many sterility challenges and patient morbidity and mortality issues secondary to contaminated compounded parenteral medicines.

To address these issues, the United States Pharmacopeial Convention (USP), a nongovernmental standards-setting organization whose standards are recognized by the Federal Food, Drug, and Cosmetic Act (FD&C Act), issued an informational general chapter on this topic in the 1990s. In 2004, USP revised the chapter, which became a general chapter devoted specifically to sterile compounding, <797> Pharmaceutical Compounding—Sterile Preparations (General Chapter <797> or <797>). <797> was revised twice: once in 2008 and the pending revision in 2019.³

REGULATORY FRAMEWORK

In the United States, the safety and efficacy of drugs are regulated at the federal level under the FD&C Act. States have jurisdiction over the practices of medicine and pharmacy. The practice of compounding has traditionally been regulated by individual state pharmacy and other health professional practice laws, and enforced by state boards of pharmacy.

In 2012, a multistate meningitis outbreak resulting from the contamination of methylprednisolone acetate, a steroid injection compounded by New England Compounding Center (NECC), caused the death of 64 people and illnesses in more than 800 people.⁴ Because of this large outbreak, and ongoing concern about large compounding operations that ship their products broadly to many facilities in anticipation of a need for a medication rather than as a result of an individual prescription, Congress enacted the Drug Quality and Security Act (DQSA).⁵ The DQSA has two key components, both of which amend the FD&C Act: Title One, The Compounding Quality Act, and Title Two, The Drug Supply Chain Security Act.

The Compounding Quality Act of DQSA established two sections that established clearly differentiated types of compounding facilities: Section 503A describes “Traditional Compounders” (such as pharmacies) and Section 503B established “Outsourcing Facilities.” For further information on this law, see PowerPak’s Current Topics in Sterile Compounding: The Drug Quality and Security Act.

STANDARDS FOR STERILE COMPOUNDING

In the United States, standards of strength, quality, purity, packaging, labeling, and naming of medicines are developed by the USP. USP’s standards are published in the U.S. Pharmacopeia and the National Formulary (USP-NF). USP was founded in 1820 to ensure that medicines were made consistently from state to state, and that they had standardized naming. USP’s standards were recognized as the official compendia for drugs marketed in the United States in the 1906 Pure Food and Drugs Act and the 1938 FD&C Act and its amendments.⁶

The FDA typically enforces USP-NF standards via the adulteration and misbranding sections of the FD&C Act. Standards for compounded medicines also appear in the USP-NF. USP’s standards comprise monographs (which describe compounding of specific mixtures), general chapters, and general notices. Physical reference standards also are called for in monograph tests as well as in some general chapters.

USP’s standards are developed or revised by the Council of Experts and its Expert Committees, a volunteer, standards-setting body. For compounding, the Compounding Expert Committee comprises experts in the fields of sterile and nonsterile compounding for human and animal drugs, microbiology, infection control, analytical chemistry, and facility certification. All new or revised USP standards undergo a formal public review and comment process. The Expert Committee members review and incorporate comments as appropriate. A “Commentary” is published to explain the rationale of whether the comment was incorporated once a standard becomes official.

USP’s standards for compounded medicines include monographs for bulk drug substances used in compounded preparations; monographs for compounded preparations, general chapters including <795> Pharmaceutical Compounding – Nonsterile Preparations (currently pending), <797> (currently pending), <800> Hazardous Drugs—Handling in Healthcare Settings (General Chapter <800> or <800>), and <825> Radiopharmaceuticals – Preparation, Compounding, Dispensing, and Repackaging (General Chapter <825> or <825>; currently pending),and general notices provisions that apply broadly to all drugs.⁷

While chapters <795>, <797>, and <825> were pending when this module was prepared, the revised chapter <800> becomes official on December 1, 2019, but USP said the chapter is “informational and not compendially applicable” until the other chapters become official. Check with state and accreditation organizations to determine how they will include <800> in their regulations and standards until <797> becomes official. In a statement posted on the USP-NF website on September 23, 2019, USP-NF stated, “USP plays no role in enforcement. State and other regulators may make their own determinations regarding the enforceability of <800>. USP remains committed to advancing public health and to promoting the quality of compounded preparations and the safe handling of hazardous drugs. USP will continue to communicate updates on the compounding chapters and the appeals process.”

USP-NF Monographs

USP has nearly 200 compounding preparations monographs in the official USP-NF, primarily for nonsterile preparations. Compounding preparation monographs include formulations and quality parameters for individual preparations and comprise formulas (ingredients and quantities), directions to correctly compound the preparation, packaging and storage information, pH, beyond-use dates (BUD) based on stability studies, and assays (for most monographs).⁸ Compounding preparation monographs are intended for specific patients who may need a certain strength or dosage form of a drug that is not commercially available, or may have an allergy to an ingredient in the drug. Compounded preparation monographs assist practitioners in compounding formulations in a consistent manner, in conformance with USP standards.

USP-NF General Chapters for Sterile Compounding

General Chapter <797> is referenced in many state and national laws and regulations. Its predecessor document, General Chapter <1206> Sterile Drug Products for Home Use, was first developed in the 1990s as an informational general chapter. In 2004, <797> was published as an official standard. It was revised in 2008 and 2019. The 2019 General Chapter <797> — which was to have become effective in December 2019 but is currently pending — describes the conditions and practices “to minimize harm, including death, to human and animal patients that could result from (1) microbial contamination (nonsterility), (2) excessive bacterial endotoxins, (3) variability from the intended strength of correct ingredients, (4) chemical and physical incompatibilities, (5) chemical and physical contaminants, and/or (6) use of ingredients of inappropriate quality.³

General Chapter <800> was published in 2016. It was developed to expand upon preparation of products containing hazardous drugs (HDs) as previously mentioned in <795> and <797>. General Chapter <800> is designed to protect health care personnel who handle HDs as well as to increase the safety in the physical environments in which HDs are prepared. It “...describes practice and quality standards for handling HDs to promote patient safety, worker safety, and environmental protection. Handling HDs includes, but is not limited to, the receipt, storage, compounding, dispensing, administration, and disposal of sterile and nonsterile products and preparations.”⁹

USP-NF General Notices and Requirements Related to Compounding

The General Notices and Requirements section of the USP-NF (general notices) includes the “basic assumptions, definitions, and default conditions for the interpretation and application” of USP-NF standards.¹⁰ Requirements in the general notices apply to all articles recognized in the USP-NF and to all general chapters unless specifically stated otherwise.

Some general notice provisions relate to compounding. Section 3.10.30 Applicability of Standards to the Practice of Compounding indicates that <795> and <797> apply to compounding practice or activity regardless of the presence or absence of individual monographs. It also indicates that USP-NF compounding general chapters do not apply to drugs compounded by outsourcing companies as defined by the FD&C Act 503B.¹¹ In addition, general notices also indicate that, as with all drugs that are recognized in the USP-NF, compounding preparations must specify on the label when their standards differ from the USP monograph. When a compounding preparation fails to meet USP-NF identity standards, or contains added substances that interfere with the monograph tests, it must have a clearly differentiating name, different from the USP-NF name.¹²

Other Requirements for Sterile Compounding

In addition to the legally enforceable USP-NF standards, the Centers for Medicare & Medicaid Services (CMS) and most state pharmacy and/or state health laws include requirements for sterile compounding. CMS Conditions of Participation has, in its State Operation Manual for Hospitals (Appendix A) and State Operations Manual for Critical Access Hospitals (Appendix W), facility requirements for sterile compounding to qualify for Medicaid and Medicare payment.^13,14 These requirements cite and excerpt <795> and <797>, refer to the FD&C Act for 503A and 503B pharmacies, and encourage hospitals and critical access hospitals to ensure they have proper facilities and trained personnel for any compounding done onsite and appropriate knowledge of and quality oversight for compounded medicines prepared offsite. These manuals also outline engaging with FDA-registered outsourcing facilities in compliance with the FD&C Act 503B and compounding pharmacies in accordance with the FD&C Act 503A.

In addition to the USP and CMS requirements, most states have incorporated excerpts of or references to <795> and <797> texts in their pharmacy and health laws and regulations. These laws are enforced by the respective state boards of pharmacy and health.

Enforcement of USP-NF Standards and Accreditation of Compounding Facilities

In the past, enforcement of pharmacy compounding has primarily resided at the state level through pharmacy and health boards. With the DQSA now in effect, the FDA also enforces USP compounding standards. Facilities and compounding professionals in organizations that are surveyed by accreditation organizations (e.g., The Joint Commission, DNV Healthcare, Healthcare Facilities Accreditation Program, Center for Improvement in Healthcare Quality) must comply with those standards, which increasingly include sections from <797> and <800>.

FDA use of USP’s compounding standards in the agency’s enforcement responsibilities emanates from DQSA section 503A, which indicates that compounded preparations must “comply with the standards of an applicable [USP] or [NF] monograph, if a monograph exists, and the [USP general] chapter on pharmacy compounding.”¹⁵ The FDA also provides further clarification on the application of USP-NF standards to pharmacy compounding through an FDA Guidance: Pharmacy Compounding of Human Drug Products under Section 503A of the FD&C Act.¹⁶ A new drug application is not required for preparations compounded by a licensed pharmacist or physician that comply with USP general chapters on pharmacy compounding using ingredients that meet standards of any relevant USP or NF monographs. FDA’s list and status of regulatory policy information provides further information related to compounding.¹⁷

The primary accrediting body for hospitals and health centers in the United States is The Joint Commission. The Joint Commission is a not-for-profit organization that accredits and certifies nearly 21,000 health care organizations and programs in the United States. The Joint Commission hospital accreditation includes an onsite survey by a Joint Commission survey team at least every 3 years.¹⁸ The Joint Commission and other accreditation organizations have started to certify medication compounding. This conformance assessment holds hospital and health-system leaders responsible for using USP chapters <795>, <797>, and <800>, for nonsterile, sterile, and hazardous preparations for assuring that quality standards on pharmaceutical compounding are effectively implemented in the organization.¹⁹

QUALITY CONTROL OF STERILE COMPOUNDING

Five key elements of quality control for sterile compounding are required for a facility to be in compliance with <797> requirements:

• Facilities and equipment
• Personnel training
• Work practices
• Environmental monitoring
• Certification

Facilities and Equipment

Primary engineering controls (PECs) are used to protect the CSP from cross-contamination and microbial contamination. PECs designed specifically for nonhazardous SCAs include laminar flow air workbenches (LAFW) and compounding aseptic isolators (CAI). These PECs are required to have unidirectional airflow at an ISO Class 5 or better at the critical site during compounding.

PECs for compounding HDs include biological safety cabinets (BSC) and compounding aseptic containment isolators (CACI) within the ISO 7 cleanroom suite or containment segregated compounding area (C-SCA). It is important to note that a LAFW or CAI must not be used for the compounding of chemotherapy drugs, because that would not protect the operator from potential contamination.

Sterile compounding facilities are designed to provide appropriate working environments to control and minimize contamination and to be well-lighted and comfortable for compounding personnel.

The 2019 revision of <797> eliminates the risk levels of CSPs and replaces that with Categories, based on the type of facility in which the CSP is mixed. Category 1 CSPs are those mixed in a Segregated Compounding Area (SCA) or C-SCA. Those types of facilities have a certified PEC or Containment Primary Engineering Control (C-PEC) but do not necessarily require an ISO-classified room. Category 2 CSPs are those mixed in a cleanroom suite, containing a PEC or C-PEC within a buffer room which is entered through an anteroom.

Facilities for Nonhazardous Sterile Compounding

There are two types of facilities used for compounding nonhazardous sterile preparations: (1) a cleanroom suite or (2) a SCA. The cleanroom suite includes an ISO Class 7 or 8 positive pressure anteroom and an ISO Class 7 positive pressure buffer room. ISO classifications limit the number of particles in the air. The smaller the ISO class, the fewer particles allowed, hence the cleaner the area needs to be. The positive pressure rooms are at a higher air pressure than adjacent spaces, which forces the airflow out of the rooms.

An SCA is a separate area or room that is designed for preparation of nonhazardous CSPs (those with a 12-hour room temperature or 24-hour refrigerated beyond-use time); it is not required to be an ISO-classified cleanroom.

The previous (2008) version of <797> allowed a combined ISO Class 7 ante/buffer room that served both functions, but this is no longer allowed in the 2019 revision because a physical barrier with a pressure differential is needed between the two rooms.³ The previous version of <797> also allowed a CAI to be placed outside the cleanroom but still use the full BUD listed. This is no longer permitted. CSPs mixed a CAI within an SCA are limited to the short BUDs of Category 1 compounds.

Facilities for Hazardous Sterile Compounding

The National Institute of Occupational Safety and Health (NIOSH) maintains a list of drugs that are hazardous to healthcare personnel; an update to this list is expected by December 2019.²⁰ Chapter <800> describes the requirements for establishing the list of a facility’s HDs that must be compounded separately, and those that may be compounded with alternative containment strategies or work practices. Antineoplastic agents in NIOSH Table 1 must be compounded in facilities that protect the compounder from contamination. Hospitals may perform an Assessment of Risk (see <800>) to determine how those HDs in NIOSH Tables 2 or 3 may be compounded.

Chapters <797> and <800> describe the required facility: either a cleanroom suite comprising an ISO 7 positive pressure anteroom and an ISO 7 negative pressure buffer room or a C-SCA. The anteroom for HD preparation requires a higher level of cleanliness (ISO 7) than required for nonhazardous drugs (ISO 8) because the air entering the negative buffer room needs to be at least as clean as the air in the buffer room. Note that the 2019 revision of <797> eliminates the allowance for a “low use exemption”. All HDs (except those agents other than antineoplastics that are specifically exempted by the facility) must be compounded in a negative pressure room to protect compounding personnel.

General Chapter <800> allows two types of designs for facilities that compound HDs: a cleanroom suite or a C-SCA, which is a separate, negative pressure room, vented to the outside, with at least 12 air changes per hour. The C-SCA does not need to be an ISO-classified cleanroom.

Other Facility Considerations

Other considerations for facilities include design, air handling, sink placement, and finishes. Facilities must be designed to minimize contamination of surfaces, to promote effective cleaning, to limit unnecessary personnel and materials traffic, and to include only furniture and equipment that is necessary for compounding. A key component is airflow and control of particulate matter. This is achieved using HEPA filtering and air handling systems that are designed to meet ISO classification standards, sweep away the particles from the compounding area and the compounders, and maintain the required facility pressure differentials. Water sources (sinks and drains) may not be placed in the buffer area. Finishes on ceiling, wall, and floor surfaces must be easily cleaned and disinfected, smooth, and impervious.

Acceptable cleanroom configurations and other design elements for sterile compounding are included in the text of <797> and the appendices of <800>.

Personnel Training and Monitoring

Training and monitoring of compounding personnel are critical components for safe and effective sterile compounding. Training must be conducted by expert sterile compounding personnel and must be documented. General Chapter <797> outlines several types of training for the compounding professional:

• Initial training must include didactic and hands-on training with observation by an expert compounding professional.³
• Ongoing training should encompass any new procedures, new types of equipment, and new drugs.
• Remedial training should address incorrect approaches, procedures, equipment use, garbing, and other such matters.
• Requalification training must be accompanied by physical tests (see below).

As with any personnel training, documentation of the training is crucial for recordkeeping purposes and certification.

Physical Tests

General Chapter <797> details requirements for simulated physical tests used to demonstrate competency in sterile compounding (see the section on Personnel Training and Monitoring), including two of critical importance.²¹

Media fill testing shows that a compounder can aseptically mix a CSP at the facility using sterile fluid culture media. The media fill test is completed before personnel are allowed to compound independently. It must then be conducted at least every 6 months.

The gloved fingertip/thumb sampling has two purposes. Initially, it must be passed before personnel are allowed to compound independently. Direct touch contamination is the most likely source of introducing microorganisms into CSPs. This test assesses an individual’s competency in garbing and hand hygiene.

The initial gloved fingertip test is performed immediately after the compounding employee completes the hand hygiene and garbing procedures. The evaluator will conduct this test to determine if any colony forming units (CFUs) are on the operator’s gloved fingertips. This test must be performed on three separate occasions with absolutely no CFU growth within the required incubation period. Compounding personnel must requalify every 6 months. For the retesting, the gloved fingertip test is performed following the media fill inside the PEC. Ideally, there will be no CFU growth for the fingertip sample retest; it is failed if more than 3 CFUs are found.

A skilled compounder must also observe proper garbing and hand hygiene of personnel every 6 months.

These simulation tests are critical in determining that personnel are garbed to compound aseptically.

Work Practices

A highly structured and monitored environment is critical to ensure that the compounding professional works competently and safely to compound sterile preparations. Four pillars are used to ensure this outcome: following policies and procedures, using appropriate BUDs, wearing personal protective equipment (PPE), and the proper cleaning of the cleanroom suite and SCA.

Policies and Procedures

When things go wrong with sterile compounding, it is often the results of inadequate attention to policy and procedures. Policies and procedures should address everything in <797> and <800>, state requirements, accreditation standards, and additional site-specific requirements. This includes monitoring and documenting daily temperature, humidity and pressure differentials; equipment (e.g., IV workflow hardware, automated compounding devices, repeater pumps); assessing risks for HD preparation; and acknowledgment of risk when handling HDs by signing a written statement. While <797> and <800> set the minimum level of compliance, many compounding pharmacies and institutions have more stringent procedures.

Beyond-Use Dates

General Chapter <797> defines BUDs as “either the date or hour and date after which a CSP must not be used. The BUD is determined from the date/time that the preparation of the CSP is initiated.”³ The CSP must be labeled with the BUD, which clearly shows the date or time after which the preparation cannot be used.

Note that BUDs do not include the infusion time. For <797> purposes, the BUD is the time up to the point of the start of the CSP administration. Naturally, the pharmacist must ensure that the stability of the CSP is retained throughout the intended administration period; this is not the same as the BUD. See Table 2 for BUDs for aseptically prepared CSPs. Revised <797> includes additional detailed information for use of single-dose containers, multiple-dose containers, pharmacy bulk packages, CSPs as components, additional of preservatives, and sterility testing.³

In addition, <797> defines BUDs for CSPs that have a preservative added or have had sterility testing performed. Note that if there is a discrepancy between the <797> BUD limits and the stability time found in the package insert or other reference, the sterile compounding professional must use the shorter of the two for the BUD.

Docking and activation of a single proprietary bag and vial system for a single patient, for immediate administration according to the product labeling, is not considered compounding. However, docking of a proprietary bag and vial system for future activation and administration is considered sterile compounding; the BUD for these sterile vial/bag systems that are attached (but not activated) in ISO 5 conditions are determined by the manufacturer, as stated in the product labeling.

Garb and Personal Protective Equipment

Appropriate garb is required under <797> standards. Along with hand hygiene, garb helps prevent microbial contamination. Garb includes gloves, gowns, hair covers, face masks, and shoe covers. Additional requirements for PPE when compounding HDs can be found in <800>.⁹ PPE for handling HDs includes gloves tested to ASTM 6978 Standard Practice for Assessment of Resistance of Medical Gloves to Permeation by Chemotherapy Drugs.²² Gowns are used to protect the compounder from HDs as well as protecting the sterile preparation. Compounders need to use a laminate gown intended for use with chemotherapy drugs when compounding HDs (unless allowed in the Assessment of Risk).

The placement of garb and PPE and the order in which it is donned is determined by the facility design. Procedures are outlined in the Personal Hygiene and Garbing section of <797>.³ In CAI/CACI devices, sterile gloves must be donned over the gloves on the sleeves inside the compounding isolator chamber.

In addition to PPE, a closed-system drug-transfer device (CSTD) protects personnel when they are compounding HDs and administering them to the patient. The CSTD enables much easier and safer sterile HD compounding and delivery. Currently, two types of CSTDs are on the market: physical barrier systems and air-cleaning systems. General Chapter <800> recommends use of a CSTD when compounding HDs and requires the use of a CSTD during their administration when dosage forms allow for it.

Cleaning and Disinfecting

Meticulous attention to cleaning and disinfecting the sterile compounding cleanroom suite and SCA/C-SCA is critical to minimize possible contamination. Cleaning and disinfecting practices and frequencies differ for areas used for compounding nonhazardous and HDs. Cleaning and disinfecting includes multiple steps that must be outlined in policies and procedures.

For compounding areas, <797> requires daily cleaning and disinfecting of each PEC, all floors, counters, and easily cleanable work surfaces in the buffer rooms and anterooms and any SCA/C-SCA; this includes high-touch areas such as telephones, pass-throughs, and refrigerator handles.

For nonhazardous areas, the compounding suite or SCA must be cleaned with a detergent.

For the hazardous compounding area, <797> and <800> require deactivation and decontamination with an oxidizer intended for use with HDs before cleaning. The area must then be cleaned with a detergent.

Only compounding personnel can clean PECs, but others who are appropriately trained and have documented competency can clean the floors.

Appropriate cleaning and disinfecting solutions and dilutions must be used. Ready-to-use solutions are preferred, since they eliminate the need to mix different concentrations. After cleaning with a detergent, sterile 70% isopropyl alcohol must be applied to the work surface inside the PEC. Sterile alcohol is used since it has been filtered and irradiated to remove spores.

Clean and disinfect all other surfaces (including walls, storage shelving, and ceilings) in the cleanroom suite and SCA/C-SCA at least monthly.

At least monthly, also use a sporicidal agent.

Environmental Monitoring

The purpose of an environmental monitoring (EM) program outlined in <797> is to demonstrate that the compounding area maintains a state of control. Engineering controls maintain a consistent environment within ISO classifications (ISO Class 5 for PECs including LAFWs, BSCs, CAIs, and CACIs, and ISO Class 7 and 8 for the compounding suites). EM programs include testing for viable (microbial) airborne particles and surface sampling. EM testing must be performed by a qualified person, such as a member of the pharmacy staff, a microbiologist, or a certifier.

Viable testing includes sampling of surfaces and other areas that might be contaminated through touching in the primary and secondary engineering control areas, as well as electronic air sampling.

Viable air testing must be performed at least every 6 months using an impaction device that captures a measured volume of air within the ISO classified areas. The device includes an agar plate. If microbial contamination is present, it will be captured on the plate, which is then incubated by a laboratory that performs environmental testing. If any growth is found, it must be addressed and corrected. The area is then retested to ensure the correction.

Surface sampling must be performed monthly in all PECs, ISO classified areas, and pass-throughs that open into ISO classified rooms. Some experts recommend having the outside certifier perform the tests every 6 months and the pharmacy personnel perform the tests in the intervening months. This way, two different laboratories review the data, which enables a system of checks and balances. If any growth is found, it must be remediated. Documentation and records-keeping of these EM records is critical.

Certification

Certification of the sterile compounding facility (hoods and rooms) by an independent certifier is required every 6 months. The certifier issues a report that should clearly indicate which areas pass, fail, or need attention. The certification process includes the use of Controlled Environment Testing Association (CETA) Guidelines (or comparable document), and the key elements include testing under dynamic/operating conditions (not “at rest”), and testing of all required components (including <797>, accrediting organizations, and in-house procedures). CETA Guidelines include all existing regulations and standards in a document designed for certification. The certification report must document airflow testing, HEPA filter integrity testing, total particle count testing, and for PECs, a dynamic airflow smoke pattern test.

Sterile compounding facilities should be ready to simulate compounding or perform cleaning to simulate the work environment for the certification process. Once certifiers have completed assessments, they provide written reports of the findings and the areas that need improvement for review with pharmacy management and leadership or other pertinent staff.

PRACTICAL APPROACHES

General Chapter <797> includes several boxes that provide practical advice for sterile compounding facilities and personnel. The boxes include procedures for:

• Glove fingertip and thumb sampling
• Media-fill testing
• Hand washing
• Hand sanitizing
• Active air sampling for viable airborne monitoring
• Surface sampling
• Cleaning and disinfecting the PEC
• Applying a sporicidal agent in the PEC
• Master Formulation Records
• Compounding Records
• Compounding Records for Individual Allergenic Extract Prescription Sets

Achieving Compliance

A lot of time, effort, and resources are needed to achieve and maintain compliance in a compounding facility with sterile compounding. Certain areas such as facilities, personnel training, aseptic techniques, and EM can be challenging in meeting requirements. In the 2018 Critical Point USP Compliance Studies, 86% of hospitals self-reported compliance with <797> and 66% self-reported compliance with <800>.²³

A gap analysis, combined with a remediation/implementation plan is the best way for sterile compounding professionals and compounding facilities to become compliant with <797>, <800>, and other requirements.

Several gap analysis tools (Table 3) are available to help with this process, as well as many consultants in the field who can help. Go forth and become fully compliant!

SUMMARY

As is evident in this program, achieving 100% compliance to <797> and <800> requirements can be difficult. With the proper facilities, personnel training and monitoring, work practices and standard operating procedures (SOPs), EM, and certification, compounding professionals can go a long way toward protecting patients—and themselves—from significant harm from CSPs. Properly incorporating <797>, <800>, and other requirements into daily and monthly routines is critical to achieve these goals.

REFERENCES

1. US Food and Drug Administration. Compounding and the FDA: questions and answers. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm339764.htm#what. Accessed June 22, 2019.
2. Myers CE. History of sterile compounding in US hospitals, learning from the tragic lessons of the past. Am J Health Syst Pharm. 2013;70(16):1414- 1427.
3. US Pharmacopeial Convention. General chapter <797> Pharmaceutical compounding: sterile preparations, USP 42/NF 37, 2019.
4. Center for Disease Control and Prevention, Multistate outbreak of fungal meningitis and other infections. https://www.cdc.gov/hai/outbreaks/meningitis.html. Accessed June 22, 2019.
5. gov. H.R.3204 — Drug Quality and Security Act. 113th Congress (2013–2014). https://www.congress.gov/bill/113th-congress/house-bill/3204. Accessed June 22, 2019.
6. US Pharmacopeial Convention Legal recognition of USP standards, https://www.usp.org/about/legal-recognition. Accessed June 22, 2019.
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8. USP compounded preparation monographs. https://www.usp.org/compounding/compounded-preparation-monographs Accessed June 22, 2019.
9. General chapter <800> hazardous drugs—handling in healthcare settings, introduction. US Pharmacopeia 42-National Formulary 37. Accessed June 22, 2019.
10. General notices, introduction. US Pharmacopeia 42-National Formulary 37. Accessed June 22, 2019.
11. General notices, section 3.10.30. Applicability of standards to the practice of compounding. US Pharmacopeia 42-National Formulary 37. Accessed June 22, 2019.
12. USP-NF. General notices section 3.20. Indicating conformance. US Pharmacopeia 42-National Formulary 37. Accessed June 22, 2019.
13. Centers for Medicare and Medicaid Services. State operations manual , appendix A, survey protocol, regulations and interpretive guidelines for hospitals. https://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/downloads/som107ap_a_hospitals.pdf. Accessed June 22, 2019.
14. Centers for Medicare and Medicaid Services. State operations manual, appendix W, survey protocol, regulations and interpretive guidelines for critical access hospitals (CAHs) and swing-beds in CAHs. https://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/downloads/som107ap_w_cah.pdf . Accessed June 22, 2019.
15. US Food and Drug Administration, Section 503A of the Federal Food, Drug, and Cosmetic Act. https://www.fda.gov/drugs/human-drug-compounding/section-503a-federal-food-drug-and-cosmetic-act. Accessed June 22, 2019.
16. US Food and Drug Administration. Pharmacy compounding of human drug products under section 503A of the Federal Food, Drug, and Cosmetic Act. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM469119.pdf. Accessed June 22, 2019.
17. US Food and Drug Administration. Regulatory policy information. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm166743.htm. Accessed June 22, 2019.
18. The Joint Commission. About The Joint Commission. https://www.jointcommission.org/about_us/about_the_joint_commission_main.aspx. Accessed June 22, 2019.
19. The Joint Commission. Requirements for the medication compounding certification, general responsibilities (MDCGR) chapter, standard MDCGR.01. https://www.jointcommission.org/assets/1/6/Medication_Compounding_v2.pdf. Accessed June 22, 2019.
20. Centers for Disease Control and Prevention. National Institute of Occupational Safety and Health. NIOSH list of antineoplastic and other hazardous drugs in healthcare settings, 2016. https://www.cdc.gov/niosh/docs/2016-161/default.html. Accessed June 22, 2019.
21. USP General Chapter <797> Pharmaceutical compounding—sterile preparations. US Pharmacopeia 42-National Formulary 37 Personnel training and evaluation. Accessed June 22, 2019.
22. ASTM D6978 - 05(2013) Standard practice for assessment of resistance of medical gloves to permeation by chemotherapy drugs, available for purchase at https://www.astm.org/Standards/D6978.htm. Accessed June 22, 2019.
23. CriticalPoint, LLC. 2018 Compliance Study Results. https://www.criticalpoint.info/tools-resources/gap-analysis/. Accessed June 22, 2019.

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