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USP General Chapter <797>: A Guide to Sterile Compounding for Pharmacy Personnel

INTRODUCTION

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, and some irrigation, ophthalmic, and inhalation preparations. Nonsterile preparations typically include oral suspensions, topical solutions, topical suspensions, topical gels, powders, ointments, creams, emulsions, suppositories, and others. 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 currently official General Chapter <797> Compounding—Sterile Preparations. At the time this monograph was prepared, <797> was in the process of being revised; following submission of thousands of comments on the initial draft, the United States Pharmacopeial Convention (USP) announced in January 2017 that it would republish the revised proposed general chapter for a second round of public comments. The new revision will likely take several years to complete and thus is not the focus of this CE program.

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

Table 1 Acronyms used in this article
Acronym Definition
C-PEC Containment primary engineering control
C-SCA Containment segregated compounding area
C-SEC Containment secondary engineering control
CSP Compounded sterile preparation
CSTD Closed system drug-transfer device
DQSA Drug Quality and Security Act
FD&C Act Federal Food, Drug, and Cosmetic Act
HD Hazardous drug
PEC Primary engineering control
PPE Personal protective equipment
SCA Segregated compounding area
SEC Secondary engineering control
TPN Total parenteral nutrition

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 IV admixtures are those LVPs or SVPs to which injections have been added.

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 rooms and hoods with high-efficiency particulate air (HEPA) filters, IV compounding rooms, 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 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>).

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.3 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).4 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 (DQSA).

The Compounding Quality Act of DQSA established two sections that established clearly differentiated types of compounding facilities: Section 503A set forth “Traditional Compounders” 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.5

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, expert 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, and analytical chemistry. 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 (primarily nonsterile), six general chapters including <797> and <800> Hazardous Drugs—Handling in Healthcare Settings (General Chapter <800> or <800>), and general notices provisions that apply broadly to all drugs.6

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).7 Compounding preparation monographs are generally used for specific patients who may need a certain strength or dosage form of a drug that is not commercially available, or may have an allergic reaction 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 a legally enforceable standard. It was revised in 2008, and has been under revision since 2015. The current (2008) General Chapter <797> describes the “conditions and practices to prevent harm, including death, to patients that could result from 1) microbial contamination (nonsterility), 2) excessive bacterial endotoxins, 3) variability in the intended strength of correct ingredients, 4) unintended chemical and physical contaminants, and 5) ingredients of inappropriate quality in compounded sterile preparations (CSPs).”8 The revisions proposed in 2015, while not finalized, are intended to “reflect new science and evidence based on updated guidance documents, best practices, and new learnings from investigations; respond to stakeholder input received...; and to clarify topics that are frequently queried and misconstrued.”9 General Chapter <797> is a legally required general chapter, enforceable by the FDA.

General Chapter <800> was published in 2016 and becomes official July 1, 2018. It was developed to expand upon the current sections addressing hazardous drugs in <797>. General Chapter <800> is designed to protect health care personnel who handle hazardous drugs as well as to increase the safety in the physical environments in which hazardous drugs are prepared. It “...describes practice and quality standards for handling hazardous drugs (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.”10 The hazardous drug information in <797> will be omitted in its next revision, instead referencing <800> for all hazardous drug information once both <800> and the new <797> are official.

USP-NF General Notices and Requirements Provisions 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.11 Requirements in the general notices apply to all articles recognized in the USP-NF and to all general chapters unless specifically stated otherwise.

There are several general notices provisions related to compounding. A new section, 3.10.30 Applicability of Standards to the Practice of Compounding, which becomes official on May 1, 2017, 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.12 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.13 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.14

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)15 and State Operations Manual for Critical Access Hospitals (Appendix W), facility requirements for sterile compounding to qualify for Medicaid and Medicare payment.16 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, which are in the process of being updated to reflect the FD&C Act amendments and updated USP-NF standards, 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 and Professionals

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) must comply with those standards, which increasingly include sections from <797> and <800>.

FDA enforcement responsibility of USP’s compounding standards 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.” 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 Federal Food, Drug, and Cosmetic Act.17 This guidance indicates that preparations compounded by a licensed pharmacist or physician qualify for an exemption from requirements of a new drug application if they are compounded in compliance with the USP general chapters on pharmacy compounding using bulk drug substances and ingredients that comply with the standards of an applicable USP or NF monograph, if one exists. FDA’s list and status of regulatory policy information provides further information related to compounding.18

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 accreditation includes an onsite survey by a Joint Commission survey team at least every 3 years.19 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 eventually <800>, once it becomes official on July 1, 2018, for nonsterile, sterile, and hazardous preparations for assuring that quality standards on pharmaceutical compounding are effectively implemented in the organization.20

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

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.

Facilities for Nonhazardous Sterile Compounding

There are two types of facilities used for compounding sterile preparations: (1) a cleanroom suite and (2) a segregated compounding area (SCA). The cleanroom suite includes an ISO Class 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.

Note that the current <797> also allows a combined ISO Class 7 ante/buffer room that serves both functions, but this likely will not be allowed in new <797> because a physical barrier with a pressure differential is needed between the two rooms.

The SCA also is permitted in <797>. This is a separate area or room that is designed for preparation of low-risk, nonhazardous CSPs (those with a 12-hour beyond-use time); it is not required to be a cleanroom.

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 level at the critical site during compounding.

Facilities for Hazardous Sterile Compounding

The current <797> allows for a cleanroom suite comprising an ISO 7 positive pressure anteroom and an ISO 7 negative pressure buffer room. The anteroom for hazardous drug preparation requires a higher level of cleanliness because the air entering the negative buffer room needs to be at least as clean as the air in the buffer room. The current <797> also provides for a “low use exemption” that includes either a biological safety cabinet (BSC)/compounding aseptic containment isolator (CACI) in a positive pressure buffer room or a CACI in a negative pressure room with 12 air changes per hour, optimally vented. Neither of these options will be allowed under <800> requirements.

In <800>, all compounding for hazardous drugs must be done in a separate area designated specifically for hazardous drug compounding. General Chapter <800> allows two types of designs for facilities that compound hazardous drugs: a cleanroom suite as allowed in current <797>, or a containment SCA (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 ISO classified.

PEC for compounding hazardous drugs include BSC and CACIs within the ISO 7 cleanroom suite or containment 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.

Other Facility Considerations

Other considerationsfor facilities include design, air handling, sink placement, and finishes. Facilities should 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. Another key component is airflow and control of particulate matter. This is achieved using HEPA filtering and heating, ventilation, and air conditioning 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 should be easily cleaned and disinfected, smooth, and impervious.

Many acceptable cleanroom configurations 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 is conducted by expert sterile compounding personnel and must be documented. General Chapter <797> outlines four types of training for the compounding professional:

  1. Initial training must include didactic and hands-on training with observation by an expert compounding professional
  2. Ongoing training should encompass any new procedures, new types of equipment, and new drugs.
  3. Remedial training should address incorrect approaches, procedures, equipment use, garbing, and other such matters.
  4. Annual 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> outlines several simulated physical tests used to demonstrate competency in sterile compounding (see the section on Personnel Training and Competency Evaluation of Garbing, Aseptic Work Practices, and Cleaning and Disinfection Procedures), including two of critical importance.21

The first test, media fill testing of aseptic work skills, demonstrates that the compounder can aseptically mix a CSP at the facility using sterile fluid bacterial culture media. The media fill test is completed before personnel are allowed to compound independently. It is conducted at least annually thereafter for low- and medium-risk compounding and semiannually for high-risk compounding.

A second test, the gloved fingertip/thumb sampling, also must be passed before personnel are allowed to compound independently. This test is performed because 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 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. Retesting is required annually for those compounders mixing low- and medium-risk preparations and semiannually for high-risk preparations. For the retesting, the gloved fingertip test is performed following the media fill. Ideally, there will be no CFU growth for the fingertip sample test; it is failed if more than 3 CFUs are found.

These simulation tests are critical in determining that personnel are compounding 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>, accreditation standards, and additional site-specific requirements. This includes monitoring and documenting daily temperature and pressure, equipment (e.g., automated compounding devices, repeater pumps), assessing risks for hazardous drug preparation, and acknowledgment of risk when handling hazardous drugs by signing a written statement.

While <797> and <800> set the minimum level of compliance, many compounding pharmacies and institutions have more stringent procedures. Unfortunately, according to Pharmacy Purchasing and Products 2016 <797> Compliance Study, only 36% of those surveyed reported full compliance with the standards.22

Beyond Use Dates

General Chapter <797> defines BUDs as “the date or time after which a CSP shall not be stored or transported. The date is determined from the date or time the preparation is compounded.”23 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 USP 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. The proposed <797> includes in-use times for single-use containers, multiple dose vials, pharmacy bulk packages, and “stock bags,” which will be helpful information to the sterile compounding professional (Table 2).24

Table 2. Beyond Use Date Limits
Risk Level Controlled Room Temperature Refrigerated Frozen
Low risk (12-hour) 12 hours 12 hours N/A
Low risk 48 hours 14 days 45 days
Medium risk 30 hours 9 days 45 days

In addition, <797> outlines risk levels for CSPs. Low-risk-level CSPs are those mixed for a single patient, and are limited to no more than three components and no more than two punctures of a vial. Medium-risk-level CSPs are those that are more complex (such as a total parenteral nutrition [TPN] solution) or made for multiple patients or one patient over multiple occasions (such as a batch). High-risk-level CSPs are those made from at least one nonsterile starting component. The lower the risk level, the longer the BUD for a CSP, if the compounded preparation is also chemically stable. The higher the risk level, the shorter the sterility-based BUD. High- risk level CSPs are far more complex preparations and require a higher level of attention by the compounding professional to maintain sterility and accuracy. 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 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.

The BUD sterility limits outlined in <797> can be exceeded by conducting specific and sophisticated sterility testing equivalent to or better than USP General Chapter <71> Sterility Tests.

Personal Protective Equipment

Appropriate PPE is required under <797> standards. Along with proper cleansing and hand hygiene, PPE helps prevent microbial contamination. PPE includes gloves, gowns, hair covers, face masks, eye protection, shoe covers, and respirators. Garb requirements are consistent between the current and proposed <797>. Hair covers, masks, and shoe covers are required for both nonhazardous and hazardous compounding, and gloves must be sterile for all sterile compounding.25

The order in which the garb is donned is important, as is where the garb is donned. Procedures are outlined in the Personal Cleansing and Garbing section of <797>.26 In CAI/CACI devices, sterile gloves must be donned over the gauntlet gloves inside the isolator chamber. PPE must be worn when working in a CAI environment, unless the CAI manufacturer provides specific information about items of garb that need not be used.

Garbing for handling hazardous drugs includes gloves tested to ASTM 6978 Standard Practice for Assessment of Resistance of Medical Gloves to Permeation by Chemotherapy Drugs. Gowns are used to protect the compounder from hazardous drugs as well as protecting the sterile preparation. Compounders should use a laminate gown intended for use with chemotherapy drugs when compounding hazardous drugs. Wear PPE when handling hazardous drugs–it’s for your protection. In addition to PPE, a closed-system drug-transfer device (CSTD) protects personnel when they are compounding hazardous drugs and administering them to the patient. The CSTD enables much easier and safer sterile hazardous drug 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 hazardous drugs 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 is critical to minimize possible contamination. Cleaning and disinfecting practices and frequencies differ for areas used for compounding nonhazardous and hazardous drugs.

For compounding areas, <797> requires daily cleaning and disinfecting of each PEC, all floors, counters, and easily cleanable work surfaces in the ISO 7 buffer area and/or ISP 8 ante-area, and any SCAs; this includes high-touch areas such as telephones and refrigerator handles. Clean and disinfect all other surfaces (including walls, storage shelving, and ceilings) in the cleanroom suite and SCA at least monthly. Only compounding personnel can clean PECs, but others who are appropriately trained can clean the floors. Appropriate cleaning and disinfecting solutions and dilutions must be used. Cleaning and disinfecting includes multiple steps that should be outlined in SOPs.

For nonhazardous areas, the compounding suite or SCA must be cleaned with germicidal detergent. After cleaning with a detergent, the PECs must be disinfected with sterile 70% isopropyl alcohol. Sterile alcohol is used since it has been filtered and irradiated to remove spores.

For the hazardous compounding area, <797> and <800> require deactivation and decontamination with an oxidizer intended for use with hazardous drugs before cleaning. The area should then be cleaned with a germicidal detergent, followed by disinfection with sterile 70% isopropyl alcohol.

Environmental Monitoring

The purpose of an environmental monitoring 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). Environmental monitoring programs include two elements: testing for nonviable particles and other air handling and testing for viable (microbial) airborne particles.

Nonviable particle testing includes particle counts from the primary and secondary engineering controls. Viability 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.

The certifier who assesses the compounding area every 6 months generally performs the electronic air sampling using a 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.

For surface sampling, <797> indicates periodic testing; quarterly testing is recommended. These tests often can be performed by the hospital laboratory, or they can be done by the certifier. Some experts recommend having an outside certifier perform the tests every 6 months and the in-house laboratory (if used) 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 environmental monitoring 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, 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.

Sterile compounding facilities should be ready to simulate compounding or perform cleaning to simulate the work environment for the certification process. Once a certifier has completed the assessment, he or she will provide a written report of the findings and the areas that need improvement for review with pharmacy management and leadership or other pertinent staff within a health system.

PRACTICAL APPROACHES

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

  • Principal Competencies, Conditions, Practices, and Quality Assurances: This appendix selectively abstracts and condenses the full text of <797> for rapid reference by compounding professionals. Some of the sections of the appendix that are highly useful from a practical perspective include the theoretical principles and practical skills of garbing procedures, aseptic work practices, achieving and maintaining ISO Class 5 environmental conditions, and cleaning and disinfection procedures.27
  • Common Disinfectants: This appendix provides a chart of the most common disinfectants used in health care for inanimate surfaces and noncritical devices, their concentration, their microbial activity, and their important chemical and physical properties.28
  • Hand Hygiene and Garbing: This appendix provides a sample form that outlines a specific order for a qualified evaluator to check for hand hygiene and garbing practices of the compounding professional secondary to the natural flaking and shedding of the skin and the human body’s carriage of bacteria and microbes.29
  • Assessing Aseptic Technique: This appendix provides a sample form for a qualified evaluator to assess aseptic technique and related practices of compounding personnel to ensure sterility in the sterile compounding process required by <797>.30
  • Cleaning and Disinfection: This appendix provides a sample form for a qualified evaluator to assess cleaning and disinfection procedures and cleaning requirements for ISO Class 5 environments, using specific cleaning and disinfection practices on a daily and monthly basis.31

Achieving compliance

A lot of time, effort, and resources are needed to achieve and maintain compliance in compounding facility with sterile compounding. Certain areas such as facilities, personal training, aseptic techniques, and environmental monitoring can be challenging in meeting requirements. 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!

Table 3. Online Resources
Resource Link
USP Compounding Compendium (includes <797> and <800>, general Notices, and other compounding- and health care practice-oriented general chapters and monographs http://www.usp.org/store/products/usp-compounding-compendium
Critical point compliance studies www.797gaptool.com
www.800gaptool.com
Summaries in Pharmacy Purchasing & Products www.pppmag.com
Joint Commission Resources Improving Safe Handling Practices for Hazardous Drugs www.hazmedsafety.com

SUMMARY

As is evident in this program, achieving 100% compliance to current and future <797> and future <800> requirements can be difficult. With the proper facilities, personnel training and monitoring, work practices and SOPs, environmental monitoring, 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, weekly, and monthly routines is critical to achieve these goals.

REFERENCES

  1. U.S. Food and Drug Administration. Compounding and the FDA: questions and answers. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm339764.htm#what. Accessed April 14, 2017.
  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. Center for Disease Control and Prevention, Multistate outbreak of fungal meningitis and other infections. https://www.cdc.gov/hai/outbreaks/meningitis.html. Accessed April 14, 2017.
  4. Congress.gov. H.R.3204 — Drug Quality and Security Act. 113th Congress (2013–2014). https://www.congress.gov/bill/113th-congress/house-bill/3204. Accessed April 14, 2017.
  5. US Pharmacopeial Convention website. USP-NF. http://www.usp.org/usp-nf. Accessed April 14, 2017.
  6. USP quality standards for compounding (fact sheet). http://www.usp.org/sites/default/files/usp_pdf/EN/aboutUSP/usp_quality_standards_for_compounding.pdf. Accessed April 14, 2017.
  7. USP compounded preparation monographs. http://www.usp.org/usp-healthcare-professionals/compounding/compounding-monographs. Accessed December 2016.
  8. Notice of intent to revise USP general chapter <797> pharmaceutical compounding—sterile preparations. http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/usp-gc-797-proposed-revisions-sep-2015.pdf. Accessed April 14, 2017.
  9. USP open microphone meeting on general chapter <797> pharmaceutical compounding—sterile preparations. October 21, 2015, slide 10. http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/usp-nf-notices/797-open-mic-slides.pdf. Accessed April 14, 2017.
  10. General chapter <800> hazardous drugs—handling in healthcare settings, introduction. US Pharmacopeia 40-National Formulary 35 (online subscription). Accessed April 14, 2017.
  11. General notices, introduction. US Pharmacopeia 40-National Formulary 35 (online subscription). Accessed April 14, 2017.
  12. General notices, section 3.10.30. Applicability of standards to the practice of compounding. US Pharmacopeia 40-National Formulary 35 (online subscription). Accessed April 14, 2017.
  13. USP-NF. General notices proposed section 3.20. Indicating conformance, as proposed in PF 42(1), January 2016 (free online subscription). Accessed April 14, 2017.
  14. USP-NF. General notices proposed section 3.10.30 Applicability of standards to the practice of compounding (new), as proposed in PF 42(1), January 2016 (free online subscription). Accessed April 14, 2017.
  15. Center for Medicare and Medicaid Services. Site operations manual for hospitals and critical access hospitals, 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 April 14, 2017.
  16. Center for Medicare and Medicaid Services. Site operations manual for hospitals and critical access hospitals, 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 April 14, 2017.
  17. 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 April 14, 2017.
  18. US Food and Drug Administration. Regulatory policy information. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/PharmacyCompounding/ucm166743.htm. Accessed April 14, 2017.
  19. The Joint Commission. About The Joint Commission. https://www.jointcommission.org/about_us/about_the_joint_commission_main.aspx. Accessed April 14, 2017.
  20. 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 April 14, 2017.
  21. USP General Chapter <797> Pharmaceutical compounding—sterile preparations. US Pharmacopeia 40-National Formulary 35 (online). Personnel training and competency evaluation of garbing, aseptic work practices, and cleaning and disinfection procedures section. Accessed April 14, 2017.
  22. State of pharmacy compounding: <797> compliance. Pharm Purch Prod. April 2016, www.pppmag.com. Accessed April 14, 2017.
  23. USP general chapter <797> pharmaceutical compounding—sterile preparations US Pharmacopeia 40-National Formulary 35 (online). Definitions section. Accessed April 14, 2017.
  24. Proposed USP general chapter <797> pharmaceutical compounding—sterile preparations, September 2015. http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/usp-gc-797-proposed-revisions-sep-2015.pdf. Accessed April 14, 2017.
  25. 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 April 14, 2017.
  26. Personal cleansing and garbing, in USP general chapter <797> pharmaceutical compounding—sterile preparations. US Pharmacopeia 40-National Formulary 35 (online subscription). Accessed April 14, 2017.
  27. Appendix I. Principal competencies, conditions, practices, and quality assurances that are required and recommended in USP Chapter <797>, in USP general chapter <797> pharmaceutical compounding—sterile preparations. US Pharmacopeia 40-National Formulary 35 (online subscription). Accessed April 14, 2017.
  28. Appendix II. Common disinfectants used in health care for inanimate surfaces and noncritical devices, and their microbial activity and properties. USP general chapter <797> pharmaceutical compounding—sterile preparations. US Pharmacopeia 40-National Formulary 35 (online subscription). Accessed April 14, 2017.
  29. Appendix III. Sample form for assessing hand hygiene and garbing related practices of compounding personnel, in USP general chapter <797> pharmaceutical compounding—sterile preparations. US Pharmacopeia 40-National Formulary 35 (online subscription). Accessed April 14, 2017.
  30. Appendix IV. Sample form for assessing aseptic technique and related practices of compounding personnel, in USP general chapter <797> pharmaceutical compounding—sterile preparations. US Pharmacopeia 40-National Formulary 35 (online subscription). Accessed April 14, 2017.
  31. Appendix V. Sample form for assessing cleaning and disinfection procedures, in USP general chapter <797> pharmaceutical compounding—sterile preparations. US Pharmacopeia 40-National Formulary 35 (online subscription). Accessed April 14, 2017.

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