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4〈797〉 Pharmaceutical Compounding—Sterile Preparationslevel for air, surface, and personnel gear are notexceeded for a specified cleanliness class.Compounding Aseptic Containment Isolator(CACI)—A compounding aseptic isolator (CAI)designed to provide worker protection fromexposure to undesirable levels of airborne drugthroughout the compounding and material transferprocesses and to provide an aseptic environmentfor compounding sterile preparations. Airexchange with the surrounding environmentshould not occur unless the air is first passedthrough a microbial retentive filter (HEPAminimum) system capable of containing airborneconcentrations of the physical size and state of thedrug being compounded. Where volatile hazardousdrugs are prepared, the exhaust air from theisolator should be appropriately removed byproperly designed building ventilation.Compounding Aseptic Isolator (CAI)—Aform of isolator specifically designed forcompounding pharmaceutical ingredients orpreparations. It is designed to maintain an asepticcompounding environment within the isolatorthroughout the compounding and material transferprocesses. Air exchange into the isolator from thesurrounding environment should not occur unlessthe air has first passed through a microbiallyretentive filter (HEPA minimum).2Critical Area—An ISO Class 5 (see Table 1)environment.Critical Site—A location that includes anycomponent or fluid pathway surfaces (e.g., vialsepta, injection ports, beakers) or openings (e.g.,opened ampuls, needle hubs) exposed and at riskof direct contact with air (e.g., ambient room orHEPA filtered), moisture (e.g., oral and mucosalsecretions), or touch contamination. Risk ofmicrobial particulate contamination of the criticalsite increases with the size of the openings andexposure time.Direct Compounding Area (DCA)—A criticalarea within the ISO Class 5 (see Table 1) primaryengineering control (PEC) where critical sites are2CETA Applications Guide for the Use of Compounding Isolators inCompounding Sterile Preparations in Healthcare Facilities,CAG-001-2005, Controlled Environment Testing Association(CETA), November 8, 2005.Revision Bulletinexposed to unidirectional HEPA-filtered air, alsoknown as first air.Disinfectant—An agent that frees frominfection, usually a chemical agent but sometimesa physical one, and that destroys disease-causingpathogens or other harmful microorganisms butmay not kill bacterial and fungal spores. It refers tosubstances applied to inanimate objects.First Air—The air exiting the HEPA filter in aunidirectional air stream that is essentially particlefree.Hazardous Drugs—Drugs are classified ashazardous if studies in animals or humans indicatethat exposures to them have a potential for causingcancer, developmental or reproductive toxicity, orharm to organs. (See current NIOSH ents and 21 USC 321 (k) and (m)]—Aterm that designates all labels and other written,printed, or graphic matter on an immediatecontainer of an article or preparation or on, or in,any package or wrapper in which it is enclosed,except any outer shipping container. The term―label‖ designates that part of the labeling on theimmediate ion of Clean Rooms and Other ControlledEnvironments 〈1116〉)—A test used to qualifyaseptic technique of compounding personnel orprocesses and to ensure that the processes used areable to produce sterile product without microbialcontamination. During this test, a microbiologicalgrowth medium such as Soybean–Casein DigestMedium is substituted for the actual drug productto simulate admixture compounding.3 The issuesto consider in the development of a media-fill testare media-fill procedures, media selection, fillvolume, incubation, time and temperature,inspection of filled units, documentation,interpretation of results, and possible correctiveactions required.Multiple-Dose Container (see General Noticesand Requirements and Containers for Injectionsunder Injections 〈1〉)—A multiple-unit container3U.S. Food and Drug Administration, Guidance for Industry, SterileDrug Products Produced by Aseptic Processing—Current GoodManufacturing Practice, September 2004.Copyright 2008 The United States Pharmacopeial ConventionAll Rights Reserved.

Revision Bulletin〈797〉 Pharmaceutical Compounding—Sterile Preparationsfor articles or preparations intended for parenteraladministration only and usually containingantimicrobial preservatives. The beyond-use date(BUD) for an opened or entered (e.g.,needle-punctured) multiple-dose container withantimicrobial preservatives is 28 days (seeAntimicrobial Effectiveness Testing 〈51〉), unlessotherwise specified by the manufacturer.Negative Pressure Room—A room that is at alower pressure than the adjacent spaces and,therefore, the net flow of air is into the room.1Pharmacy Bulk Package (see Containers forInjections under Injections 〈1〉)—A container of asterile preparation for parenteral use that containsmany single doses. The contents are intended foruse in a pharmacy admixture program and arerestricted to the preparation of admixtures forinfusion or, through a sterile transfer device, forthe filling of empty sterile syringes. The closureshall be penetrated only one time after constitutionwith a suitable sterile transfer device or dispensingset, which allows measured dispensing of thecontents. The pharmacy bulk package is to be usedonly in a suitable work area such as a laminar flowhood (or an equivalent clean air compoundingarea).Where a container is offered as a pharmacy bulkpackage, the label shall (a) state prominently―Pharmacy Bulk Package—Not for DirectInfusion,‖ (b) contain or refer to information onproper techniques to help ensure safe use of theproduct, and (c) bear a statement limiting the timeframe in which the container may be used once ithas been entered, provided it is held under thelabeled storage conditions.Primary Engineering Control (PEC)—Adevice or room that provides an ISO Class 5 (seeTable 1) environment for the exposure of criticalsites when compounding CSPs. Such devicesinclude, but may not be limited to, laminar airflowworkbenches (LAFWs), biological safety cabinets(BSCs), compounding aseptic isolators (CAIs),and compounding aseptic containment isolators(CACIs).Preparation—A preparation, or a CSP, that is asterile drug or nutrient compounded in a licensedpharmacy or other healthcare-related facilitypursuant5to the order of a licensed prescriber; thearticle may or may not contain sterile products.Product—A commercially manufactured steriledrug or nutrient that has been evaluated for safetyand efficacy by the FDA. Products areaccompanied by full prescribing information,which is commonly known as the FDA-approvedmanufacturer‘s labeling or product package insert.Positive Pressure Room—A room that is at ahigher pressure than the adjacent spaces and,therefore, the net airflow is out of the room.1Single-Dose Container (see General Noticesand Requirements and Containers for Injectionsunder Injections 〈1〉)—A single-dose container is asingle-unit container for articles (see GeneralNotices and Requirements) or preparationsintended for parenteral administration only. It isintended for a single use. A single-dose containeris labeled as such. Examples of single-dosecontainers include prefilled syringes, cartridges,fusion-sealed containers, and closure-sealedcontainers when so labeled.Segregated Compounding Area—A designatedspace, either a demarcated area or room, that isrestricted to preparing low-risk level CSPs with12hour or less BUD. Such area shall contain adevice that provides unidirectional airflow of ISOClass 5 (see Table 1) air quality for preparation ofCSPs and shall be void of activities and materialsthat are extraneous to sterile compounding.Sterilizing Grade Membranes—Membranesthat are documented to retain 100% of a culture of107 microorganisms of a strain of Brevundimonas(Pseudomonas) diminuta per square centimeter ofmembrane surface under a pressure of not less than30 psi (2.0 bar). Such filter membranes arenominally at 0.22-mm or 0.2-mm nominal poresize, depending on the manufacturer‘s practice.Sterilization by Filtration—Passage of a fluidor solution through a sterilizing grade membraneto produce a sterile effluent.Terminal Sterilization—The application of alethal process (e.g., steam under pressure orautoclaving) to sealed containers for the purposeof achieving a predetermined sterility assuranceCopyright 2008 The United States Pharmacopeial ConventionAll Rights Reserved.

6〈797〉 Pharmaceutical Compounding—Sterile Preparationslevel of usually less than 10-6, or a probability ofless than one in one million of a nonsterile unit.3Unidirectional Flow (see footnote 3)—Anairflow moving in a single direction in a robustand uniform manner and at sufficient speed toreproducibily sweep particles away from thecritical processing or testing area.RESPONSIBILITY OF COMPOUNDINGPERSONNELCompounding personnel are responsible forensuring that CSPs are accurately identified,measured, diluted, and mixed and are correctlypurified, sterilized, packaged, sealed, labeled,stored, dispensed, and distributed. Theseperformance responsibilities include maintainingappropriate cleanliness conditions and providinglabeling and supplementary instructions for theproper clinical administration of CSPs.Compounding supervisors shall ensure, througheither direct measurement or appropriateinformation sources, that specific CSPs maintaintheir labeled strength within monograph limits forUSP articles, or within 10% if not specified, untiltheir BUDs. All CSPs are prepared in a mannerthat maintains sterility and minimizes theintroduction of particulate matter.A written quality assurance procedure includesthe following in-process checks that are applied, asappropriate, to specific CSPs: accuracy andprecision of measuring and weighing; therequirement for sterility; methods of sterilizationand purification; safe limits and ranges for strengthof ingredients, bacterial endotoxins, andparticulate matter; pH; labeling accuracy andcompleteness; BUD assignment; and packagingand storage requirements. The dispenser shall,when appropriate and practicable, obtain andevaluate results of testing for identity, strength,purity, and sterility before a CSP is dispensed.Qualified licensed healthcare professionals whosupervise compounding and dispensing of CSPsshall ensure that the following objectives areachieved:1.Compounding personnel areadequately skilled, educated, instructed, andtrained to2.3.4.5.6.7.Revision Bulletincorrectly perform and document the followingactivities in their sterile compounding duties:a. perform antiseptic hand cleansing anddisinfection of nonsterile compoundingsurfaces;b. select and appropriately don protectivegarb;c. maintain or achieve sterility of CSPs inISO Class 5 (see Table 1) PEC devicesand protect personnel and compoundingenvironments from contamination by radioactive, cytotoxic, and chemotoxicdrugs (see Hazardous Drugs as CSPs andRadiopharmaceuticals as CSPs);d. identify, weigh, and measure ingredients;ande. manipulate sterile products aseptically,sterilize high-risk level CSPs, and labeland quality inspect CSPs.Ingredients have their correct identity, quality,and purity.Opened or partially used packages ofingredients for subsequent use in CSPs areproperly stored under restricted accessconditions in the compounding facility. Suchpackages cannot be used when visualinspection detects unauthorized breaks in thecontainer, closure, and seal; when the contentsdo not possess the expected appearance,aroma, and texture; when the contents do notpass identification tests specified by thecompounding facility; and when either theBUD or expiration date has been exceeded.Water-containing CSPs that are nonsterileduring any phase of the compoundingprocedure are sterilized within 6 hours aftercompleting the preparation in order tominimize the generation of bacterialendotoxins.Sterilization methods achieve sterility ofCSPs while maintaining the labeled strengthof active ingredients and the physical integrityof packaging.Measuring, mixing, sterilizing, and purifyingdevices are clean, appropriately accurate, andeffective for their intended use.Potential harm from added substances andCopyright 2008 The United States Pharmacopeial ConventionAll Rights Reserved.

Revision Bulletin〈797〉 Pharmaceutical Compounding—Sterile Preparationsdifferences in rate and extent ofbioavailability of active ingredients for otherthan oral route of administration are carefullyevaluated before such CSPs are dispensed andadministered.8. Packaging selected for CSPs is appropriate topreserve the sterility and strength until theBUD.9. While being used, the compoundingenvironment maintains the sterility or thepresterilizationpurity,whicheverisappropriate, of the CSP.10. Labels on CSPs list the names and amounts orconcentrations of active ingredients, and thelabels or labeling of injections (seePreservation, Packaging, Storage, andLabeling in the General Notices andRequirements) list the names and amounts orconcentrations of all ingredients (seeInjections 〈1〉). Before being dispensed oradministered, the clarity of solutions isvisually confirmed; also, the identity andamounts of ingredients, procedures to prepareand sterilize CSPs, and specific releasecriteria are reviewed to ensure their accuracyand completeness.11. BUDs are assigned on the basis of directtesting or extrapolation from reliable literaturesources and other documentation (seeStability Criteria and Beyond-Use reparations〈795〉).12. Procedures for measuring, mixing, dilution,purification, sterilization, packaging, andlabeling conform to the correct sequence andquality established for the specified CSP.13. Deficiencies in compounding, labeling,packaging, and quality testing and inspectioncan be rapidly identified and corrected.14. When time and personnel availability sopermit, compounding manipulations andproceduresareseparatedfrompostcompounding quality inspection andreview before CSPs are dispensed.This chapter emphasizes the need to maintainhigh standards for the quality and control ofprocesses, components, and environments and for7the skill and knowledge of personnel who prepareCSPs. The rigor of in-process quality-controlchecks and of postcompounding quality inspectionand testing increases with the potential hazard ofthe route of administration. For ntamination, large errors in strength of correctingredients, and incorrect ingredients in CSPs arepotentially more dangerous to patients when theCSPs are administered into the vascular andcentral nervous systems than when administeredby most other routes.CSP MICROBIAL CONTAMINATION RISKLEVELSThe three contamination categories for CSPsdescribed in this section are assigned primarilyaccording to the potential for microbialcontamination during the compounding of low-risklevel CSPs and medium-risk level CSPs or thepotential for not sterilizing high-risk level CSPs,any of which would subject patients to risk ofharm, including death. High-risk level CSPs mustbe sterilized before being administered to patients.The appropriate risk level—low, medium, orhigh—is assigned according to the correspondingprobability of contaminating a CSP with (1)microbialcontamination(e.g.,microbialorganisms, spores, endotoxins) and (2) chemicaland physical contamination (e.g., foreignchemicals, physical matter). Potential sources ofcontamination include, but are not limited to, solidand liquid matter from compounding personnel andobjects; non-sterile components employed priate conditions within the lizationprocedureswithaqueouspreparations; and nonsterile dosage forms used tocompound CSPs.The characteristics described below for low-,medium-, and high-risk level CSPs are intended asa guide to the breadth and depth of care necessaryin compounding, but they are neither exhaustivenor prescriptive. The licensed healthcareprofessionals who supervise compounding areresponsible for determining the procedural andenvironmentalCopyright 2008 The United States Pharmacopeial Convention All Rights Reserved.

8〈797〉 Pharmaceutical Compounding—Sterile Preparationsquality practices and attributes that arenecessary for the risk level they assign to specificCSPs.These risk levels apply to the quality of CSPsimmediately after the final aseptic mixing orfilling or immediately after the final sterilization,unless precluded by the specific characteristics ofthe preparation. Upon subsequent storage andshipping of freshly finished CSPs, an increase inthe risks of chemical degradation of ingredients,contamination from physical damage to packaging,and permeability of plastic and elastomericpackaging is expected. In such cases,compounding personnel are responsible forconsidering the potential additional risks to theintegrity of CSPs when assigning BUDs. Thepre-administrationstoragedurationandtemperature limits specified in the followingsubsections apply in the absence of direct sterilitytesting results that justify different limits forspecific CSPs.Low-Risk Level CSPsCSPs compounded under all the followingconditions are at a low risk of contamination.Low-Risk Conditions—1. The CSPs are compounded with asepticmanipulations entirely within ISO Class 5(see Table 1) or better air quality using onlysterile ingredients, products, components, anddevices.2. The compounding involves only transfer,measuring, and mixing manipulations usingnotmorethanthreecommerciallymanufactured packages of sterile products andnot more than two entries into any one sterilecontainer or package (e.g., bag, vial) of sterileproduct or administration container/device toprepare the CSP.3. Manipulations are limited to asepticallyopening ampuls, penetrating disinfectedstoppers on vials with sterile needles andsyringes, and transferring sterile liquids insterile syringes to sterile administrationdevices, package containers of other sterileproducts, and containers for storage anddispensing.Revision Bulletin4. For a low-risk level preparation, in the absenceof passing a sterility test (see Sterility Tests〈71〉), the storage periods cannot exceed thefollowing time periods: before administration,the CSPs are properly stored and are exposedfor not more than 48 hours at controlled roomtemperature (see General Notices andRequirements), for not more than 14 days at acold temperature (see General Notices andRequirements), and for 45 days in solid frozenstate between 25 and 10 .Examples of Low-Risk Compounding—1. Single-volume transfers of sterile dosageforms from ampuls, bottles, bags, and vialsusing sterile syringes with sterile needles,other administration devices, and other sterilecontainers. The solution content of ampulsshould be passed through a sterile filter toremove

nurses, pharmacy technicians, and physicians. These terms recognize that most sterile compounding is performed by or under the supervision of pharmacists in pharmacies and also that this chapter applies to all healthcare personnel who prepare, store, and transport CSPs. For the pur