36C24818R0107-004.pdf

Revision Bulletin 〈797〉 Pharmaceutical Compounding—Sterile Preparations 1

Change to read: quality standards for CSPs of drugs and nutrients based on current scientific information and best sterile compounding practices. The use of technol-ogies, techniques, materials, and procedures other than those described in this chapter is not prohib-

〈797〉 PHARMACEUTICAL ited so long as they have been proven to be equiva-lent or superior with statistical significance toCOMPOUNDING— those described herein. The standards in this chap-

STERILE PREPARATIONS ter do not pertain to the clinical administration of CSPs to patients via application, implantation, in-fusion, inhalation, injection, insertion, instillation, and irrigation, which are the routes of administra-INTRODUCTION tion. Four specific categories of CSPs are de-

The objective of this chapter is to describe con- scribed in this chapter: low-risk level, medium-risk ditions and practices to prevent harm, including level, and high-risk level, and immediate use. Ster-death, to patients that could result from (1) micro- ile compounding differs from nonsterile com-bial contamination (nonsterility), (2) excessive pounding (see Pharmaceutical Compound-bacterial endotoxins, (3) variability in the intended ing—Nonsterile Preparations 〈795〉 and Good strength of correct ingredients that exceeds either Compounding Practices 〈1075〉) primarily by re-monograph limits for official articles (see “offi- quiring the maintenance of sterility when com-cial” and “article” in the General Notices and Re- pounding exclusively with sterile ingredients and quirements) or 10% for nonofficial articles, (4) un- components ( i.e., with immediate-use CSPs, low-intended chemical and physical contaminants, and risk level CSPs, and medium-risk level CSPs) and

(5) ingredients of inappropriate quality in com- the achievement of sterility when compounding pounded sterile preparations (CSPs). Contami- with nonsterile ingredients and components (i.e., nated CSPs are potentially most hazardous to pa- with high-risk level CSPs). Some differences be-tients when administered into body cavities, tween standards for sterile compounding in this central nervous and vascular systems, eyes, and chapter and those for nonsterile compounding in joints, and when used as baths for live organs and Pharmaceutical Compounding—Nonsterile Prepa-tissues. When CSPs contain excessive bacterial en- rations 〈795〉 include, but are not limited to, ISO-dotoxins (see Bacterial Endotoxins Test 〈85〉), they classified air environments (see Table 1); person-are potentially most hazardous to patients when nel garbing and gloving; personnel training and administered into the central nervous system. testing in principles and practices of aseptic ma-

Despite the extensive attention in this chapter to nipulations and sterilization; environmental quality the provision, maintenance, and evaluation of air specifications and monitoring; and disinfection of quality, the avoidance of direct or physical contact gloves and surfaces of ISO Class 5 (see Table 1) contamination is paramount. It is generally ac- sources.

knowledged that direct or physical contact of criti-cal sites of CSPs with contaminants, especially mi-crobial sources, poses the greatest probability of risk to patients. Therefore, compounding personnel must be meticulously conscientious in precluding contact contamination of CSPs both within and outside ISO Class 5 (see Table 1) areas.

To achieve the above five conditions and prac-tices, this chapter provides minimum practice and

Copyright 2008 The United States Pharmacopeial Convention All Rights Reserved.

2 〈797〉 Pharmaceutical Compounding—Sterile Preparations Revision Bulletin

Table 1. ISO Classification of Particulate Mat- thalmic drops and ointments, and tissue ter in Room Air (limits are in particles of 0.5 implants.

µm and larger per cubic meter [current ISO] and (2) Manufactured sterile products that are either cubic feet [former Federal Standard No. 209E, prepared strictly according to the instructions

FS 209E])*

appearing in manufacturers’ approved label-ing (product package inserts) or prepared dif-Class Name Particle Count ferently than published in such labeling.FS [NOTE—The FDA states that “CompoundingISO U.S. FS 209E, does not include mixing, reconstituting, orClass 209E ISO, m3 ft3 similar acts that are performed in accordance3 Class 1 35.2 1 with the directions contained in approved la-4 Class 10 352 10 beling provided by the product’s manufac-

5 Class 100 3,520 100 turer and other manufacturer directions con-

6 Class 1,000 35,200 1,000 sistent with that labeling” [(21 USC 321 (k) 7 Class 10,000 352,000 10,000 and (m)]. However, the FDA-approved label- 8 Class 100,000 3,520,000 100,000 ing (product package insert) rarely describes

Adapted from former Federal Standard No. 209E, General Servic- environmental quality (e.g., ISO Class air des-es Administration, Washington, DC, 20407 (September 11, 1992) ignation, exposure durations to non-ISOand ISO 14644-1 : 1999, Cleanrooms and associated controlled en-vironments—Part 1: Classification of air cleanliness. For example, classified air, personnel garbing and gloving, 3,520 particles of 0.5 µm per m3 or larger (ISO Class 5) is equiva-and other aseptic precautions by which sterilelent to 100 particles per ft3 (Class 100) (1 m3 = 35.2 ft3).

products are to be prepared for administra-The standards in this chapter are intended to ap-tion). Beyond-use exposure and storage datesply to all persons who prepare CSPs and all places or times (see General Notices and Require-where CSPs are prepared (e.g., hospitals and other ments and Pharmaceutical Compound-healthcare institutions, patient treatment clinics, ing—Nonsterile Preparations 〈795〉) for ster-pharmacies, physicians’ practice facilities, and ile products that have been either opened orother locations and facilities in which CSPs are prepared for administration are not specifiedprepared, stored, and transported). Persons who in all package inserts for all sterile products.perform sterile compounding include pharmacists, Furthermore, when such durations are speci-nurses, pharmacy technicians, and physicians.

fied, they may refer to chemical stability andThese terms recognize that most sterile compound-not necessarily to microbiological purity oring is performed by or under the supervision of safety.]pharmacists in pharmacies and also that this chap-ter applies to all healthcare personnel who prepare, ORGANIZATION OF THIS CHAPTERstore, and transport CSPs. For the purposes of this chapter, CSPs include any of the following:

The sections in this chapter are organized to fa-(1) Compounded biologics, diagnostics, drugs, cilitate the practitioner’s understanding of the fun-nutrients, and radiopharmaceuticals, including damental accuracy and quality practices for pre-but not limited to the following dosage forms paring CSPs. They provide a foundation for thethat must be sterile when they are adminis-development and implementation of essential pro-tered to patients: aqueous bronchial and nasal cedures for the safe preparation of low-risk, med-inhalations, baths and soaks for live organs ium-risk, and high-risk level CSPs and immediate-and tissues, injections (e.g., colloidal disper-use CSPs, which are classified according to the po-sions, emulsions, solutions, suspensions), irri-tential for microbial, chemical, and physical con-gations for wounds and body cavities, oph-tamination. The chapter is divided into the follow-ing main sections:

Revision Bulletin 〈797〉 Pharmaceutical Compounding—Sterile Preparations 3

• Definitions entry, CSP labeling, and other high-particulate-generating activities are performed. It is also a• Responsibility of Compounding Personnel transition area that (1) provides assurance that• CSP Microbial Contamination Risk Levels pressure relationships are constantly maintained so• Personnel Training and Evaluation in Aseptic that air flows from clean to dirty areas and (2) re-Manipulation Skills duces the need for the heating, ventilating, and air-• Immediate-Use CSPs conditioning (HVAC) control system to respond to• Single-Dose and Multiple-Dose Containers large disturbances.1 • Hazardous Drugs as CSPs

• Radiopharmaceuticals as CSPs Aseptic Processing (see Microbiological Evalu-

• Allergen Extracts as CSPs ation of Clean Rooms and Other Controlled Envi-

• Verification of Compounding Accuracy and ronments 〈1116〉)—A mode of processing pharma-

Sterility ceutical and medical products that involves the

• Environmental Quality and Control separate sterilization of the product and of the

• Suggested Standard Operating Procedures package (containers–closures or packaging ma-

(SOPs) terial for medical devices) and the transfer of the

• Elements of Quality Control product into the container and its closure under at

• Verification of Automated Compounding De- least ISO Class 5 (see Table 1) conditions.

vices (ACDs) for Parenteral Nutrition Beyond-Use Date (BUD) (see General Notices Compounding and Requirements and Pharmaceutical Com-

• Finished Preparation Release Checks and pounding—Nonsterile Preparations 〈795〉)—For Tests the purpose of this chapter, the date or time after

• Storage and Beyond-Use Dating which a CSP shall not be stored or transported.

• Maintaining Sterility, Purity, and Stability of The date is determined from the date or time the

Dispensed and Distributed CSPs preparation is compounded.

• Patient or Caregiver Training

Biological Safety Cabinet (BSC)—A ventilated• Patient Monitoring and Adverse Events cabinet for CSPs, personnel, product, and environ-Reporting mental protection having an open front with in-• Quality Assurance (QA) Program ward airflow for personnel protection, downward• Abbreviations and Acronyms high-efficiency particulate air (HEPA)-filtered• Appendices I–V laminar airflow for product protection, and HEPA-The requirements and recommendations in this filtered exhausted air for environmental protection.chapter are summarized in Appendix I. A list of ab-

Buffer Area—An area where the primary engi-breviations and acronyms is included at the end of neering control (PEC) is physically located. Activ-the main text, before the Appendices.

ities that occur in this area include the preparationAll personnel who prepare CSPs shall be re-and staging of components and supplies used whensponsible for understanding these fundamental compounding CSPs.practices and precautions, for developing and im-plementing appropriate procedures, and for contin- Clean Room (see Microbiological Evaluation of ually evaluating these procedures and the quality Clean Rooms and Other Controlled Environments of final CSPs to prevent harm. 〈1116〉 and also the definition of Buffer Area)—A room in which the concentration of airborne parti-cles is controlled to meet a specified airborne par-DEFINITIONS ticulate cleanliness class. Microorganisms in the

Ante-Area—An ISO Class 8 (see Table 1) or environment are monitored so that a microbial better area where personnel hand hygiene and 1See American Society of Heating, Refrigerating and Air-Condi-garbing procedures, staging of components, order tioning Engineers, Inc. (ASHRAE), Laboratory Design Guide.

4 〈797〉 Pharmaceutical Compounding—Sterile Preparations Revision Bulletin level for air, surface, and personnel gear are not exposed to unidirectional HEPA-filtered air, also exceeded for a specified cleanliness class. known as first air.

Compounding Aseptic Containment Isolator Disinfectant—An agent that frees from infec- (CACI)—A compounding aseptic isolator (CAI) tion, usually a chemical agent but sometimes a designed to provide worker protection from expo- physical one, and that destroys disease-causing sure to undesirable levels of airborne drug pathogens or other harmful microorganisms but throughout the compounding and material transfer may not kill bacterial and fungal spores. It refers to processes and to provide an aseptic environment substances applied to inanimate objects.

for compounding sterile preparations. Air ex- First Air—The air exiting the HEPA filter in a change with the surrounding environment should unidirectional air stream that is essentially particle not occur unless the air is first passed through a free.

microbial retentive filter (HEPA minimum) system Hazardous Drugs—Drugs are classified as haz-capable of containing airborne concentrations of ardous if studies in animals or humans indicate the physical size and state of the drug being com- that exposures to them have a potential for causing pounded. Where volatile hazardous drugs are pre- cancer, developmental or reproductive toxicity, or pared, the exhaust air from the isolator should be harm to organs. (See current NIOSH publication.)

appropriately removed by properly designed build- Labeling [see General Notices and Require-ing ventilation. ments and 21 USC 321 (k) and (m)]—A term that

Compounding Aseptic Isolator (CAI)—A designates all labels and other written, printed, or form of isolator specifically designed for com- graphic matter on an immediate container of an ar-pounding pharmaceutical ingredients or prepara- ticle or preparation or on, or in, any package or tions. It is designed to maintain an aseptic com- wrapper in which it is enclosed, except any outer pounding environment within the isolator shipping container. The term “label” designates throughout the compounding and material transfer that part of the labeling on the immediate processes. Air exchange into the isolator from the container.

surrounding environment should not occur unless Media-Fill Test (see Microbiological Evalua-the air has first passed through a microbially reten- tion of Clean Rooms and Other Controlled Envi-tive filter (HEPA minimum).2 ronments 〈1116〉)—A test used to qualify aseptic

Critical Area—An ISO Class 5 (see Table 1) technique of compounding personnel or processes environment. and to ensure that the processes used are able to

Critical Site—A location that includes any com- produce sterile product without microbial contami-ponent or fluid pathway surfaces (e.g., vial septa, nation. During this test, a microbiological growth injection ports, beakers) or openings (e.g., opened medium such as Soybean–Casein Digest Medium ampuls, needle hubs) exposed and at risk of direct is substituted for the actual drug product to simu-contact with air (e.g., ambient room or HEPA fil- late admixture compounding.3 The issues to con-tered), moisture (e.g., oral and mucosal secre- sider in the development of a media-fill test are tions), or touch contamination. Risk of microbial media-fill procedures, media selection, fill volume, particulate contamination of the critical site in- incubation, time and temperature, inspection of creases with the size of the openings and exposure filled units, documentation, interpretation of re-time. sults, and possible corrective actions required.

Direct Compounding Area (DCA)—A critical Multiple-Dose Container (see General Noticesarea within the ISO Class 5 (see Table 1) primary and Requirements and Containers for Injectionsengineering control (PEC) where critical sites are under Injections 〈1〉)—A multiple-unit container

2CETA Applications Guide for the Use of Compounding Isolators in Compounding Sterile Preparations in Healthcare Facilities, CAG- 3U.S. Food and Drug Administration, Guidance for Industry, Sterile 001-2005, Controlled Environment Testing Association (CETA), Drug Products Produced by Aseptic Processing—Current Good November 8, 2005. Manufacturing Practice, September 2004.

Revision Bulletin 〈797〉 Pharmaceutical Compounding—Sterile Preparations 5 for articles or preparations intended for parenteral suant to the order of a licensed prescriber; the arti-administration only and usually containing antimi- cle may or may not contain sterile products.

crobial preservatives. The beyond-use date (BUD) Product—A commercially manufactured sterile for an opened or entered (e.g., needle-punctured) drug or nutrient that has been evaluated for safety multiple-dose container with antimicrobial pre- and efficacy by the FDA. Products are accompa-servatives is 28 days (see Antimicrobial Effective- nied by full prescribing information, which is com-ness Testing 〈51〉), unless otherwise specified by monly known as the FDA-approved manufactur-the manufacturer. er’s labeling or product package insert.

Negative Pressure Room—A room that is at a Positive Pressure Room—A room that is at a lower pressure than the adjacent spaces and, there- higher pressure than the adjacent spaces and, fore, the net flow of air is into the room.1 therefore, the net airflow is out of the room.1

Pharmacy Bulk Package (see Containers for Single-Dose Container (see General Notices Injections under Injections 〈1〉)—A container of a and Requirements and Containers for Injections sterile preparation for parenteral use that contains under Injections 〈1〉)—A single-dose container is a many single doses. The contents are intended for single-unit container for articles (see General No-use in a pharmacy admixture program and are re- tices and Requirements) or preparations intended stricted to the preparation of admixtures for infu- for parenteral administration only. It is intended sion or, through a sterile transfer device, for the for a single use. A single-dose container is labeled filling of empty sterile syringes. The closure shall as such. Examples of single-dose containers in-be penetrated only one time after constitution with clude prefilled syringes, cartridges, fusion-sealed a suitable sterile transfer device or dispensing set, containers, and closure-sealed containers when so which allows measured dispensing of the contents. labeled.

The pharmacy bulk package is to be used only in a

Segregated Compounding Area—A designatedsuitable work area such as a laminar flow hood (or space, either a demarcated area or room, that is re-an equivalent clean air compounding area).

stricted to preparing low-risk level CSPs with 12-Where a container is offered as a pharmacy bulk hour or less BUD. Such area shall contain a devicepackage, the label shall (a) state prominently that provides unidirectional airflow of ISO Class 5“Pharmacy Bulk Package—Not for Direct Infu- (see Table 1) air quality for preparation of CSPssion,” (b) contain or refer to information on proper and shall be void of activities and materials thattechniques to help ensure safe use of the product, are extraneous to sterile compounding.and (c) bear a statement limiting the time frame in

Sterilizing Grade Membranes—Membraneswhich the container may be used once it has been that are documented to retain 100% of a culture ofentered, provided it is held under the labeled stor- 107 microorganisms of a strain of Brevundimonasage conditions.

(Pseudomonas) diminuta per square centimeter ofPrimary Engineering Control (PEC)—A de-membrane surface under a pressure of not less thanvice or room that provides an ISO Class 5 (see Ta- 30 psi (2.0 bar). Such filter membranes are nomi-ble 1) environment for the exposure of critical sites nally at 0.22-µm or 0.2-µm nominal pore size, de-when compounding CSPs. Such devices include, pending on the manufacturer’s practice.but may not be limited to, laminar airflow work-

Sterilization by Filtration—Passage of a fluidbenches (LAFWs), biological safety cabinets or solution through a sterilizing grade membrane(BSCs), compounding aseptic isolators (CAIs), to produce a sterile effluent.and compounding aseptic containment isolators

(CACIs). Terminal Sterilization—The application of a Preparation—A preparation, or a CSP, that is a lethal process (e.g., steam under pressure or sterile drug or nutrient compounded in a licensed autoclaving) to sealed containers for the purpose pharmacy or other healthcare-related facility pur- of achieving a predetermined sterility assurance

6 〈797〉 Pharmaceutical Compounding—Sterile Preparations Revision Bulletin level of usually less than 10−6, or a probability of correctly perform and document the following less than one in one million of a nonsterile unit.3 activities in their sterile compounding duties:

a. perform antiseptic hand cleansing andUnidirectional Flow (see footnote 3)—An air-disinfection of nonsterile compoundingflow moving in a single direction in a robust and surfaces;uniform manner and at sufficient speed to

b. select and appropriately don protectivereproducibily sweep particles away from the criti-garb;cal processing or testing area.

c. maintain or achieve sterility of CSPs in ISO Class 5 (see Table 1) PEC devicesRESPONSIBILITY OF COMPOUNDING and protect personnel and compoundingPERSONNEL environments from contamination by ra-

Compounding personnel are responsible for en- dioactive, cytotoxic, and chemotoxic suring that CSPs are accurately identified, meas- drugs (see Hazardous Drugs as CSPs and ured, diluted, and mixed and are correctly purified, Radiopharmaceuticals as CSPs);

sterilized, packaged, sealed, labeled, stored, dis- d. identify, weigh, and measure ingredients;

pensed, and distributed. These performance re- and sponsibilities include maintaining appropriate e. manipulate sterile products aseptically, cleanliness conditions and providing labeling and sterilize high-risk level CSPs, and label supplementary instructions for the proper clinical and quality inspect CSPs.

administration of CSPs. 2. Ingredients have their correct identity, quality, Compounding supervisors shall ensure, through and purity.

either direct measurement or appropriate informa- 3. Opened or partially used packages of ingredi-tion sources, that specific CSPs maintain their la- ents for subsequent use in CSPs are properly beled strength within monograph limits for USP stored under restricted access conditions in articles, or within 10% if not specified, until their the compounding facility. Such packages can- BUDs. All CSPs are prepared in a manner that not be used when visual inspection detects un-maintains sterility and minimizes the introduction authorized breaks in the container, closure, of particulate matter. and seal; when the contents do not possess the

A written quality assurance procedure includes expected appearance, aroma, and texture;

the following in-process checks that are applied, as when the contents do not pass identification appropriate, to specific CSPs: accuracy and preci- tests specified by the compounding facility;

sion of measuring and weighing; the requirement and when either the BUD or expiration date for sterility; methods of sterilization and purifica- has been exceeded.

tion; safe limits and ranges for strength of ingredi- 4. Water-containing CSPs that are nonsterile ents, bacterial endotoxins, and particulate matter; during any phase of the compounding proce-pH; labeling accuracy and completeness; BUD as- dure are sterilized within 6 hours after com-signment; and packaging and storage require- pleting the preparation in order to minimize ments. The dispenser shall, when appropriate and the generation of bacterial endotoxins.

practicable, obtain and evaluate results of testing 5. Sterilization methods achieve sterility of for identity, strength, purity, and sterility before a CSPs while maintaining the labeled strength CSP is dispensed. Qualified licensed healthcare of active ingredients and the physical integrity professionals who supervise compounding and dis- of packaging.

pensing of CSPs shall ensure that the following 6. Measuring, mixing, sterilizing, and purifying objectives are achieved: devices are clean, appropriately accurate, and

1. Compounding personnel are adequately effective for their intended use.

skilled, educated, instructed, and trained to 7. Potential harm from added substances and

Revision Bulletin 〈797〉 Pharmaceutical Compounding—Sterile Preparations 7 differences in rate and extent of bioavailabil- the skill and knowledge of personnel who prepare ity of active ingredients for other than oral CSPs. The rigor of in-process quality-control route of administration are carefully evaluated checks and of postcompounding quality inspection before such CSPs are dispensed and and testing increases with the potential hazard of administered. the route of administration. For example, nonste-

8. Packaging selected for CSPs is appropriate to rility, excessive bacterial endotoxin contamination, preserve the sterility and strength until the large errors in strength of correct ingredients, and BUD. incorrect ingredients in CSPs are potentially more

9. While being used, the compounding environ- dangerous to patients when the CSPs are adminis-ment maintains the sterility or the presteriliza- tered into the vascular and central nervous systems tion purity, whichever is appropriate, of the than when administered by most other routes.

CSP.

10. Labels on CSPs list the names and amounts or CSP MICROBIAL CONTAMINATION RISK concentrations of active ingredients, and the LEVELS labels or labeling of injections (see Preserva-

The three contamination categories for CSPs de-tion, Packaging, Storage, and Labeling in the scribed in this section are assigned primarily ac-General Notices and Requirements) list the cording to the potential for microbial contamina-names and amounts or concentrations of all tion during the compounding of low-risk levelingredients (see Injections 〈1〉). Before being CSPs and medium-risk level CSPs or the potentialdispensed or administered, the clarity of solu-for not sterilizing high-risk level CSPs, any oftions is visually confirmed; also, the identity which would subject patients to risk of harm, in-and amounts of ingredients, procedures to cluding death. High-risk level CSPs must be steril-prepare and sterilize CSPs, and specific re-ized before being administered to patients. The ap-lease criteria are reviewed to ensure their ac-propriate risk level—low, medium, or high—iscuracy and completeness.

assigned according to the corresponding probabil-11. BUDs are assigned on the basis of direct test-ity of contaminating a CSP with (1) microbial con-ing or extrapolation from reliable literature tamination (e.g., microbial organisms, spores, en-sources and other documentation (see Stabil-dotoxins) and (2) chemical and physicality Criteria and Beyond-Use Dating under contamination (e.g., foreign chemicals, physicalPharmaceutical Compounding—Nonsterile matter). Potential sources of contamination in-Preparations 〈795〉).

clude, but are not limited to, solid and liquid mat-12. Procedures for measuring, mixing, dilution, ter from compounding personnel and objects; non-purification, sterilization, packaging, and la-sterile components employed and incorporatedbeling conform to the correct sequence and before terminal sterilization; inappropriate condi-quality established for the specified CSP.

tions within the restricted compounding environ-13. Deficiencies in compounding, labeling, pack-ment; prolonged presterilization procedures withaging, and quality testing and inspection can aqueous preparations; and nonsterile dosage formsbe rapidly identified and corrected.

used to compound CSPs.14. When time and personnel availability so per-mit, compounding manipulations and proce- The characteristics described below for low-, dures are separated from postcompounding medium-, and high-risk level CSPs are intended as quality inspection and review before CSPs are a guide to the breadth and depth of care necessary dispensed. in compounding, but they are neither exhaustive

This chapter emphasizes the need to maintain nor prescriptive. The licensed healthcare profes-high standards for the quality and control of sionals who supervise compounding are responsi-processes, components, and environments and for ble for determining the procedural and environ-

8 〈797〉 Pharmaceutical Compounding—Sterile Preparations Revision Bulletin mental quality practices and attributes that are 4. For a low-risk level preparation, in the ab-necessary for the risk level they assign to specific sence of passing a sterility test (see Sterility CSPs. Tests 〈71〉), the storage periods cannot exceed the following time periods: before administra-These risk levels apply to the quality of CSPs tion, the CSPs are properly stored and are ex-immediately after the final aseptic mixing or fill-posed for not more than 48 hours at controlleding or immediately after the final sterilization, un-room temperature (see General Notices andless precluded by the specific characteristics of the Requirements), for not more than 14 days at apreparation. Upon subsequent storage and shipping cold temperature (see General Notices andof freshly finished CSPs, an increase in the risks of Requirements), and for 45 days in solid frozenchemical degradation of ingredients, contamina-state between −25° and −10°.tion from physical damage to packaging, and per-meability of plastic and elastomeric packaging is Examples of Low-Risk Compounding— expected. In such cases, compounding personnel 1. Single-volume transfers of sterile dosage are responsible for considering the potential addi- forms from ampuls, bottles, bags, and vials tional risks to the integrity of CSPs when assigning using sterile syringes with sterile needles, BUDs. The pre-administration storage duration other administration devices, and other sterile and temperature limits specified in the following containers. The solution content of ampuls subsections apply in the absence of direct sterility should be passed through a sterile filter to re-testing results that justify different limits for spe- move any particles.

cific CSPs.

2. Simple aseptic measuring and transferring with not more than three packages of manu-

Low-Risk Level CSPs factured sterile products, including an infu-sion or diluent solution to compound drug ad-CSPs compounded under all the following con-mixtures and nutritional solutions.ditions are at a low risk of contamination.

Low-Risk Level CSPs with 12-Hour or LessLow-Risk Conditions— BUD—If the PEC is a CAI or CACI that does not1. The CSPs are compounded with aseptic ma-meet the requirements described in Placement ofnipulations entirely within ISO Class 5 (see Primary Engineering Controls or is a laminar air-Table 1) or better air quality using only sterile flow workbench (LAFW) or a biological safetyingredients, products, components, and cabinet (BSC) that cannot be located within andevices.

ISO Class 7 (see Table 1) buffer area, then only2. The compounding involves only transfer, low-risk level nonhazardous and radi-measuring, and mixing manipulations using opharmaceutical CSPs pursuant to a physician’snot more than three commercially manufac-order for a specific patient may be prepared, andtured packages of sterile products and not administration of such CSPs shall commencemore than two entries into any one sterile within 12 hours of preparation or as recommendedcontainer or package (e.g., bag, vial) of sterile in the manufacturers’ package insert, whichever isproduct or administration container/device to less. Low-risk level CSPs with a 12-hour or lessprepare the CSP.

BUD shall meet all of the following four criteria:3. Manipulations are limited to aseptically open-ing ampuls, penetrating disinfected stoppers 1. PECs (LAFWs, BSCs, CAIs, CACIs,) shall on vials with sterile needles and syringes, and be certified and maintain ISO Class 5 (see Ta-transferring sterile liquids in sterile syringes ble 1) as described in Facility Design and En-to sterile administration devices, package con- vironmental Controls for exposure of critical tainers of other sterile products, and con- sites and shall be in a segregated compound-tainers for storage and dispensing. ing area restricted to sterile compounding ac-

Revision Bulletin 〈797〉 Pharmaceutical Compounding—Sterile Preparations 9 tivities that minimize the risk of CSP 3. Review of all orders and packages of ingredi-contamination. ents to ensure that the correct identity and

2. The segregated compounding area shall not amounts of ingredients were compounded.

be in a location that has unsealed windows or 4. Visual inspection of CSPs to ensure the ab-doors that connect to the outdoors or high sence of particulate matter in solutions, the traffic flow, or that is adjacent to construction absence of leakage from vials and bags, and sites, warehouses, or food preparation. Note the accuracy and thoroughness of labeling.

that this list is not intended to be all Media-Fill Test Procedure—This test or an inclusive. equivalent test is performed at least annually by

3. Personnel shall follow the procedures de- each person authorized to compound in a low-risk scribed in Personnel Cleansing and Garbing level environment under conditions that closely and Additional Personnel Requirements prior simulate the most challenging or stressful condi-to compounding. Sinks should not be located tions encountered during compounding of low-risk adjacent to the ISO Class 5 (see Table 1) level CSPs. Once begun, this test is completed PEC. Sinks should be separated from the im- without interruption. Example of test procedure:

mediate area of the ISO Class 5 (see Table 1) within an ISO Class 5 (see Table 1) air quality en- PEC device. vironment, three sets of four 5-mL aliquots of ster-

4. The specifications in Cleaning and Disinfect- ile Soybean–Casein Digest Medium (also known ing the Sterile Compounding Areas, Person- as trypticase soy broth or trypticase soy agar nel Training and Competency Evaluation of [TSA]) are transferred with the same sterile 10-mL Garbing, Aseptic Work Practices and Clean- syringe and vented needle combination into separ-ing/Disinfection Procedures, and Viable and ate sealed, empty, sterile 30-mL clear vials (i.e., Nonviable Environmental Sampling (ES) four 5-mL aliquots into each of three 30-mL vials).

Testing shall be followed as described in the Sterile adhesive seals are aseptically affixed to the chapter. rubber closures on the three filled vials, then the

Compounding personnel must recognize that the vials are incubated at 20° to 25° or at 30° to 35° absence of an ISO Class 7 (see Table 1) buffer for a minimum of 14 days. If two temperatures are area environment in a general uncontrolled envi- used for incubation of media-filled samples, then ronment increases the potential of microbial con- these filled containers should be incubated for at tamination, and administration durations of least 7 days at each temperature (see Microbiologi-microbially contaminated CSPs exceeding a few cal Evaluation of Clean Rooms and Other Con-hours increase the potential for clinically signifi- trolled Environments 〈1116〉). Inspect for micro-cant microbial colonization, and thus for patient bial growth over 14 days as described in Personnel harm, especially in critically ill or immunocom- Training and Competency Evaluation of Garbing, promised patients. Aseptic Work Practices and Cleaning/Disinfection

Quality Assurance—Quality assurance prac- Procedures.

tices include, but are not limited to the following:

1. Routine disinfection and air quality testing of Medium-Risk Level CSPs the direct compounding environment to mini- When CSPs are compounded aseptically undermize microbial surface contamination and

Low-Risk Conditions and one or more of the fol-maintain ISO Class 5 (see Table 1) air quality.

lowing conditions exists, such CSPs are at a med-2. Visual confirmation that compounding per-ium risk of contamination.sonnel are properly donning and wearing ap-

Medium-Risk Conditions—propriate items and types of protective gar-ments, including eye protection and face 1. Multiple individual or small doses of sterile masks. products are combined or pooled to prepare a

10 〈797〉 Pharmaceutical Compounding—Sterile Preparations Revision Bulletin

CSP that will be administered either to multi- vironment, six 100-mL aliquots of sterile ple patients or to one patient on multiple Soybean–Casein Digest Medium are aseptically occasions. transferred by gravity through separate tubing sets

2. The compounding process includes complex into separate evacuated sterile containers. The six aseptic manipulations other than the single- containers are then arranged as three pairs, and a volume transfer. sterile 10-mL syringe and 18-gauge needle combi-

3. The compounding process requires unusually nation is used to exchange two 5-mL aliquots of long duration, such as that required to com- medium from one container to the other container plete dissolution or homogeneous mixing. in the pair. For example, after a 5-mL aliquot from

4. For a medium-risk preparation, in the absence the first container is added to the second container of passing a sterility test (see Sterility Tests in the pair, the second container is agitated for 10 〈71〉), the storage periods cannot exceed the seconds, then a 5-mL aliquot is removed and re-following time periods: before administration, turned to the first container in the pair. The first the CSPs are properly stored and are exposed container is then agitated for 10 seconds, and the for not more than 30 hours at controlled room next 5-mL aliquot is transferred from it back to the temperature (see General Notices and Re- second container in the pair. Following the two quirements), for not more than 9 days at a 5-mL aliquot exchanges in each pair of containers, cold temperature (see General Notices and a 5-mL aliquot of medium from each container is Requirements), and for 45 days in solid frozen aseptically injected into a sealed, empty, sterile state between −25° and −10°. 10-mL clear vial, using a sterile 10-mL syringe

Examples of Medium-Risk Compounding— and vented needle. Sterile adhesive seals are asep-

1. Compounding of total parenteral nutrition flu- tically affixed to the rubber closures on the three ids using manual or automated devices during filled vials, then the vials are incubated at 20° to which there are multiple injections, detach- 25° or at 30° to 35° for a minimum of 14 days. If ments, and attachments of nutrient source two temperatures are used for incubation of media-products to the device or machine to deliver filled samples, then these filled containers should all nutritional components to a final sterile be incubated for at least 7 days at each temperature container. (see Microbiological Evaluation of Clean Rooms

2. Filling of reservoirs of injection and infusion and Other Controlled Environments 〈1116〉). In-devices with more than three sterile drug spect for microbial growth over 14 days as de-products and evacuation of air from those res- scribed in Personnel Training and Competency ervoirs before the filled device is dispensed. Evaluation of Garbing, Aseptic Work Practices

3. Transfer of volumes from multiple ampuls or and Cleaning/Disinfection Procedures.

vials into one or more final sterile containers.

Quality Assurance—Quality assurance proce- High-Risk Level CSPs dures for medium-risk level CSPs include all those

CSPs compounded under any of the followingfor low-risk level CSPs, as well as a more chal-conditions are either contaminated or at a high risklenging media-fill test passed annually or more to become contaminated.frequently.

High-Risk Conditions—Media-Fill Test Procedure—This test or an

1. Nonsterile ingredients, including manufac-equivalent test is performed at least annually under tured products not intended for sterile routesconditions that closely simulate the most challeng-of administration (e.g., oral), are incorporateding or stressful conditions encountered during or a nonsterile device is employed before ter-compounding. Once begun, this test is completed minal sterilization.without interruption. Example of test procedure:

within an ISO Class 5 (see Table 1) air quality en- 2. Any of the following are exposed to air qual-

Revision Bulletin 〈797〉 Pharmaceutical Compounding—Sterile Preparations 11 ity worse than ISO Class 5 (see Table 1) for matter. Sterilization of high-risk level CSPs by fil-more than 1 hour (see Immediate-Use tration shall be performed with a sterile 0.2-µm or CSPs): 0.22-µm nominal pore size filter entirely within an

• sterile contents of commercially manu- ISO Class 5 (see Table 1) or superior air quality factured products, environment.

• CSPs that lack effective antimicrobial Examples of High-Risk Conditions— preservatives, and 1. Dissolving nonsterile bulk drug and nutrient

• sterile surfaces of devices and containers powders to make solutions that will be termi-for the preparation, transfer, sterilization, nally sterilized.

and packaging of CSPs. 2. Exposing the sterile ingredients and compo-

3. Compounding personnel are improperly nents used to prepare and package CSPs to garbed and gloved (see Personnel Cleansing room air quality worse than ISO Class 5 (see and Use of Barrier Protective Equipment). Table 1) for more than 1 hour (see Immediate-

4. Nonsterile water-containing preparations are Use CSPs).

stored for more than 6 hours before being 3. Measuring and mixing sterile ingredients in sterilized. nonsterile devices before sterilization is

5. It is assumed, and not verified by examination performed.

of labeling and documentation from suppliers

4. Assuming, without appropriate evidence oror by direct determination, that the chemical direct determination, that packages of bulk in-purity and content strength of ingredients gredients contain at least 95% by weight ofmeet their original or compendial specifica-their active chemical moiety and have nottions in unopened or in opened packages of been contaminated or adulterated betweenbulk ingredients (see Ingredient Selection uses.under Pharmaceutical Compounding—Non-

Quality Assurance—Quality assurance proce-sterile Preparations 〈795〉).

dures for high-risk level CSPs include all those forFor a sterilized high-risk level preparation, in the low-risk level CSPs. In addition, a media-fill testabsence of passing a sterility test, the storage pe-that represents high-risk level compounding is per-riods cannot exceed the following time periods:

formed semiannually by each person authorized tobefore administration, the CSPs are properly compound high-risk level CSPs.stored and are exposed for not more than 24 hours

Media-Fill Test Procedure for CSPs Sterilizedat controlled room temperature (see General No-by Filtration—This test or an equivalent test istices and Requirements), for not more than 3 days performed under conditions that closely simulateat a cold temperature (see General Notices and Re-the most challenging or stressful conditions en-quirements), and for 45 days in solid frozen state countered when compounding high-risk levelbetween −25° and −10°. [NOTE—Sterility tests for CSPs. Once begun, this test is completed withoutautoclaved CSPs are not required unless they are interruption. Example of test procedure (in the fol-prepared in batches of more than 25 units.] lowing sequence):All nonsterile measuring, mixing, and purifying

1. Dissolve 3 g of nonsterile commercially avail-devices are rinsed thoroughly with sterile, pyro-able Soybean–Casein Digest Medium in 100gen-free water, and then thoroughly drained or mL of nonbacteriostatic water to make a 3%dried immediately before use for high-risk com-nonsterile solution.pounding. All high-risk level CSP solutions sub-jected to terminal sterilization are prefiltered by 2. Draw 25 mL of the medium into each of three passing through a filter with a nominal pore size 30-mL sterile syringes. Transfer 5 mL from not larger than 1.2 µm preceding or during filling each syringe into separate sterile 10-mL vials.

into their final containers to remove particulate These vials are the positive controls to gener-

12 〈797〉 Pharmaceutical Compounding—Sterile Preparations Revision Bulletin ate exponential microbial growth, which is in- Media-Fill Challenge Testing—The skill of dicated by visible turbidity upon incubation. personnel to aseptically prepare CSPs may be evaluated using sterile fluid bacterial culture me-3. Under aseptic conditions and using aseptic dia-fill verification3 (i.e., sterile bacterial culturetechniques, affix a sterile 0.2-µm or 0.22-µm medium transfer via a sterile syringe and needle).nominal pore size filter unit and a 20-gauge Media-fill testing is used to assess the quality ofneedle to each syringe. Inject the next 10 mL the aseptic skill of compounding personnel. Me-from each syringe into three separate 10-mL dia-fill tests represent the most challenging orsterile vials. Repeat the process for three more stressful conditions actually encountered by thevials. Label all vials, affix sterile adhesive personnel being evaluated when they prepare par-seals to the closure of the nine vials, and incu-ticular risk level CSPs and when sterilizing high-bate them at 20° to 25° or at 30° to 35° for a risk level CSPs. Media-fill challenge tests thatminimum of 14 days. If two temperatures are simulate high-risk level compounding are alsoused for incubation of media-filled samples, used to verify the capability of the compoundingthen these filled containers should be incu-environment and process to produce a sterilebated for at least 7 days at each temperature preparation.(see Microbiological Evaluation of Clean

Rooms and Other Controlled Environments Commercially available sterile fluid culture me- 〈1116〉). Inspect for microbial growth over 14 dia, such as Soybean–Casein Digest Medium (see days as described in Personnel Training and Sterility Tests 〈71〉), shall be able to promote expo- Competency Evaluation of Garbing, Aseptic nential colonization of bacteria that are most likely Work Practices and Cleaning/Disinfection to be transmitted to CSPs from the compounding Procedures. personnel and environment. Media-filled vials are generally incubated at 20° to 25° or at 30° to 35° for a minimum of 14 days. If two temperatures arePERSONNEL TRAINING AND used for incubation of media-filled samples, thenEVALUATION IN ASEPTIC these filled containers should be incubated for atMANIPULATION SKILLS least 7 days at each temperature (see Microbiologi-

Personnel who prepare CSPs shall be trained cal Evaluation of Clean Rooms and Other Con-conscientiously and skillfully by expert personnel trolled Environments 〈1116〉). Failure is indicated and through audio–video instructional sources and by visible turbidity in the medium on or before 14 professional publications in the theoretical princi- days.

ples and practical skills of aseptic manipulations and in achieving and maintaining ISO Class 5 (see IMMEDIATE-USE CSPs Table 1) environmental conditions before they be-gin to prepare CSPs. Compounding personnel shall The immediate-use provision is intended only perform didactic review and pass written and me- for those situations where there is a need for emer-dia-fill testing of aseptic manipulative skills ini- gency or immediate patient administration of a tially, at least annually thereafter for low- and CSP. Such situations may include cardiopulmo-medium-risk level compounding, and semiannu- nary resuscitation, emergency room treatment, ally for high-risk level compounding. Compound- preparation of diagnostic agents, or critical therapy ing personnel who fail written tests or whose me- where the preparation of the CSP under conditions dia-fill test vials result in gross microbial described for Low-Risk Level CSPs subjects the colonization shall be immediately re-instructed patient to additional risk due to delays in therapy.

and re-evaluated by expert compounding person- Immediate-use CSPs are not intended for storage nel to ensure correction of all aseptic practice for anticipated needs or batch compounding. Prep-deficiencies. arations that are medium-risk level and high-risk

Revision Bulletin 〈797〉 Pharmaceutical Compounding—Sterile Preparations 13 level CSPs shall not be prepared as immediate-use significant microbial colonization and thus for pa- CSPs. tient harm, especially in critically ill or immu-

Immediate-use CSPs are exempt from the re- nocompromised patients.

quirements described for Low-Risk Level CSPs

SINGLE-DOSE AND MULTIPLE-DOSEonly when all of the following criteria are met:

CONTAINERS1. The compounding process involves simple transfer of not more than three commercially Opened or needle-punctured single-dose con-manufactured packages of sterile nonhazard-tainers, such as bags, bottles, syringes, and vials of ous products or diagnostic radiopharmaceuti-sterile products and CSPs shall be used within 1 cal products from the manufacturers’ original hour if opened in worse than ISO Class 5 (see Ta-containers and not more than two entries into ble 1) air quality (see Immediate-Use CSPs), and any one container or package (e.g., bag, vial) any remaining contents must be discarded. Single-of sterile infusion solution or administration dose vials exposed to ISO Class 5 (see Table 1) or container/device. For example, anti-neoplas-cleaner air may be used up to 6 hours after initial tics shall not be prepared as immediate-use needle puncture. Opened single-dose ampuls shall

CSPs because they are hazardous drugs.

not be stored for any time period. Multiple-dose

2. Unless required for the preparation, the com-containers (e.g., vials) are formulated for removal pounding procedure is a continuous process of portions on multiple occasions because they not to exceed 1 hour.

usually contain antimicrobial preservatives. The

3. During preparation, aseptic technique is fol- BUD after initially entering or opening (e.g., nee-lowed and, if not immediately administered, dle-punctured) multiple-dose containers is 28 days the finished CSP is under continuous supervi- (see Antimicrobial Effectiveness Testing 〈51〉) un-sion to minimize the potential for contact with less otherwise specified by the manufacturer.

nonsterile surfaces, introduction of particulate matter or biological fluids, mix-ups with other HAZARDOUS DRUGS AS CSPs CSPs, and direct contact of outside surfaces.

4. Administration begins not later than 1 hour Although the potential therapeutic benefits of following the start of the preparation of the compounded sterile hazardous drug preparations CSP. generally outweigh the risks of their adverse ef-

5.…