USP35-NF30 Chapter 797

USP–NF General Chapter <797> Pharmaceutical Compounding— Sterile Preparations Copyright ©2011 The United States Pharmacopeial Convention USP 35 NF 30 2 0 1 2 USP 35 Physical Tests / 〈797〉 Pharmaceutical Compounding±Sterile 1 Table 1. ISO Classification of Particulate Matter in Room Air (limits are in particles of 0.5 µm and larger per cubic meter [current〈797〉 PHARMACEUTICAL ISO] and cubic feet [former Federal Standard No. 209E, FS 209E])* Class Name Particle CountCOMPOUNDING±STERILE FS 209E, ISO Class U.S. FS 209E ISO, m3 ft3PREPARATIONS 3 Class 1 35.2 1 4 Class 10 352 10 5 Class 100 3,520 100 6 Class 1,000 35,200 1,000 INTRODUCTION 7 Class 10,000 352,000 10,000 8 Class 100,000 3,520,000 100,000 The objective of this chapter is to describe conditions and *Adapted from former Federal Standard No. 209E, General Servicespractices to prevent harm, including death, to patients that Administration, Washington, DC, 20407 (September 11, 1992) andcould result from (1) microbial contamination (nonsterility), ISO 14644-1:1999, Cleanrooms and associated controlled environ-(2) excessive bacterial endotoxins, (3) variability in the in- mentsÐPart 1: Classification of air cleanliness. For example, 3,520tended strength of correct ingredients that exceeds either particles of 0.5 µm per m3 or larger (ISO Class 5) is equivalent tomonograph limits for official articles (see ªofficialº and ªarti- 100 particles per ft3 (Class 100) (1 m3 = 35.2 ft3).cleº in the General Notices and Requirements) or 10% for nonofficial articles, (4) unintended chemical and physical The standards in this chapter are intended to apply to all contaminants, and (5) ingredients of inappropriate quality in persons who prepare CSPs and all places where CSPs are compounded sterile preparations (CSPs). Contaminated prepared (e.g., hospitals and other healthcare institutions, CSPs are potentially most hazardous to patients when ad- patient treatment clinics, pharmacies, physicians' practice fa- ministered into body cavities, central nervous and vascular cilities, and other locations and facilities in which CSPs are systems, eyes, and joints, and when used as baths for live prepared, stored, and transported). Persons who perform organs and tissues. When CSPs contain excessive bacterial sterile compounding include pharmacists, nurses, pharmacy endotoxins (see Bacterial Endotoxins Test 〈85〉), they are po- technicians, and physicians. These terms recognize that tentially most hazardous to patients when administered into most sterile compounding is performed by or under the su- the central nervous system. pervision of pharmacists in pharmacies and also that this Despite the extensive attention in this chapter to the pro- chapter applies to all healthcare personnel who prepare, vision, maintenance, and evaluation of air quality, the avoid- store, and transport CSPs. For the purposes of this chapter, ance of direct or physical contact contamination is para- CSPs include any of the following: mount. It is generally acknowledged that direct or physical (1) Compounded biologics, diagnostics, drugs, nutrients, contact of critical sites of CSPs with contaminants, especially and radiopharmaceuticals, including but not limited microbial sources, poses the greatest probability of risk to to the following dosage forms that must be sterile patients. Therefore, compounding personnel must be metic- when they are administered to patients: aqueous ulously conscientious in precluding contact contamination of bronchial and nasal inhalations, baths and soaks for CSPs both within and outside ISO Class 5 (see Table 1) ar- live organs and tissues, injections (e.g., colloidal dis- eas. persions, emulsions, solutions, suspensions), irrigations To achieve the above five conditions and practices, this for wounds and body cavities, ophthalmic drops and chapter provides minimum practice and quality standards ointments, and tissue implants. for CSPs of drugs and nutrients based on current scientific (2) Manufactured sterile products that are either prepared information and best sterile compounding practices. The use strictly according to the instructions appearing in of technologies, techniques, materials, and procedures other manufacturers' approved labeling (product package than those described in this chapter is not prohibited so inserts) or prepared differently than published in such long as they have been proven to be equivalent or superior labeling. [NOTEÐThe FDA states that ªCompounding with statistical significance to those described herein. The does not include mixing, reconstituting, or similar acts standards in this chapter do not pertain to the clinical ad- that are performed in accordance with the directions ministration of CSPs to patients via application, implantation, contained in approved labeling provided by the prod- infusion, inhalation, injection, insertion, instillation, and irri- uct's manufacturer and other manufacturer directions gation, which are the routes of administration. Four specific consistent with that labelingº [21 USC 321 (k) and categories of CSPs are described in this chapter: low-risk (m)]. However, the FDA-approved labeling (product level, medium-risk level, and high-risk level, and immediate package insert) rarely describes environmental quality use. Sterile compounding differs from nonsterile compound- (e.g., ISO Class air designation, exposure durations to ing (see Pharmaceutical CompoundingÐNonsterile Prepara- non-ISO classified air, personnel garbing and gloving, tions 〈795〉 and Good Compounding Practices 〈1075〉) prima- and other aseptic precautions by which sterile prod- rily by requiring the maintenance of sterility when ucts are to be prepared for administration). Beyond- compounding exclusively with sterile ingredients and com- use exposure and storage dates or times (see General ponents (i.e., with immediate-use CSPs, low-risk level CSPs, Notices and Requirements and Pharmaceutical Com- and medium-risk level CSPs) and the achievement of sterility poundingÐNonsterile Preparations 〈795〉) for sterile when compounding with nonsterile ingredients and compo- products that have been either opened or prepared nents (i.e., with high-risk level CSPs). Some differences be- for administration are not specified in all package in- tween standards for sterile compounding in this chapter and serts for all sterile products. Furthermore, when such those for nonsterile compounding in Pharmaceutical Com- durations are specified, they may refer to chemical poundingÐNonsterile Preparations 〈795〉 include, but are not stability and not necessarily to microbiological purity limited to, ISO-classified air environments (see Table 1); per- or safety.] sonnel garbing and gloving; personnel training and testing in principles and practices of aseptic manipulations and ster- ORGANIZATION OF THIS CHAPTERilization; environmental quality specifications and monitor- ing; and disinfection of gloves and surfaces of ISO Class 5 The sections in this chapter are organized to facilitate the(see Table 1) sources. practitioner's understanding of the fundamental accuracy and quality practices for preparing CSPs. They provide a 2 〈797〉 Pharmaceutical Compounding±Sterile / Physical Tests USP 35 foundation for the development and implementation of es- filtered laminar airflow for product protection, and HEPA- sential procedures for the safe preparation of low-risk, me- filtered exhausted air for environmental protection. dium-risk, and high-risk level CSPs and immediate-use CSPs, Buffer AreaÐAn area where the primary engineering which are classified according to the potential for microbial, control (PEC) is physically located. Activities that occur in chemical, and physical contamination. The chapter is di- this area include the preparation and staging of components vided into the following main sections: and supplies used when compounding CSPs. · Definitions Clean Room (see Microbiological Evaluation of Clean· Responsibility of Compounding Personnel Rooms and Other Controlled Environments 〈1116〉 and also· CSP Microbial Contamination Risk Levels the definition of Buffer Area)ÐA room in which the concen-· Personnel Training and Evaluation in Aseptic Manipula- tration of airborne particles is controlled to meet a specifiedtion Skills airborne particulate cleanliness class. Microorganisms in the· Immediate-Use CSPs environment are monitored so that a microbial level for air,· Single-Dose and Multiple-Dose Containers surface, and personnel gear are not exceeded for a specified· Hazardous Drugs as CSPs cleanliness class.· Radiopharmaceuticals as CSPs Compounding Aseptic Containment Isolator (CACI)з Allergen Extracts as CSPs A compounding aseptic isolator (CAI) designed to provide· Verification of Compounding Accuracy and Sterility worker protection from exposure to undesirable levels of air-· Environmental Quality and Control borne drug throughout the compounding and material· Suggested Standard Operating Procedures (SOPs) transfer processes and to provide an aseptic environment for· Elements of Quality Control compounding sterile preparations. Air exchange with the· Verification of Automated Compounding Devices surrounding environment should not occur unless the air is(ACDs) for Parenteral Nutrition Compounding first passed through a microbial retentive filter (HEPA mini-· Finished Preparation Release Checks and Tests mum) system capable of containing airborne concentrations· Storage and Beyond-Use Dating of the physical size and state of the drug being com-· Maintaining Sterility, Purity, and Stability of Dispensed pounded. Where volatile hazardous drugs are prepared, theand Distributed CSPs exhaust air from the isolator should be appropriately re-· Patient or Caregiver Training moved by properly designed building ventilation.· Patient Monitoring and Adverse Events Reporting Compounding Aseptic Isolator (CAI)ÐA form of isola-· Quality Assurance (QA) Program tor specifically designed for compounding pharmaceutical· Abbreviations and Acronyms ingredients or preparations. It is designed to maintain an· Appendices I±V aseptic compounding environment within the isolatorThe requirements and recommendations in this chapter throughout the compounding and material transferare summarized in Appendix I. A list of abbreviations and processes. Air exchange into the isolator from the surround-acronyms is included at the end of the main text, before the ing environment should not occur unless the air has firstAppendices. passed through a microbially retentive filter (HEPA mini-All personnel who prepare CSPs shall be responsible for mum).2understanding these fundamental practices and precautions, for developing and implementing appropriate procedures, Critical AreaÐAn ISO Class 5 (see Table 1) environment. and for continually evaluating these procedures and the Critical SiteÐA location that includes any component or quality of final CSPs to prevent harm. fluid pathway surfaces (e.g., vial septa, injection ports, beak- ers) or openings (e.g., opened ampuls, needle hubs) ex- posed and at risk of direct contact with air (e.g., ambientDEFINITIONS room or HEPA filtered), moisture (e.g., oral and mucosal se- cretions), or touch contamination. Risk of microbial particu- Ante-AreaÐAn ISO Class 8 (see Table 1) or better area late contamination of the critical site increases with the size where personnel hand hygiene and garbing procedures, of the openings and exposure time. staging of components, order entry, CSP labeling, and other Direct Compounding Area (DCA)ÐA critical area withinhigh-particulate-generating activities are performed. It is also the ISO Class 5 (see Table 1) primary engineering controla transition area that (1) provides assurance that pressure (PEC) where critical sites are exposed to unidirectional HEPA-relationships are constantly maintained so that air flows filtered air, also known as first air.from clean to dirty areas and (2) reduces the need for the DisinfectantÐAn agent that frees from infection, usuallyheating, ventilating, and air-conditioning (HVAC) control a chemical agent but sometimes a physical one, and thatsystem to respond to large disturbances.1 destroys disease-causing pathogens or other harmful micro-Aseptic Processing (see Microbiological Evaluation of organisms but may not kill bacterial and fungal spores. ItClean Rooms and Other Controlled Environments 〈1116〉)ÐA refers to substances applied to inanimate objects.mode of processing pharmaceutical and medical products First AirÐThe air exiting the HEPA filter in a unidirec-that involves the separate sterilization of the product and of tional air stream that is essentially particle free.the package (containers±closures or packaging material for medical devices) and the transfer of the product into the Hazardous DrugsÐDrugs are classified as hazardous if container and its closure under at least ISO Class 5 (see studies in animals or humans indicate that exposures to Table 1) conditions. them have a potential for causing cancer, development or reproductive toxicity, or harm to organs. (See current NI-Beyond-Use Date (BUD) (see General Notices and Re- OSH publication.)quirements and Pharmaceutical CompoundingÐNonsterile Preparations 〈795〉)ÐFor the purpose of this chapter, the Labeling [see General Notices and Requirements and 21 date or time after which a CSP shall not be stored or trans- USC 321 (k) and (m)]ÐA term that designates all labels and ported. The date is determined from the date or time the other written, printed, or graphic matter on an immediate preparation is compounded. container of an article or preparation or on, or in, any pack- age or wrapper in which it is enclosed, except any outerBiological Safety Cabinet (BSC)ÐA ventilated cabinet shipping container. The term ªlabelº designates that part offor CSPs, personnel, product, and environmental protection the labeling on the immediate container.having an open front with inward airflow for personnel pro- tection, downward high-efficiency particulate air (HEPA)- 2 CETA Applications Guide for the Use of Compounding Isolators in Compounding Sterile Preparations in Healthcare Facilities, CAG-001-2005, Controlled Environ-1 See American Society of Heating, Refrigerating and Air-Conditioning Engineers, ment Testing Association (CETA), November 8, 2005.Inc. (ASHRAE), Laboratory Design Guide. USP 35 Physical Tests / 〈797〉 Pharmaceutical Compounding±Sterile 3 Media-Fill Test (see Microbiological Evaluation of Clean amples of single-dose containers include prefilled syringes, Rooms and Other Controlled Environments 〈1116〉)ÐA test cartridges, fusion-sealed containers, and closure-sealed con- used to qualify aseptic technique of compounding personnel tainers when so labeled. or processes and to ensure that the processes used are able Segregated Compounding AreaÐA designated space, to produce sterile product without microbial contamination. either a demarcated area or room, that is restricted to pre- During this test, a microbiological growth medium such as paring low-risk level CSPs with 12-hour or less BUD. Such Soybean±Casein Digest Medium is substituted for the actual area shall contain a device that provides unidirectional air- drug product to simulate admixture compounding.3 The is- flow of ISO Class 5 (see Table 1) air quality for preparation sues to consider in the development of a media-fill test are of CSPs and shall be void of activities and materials that are media-fill procedures, media selection, fill volume, incuba- extraneous to sterile compounding. tion, time and temperature, inspection of filled units, docu- Sterilizing Grade MembranesÐMembranes that arementation, interpretation of results, and possible corrective documented to retain 100% of a culture of 107 microorgan-actions required. isms of a strain of Brevundimonas (Pseudomonas) diminuta Multiple-Dose Container (see General Notices and Re- per square centimeter of membrane surface under a pres- quirements and Containers for Injections under Injections sure of not less than 30 psi (2.0 bar). Such filter membranes〈1〉)ÐA multiple-unit container for articles or preparations are nominally at 0.22-µm or 0.2-µm nominal pore size, de- intended for parenteral administration only and usually con- pending on the manufacturer's practice. taining antimicrobial preservatives. The beyond-use date Sterilization by FiltrationÐPassage of a fluid or solution(BUD) for an opened or entered (e.g., needle-punctured) through a sterilizing grade membrane to produce a sterilemultiple-dose container with antimicrobial preservatives is effluent.28 days (see Antimicrobial Effectiveness Testing 〈51〉), unless Terminal SterilizationÐThe application of a lethal pro-otherwise specified by the manufacturer. cess (e.g., steam under pressure or autoclaving) to sealedNegative Pressure RoomÐA room that is at a lower containers for the purpose of achieving a predetermined ste-pressure than the adjacent spaces and, therefore, the net rility assurance level of usually less than 10−6, or a probabil-flow of air is into the room.1 ity of less than one in one million of a nonsterile unit.3 Pharmacy Bulk Package (see Containers for Injections Unidirectional Flow (see footnote 3)ÐAn airflow movingunder Injections 〈1〉)ÐA container of a sterile preparation for in a single direction in a robust and uniform manner and atparenteral use that contains many single doses. The con- sufficient speed to reproducibly sweep particles away fromtents are intended for use in a pharmacy admixture pro- the critical processing or testing area.gram and are restricted to the preparation of admixtures for infusion or, through a sterile transfer device, for the filling of empty sterile syringes. The closure shall be penetrated only RESPONSIBILITY OF COMPOUNDING one time after constitution with a suitable sterile transfer PERSONNELdevice or dispensing set, which allows measured dispensing of the contents. The pharmacy bulk package is to be used Compounding personnel are responsible for ensuring thatonly in a suitable work area such as a laminar flow hood (or CSPs are accurately identified, measured, diluted, and mixedan equivalent clean air compounding area). and are correctly purified, sterilized, packaged, sealed, la-Where a container is offered as a pharmacy bulk package, beled, stored, dispensed, and distributed. These perfor-the label shall (a) state prominently ªPharmacy Bulk Pack- mance responsibilities include maintaining appropriateageÐNot for Direct Infusion,º (b) contain or refer to infor- cleanliness conditions and providing labeling and supple-mation on proper techniques to help ensure safe use of the mentary instructions for the proper clinical administration ofproduct, and (c) bear a statement limiting the time frame in CSPs.which the container may be used once it has been entered, Compounding supervisors shall ensure, through either di-provided it is held under the labeled storage conditions. rect measurement or appropriate information sources, that Primary Engineering Control (PEC)ÐA device or room specific CSPs maintain their labeled strength within mono- that provides an ISO Class 5 (see Table 1) environment for graph limits for USP articles, or within 10% if not specified, the exposure of critical sites when compounding CSPs. Such until their BUDs. All CSPs are prepared in a manner that devices include, but may not be limited to, laminar airflow maintains sterility and minimizes the introduction of particu- workbenches (LAFWs), biological safety cabinets (BSCs), late matter. compounding aseptic isolators (CAIs), and compounding A written quality assurance procedure includes the follow- aseptic containment isolators (CACIs). ing in-process checks that are applied, as appropriate, to PreparationÐA preparation, or a CSP, that is a sterile specific CSPs: accuracy and precision of measuring and drug or nutrient compounded in