36E77619R0017-026.pdf

BRIEFING

〈797〉 Pharmaceutical Compounding—Sterile Preparations, USP 41 page 6554 and PF 41(6) [Nov.–Dec. 2015].

Based on the number and significance of public comments received in response to the revision proposal published in PF 41(6), the USP Compounding Expert Committee is proposing to revise this chapter. The current proposed chapter in PF 44(5) [Sept.–Oct. 2018] is posted online at http://www.uspnf.com/notices/general-chapter-797-proposed-revisions with line numbers. Submit comments using the form available at https://usp.az1.qualtrics.com/jfe/form/SV_3dDhnN2ZVCYh5yJ.

The Expert Committee seeks stakeholder feedback on the proposed revisions to the chapter, including the following major changes:

1. Reorganization of the chapter to include section and subsection numbers. Placement of procedural information in boxes.

2. Definition of the scope of the chapter to include sterile compounding activities and exclude administration of medication (e.g., withdrawing doses for administration).

3. Simplified compounded sterile preparation (CSP) microbial risk levels from three (low, medium, and high) to two—Category 1 CSPs and Category 2 CSPs. Category 1 and 2 CSPs are distinguished primarily by the facility in which they are made and the time period within which they must be used, i.e., the beyond-use date (BUD).

• Category 1 CSPs have a shorter BUD and may be prepared in an unclassified segregated compounding area (SCA).

• Category 2 CSPs have a longer BUD and must be prepared in a cleanroom suite (buffer room with ante-room).

4. Addition of guidance on use and storage of opened or needle-punctured conventionally manufactured products and CSPs.

5. Addition of information on notification and recall of CSPs that have out-of-specification results.

6. Clarification of requirements for compounding allergenic extract prescription sets.

7. Removal of information related to handling of hazardous drugs and addition of references to Hazardous Drugs—Handling in Healthcare Settings 〈800〉.

8. Removal of the section on radiopharmaceuticals as CSPs and addition of a reference to Radiopharmaceuticals—Preparation, Compounding, Dispensing, and Repackaging 〈825〉. General chapter 〈825〉 is also proposed for public comment in PF 44(5).

http://www.uspnf.com/notices/general-chapter-797-proposed-revisions https://usp.az1.qualtrics.com/jfe/form/SV_3dDhnN2ZVCYh5yJ

Additionally, the Expert Committee is considering the development of new resource(s) to assist compounders in extending BUDs for Category 2 CSPs to include criteria for validated stability-indicating assays and testing for sterility, endotoxins, container-closure integrity, and particulate matter. The resource(s) are intended to guide correct interpretation and application of testing results.

Minor editorial changes have been made to update the chapter to current USP style.

(CMP: J. Sun.)

Correspondence Number—C204411

〈797〉 PHARMACEUTICAL

COMPOUNDING—STERILE

PREPARATIONS

Add the following:

TABLE OF CONTENTS

1. INTRODUCTION AND SCOPE

1.1 Scope

1.2 Factors Affecting the Risks Associated with CSPs

1.3 CSP Categories

2. PERSONNEL QUALIFICATIONS—TRAINING, EVALUATION, AND

REQUALIFICATION

2.1 Demonstrating Proficiency in Core Competencies

2.2 Demonstrating Competency in Garbing and Hand Hygiene

2.3 Competency Testing in Aseptic Manipulation

2.4 Reevaluation, Retraining, and Requalification

3. PERSONAL HYGIENE AND GARBING

3.1 Personnel Preparation

3.2 Hand Hygiene

3.3 Garbing Requirements

4. FACILITIES AND ENGINEERING CONTROLS

4.1 Protection from Airborne Contaminants

4.2 Facility Design and Environmental Controls

4.3 Creating Areas to Achieve Easily Cleanable Conditions

4.4 Water Sources

4.5 Placement and Movement of Materials

4.6 Certification and Recertification

5. MICROBIOLOGICAL AIR AND SURFACE MONITORING

5.1 General Monitoring Requirements

5.2 Monitoring Air Quality for Viable Airborne Particles

5.3 Monitoring Surfaces for Viable Particles

6. CLEANING AND DISINFECTING COMPOUNDING AREAS

6.1 Cleaning, Disinfecting, and Sporicidal Agents

6.2 Cleaning Supplies

6.3 Cleaning and Disinfecting the PEC

6.4 Cleaning and Disinfecting Compounding Supplies for the

Classified Areas and SCAs

6.5 Disinfecting Critical Sites within the PEC

7. EQUIPMENT, SUPPLIES, AND COMPONENTS

7.1 Equipment

7.2 Supplies

7.3 Components

8. STERILIZATION AND DEPYROGENATION

8.1 Depyrogenation

8.2 Sterilization by Filtration

8.3 Sterilization by Steam Heat

8.4 Sterilization by Dry Heat

9. SOPs AND MASTER FORMULATION AND COMPOUNDING RECORDS

9.1 Creating and Following SOPs

9.2 Creating Master Formulation Records

9.3 Creating Compounding Records

10. RELEASE TESTING

10.1 Visual Inspection

10.2 Sterility Testing

10.3 Bacterial Endotoxins Testing

11. LABELING

12. ESTABLISHING BEYOND-USE DATES

12.1 Terminology

12.2 Parameters to Consider in Establishing a BUD

12.3 Establishing a BUD for a CSP

12.4 Multiple-Dose CSPs

13. USE OF CONVENTIONALLY MANUFACTURED PRODUCTS

13.1 Use of Conventionally Manufactured Single-Dose

Containers

13.2 Use of Conventionally Manufactured Multiple-Dose

Containers

13.3 Use of a Conventionally Manufactured Pharmacy Bulk

Package

14. USE OF CSPs AS COMPONENTS

14.1 Use of Compounded Single-Dose Containers

14.2 Use of Compounded Stock Solutions

14.3 Use of Compounded Multiple-Dose Containers

15. QUALITY ASSURANCE AND QUALITY CONTROL

15.1 Notification About and Recall of Out-of-Specification

Dispensed CSPs

15.2 Complaint Handling

15.3 Adverse Event Reporting

16. CSP STORAGE, HANDLING, PACKAGING, SHIPPING, AND

TRANSPORT

16.1 Handling and Storing CSPs

16.2 Packaging of CSPs

16.3 Shipping and Transporting CSPs

17. DOCUMENTATION

18. COMPOUNDING ALLERGENIC EXTRACTS

GLOSSARY

APPENDICES

Appendix 1: Acronyms Appendix 2: Example Designs for Sterile Non-Hazardous Compounding Areas

2S(USP42)

Change to read:

INTRODUCTION

The objective of this chapter is to describe 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 that exceeds either monograph limits for official articles (see General Notices, 2.20 Official Articles (CN 1-May-2018) or 10% for nonofficial articles, (4) unintended chemical and physical contaminants, and (5) ingredients of inappropriate quality in compounded sterile preparations (CSPs). Contaminated CSPs are potentially most hazardous to patients when administered into body cavities, central nervous and vascular systems, eyes, and joints, and when used as baths for live organs and tissues. When CSPs contain excessive bacterial endotoxins (see Bacterial Endotoxins Test 〈85〉), they are potentially most hazardous to patients when administered into the central nervous system.

Despite the extensive attention in this chapter to the provision, maintenance, and evaluation of air quality, the avoidance of direct or physical contact contamination is paramount. It is generally acknowledged that direct or physical contact of critical sites of CSPs with contaminants, especially microbial 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 practices, this chapter provides minimum practice and quality standards for CSPs of drugs and nutrients based on current scientific information and best sterile compounding practices. The use of technologies, techniques, materials, and procedures other than those described in this chapter is not prohibited so long as they have been proven to be equivalent or superior with statistical significance to those described herein. The standards in this chapter do not pertain to the clinical administration of CSPs to patients via application, implantation, infusion, inhalation, injection, insertion, instillation, and irrigation, which are the routes of administration. Four specific categories of CSPs are described in this chapter: low-risk level, medium-risk level, and high-risk level, and immediate use. Sterile compounding differs from nonsterile compounding (see Pharmaceutical Compounding—Nonsterile Preparations 〈795〉 ) primarily by requiring the maintenance of sterility when compounding exclusively with sterile ingredients and components (i.e., with immediate-use CSPs, low-risk level CSPs, and medium-risk level CSPs) and the achievement of sterility when compounding with nonsterile ingredients and components (i.e., with high-risk level CSPs). Some differences between standards for sterile compounding in this chapter and those for nonsterile compounding in Pharmaceutical Compounding—Nonsterile Preparations 〈795〉 include, but are not limited to, ISO-classified air environments (see Table 1); personnel garbing and gloving; personnel training and testing in principles and practices of aseptic manipulations and sterilization; environmental quality specifications and monitoring; and disinfection of gloves and surfaces of ISO Class 5 (see Table 1) sources.

Table 1. ISO Classification of Particulate Matter in Room Air (limits are in particles of 0.5 µm and larger per cubic meter [current ISO] and cubic feet [former Federal Standard No. 209E, FS 209E])*

Class Name Particle Count

ISO Class U.S. FS 209E ISO, m3 FS 209E, ft3 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 7 Class 10,000 352,000 10,000 8 Class 100,000 3,520,000 100,000

* Adapted from former Federal Standard No. 209E, General Services Administration, Washington, DC, 20407 (September 11, 1992) and ISO 14644-1:1999, Cleanrooms and associated controlled environments—Part 1:

Classification of air cleanliness. For example, 3,520 particles of 0.5 µm per m3 or larger (ISO Class 5) is equivalent to 100 particles per ft3 (Class 100) (1 m3 = 35.2 ft3).

The standards in this chapter are intended to apply to all persons who prepare CSPs and all places where CSPs are prepared (e.g., hospitals and other healthcare institutions, patient treatment clinics, pharmacies, physicians' practice facilities, and other locations and facilities in which CSPs are prepared, stored, and transported). Persons who perform sterile compounding include pharmacists, 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 purposes of this chapter, CSPs include any of the following:

1. Compounded biologics, diagnostics, drugs, nutrients, and radiopharmaceuticals, including but not limited to the following dosage forms that must be sterile when they are administered to patients: aqueous bronchial and nasal inhalations, baths and soaks for live organs and tissues, injections (e.g., colloidal dispersions, emulsions, solutions, suspensions), irrigations for wounds and body cavities, ophthalmic drops and ointments, and tissue implants.

2. Manufactured sterile products that are either prepared strictly according to the instructions appearing in manufacturers' approved labeling (product package inserts) or prepared differently than published in such labeling. [NOTE—The FDA states that “Compounding does not include mixing, reconstituting, or similar acts that are performed in accordance with the directions contained in approved labeling provided by the product's manufacturer and other manufacturer directions consistent with that labeling” [21 USC 321

(k) and (m)]. However, the FDA-approved labeling (product package insert) rarely describes environmental quality (e.g., ISO Class air designation, exposure durations to non-ISO classified air, personnel garbing and gloving, and other aseptic precautions by which sterile products are to be prepared for administration). Beyond-use exposure and storage dates or times (see Labeling 〈7〉] (CN 1-May-2018) and Pharmaceutical Compounding—Nonsterile Preparations 〈795〉) for sterile products that have been either opened or prepared for administration are not specified in all package inserts for all sterile products. Furthermore, when such durations are specified, they may refer to chemical stability and not necessarily to microbiological purity or safety.

ORGANIZATION OF THIS CHAPTER

The sections in this chapter are organized to facilitate the practitioner's understanding of the fundamental accuracy and quality practices for preparing CSPs. They provide a foundation for the development and implementation of essential procedures for the safe preparation of low-risk, medium-risk, and high-risk level CSPs and immediate-use CSPs, which are classified according to the potential for microbial, chemical, and physical contamination. The chapter is divided into the following main sections:

• Responsibility of Compounding Personnel

• CSP Microbial Contamination Risk Levels

• Personnel Training and Evaluation in Aseptic Manipulation Skills

• Immediate-Use CSPs

• Single-Dose and Multiple-Dose Containers

• Hazardous Drugs as CSPs

• Radiopharmaceuticals as CSPs

• Allergen Extracts as CSPs

• Verification of Compounding Accuracy and Sterility

• Environmental Quality and Control

• Suggested Standard Operating Procedures (SOPs)

• Elements of Quality Control

• Verification of Automated Compounding Devices (ACDs) for Parenteral

Nutrition Compounding

• Finished Preparation Release Checks and Tests

• Storage and Beyond-Use Dating

• Maintaining Sterility, Purity, and Stability of Dispensed and Distributed

CSPs

• Patient or Caregiver Training

• Patient Monitoring and Adverse Events Reporting

• Quality Assurance (QA) Program

• Abbreviations and Acronyms

• Glossary

• Appendices I–V

The requirements and recommendations in this chapter are summarized in Appendix I. A list of abbreviations and acronyms is included at the end of the main text, before the Appendices.

All personnel who prepare CSPs shall be responsible for understanding these fundamental practices and precautions, for developing and implementing appropriate procedures, and for continually evaluating these procedures and the quality of final CSPs to prevent harm.

RESPONSIBILITY OF COMPOUNDING PERSONNEL

Compounding personnel are responsible for ensuring that CSPs are accurately identified, measured, diluted, and mixed and are correctly purified, sterilized, packaged, sealed, labeled, stored, dispensed, and distributed. These performance responsibilities include maintaining appropriate cleanliness conditions and providing labeling and supplementary instructions for the proper clinical administration of CSPs.

Compounding supervisors shall ensure, through either direct measurement or appropriate information sources, that specific CSPs maintain their labeled strength within monograph limits for USP articles, or within 10% if not specified, until their BUDs. All CSPs are prepared in a manner that maintains sterility and minimizes the introduction of particulate matter.

A written quality assurance procedure includes the following in-process checks that are applied, as appropriate, to specific CSPs: accuracy and precision of measuring and weighing; the requirement for sterility; methods of sterilization and purification; safe limits and ranges for strength of ingredients, bacterial endotoxins, and particulate matter; pH; labeling accuracy and completeness; BUD assignment; and packaging and storage requirements. The dispenser shall, when appropriate and practicable, obtain and evaluate results of testing for identity, strength, purity, and sterility before a CSP is dispensed. Qualified licensed healthcare professionals who supervise compounding and dispensing of CSPs shall ensure that the following objectives are achieved:

1. Compounding personnel are adequately skilled, educated, instructed, and trained to correctly perform and document the following activities in their sterile compounding duties:

a. perform antiseptic hand cleansing and disinfection of nonsterile compounding surfaces;

b. select and appropriately don protective garb;

c. maintain or achieve sterility of CSPs in ISO Class 5 (see Table

1) PEC devices and protect personnel and compounding environments from contamination by radioactive, cytotoxic, and chemotoxic drugs (see Hazardous Drugs as CSPs and Radiopharmaceuticals as CSPs);

d. identify, weigh, and measure ingredients; and

e. manipulate sterile products aseptically, sterilize high-risk level

CSPs, and label and quality inspect CSPs.

2. Ingredients have their correct identity, quality, and purity.

3. Opened or partially used packages of ingredients for subsequent use in CSPs are properly stored under restricted access conditions in the compounding facility. Such packages cannot be used when visual inspection detects unauthorized breaks in the container, closure, and seal; when the contents do not possess the expected appearance, aroma, and texture; when the contents do not pass identification tests specified by the compounding facility; and when either the BUD or expiration date has been exceeded.

4. Water-containing CSPs that are nonsterile during any phase of the compounding procedure are sterilized within 6 hours after completing the preparation in order to minimize the generation of bacterial endotoxins.

5. Sterilization methods achieve sterility of CSPs while maintaining the labeled strength of active ingredients and the physical integrity of packaging.

6. Measuring, mixing, sterilizing, and purifying devices are clean, appropriately accurate, and effective for their intended use.

7. Potential harm from added substances and differences in rate and extent of bioavailability of active ingredients for other than oral route of administration are carefully evaluated before such CSPs are dispensed and administered.

8. Packaging selected for CSPs is appropriate to preserve the sterility and strength until the BUD.

9. While being used, the compounding environment maintains the sterility or the presterilization purity, whichever is appropriate, of the

CSP.

10. Labels on CSPs list the names and amounts or concentrations of active ingredients, and the labels or labeling of injections (CN 1-May-

2018) list the names and amounts or concentrations of all ingredients (see Labeling 〈7〉). Before being dispensed or administered, the clarity of solutions is visually confirmed; also, the identity and amounts of ingredients, procedures to prepare and sterilize CSPs, and specific release criteria are reviewed to ensure their accuracy and completeness.

11. BUDs are assigned on the basis of direct testing or extrapolation from reliable literature sources and other documentation (see Stability Criteria and Beyond-Use Dating underPharmaceutical Compounding—Nonsterile Preparations 〈795〉).

12. Procedures for measuring, mixing, dilution, purification, sterilization, packaging, and labeling conform to the correct sequence and quality established for the specified CSP.

13. Deficiencies in compounding, labeling, packaging, and quality testing and inspection can be rapidly identified and corrected.

14. When time and personnel availability so permit, compounding manipulations and procedures are separated from postcompounding quality inspection and review before CSPs are dispensed.

This chapter emphasizes the need to maintain high standards for the quality and control of processes, components, and environments and for the skill and knowledge of personnel who prepare CSPs. The rigor of in-process quality-control checks and of postcompounding quality inspection and testing increases with the potential hazard of the route of administration. For example, nonsterility, excessive bacterial endotoxin contamination, large errors in strength of correct ingredients, and incorrect ingredients in CSPs are potentially more dangerous to patients when the CSPs are administered into the vascular and central nervous systems than when administered by most other routes.

CSP MICROBIAL CONTAMINATION RISK LEVELS

The three contamination categories for CSPs described in this section are assigned primarily according to the potential for microbial contamination during the compounding of low-risk level CSPs and medium-risk level CSPs or the potential for not sterilizing high-risk level CSPs, any of which would subject patients to risk of harm, including death. High-risk level CSPs must be sterilized before being administered to patients. The appropriate risk level—low, medium, or high—is assigned according to the corresponding probability of contaminating a CSP with (1) microbial contamination (e.g., microbial organisms, spores, endotoxins) and (2) chemical and physical contamination (e.g., foreign chemicals, physical matter). Potential sources of contamination include, but are not limited to, solid and liquid matter from compounding personnel and objects; nonsterile components employed and incorporated before terminal sterilization; inappropriate conditions within the restricted compounding environment; prolonged presterilization procedures with aqueous preparations; and nonsterile dosage forms used to compound CSPs.

The characteristics described below for low-, medium-, and high-risk level CSPs are intended as a guide to the breadth and depth of care necessary in compounding, but they are neither exhaustive nor prescriptive. The licensed healthcare professionals who supervise compounding are responsible for determining the procedural and environmental quality practices and attributes that are necessary for the risk level they assign to specific CSPs.

These risk levels apply to the quality of CSPs immediately after the final aseptic mixing or filling or immediately after the final sterilization, unless precluded by the specific characteristics of the preparation. Upon subsequent storage and shipping of freshly finished CSPs, an increase in the risks of chemical degradation of ingredients, contamination from physical damage to packaging, and permeability of plastic and elastomeric packaging is expected. In such cases, compounding personnel are responsible for considering the potential additional risks to the integrity of CSPs when assigning BUDs. The pre-administration storage duration and temperature limits specified in the following subsections apply in the absence of direct sterility testing results that justify different limits for specific CSPs.

Low-Risk Level CSPs CSPs compounded under all the following conditions are at a low risk of contamination.

Low-Risk Conditions—

1. The CSPs are compounded with aseptic manipulations entirely within ISO Class 5 (see Table 1) or better air quality using only sterile ingredients, products, components, and devices.

2. The compounding involves only transfer, measuring, and mixing manipulations using not more than three commercially manufactured packages of sterile products and not more than two entries into any one sterile container or package (e.g., bag, vial) of sterile product or administration container/device to prepare the CSP.

3. Manipulations are limited to aseptically opening ampuls, penetrating disinfected stoppers on vials with sterile needles and syringes, and transferring sterile liquids in sterile syringes to sterile administration devices, package containers of other sterile products, and containers for storage and dispensing.

4. For a low-risk level preparation, in the absence of passing a sterility test (see Sterility Tests 〈71〉), the storage periods cannot exceed the following time periods: before administration, the CSPs are properly stored and are exposed for not more than 48 hours at controlled room temperature (see Packaging and Storage Requirements 〈659〉), (CN 1-May-2018) for not more than 14 days at a cold temperature (see Packaging and Storage Requirements 〈659〉), (CN 1-May-2018) and for 45 days in solid frozen state between −25° and −10°.

Examples of Low-Risk Compounding—

1. Single-volume transfers of sterile dosage forms from ampuls, bottles, bags, and vials using sterile syringes with sterile needles, other administration devices, and other sterile containers. The solution content of ampuls should be passed through a sterile filter to remove any particles.

2. Simple aseptic measuring and transferring with not more than three packages of manufactured sterile products, including an infusion or diluent solution to compound drug admixtures and nutritional solutions.

Low-Risk Level CSPs with 12-Hour or Less BUD—If the PEC is a CAI or CACI that does not meet the requirements described in Placement of Primary Engineering Controls or is a laminar airflow workbench (LAFW) or a biological safety cabinet (BSC) that cannot be located within an ISO Class 7 (see Table 1) buffer area, then only low-risk level nonhazardous and radiopharmaceutical CSPs pursuant to a physician's order for a specific patient may be prepared, and administration of such CSPs shall commence within 12 hours of preparation or as recommended in the manufacturers' package insert, whichever is less. Low-risk level CSPs with a 12-hour or less BUD shall meet all of the following four criteria:

1. PECs (LAFWs, BSCs, CAIs, CACIs,) shall be certified and maintain ISO Class 5 (see Table 1) as described in Facility Design and Environmental Controls for exposure of critical sites and shall be in a segregated compounding area restricted to sterile compounding activities that minimize the risk of CSP contamination.

2. The segregated compounding area shall not be in a location that has unsealed windows or doors that connect to the outdoors or high traffic flow, or that is adjacent to construction sites, warehouses, or food preparation. Note that this list is not intended to be all inclusive.

3. Personnel shall follow the procedures described in Personnel Cleansing and Garbing and Additional Personnel Requirements prior to compounding. Sinks should not be located adjacent to the ISO Class 5 (see Table 1) PEC. Sinks should be separated from the immediate area of the ISO Class 5 (see Table 1) PEC device.

4. The specifications in Cleaning and Disinfecting the Sterile Compounding Areas, Personnel Training and Competency Evaluation of Garbing, Aseptic Work Practices and Cleaning/Disinfection Procedures, and Viable and Nonviable Environmental Sampling (ES) Testing shall be followed as described in the chapter.

Compounding personnel must recognize that the absence of an ISO Class 7 (see Table 1) buffer area environment in a general uncontrolled environment increases the potential of microbial contamination, and administration durations of microbially contaminated CSPs exceeding a few hours increase the potential for clinically significant microbial colonization, and thus for patient harm, especially in critically ill or immunocompromised patients.

Quality Assurance—Quality assurance practices include, but are not limited to the following:

1. Routine disinfection and air quality testing of the direct compounding environment to minimize microbial surface contamination and maintain ISO Class 5 (see Table 1) air quality.

2. Visual confirmation that compounding personnel are properly donning and wearing appropriate items and types of protective garments, including eye protection and face masks.

3. Review of all orders and packages of ingredients to ensure that the correct identity and amounts of ingredients were compounded.

4. Visual inspection of CSPs to ensure the absence of particulate matter in solutions, the absence of leakage from vials and bags, and the accuracy and thoroughness of labeling.

Media-Fill Test Procedure—This test or an equivalent test is performed at least annually by each person authorized to compound in a low-risk level environment under conditions that closely simulate the most challenging or stressful conditions encountered during compounding of low-risk level CSPs.

Once begun, this test is completed without interruption. Example of test procedure: within an ISO Class 5 (see Table 1) air quality environment, three sets of four 5-mL aliquots of sterile Soybean–Casein Digest Medium (also known as trypticase soy broth or trypticase soy agar [TSA]) are transferred with the same sterile 10-mL syringe and vented needle combination into separate sealed, empty, sterile 30-mL clear vials (i.e., four 5-mL aliquots into each of three 30-mL vials). Sterile adhesive seals are aseptically affixed to the rubber closures on the three filled vials, then the vials are incubated at 20° to 25° or at 30° to 35° for a minimum of 14 days.

If two temperatures are used for incubation of media-filled samples, then these filled containers should be incubated for at least 7 days at each temperature (see Microbiological Control and Monitoring of Aseptic Processing Environments 〈1116〉). Inspect for microbial growth over 14 days as described in Personnel Training and Competency Evaluation of Garbing, Aseptic Work Practices and Cleaning/Disinfection Procedures.

Medium-Risk Level CSPs When CSPs are compounded aseptically under Low-Risk Conditions and one or more of the following conditions exists, such CSPs are at a medium risk of contamination.

Medium-Risk Conditions—

1. Multiple individual or small doses of sterile products are combined or pooled to prepare a CSP that will be administered either to multiple patients or to one patient on multiple occasions.

2. The compounding process includes complex aseptic manipulations other than the single-volume transfer.

3. The compounding process requires unusually long duration, such as that required to complete dissolution or homogeneous mixing.

4. For a medium-risk preparation, in the absence of passing a sterility test (see Sterility Tests 〈71〉), the storage periods cannot exceed the following time periods: before administration, the CSPs are properly stored and are exposed for not more than 30 hours at controlled room temperature (see Packaging and Storage Requirements 〈659〉), (CN 1-May-2018) for not more than 9 days at a cold temperature (see Packaging and Storage Requirements 〈659〉), (CN 1-May-2018) and for 45 days in solid frozen state between −25° and −10°.

Examples of Medium-Risk Compounding—

1. Compounding of total parenteral nutrition fluids using manual or automated devices during which there are multiple injections, detachments, and attachments of nutrient source products to the device or machine to deliver all nutritional components to a final sterile container.

2. Filling of reservoirs of injection and infusion devices with more than three sterile drug products and evacuation of air from those reservoirs before the filled device is dispensed.

3. Transfer of volumes from multiple ampuls or vials into one or more final sterile containers.

Quality Assurance—Quality assurance procedures for medium-risk level CSPs include all those for low-risk level CSPs, as well as a more challenging media-fill test passed annually or more frequently.

Media-Fill Test Procedure—This test or an equivalent test is performed at least annually under conditions that closely simulate the most challenging or stressful conditions encountered during compounding. Once begun, this test is completed without interruption. Example of test procedure: within an ISO Class 5 (see Table 1) air quality environment, six 100-mL aliquots of sterile

Soybean–Casein Digest Medium are aseptically transferred by gravity through separate tubing sets into separate evacuated sterile containers. The six containers are then arranged as three pairs, and a sterile 10-mL syringe and 18-gauge needle combination is used to exchange two 5-mL aliquots of medium from one container to the other container in the pair. For example, after a 5-mL aliquot from the first container is added to the second container in the pair, the second container is agitated for 10 seconds, then a 5-mL aliquot is removed and returned to the first container in the pair. The first container is then agitated for 10 seconds, and the next 5-mL aliquot is transferred from it back to the second container in the pair. Following the two 5-mL aliquot exchanges in each pair of containers, a 5-mL aliquot of medium from each container is aseptically injected into a sealed, empty, sterile 10-mL clear vial, using a sterile 10-mL syringe and vented needle.

Sterile adhesive seals are aseptically affixed to the rubber closures on the three filled vials, then the vials are incubated at 20° to 25° or at 30° to 35° for a minimum of 14 days. If two temperatures are used for incubation of media-filled samples, then these filled containers should be incubated for at least 7 days at each temperature (see Microbiological Control and Monitoring of Aseptic Processing Environments 〈1116〉). Inspect for microbial growth over 14 days as described in Personnel Training and Competency Evaluation of Garbing, Aseptic Work Practices and Cleaning/Disinfection Procedures.

High-Risk Level CSPs CSPs compounded under any of the following conditions are either contaminated or at a high risk to become contaminated.

High-Risk Conditions—

1. Nonsterile ingredients, including manufactured products not intended for sterile routes of administration (e.g., oral), are incorporated or a nonsterile device is employed before terminal sterilization.

2. Any of the following are exposed to air quality worse than ISO Class 5 (see Table 1) for more than 1 hour (see Immediate-Use CSPs):

• sterile contents of commercially manufactured products,

• CSPs that lack effective antimicrobial preservatives, and

• sterile surfaces of devices and containers for the preparation, transfer, sterilization, and packaging of CSPs.

3. Compounding personnel are improperly garbed and gloved (see

Personnel Cleansing and Use of Barrier Protective Equipment).

4. Nonsterile water-containing preparations are stored for more than 6 hours before being sterilized.

5. It is assumed, and not verified by examination of labeling and documentation from suppliers or by direct determination, that the chemical purity and content strength of ingredients meet their original or compendial specifications in unopened or in opened packages of bulk ingredients (see Ingredient Selection underPharmaceutical Compounding—Nonsterile Preparations 〈795〉).

For a sterilized high-risk level preparation, in the absence of passing a sterility test, the storage periods cannot exceed the following time periods:

before administration, the CSPs are properly stored and are exposed for not more than 24 hours at controlled room temperature (see Packaging and Storage Requirements 〈659〉), (CN 1-May-2018) for not more than 3 days at a cold temperature (see Packaging and Storage Requirements 〈659〉), (CN 1-May-2018) and for 45 days in solid frozen state between −25° and −10°. [NOTE— Sterility tests for autoclaved CSPs are not required unless they are prepared in batches of more than 25 units.] All nonsterile measuring, mixing, and purifying devices are rinsed thoroughly with sterile, pyrogen-free water, and then thoroughly drained or dried immediately before use for high-risk compounding. All high-risk level CSP solutions subjected to terminal sterilization are prefiltered by passing through a filter with a nominal pore size not larger than 1.2 µm preceding or during filling into their final containers to remove particulate matter.

Sterilization of high-risk level CSPs by filtration shall be performed with a sterile 0.2-µm or 0.22-µm nominal pore size filter entirely within an ISO Class 5 (see Table 1) or superior air quality environment.

Examples of High-Risk Conditions—

1. Dissolving nonsterile bulk drug and nutrient powders to make solutions that will be terminally sterilized.

2. Exposing the sterile ingredients and components used to prepare and package CSPs to room air quality worse than ISO Class 5 (see Table

1) for more than 1 hour (see Immediate-Use CSPs).

3. Measuring and mixing sterile ingredients in nonsterile devices before sterilization is performed.

4. Assuming, without appropriate evidence or direct determination, that packages of bulk ingredients contain at least 95% by weight of their active chemical moiety and have not been contaminated or adulterated between uses.

Quality Assurance—Quality assurance procedures for high-risk level CSPs include all those for low-risk level CSPs. In addition, a media-fill test that represents high-risk level compounding is performed semiannually by each person authorized to compound high-risk level CSPs.

Media-Fill Test Procedure for CSPs Sterilized by Filtration—This test or an equivalent test is performed under conditions that closely simulate the most challenging or stressful conditions encountered when compounding high-risk level CSPs. Once begun, this test is completed without interruption.

Example of test procedure (in the following sequence):

1. Dissolve 3 g of nonsterile commercially available Soybean–Casein Digest Medium in 100 mL of nonbacteriostatic water to make a 3% nonsterile solution.

2. Draw 25 mL of the medium into each of three 30-mL sterile syringes.

Transfer 5 mL from each syringe into separate sterile 10-mL vials.

These vials are the positive controls to generate exponential microbial growth, which is indicated by visible turbidity upon incubation.

3. Under aseptic conditions and using aseptic techniques, affix a sterile 0.2-µm or 0.22-µm nominal pore size filter unit and a 20-gauge needle to each syringe. Inject the next 10 mL from each syringe into three separate 10-mL sterile vials. Repeat the process for three more vials. Label all vials, affix sterile adhesive seals to the closure of the nine vials, and incubate them at 20° to 25° or at 30° to 35° for a minimum of 14 days. If two temperatures are used for incubation of media-filled samples, then these filled containers should be incubated for at least 7 days at each temperature (see Microbiological Control and Monitoring of Aseptic Processing Environments 〈1116〉). Inspect for microbial growth over 14 days as described in Personnel Training and Competency Evaluation of Garbing, Aseptic Work Practices and Cleaning/Disinfection Procedures.

PERSONNEL TRAINING AND EVALUATION IN ASEPTIC

MANIPULATION SKILLS

Personnel who prepare CSPs shall be trained conscientiously and skillfully by expert personnel and through audio–video instructional sources and professional publications in the theoretical principles and practical skills of aseptic manipulations and in achieving and maintaining ISO Class 5 (see Table 1) environmental conditions before they begin to prepare CSPs.

Compounding personnel shall perform didactic review and pass written and media-fill testing of aseptic manipulative skills initially, at least annually thereafter for low- and medium-risk level compounding, and semiannually for high-risk level compounding. Compounding personnel who fail written tests or whose media-fill test vials result in gross microbial colonization shall be immediately re-instructed and re-evaluated by expert compounding personnel to ensure correction of all aseptic practice deficiencies.

Media-Fill Challenge Testing—The skill of personnel to aseptically prepare CSPs may be evaluated using sterile fluid bacterial culture media-fill verification1 (i.e., sterile bacterial culture medium transfer via a sterile syringe and needle). Media-fill testing is used to assess the quality of the aseptic skill of compounding personnel. Media-fill tests represent the most challenging or stressful conditions actually encountered by the personnel being evaluated when they prepare particular risk level CSPs and when sterilizing high-risk level CSPs. Media-fill challenge tests that simulate high-risk level compounding are also used to verify the capability of the compounding environment and process to produce a sterile preparation.

Commercially available sterile fluid culture media, such as Soybean–Casein Digest Medium (see Sterility Tests 〈71〉), shall be able to promote exponential colonization of bacteria that are most likely to be transmitted to CSPs from the compounding 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 are used for incubation of media-filled samples, then these filled containers should be incubated for at least 7 days at each temperature (see Microbiological Control and Monitoring of Aseptic Processing Environments 〈1116〉). Failure is indicated by visible turbidity in the medium on or before 14 days.

IMMEDIATE-USE CSPS

The immediate-use provision is intended only for those situations where there is a need for emergency or immediate patient administration of a CSP.

Such situations may include cardiopulmonary resuscitation, emergency room treatment, preparation of diagnostic agents, or critical therapy where the preparation of the CSP under conditions described for Low-Risk Level CSPs subjects the patient to additional risk due to delays in therapy. Immediate-use CSPs are not intended for storage for anticipated needs or batch compounding. Preparations that are medium-risk level and high-risk level CSPs shall not be prepared as immediate-use CSPs.

Immediate-use CSPs are exempt from the requirements described for Low- Risk Level CSPs only when all of the following criteria are met:

1. The compounding process involves simple transfer of not more than three commercially manufactured packages of sterile nonhazardous products or diagnostic radiopharmaceutical products from the manufacturers' original containers and not more than two entries into any one container or package (e.g., bag, vial) of sterile infusion solution or administration container/device. For example, anti-neoplastics shall not be prepared as immediate-use CSPs because they are hazardous drugs.

2. Unless required for the preparation, the compounding procedure is a continuous process not to exceed 1 hour.

3. During preparation, aseptic technique is followed and, if not immediately administered, the finished CSP is under continuous supervision to minimize the potential for contact with nonsterile surfaces, introduction of particulate matter or biological fluids, mix-ups with other CSPs, and direct contact of outside surfaces.

4. Administration begins not later than 1 hour following the start of the preparation of the CSP.

5. Unless immediately and completely administered by the person who prepared it or immediate and complete administration is witnessed by the preparer, the CSP shall bear a label listing patient identification information, the names and amounts of all ingredients, the name or initials of the person who prepared the CSP, and the exact 1-hour BUD and time.

6. If administration has not begun within 1 hour following the start of preparing the CSP, the CSP shall be promptly, properly, and safely discarded.

Compounding in worse than ISO Class 5 (see Table 1) conditions increases the likelihood of microbial contamination, and administration durations of microbially contaminated CSPs exceeding a few hours increase the potential for clinically significant microbial colonization and thus for patient harm, especially in critically ill or immunocompromised patients.

SINGLE-DOSE AND MULTIPLE-DOSE CONTAINERS

Opened or needle-punctured single-dose containers, such as bags, bottles, syringes, and vials of sterile products and CSPs shall be used within 1 hour if opened in worse than ISO Class 5 (see Table 1) air quality (see Immediate- Use CSPs), and any remaining contents must be discarded. Single-dose vials exposed to ISO Class 5 (see Table 1) or cleaner air may be used up to 6 hours after initial needle puncture. Opened single-dose ampuls shall not be stored for any time period. Multiple-dose containers (e.g., vials) are formulated for removal of portions on multiple occasions because they usually contain antimicrobial preservatives. The BUD after initially entering or opening (e.g., needle-punctured) multiple-dose containers is 28 days (see Antimicrobial Effectiveness Testing 〈51〉) unless otherwise specified by the manufacturer.

HAZARDOUS DRUGS AS CSPS

Although the potential therapeutic benefits of compounded sterile hazardous drug preparations generally outweigh the risks of their adverse effects in ill patients, exposed healthcare workers risk similar adverse effects with no therapeutic benefit. Occupational exposure to hazardous drugs can result in (1) acute effects, such as skin rashes; (2) chronic effects, including adverse reproductive events; and (3) possibly cancer (see Appendix A of NIOSH Publication no. 2004-165).

Hazardous drugs shall be prepared for administration only under conditions that protect the healthcare workers and other personnel in the preparation and storage areas. Hazardous drugs shall be stored separately from other inventory in a manner to prevent contamination and personnel exposure.

Many hazardous drugs have sufficient vapor pressures that allow volatilization at room temperature; thus storage is preferably within a containment area such as a negative pressure room. The storage area should have sufficient general exhaust ventilation, at least 12 air changes per hour (ACPH)2 to dilute and remove any airborne contaminants.

Hazardous drugs shall be handled with caution at all times using appropriate chemotherapy gloves during receiving, distribution, stocking, inventorying, preparation for administration, and disposal. Hazardous drugs shall be prepared in an ISO Class 5 (see Table 1) environment with protective engineering controls in place and following aseptic practices specified for the appropriate contamination risk levels defined in this chapter. Access shall be limited to areas where drugs are stored and prepared to protect persons not involved in drug preparation.

All hazardous drugs shall be prepared in a BSC3 or a CACI that meets or exceeds the standards for CACI in this chapter. The ISO Class 5 (see Table

1) BSC or CACI shall be placed in an ISO Class 7 (see Table 1) area that is physically separated (i.e., a different area from other preparation areas) and optimally has not less than 0.01-inch water column negative pressure to adjacent positive pressure ISO Class 7 (see Table 1) or better ante-areas, thus providing inward airflow to contain any airborne drug. A pressure indicator shall be installed that can be readily monitored for correct room pressurization. The BSC and CACI optimally should be 100% vented to the outside air through HEPA filtration.

If a CACI that meets the requirements of this chapter is used outside of a buffer area, the compounding area shall maintain a minimum negative pressure of 0.01-inch water column and have a minimum of 12 ACPHs.

When closed-system vial-transfer devices (CSTDs) (i.e., vial-transfer systems that allow no venting or exposure of hazardous substance to the environment) are used, they shall be used within the ISO Class 5 (see Table

1) environment of a BSC or CACI. The use of a CSTD is preferred because of their inherent closed system process. In facilities that prepare a low volume of hazardous drugs, the use of two tiers of containment (e.g., CSTD within a BSC or CACI that is located in a non-negative pressure room) is acceptable.

Appropriate personnel protective equipment (PPE) shall be worn when compounding in a BSC or CACI and when using CSTD devices. PPE should include gowns, face masks, eye protection, hair covers, shoe covers or dedicated shoes, double gloving with sterile chemo-type gloves, and compliance with manufacturers' recommendations when using a CACI.

All personnel who compound hazardous drugs shall be fully trained in the storage, handling, and disposal of these drugs. This training shall occur prior to preparing or handling hazardous CSPs, and its effectiveness shall be verified by testing specific hazardous drugs preparation techniques. Such verification shall be documented for each person at least annually. This training shall include didactic overview of hazardous drugs, including mutagenic, teratogenic, and carcinogenic properties, and it shall include ongoing training for each new hazardous drug that enters the marketplace.

Compounding personnel of reproductive capability shall confirm in writing that they understand the risks of handling hazardous drugs. The training shall include at least the following: (1) safe aseptic manipulation practices;

(2) negative pressure techniques when utilizing a BSC or CACI; (3) correct use of CSTD devices; (4) containment, cleanup, and disposal procedures for breakages and spills; and (5) treatment of personnel contact and inhalation exposure.

NOTE—Because standards of assay and unacceptable quantities of contamination of each drug have not been established in the literature, the following paragraph is a recommendation only. Future standards will be adopted as these assay methods are developed and proven.

In order to ensure containment, especially in operations preparing large volumes of hazardous drugs, environmental sampling to detect uncontained hazardous drugs should be performed routinely (e.g., initially as a benchmark and at least every 6 months or more often as needed to verify containment). This sampling should include surface wipe sampling of the working area of BSCs and CACIs; counter tops where finished preparations are placed; areas adjacent to BSCs and CACIs, including the floor directly under the working area; and patient administration areas. Common marker hazardous drugs that can be assayed include cyclophosphamide, ifosfamide, methotrexate, and fluorouracil. If any measurable contamination (cyclophosphamide levels greater than 1.00 ng per cm2 have been found to cause human uptake) is found by any of these quality assurance procedures, practitioners shall make the decision to identify, document, and contain the cause of contamination. Such action may include retraining, thorough cleaning (utilizing high-pH soap and water), and improving engineering controls. Examples of improving engineering controls are (1) venting BSCs or CACIs 100% to the outside, (2) implementing a CSTD, or (3) re-assessing types of BSCs or CACIs.

Disposal of all hazardous drug wastes shall comply with all applicable federal and state regulations.