BRIEFING 〈797〉 Pharmaceutical Compounding—Sterile

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). 〈〉〈〉 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

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