2008 ASHP Summer Meeting Seattle, Washington Educational Session Abstracts

Transcription

1 2008 ASHP Summer Meeting Seattle, Washington Educational Session Abstracts 116 USP <797> Update 2008 and Personnel-Related Environmental Sampling Trissel, L.A. TriPharma Research, P.O. Box 265, Cashiers, NC 28717, USA. Kastango, E.S. Abstract: The United States Pharmacopeia (USP) has published revisions to USP Chapter <797>, the national quality standards for sterile compounding. The revised quality standards become the current standard as of June, This presentation provides an overview of the content of the USP Chapter <797> with a focus on the new and changed standards to aid practitioners in understanding and interpreting the needed quality assurance measures to protect patients from erroneous and contaminated sterile compounded preparations. Chapter <797> contains standards that begin with defining the responsibilities of compounding personnel. The Chapter also includes discussion and description of various quality assurance steps involving environmental control and monitoring, quality testing of compounded dosage forms, personnel aseptic technique evaluation, determination of product risk, storage and beyond use dating, topics for standard operating procedures, and more. The presentation will focus on these quality assurance components that need to be considered and addressed to safely provide compounded sterile products for use in patient care. Learning Objectives: 1. Outline recent revisions of USP Chapter <797> requirements. 2. Explain the rationale for many of the changed standards. 3. Explain the implications for pharmacists of changes in USP chapter <797> standards. 4. Describe five principal new sections of USP Chapter <797> needed to achieve USP chapter <797> compliance for compounding sterile preparations. Self-Assessment Questions: 1. The revisions to the quality standards of USP Chapter <797> are few in number and minor in nature. a. True

2 2008 ASHP Summer Meeting Seattle, Washington Educational Session Abstracts b. False 2. Sterile drugs compounded according to the Immediate Use category requirements: a. Allow home care pharmacies get around the quality requirements of <797>. b. Are for use within 1 hour after the start of compounding. c. Eliminate the need for a laminar airflow hood or isolator for compounding parenteral nutrition (TPN and TNA) admixtures. d. May not be stored overnight for use the next day after compounding. e. Both b and d. 3. For hazardous drugs, such as cancer chemotherapy: a. Compounding must be performed in biological safety cabinets or compounding aseptic containment isolators vented to the outside and located in a separate negative airflow ISO 7 buffer room. b. Closed-system vial transfer devices provide a suitable substitute for biological safety cabinets and compounding aseptic containment isolators. c. The requirements of <797> for hazardous drugs are to be followed no matter how few doses are compounded. d. Personal protective garb is not needed if a biological safety cabinet is used. 4. USP Chapter <797> specifies the cleaning and disinfection frequencies of sterile compounding facilities. Which of these cleaning and disinfection frequencies is incorrect? a. Floors daily. b. Biological safety cabinets, laminar airflow workbenches, and compounding aseptic isolators daily. c. Work counters daily. d. Walls and storage shelves monthly. e. Ceilings monthly. 5. For compounding aseptic isolators (CAIs), which of the following are correct? a. Placement in an ISO class 7 buffer room may be needed depending on the CAI design and functionality. b. Personnel protective garb may be required unless the CAI manufacturer has proven that the garb is unnecessary.

3 2008 ASHP Summer Meeting Seattle, Washington Educational Session Abstracts c. CAIs must be validated at the use site to maintain an ISO class 5 environment under dynamic (in-use) working conditions. d. CAIs must maintain unidirectional airflow at the critical sites. e. All of the above Answers: 1. b; 2. e; 3. a; 4. b; 5. e

4 USP Chapter <797> Update 2008 Lawrence A. Trissel Research Consultant TriPharma Research Disclaimer Although I am a member of the USP Sterile Compounding Committee, I am speaking in my individual capacity and not as a member of the Committee or as a USP representative. The views and opinions presented are entirely my own. They do not necessarily reflect the views of USP, ASHP or any other organization, nor should they be construed as an official explanation or interpretation of <797>.

5 Changes and Clarifications in <797> Introduction (Revised) Definitions section (new) Immediate-Use category (new) Low-Risk Level with 12 hour BUD (new) Single & multiple-dose containers (new) Proprietary vial/bag systems (new) Hazardous drugs (revised) Changes and Clarifications in <797> Radiopharmaceuticals (revised) Allergen Extract CSPs (new) Cleaning and disinfecting facilities (revised) Personnel cleansing and garbing (revised) Environmental controls (revised) Environmental sampling (revised)

6 Changes and Clarifications in <797> Filter integrity testing for High Risk Level compounding (new) Microbiological BUD (revised) Shall vs. Should Table (new) Clarified language throughout Key to Understanding <797>: Read Chapter <797>!!

7 Introduction Complete revision to be more explicit Acknowledges direct contact is the principal source of contamination in CSPs New robust Definitions section for over 2 dozen key terms Alternative technologies proven equivalent or superior to conventional work practices are OK 797 applies to CSPs given via application, implantation, inhalation, injection, insertion, instillation, and irrigation Responsibilities of Compounding Personnel in <797> 14 areas of responsibility are cited Emphasizes training and education Emphasizes compounding accuracy Emphasizes avoiding contamination Emphasizes patient safety

8 CSP Risk Categories Immediate Use CSPs Low-Risk Level Low-Risk Level w/12 hour or less BUD Medium-Risk Level High-Risk Level Immediate-Use Category Exempt from all requirements in <797> Only simple aseptic measuring and transfer are needed NMT 3 sterile non-hazardous drugs No delays/interruptions No contact contamination of ingredients or critical sites

9 Immediate-Use Category Dose must be labeled if not administered by the preparer Administration must begin within 1 hour after the start of preparation Dose must be discarded if administration has not begun within 1 hour after the start of preparation (No storing. No recycling.) Immediate-Use Category Some Examples: At a patient s bedside In an ambulance In an ER In a Code situation

10 Low-Risk Level CSPs Low-Risk Level remains largely unchanged Compounded from NMT 3 commercial sterile containers using commercial sterile devices Maintained in ISO Class 5 environment in an ISO 7 buffer area at all times Only a few basic, closed-system, simple aseptic transfers and manipulations Is Low-Risk Level Really Low Risk of Contamination? Research study of 1035 tuberculin syringe media fills sealed with tip caps Scrubbed, gowned and gloved Techs performed at the end of the day Upon incubation, no growth was observed This simplest of preparations does appear to be at a lower risk of contamination Trissel LA, Ogundele AB, Ingram DS et al. Using a media fill simulation to establish a benchmark microbiological contamination rate for low risk level compounding. AJHP. 2003;60:

11 Missing Research Determination of the potential contamination rate of aseptic compounding of iv bags with two drug containers added. Is this really a low risk of contamination? Low-Risk Level w/12 hour BUD New subsection for an ISO 5 device in an uncontrolled air environment Must be in a segregated compounding area not in a high traffic area All personnel cleansing and garbing requirements apply No Hazardous Drugs Administration must begin within 12 hours or as stated in the package insert, whichever is less

12 Medium-Risk Level CSPs Four or more sterile commercial drug containers Multiple pooled sterile commercial products for multiple patients or one patient multiple times Complex aseptic manipulations Compounding requires long duration Is Medium-Risk Level really higher risk than Low-Risk Level? Evaluated 2 years of media fill tests of aseptic technique over 600 tests Gowning and gloving not required 10-step complicated preparation A trainer provided guidance as to proper technique Contamination rate was found to be 5.2%!!! Trissel LA, Gentempo JA, Anderson RW et al. Using a media fill simulation to evaluate the microbial contamination rate for USP medium risk level compounding. AJHP. 2005;62:285-8.

13 Reducing the Contamination Rate by Changing Work Practices Evaluated 2 more years of media fill tests of aseptic technique using the same 10-step preparation Year 1- gowns and non-sterile gloves required with initial 70% IPA wiping reduced to about 1% contamination Year 2- Sterile gloves with repeated 70% IPA wiping of gloves reduced to 0.3% contamination Trissel LA, Gentempo JA, Saenz LM et al. Reducing the microbial contamination rate of pharmacy-compounded sterile preparations: Evaluation of two simple and inexpensive work practice changes. AJHP. 2007;64: High-Risk Level CSPs Prepared from non-sterile ingredients Preparation from sterile ingredients but exposed to less than ISO Class 5 More than 6 hour delay from compounding to sterilization Purity of components is assumed but not verified by documentation Sterilization by filtration - the manufacturer s recommended integrity test must be performed on the filter

14 Is High-Risk Level compounding really high risk? Unfortunately, High-Risk Level compounding has led to repeated and numerous episodes with many injuries and deaths among patients The potential for mass casualties occurring makes this compounding much more risky Low- and Medium-Risk Level compounding contamination typically impact fewer patients Failure to sterilize properly has been the principal problem in High-Risk Level compounding Old Expired BUD Paradigm Assume the compounded preparation is sterile Base the BUD solely on the drug s chemical stability

15 Chapter<797> BUD Paradigm Recognize the possibility that the preparation was inadvertently contaminated during compounding For patient safety, base the BUD on the drug s chemical stability in conjunction with microbiological limits, whichever is shorter Calculated Microbial Growth Cundell AM, USP Committee on Analytical Microbiology, Pharmacopeial Forum 2002; 28 (6) Stimuli to the Revision Process Time (Hours) Microbial Count (CFU per ml) , X X 10 9

16 <797> Microbiological BUD There is an ever-present chance, indeed likelihood, that some CSPs will be inadvertently contaminated Time and warm temperatures are the enemy, speeding the potential for growth of dangerous amounts of microbial contamination Guidance for limits is needed to avoid unacceptable risks of harming patients Microbiological Beyond-Use Dating Risk Category Immediate Use Low Room Temp 1 hour 48 hours Refrigerator 1 hour 14 days Freezer ( -10 C) N/A 45 days Low w/ 12-hr BUD 12 hours or less 12 hours or less N/A Medium 30 hours 9days 45 days High 24 hours 3 days 45 days

17 Single/Multiple Dose Vials Definitions of SDV and MDV are in the USP General Notices and Requirements Single dose vials Opened or punctured in ISO 5 environment may be used for up to 6 hours. Opened or punctured in worse than ISO 5 must be used within 1 hour or discarded. Single dose ampuls must be discarded after opening and not stored for any time period Single/Multiple Dose Vials Multiple dose vials Contain antimicrobial preservative(s) Designed for entry on multiple occasions. BUD 28 days after initial entry unless specified otherwise by the manufacturer. BUD of 28 days based on USP <51> Antimicrobial Preservative Testing

18 Proprietary Bag/Vial Systems ADD-Vantage; Add-a-Vial, Minibag Plus, etc. Follow the manufacturer s instructions for handling and storing. These devices and their instructions have been approved by the FDA Hazardous Drugs Section extensively revised NIOSH Guidelines for guidance BSC or CACI required Hazardous drug storage and preparation in separate negative pressure ISO 7 with ISO 7 ante area

19 Hazardous Drugs Personnel protection specified Use of closed-system transfer devices must be within BSC or CACI Disposal according to state and federal regulations Allergen Extracts Intradermal and subcutaneous MDVs and SDVs (No IV or IT) Unpreserved allergen extracts must fully comply with all aspects of <797> Allergen extracts are exempt from personnel, environment, and storage requirements only if all of the following criteria are met:

20 Allergen Extracts Personnel perform hand hygiene with alcohol-based surgical hand scrub Hair and beard covers, gown, face mask, and sterile gloves are used Compounded by simple aseptic transfer Must contain an effective amount of antimicrobial preservative For one patient only Allergen Extracts Gloves are intermittently disinfected with sterile 70% IPA during preparation Vial stoppers and ampul necks are disinfected with sterile 70% IPA Direct contact contamination is avoided Allergen extract is labeled with a specific patient name and BUD

21 Cleaning and Disinfecting Facilities Based on Infection Control Advisory Committee recommendations Goal: Reduce bioburden in compounding areas Use of disinfecting agent such as sterile 70% IPA Performed in ISO 5 environment: 1. At the beginning of each work shift 2. At the beginning of each batch 3. At least every 30 minutes 4. When surface contamination is known or suspected Cleaning and Disinfecting Facilities Cleaning should proceed from buffer area (cleanroom) to ante area Use suitable dedicated mops, etc. and disinfecting cleaners Floors, counters, work surfaces at least daily Walls, ceilings, shelving at least monthly

22 Personnel Cleansing and Garbing Remove outer garments and jewelry (including piercings above the neck) Garb order from dirtiest to cleanest Don shoe covers, hair covers, face masks Perform hand/arm hygiene Don disposable gowns Personnel Cleansing and Garbing Cleanse hands and arms with alcohol-based surgical hand scrub with persistent activity After hands and arms are dry, don sterile powder-free gloves compatible with sterile 70% IPA Repeatedly apply sterile 70% IPA to contact areas of gloves whenever nonsterile surfaces are touched (e.g., vials, counter tops, carts)

23 Direct Contact is the Most Likely Source of Contamination in CSPs Personnel Cleansing and Garbing All of the cleansing, garbing and gloving requirements also apply to compounding in CAIs and CACIs. Exception: If the manufacturer of the CAI or CACI provides written documentation of statistically validated testing supporting any garbing component(s) that are not required. Do your Due Diligence to verify the accuracy of any such claim.

24 Environmental Controls Aimed at creating ISO 5, 7, and 8 environments ISO 5 LAFW, BSC, CAI, CACI are Primary Engineering Controls Must maintain ISO 5 during dynamic (in use) working conditions Unidirectional airflow specified Environmental Controls ISO 7 buffer area and ISO 8 (or 7) ante area are Secondary engineering controls Must maintain ISO 7 or 8 during dynamic (in use) working conditions Airflow and balance testing required at the installation site Only personnel and materials essential for compounding and cleaning are permitted

25 Environmental Controls ISO 5 Primary engineering control (LAFW, BSC, CAI, CACI) to be in an ISO 7 environment Exception: CAI if its design provides ISO 5 and isolation from the room during dynamic operating conditions as placed and tested at your site (including transferring materials in and out) using CETA testing requirements Do your Due Diligence to verify the accuracy of any such claim Missing Research Paucity of independent research evaluations and comparisons of pharmacy applications of primary and secondary engineering controls.

26 Other Changes in <797> Radiopharmaceuticals quality assurance based on Radiopharmaceuticals Advisory Committee recommendations Simplified environmental sampling Expanded explanatory and descriptive material in many sections Should vs. Shall table Clarified language throughout (We hope!) Remember USP <797> is about much more than cleanrooms, hoods, and isolators These Magic Boxes will NOT create a sterile preparation Poor work practices contaminate more CSPs than any other single cause

27 Remember Preparing CSPs safely is NOT So easy a cave man can do it!! Specialized education and training, proper environments and work practices, and repeated reassessment are all required to protect patients. Remember YOU are the key ingredient

28 Thank You!