USP <797> and Environmental Sampling Participants will be in listen only mode. 9 a.m. (PT) Download the PDF: https://www.emlab.com/m/media/usp797-webinar.pdf Presented by: Michael Berg, Ph.D.
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Outline Overview History Sampling Suggested changes Investigation of excursions & remediation USP800 3
USP <797> A chapter of the United States Pharmacopeia National Formulary (USP-NF). USP-NF establishes standards for medicines, food ingredients and dietary supplements. USP <797> establishes best practices and regulations for the production of compounded sterile preparations. 4
Abbreviations and Terms USP-NF: United States Pharmacopeia National Formulary CSP: Compounded Sterile Preparation PEC: Primary Engineering Controls BUD: Beyond Use Dating DCA: Direct Compounding Area Buffer Room Ante Room 5
Where Does USP <797> Apply? Any facility producing CSPs and any personnel who perform compounding are subject to regulation by USP <797>. The Act of Compounding determines regulation, not the nature of the facility. Requirements of USP <797> depend on the nature of the compounding being performed. 6
What is Compounding? Compounding means any of the following activities occurring in a licensed pharmacy, by or under the supervision of a licensed pharmacist, pursuant to a prescription: Altering the dosage form or delivery system of a drug Altering the strength of a drug Combining components or active ingredients Preparing a drug product from chemicals or bulk drug substances 7
Examples of CSP Injections Total Parenteral Nutrition (TPN) Aqueous bronchial inhalations Baths and soaks for live organs and tissues Irrigations for internal body cavities Ophthalmics (eye) Implants 8
Examples of NOT Compounding FDA approved, sterile, sealed and self contained reconstitution devices obtained directly from the manufacturer. Pills, solutions and other medications that come pre-mixed from the manufacturer and are only dispensed by the pharmacy. 9
Cleanroom Design Ante Room Buffer Room ISO 8 ISO 7 PEC (ISO 5) 10
Cleanroom: Hazardous Compounding Ante Room Buffer Room ISO 7 ISO 7 PEC (ISO 5) 11
BUD <12 Hours Low Risk Non-Hazardous For low-risk level, nonhazardous CSP only with 12 hour or less BUD. No buffer (ISO 7) but segregated area is required (e.g. away from sinks and windows). 12
Mission Mission of the chapter: To prevent harm Microbial contamination Excessive bacterial endotoxin Variability in intended strength that exceed limits Use of ingredients of inappropriate quality Unintended physical and chemical contaminants 13
History Chapter <797> Published 11/2003 Official 1/2004 Revision released 12/2007 Official 6/2008 Out for public comment 9/2015 Enforceable by FDA and 28 State Board of Pharmacies (more or less) Based on current scientific information and best sterile compounding practices Recognized as the national standard of practice Provides practice and quality standards for compounding sterile preparations 14
Current Revision of Chapter <797> When will the final revision to General Chapter <797> be published? Based on the nature and significance of the public comments received, the chapter will be republished in the Pharmacopeial Forum for another round of public comments. The Compounding Expert Committee is currently reviewing all of the public comments submitted on the proposed revisions to General Chapter <797>. The chapter is currently being revised based on the public input received. Due to the high volume of comments received, USP does not have a date for the republication. Is <797> still enforceable? Although General Chapter <797> is undergoing revision, the published version of the chapter which became official on June 1, 2008 is currently the official and enforceable standard. Source: www.usp.org 15
History Outbreaks 2001 Walnut Creek, CA 40 patients exposed (Serratia bacterium), 4 developed meningitis, 1 fatality 2004 - USP<797> official 2008 - USP<797> revised 2000 2017 2001 - FDA found that 34% of CSPs tested had deficiencies. 1 2002 North Carolina patients exposed to Exophiala dermatitidis, 4 developed meningitis, 1 fatality 2012 Framingham, MA Fungal meningitis Case count: 751 Fatalities: 64 1 US Food and Drug Administration. Report: Limited FDA Survey of Compounded Drug Products. http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/pharmacycompounding/ucm155725.htm. 6/18/2009, accessed 8/19/2009 16
Framingham, Massachusetts (2012) Fungal meningitis outbreak caused by contaminated vials from the New England Compounding Center (NECC), Framingham, MA The case count is now 751 and the death toll 64 1 Company had a history of complaints and noncompliance. 2012 investigations demonstrated a basic lack of compliance with USP<797> or with safe compounding. 1 http://www.cdc.gov/hai/outbreaks/meningitis.html (Oct 29, 2013) 17
Framingham, Massachusetts (2012) 1 http://www.cdc.gov/hai/outbreaks/meningitis-map-large.html (Oct 29, 2013) 18
Enforcement FDA enforcement (dependent upon mass casualties). Requirement in many states for certification. Joint Commission on Accreditation of Healthcare Organizations (JCAHO) launched a new Medication Compounding Certification in 2017. 19
USP Revision Suggested Changes 1. Reorganization of existing sections. 2. Collapsing of three risk categories (low-, medium-, and high-risk) into two categories (Category 1 and 2). 3. Removal of information on handling hazardous drugs and added cross-references to <800> Hazardous Drugs Handling in Healthcare Settings. 4. Personnel monitoring (quarterly), Air and surface sampling (monthly). 5. Introduction of the terminology in-use time. 20
Risk Levels Low Risk 1) Low Risk CSPs are compounded with aseptic manipulations within ISO Class 5 using only sterile components. Compounding only involves transfer, measuring and mixing manipulations using no more than 3 sterile products. CSP administered within following time periods: room temp 48 hours, refrigerated 14 days, frozen 45 days. 21
Risk Levels Medium Risk 2) Medium Risk CSPs that will be administered either to multiple patients or to one patient on multiple occasions. Compounding process includes complex aseptic manipulations other than single-volume transfer. Compounding process requires unusually long duration. Examples: Compounding of total parenteral nutrition fluids. Filling reservoirs of injection devices with more than 3 sterile products. 22
Risk Levels High Risk 3) High Risk Produced with non-sterile components, or process exposes components to conditions worse than ISO 5 for more than 1 hour. Requires terminal sterilization. Same environmental requirements as medium risk, except more extensive environmental testing is required. 23
Special Circumstances: Low Risk, BUD Less Than 12 Hours If, and only if, the following conditions are met: Low risk compound used within 12 hours. Primary Engineering Control has been demonstrated to maintain ISO 5 during operations and transfer of material as delineated in CETA CAG-002-2006. Surrounding area can be easily cleaned. Then the ISO 5 Primary Engineering Control may be located in an out of the way area (away from sinks, windows, doors to the exterior, traffic flow, etc.) that does not meet ISO 7 conditions. 24
Urgent-Use CSPs In Rare (Emergency) Circumstances CSP is urgently needed Single patient Compounding <1hour Immediate administration of the CSP CSP may be prepared in worse than ISO5 conditions. 25
New Risk Categories Factors 1) Conditions under which the CSPs are made Batch size Complexity and length of compounding procedure and complexity of compounding operation Inherent nature of the CSP (e.g. supporting microbial growth) 2) Time within which CSPs will be used BUD <12 hrs (RT) or <24 hrs (refrigerated) 26
Proposed Category 1 CSP PEC placement Not in ISO classified air Sterility Testing Not required Endotoxin Testing Not required BUD 12 hours RT or 24 hours refrigerated 27
Environmental Monitoring Primary engineering control (PEC) Category 1 Category 2 Buildings and Facilities Not required to be placed in a classified area Not required to be placed in a classified area Recertification Every 6 months Every 6 months Nonviable airborne monitoring Viable airborne monitoring Environmental Monitoring Every 6 months Monthly Every 6 months Monthly Surface sampling Monthly Monthly 28
Personnel Qualifications Current Proposed Visual observation of hand hygiene and garbing Gloved fingertip sampling Media fill testing Prior to compounding and during media fill testing Prior to compounding and during media fill testing Annually for low and medium risk level, Semiannually for high risk level Quarterly Quarterly Quarterly 29
Environmental Sampling Types Non-viable Viable Air Surface Gloved finger tip Media fill test 30
Non-Viable Particle Sampling Once every six months When Primary Engineering Controls are moved or altered In response to major servicing of the area around the PEC Locations to be sampled: each ISO 5 area, ISO 7 buffer area and ISO 8 ante area ISO 14644: # samples=square Root of the clean room area, at least 1 minute & 2 Liters / sample 31
Total Particle Count ISO 14644: Rule of thumb: # samples=square Root of the clean room area, at least 1 minute & 2 Liters / sample Area [m2] less than or equal to Minimum # of samples locations 2 1 10 5 32 8 56 11 104 16 190 21 500 26 32
ISO 14644 and FED-STD-209E Number of Particles per Cubic Meter by Micrometer Size ISO Class 0.1 µm 0.2 µm 0.3 µm 0.5 µm 1 µm 5 µm FED STD 209 Class ISO 1 10 2 ISO 2 100 24 10 4 ISO 3 1,000 237 102 35 8 1 ISO 4 10,000 2,370 1,020 352 83 10 ISO 5 100,000 23,700 10,200 3,520 832 29 100 ISO 6 1,000,000 237,000 102,000 35,200 8,320 293 1000 ISO 7 352,000 83,200 2,930 10000 ISO 8 3,520,000 832,000 29,300 100000 ISO 9 35,200,000 8,320,000 293,000 33
Viable Particle Sampling Personnel qualification: Gloved finger tip test, media fill test (annually or semi-annually) Typically conducted by the head pharmacist/trainer. Air sampling: Currently every six months (proposed monthly) Sampler gets fully garbed Prepare equipment in ante room Load sampler aseptically Position sampler Sampling (stand back or leave immediate area) Remove and close plate 34
Viable Testing: Gloved Fingertip Use two plates with nutrient agar containing neutralizing agents (e.g. lecithin and polysorbate 80). Do NOT disinfect gloves. Collect a gloved fingertip and thumb sample from both hands (separate plates) by lightly pressing each fingertip into the agar. 35
Viable Testing: Media Fill Test Manipulations: All sterile ingredients: Transfer sterile culture medium into the same type of containerclosure systems. Some non-sterile ingredients: Prepare nonsterile culture medium and manipulate accordingly. Media incubation: Incubate media-filled vials at 20 35 for a minimum of 14 days. 36
Viable Testing: Air Sampling Air sampling in all classified areas Volumetric sampling: At least 400-1000 liters sample volume (min. of 1000 liters proposed) During typical operating conditions at least semiannually (monthly proposed) Use general microbiological growth medium (e.g. TSA or Soybean Casein Digest Medium) 37
Viable Testing: Air Sampling Decontaminate sampling equipment Examine media for contamination Sample at least 400 1000 liters (1000 L minimum proposed) Close the plate, label & transport to lab/incubator Bacteria testing (e.g. TSA, 2 3 days at 30 C - 35 C incubation) Fungal testing (e.g. MEA, 5 7 days at 26 C - 30 C incubation) Proposed: dual incubation, one medium 38
Viable Testing: Air Sampling ISO Class Air Sampling Action Levels (CFU/m3)* 5 >1 7 >10 8 >100 * All action levels must be based on sampling in the vicinity of exposed materials/articles during compounding operations. 39
Viable Testing: Surface Sampling Testing for contamination of work surfaces Evaluate disinfection and cleaning procedures Must be performed in all ISO classified area Must be performed at the conclusion of compounding activities but before cleaning/disinfection Media must be supplemented with additives to neutralize effects of disinfectants (e.g. TSA with lecithin and polysorbate 80) Sampling must be conducted periodically (proposed: monthly) 40
Viable Testing: Surface Sampling Contact Plates or Paddles (24 36 cm 2 ) Easy to use Accurate Less handling Swabs Can sample curved surfaces Convenient Less expensive 41
Viable Testing: Surface Sampling ISO Class Currently Work Surfaces* (CFU per plate or per sample) Non-work Surfaces (CFU per plate or per sample) 5 >3 >3 N/A 7 >5 >5 >10 8 >100 >25 >50 * Work surfaces are those surfaces that are in direct contact with materials used in compounding. These action levels are based on the expectation that materials will be disinfected before introduction to an ISO Class 5 area. 42
Actionable Organisms CFU count below the action Characterization must be performed (Microbial Characterization, Identification, and Strain Typing USP<1113>). Highly pathogenic microorganisms (e.g., gram-negative rods, coagulase positive staphylococcus, molds and yeasts) are potentially fatal to patients receiving CSPs and must be immediately remedied through cleaning and disinfection, regardless of CFU count. If levels measured during viable air sampling exceed the levels, the genus must be identified, and when possible, identify the species of any microorganism recovered, with the assistance of a credentialed microbiology laboratory. 43
Investigations and Excursions Physical Factors Threshold failure or Excursion PEC Cleaning Environmental conditions Personnel Factors Hand washing & garbing Training 44
Cleaning and Disinfection Site PEC (except for isolator) Isolator Work surfaces outside the PEC Floors Walls Ceilings Storage Shelving Minimum Frequency* beginning and end of each shift; before each batch; every 30 min; after spills each time it is opened; decontaminate closed isolator Daily Daily Monthly Monthly Monthly * If compounding is done less frequently than the cleaning frequencies cleaning must occur before each compounding session begins. 45
Disinfectants (Appendix II) 46
Quality Control Documentation is Key to Providing Good USP Services Copy or original certificate of sterility Equipment calibration and training certificates Maps to indicate environmental samples Document time of sampling also in reference to other activities Records for cleaning activities, investigations, results of monitoring 47
USP <800> (Hazardous Drugs) Hazardous Drugs - Handling in Healthcare Settings Created to identify requirements for receipt, storage, mixing, preparing, compounding, dispensing, and administration of hazardous drugs to protect the patient, healthcare personnel, and environment. 48
USP <800> (Hazardous Drugs) The ChemoAlert Kit Self-contained wipe kit all contents needed to collect and return samples to the lab for analysis Tests for 1-10 different drug targets from a single swab or for Platinum (Pt) containing drugs Has 6 easy steps to collect a surface sample Prepaid shipping included FedEx, using the provided insulated container Results in 15 business days or less 49
USP <800> (Hazardous Drugs) Glove Boxes & Hoods Patient Infusion Floors & Corners Telephones Light Switches Computer Keyboards Etc. 50
USP <800> (Hazardous Drugs) USP <797> MIX 5-FLUOROURACIL CYCLOPHOSPHAMIDE IFOSFAMIDE METHOTREXATE View the draft version of USP800 at: http://www.usp.org/sites/default/files/usp_pdf/en/m7808_pre-post.pdf 51
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Questions 55
Continuing Education Units (CEUs) To receive a certificate of attendance, you must complete the survey after the webinar: Click on the survey link in the Thank you email (sent 1 hour after this webinar). Complete survey within 24 hours. You will receive an email in 2-3 weeks when your certificate is ready. 56
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