I NEED TO KNOW? 1 www.fda.gov Introductions CDR Mary McGarry, BS, - PowerPoint PPT Presentation

Pharmacy Compounding Overview and Insanitary Conditions CERTIFICATION REPORTS, WHAT DO I NEED TO KNOW? 1 www.fda.gov

Introductions • CDR Mary McGarry, BS, PharmD, MS, RAC, CPGP • CDR Stacey Degarmo, PharmD, BCPS, CPH, CPGP • Compliance Officers • FDA, Center for Drug Evaluation and Research, Office of Compliance, Office of Manufacturing Quality, Global Compliance Branch 1 (Pharmacy Compounding) 2 www.fda.gov

Disclaimer • We (I) have no conflicts of interest to disclose • The opinions in this presentation reflect the views of the authors and should not be construed to represent FDA’s views or policies on Compounding Pharmacy Practices 3 www.fda.gov

Agenda • Pharmacy Compounding History • Review of Compounding Regulations • Insanitary Conditions • USP <797> Certification Requirements • How to Ensure your report meets USP <797> requirements – Report Breakdown • Report Examples • Keys for a Robust Environmental Monitoring Program • Questions 4 www.fda.gov

Compounding Background • Oversight of traditional pharmacy compounding was done by state boards of pharmacy • USP <797> guidelines were used as industry standard/best practices • Regulatory changes following the 2012 fungal meningitis outbreak led to increased oversight by the FDA and legal enforceability of USP <797> in most states 5 www.fda.gov

Drug Quality and Security Act (DQSA) • Amends the Federal Food, Drug and Cosmetic Act (FDCA) with respect to human drug compounding and drug supply chain security • Title 1, the Compounding Quality Act , contains provisions relating to the oversight of compounding of human drugs • Enacted by Congress on November 27, 2013 6 www.fda.gov

FDCA Section 503A • Section 503A describes conditions under which certain compounded human drug products are entitled to exemptions from three sections of the FDCA:  FDA approval prior to marketing (section 505)  Compliance with current good manufacturing practices (cGMP) (section 501(a)(2)(B))  Labeling with adequate directions for use (section 502(f)(1)) • Some federal requirements still apply to pharmacies that meet the requirements of 503A (i.e. NO INSANITARY CONDITIONS ) 7 www.fda.gov

Compounding Quality Act • Removes provisions of 503A related to solicitation of prescriptions and advertising/promotion that were found to be unconstitutional • Clarifies that section 503A will be applicable to compounders nationwide • Adds new section 503B related to “Outsourcing Facilities” 8 www.fda.gov

503B Outsourcing Facilities • Engaged in the compounding of at least some sterile drug products • Facility registration is voluntary • Registered facilities complying with 503B are exempt from two FDCA sections: – FDA approval prior to marketing (section 505) – Labeling with adequate directions for use (section 502(f)(1)) • Subject to cGMP requirements and increased federal oversight (routine FDA inspections) 9 www.fda.gov

503B Outsourcing Facilities • Allows production of compounded products without individual patient prescriptions • Can have some patient specific and some non- patient specific compounding but ALL would be subject to cGMP requirements • Does not have to be a licensed pharmacy • Compounding does have to be done by or under direct supervision of a licensed pharmacist • No wholesaling allowed 10 www.fda.gov

Insanitary Conditions - Defined • Insanitary conditions are conditions that could cause a drug to become contaminated with filth or rendered injurious to health • Drug does not have to actually be contaminated • Drugs produced under insanitary conditions are considered adulterated under federal law • Prohibited under section 501(a)(2)(A) of FDCA • Neither section 503A nor section 503B provides an exemption to the insanitary conditions prohibitions 11 www.fda.gov

Which of these would be an Insanitary Condition? A. Giving your dog a bed in close proximity to a compounding area B. Office style top-loaded drinking water used for formulating sterile products C. Coffee filters used to filter particulates D. Toaster ovens used for dry heat sterilization and depyrogenation E. Kitchen dishwasher and detergent used to clean sterile compounding equipment and utensils F. All of the above 12 www.fda.gov

Which of these would be an Insanitary Condition?  F. All of the above How many of these conditions have been observed by FDA investigators??? • ALL of them 13 www.fda.gov

Insanitary Conditions – Examples • • Mold and/or bacterial Animals (pets or otherwise) in contamination facility in close proximity to the compounding room • Sources of non-microbial • contamination in production Insects in cleanrooms, ceilings areas • Performing aseptic manipulations • Wood surfaces in cleanrooms with exposed hair or skin (hands, wrists, forehead, mouth, or legs) • Poor aseptic technique • Standing water or evidence of • Renovations in the immediate leakage in production or adjacent compounding area areas • Handling hazardous, sensitizing, • Improper gowning or highly potent drugs without • adequate controls to prevent Failure to disinfect or change cross-contamination sterile gloves when sterility or integrity may have been • Exposing sterile drugs and compromised materials to less than ISO 5 quality air 14 www.fda.gov

Photos of Insanitary Conditions Visible microbial contamination 15 www.fda.gov

Photos of Insanitary Conditions Table for ISO-5 is laminated particle board 16 www.fda.gov

Photos of Insanitary Conditions HEPA filters visibly dirty 17 www.fda.gov

Photos of Insanitary Conditions Sleeve of the glove box is damaged 18 www.fda.gov

Photos of Insanitary Conditions Exposed legs of gowned employee working in the cleanroom 19 www.fda.gov

Photos of Insanitary Conditions • The HEPA filter located immediately above the ISO 5 workbench was observed to have been stained on the filter surface • The HEPA filter stain was due to drug product which had exploded due to excessive pressure applied when forcing non-sterile product through a sterilizing filter. The device used to force the product through the sterilizing filter was a stainless steel caulking gun 20 www.fda.gov

Insanitary Conditions – Why do they matter??? • Drug Contamination • Patient Injury • “Drug products prepared, packed, or held under insanitary conditions could be contaminated and cause serious adverse events, including death” – FDA Guidance on Insanitary Conditions • Note: Image above shows fungal growth in a patient’s spinal fluid sample following the injection of a contaminated CSP into the patient’s spinal column 21 www.fda.gov

FDA Guidance for Industry • On 9/25/18, FDA released a revised guidance on Insanitary Conditions at Compounding Facilities • Available at: https://www.fda.gov/downloads/Drugs/GuidanceCompli anceRegulatoryInformation/Guidances/UCM514666.pdf • Note: “ Guidances for Industry” are intended to explain FDA’s current thinking and/or expectations related to a given topic 22 www.fda.gov

Switching Gears… CLEANROOM AND HEPA CERTIFICATION REPORTS 23

How HEPA Filters Work • The HEPA filter is a particulate filter. • The HEPA filter retains airborne particles and microorganisms, however gases pass freely through the filter • HEPA filters retain particulate matter by several mechanisms working together including: – Sieving, Interception, Inertial Impaction and Diffusion 24 www.fda.gov

USP <797> Certification Requirements • Requires certification every 6 months under dynamic conditions – Dynamic conditions – during simulation of product manipulations and material transfers – Static conditions – the room is at “rest” – no workers performing manipulations inside the hood or moving around room • Recertification also required when the device or room is relocated or altered or major service to the facility is performed • References CETA Certification Guide for Sterile Compounding Facilities as the standard for certification procedures (CAG-003- 2006) 25 www.fda.gov

FDA Recommendations • FDA also recommends that facilities certify the ISO 5 area every six months – If the ISO 5 area is not certified every six months or does not pass all certification requirements, there is no assurance that the ISO 5 area is working properly (e.g., generating unidirectional ISO 5 airflow) 26 www.fda.gov

Requirements • How do you ensure your report meets requirements? – What should I look for? – What do these numbers mean? – What is a patch? – When should I seek additional guidance? – Should I wait for the report to be issued or should I get the raw data on the date of the certification? 27 www.fda.gov

Test Certification Report • Name and address of testing organization • Date of Testing • No and year of the publication of the relevant part of ISO14644 (i.e. ISO 14644:1 1-2015) • Location of cleanroom • Specific representation of locations (diagrams if necessary) • ISO Class • Occupancy • Particle count sizes considered • Test method used • Identification of test instrument/s and calibration certificates • Test Results Reference: Moldenhauer, J (2017) Environmental Monitoring A 28 Comprehensive Handbook, Volume 8, Bethesda, MD:DHI

Step by Step Overview REPORT BREAKDOWN 29