CDER Compliance Update Donald D. Ashley, JD 22 nd Annual GMP by the Sea August 30, 2017 www.fda.gov
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Office of Compliance Structure Office of Compliance Office of Drug Security, Integrity and Response (ODSIR) Office of Unapproved Drugs and Labeling Compliance (OUDLC) Office of Manufacturing Quality (OMQ) Office of Program and Regulatory Operations (OPRO) Office of Scientific Investigations (OSI) www.fda.gov 3
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Office of Scientific Investigations FY17 Activities Collaborated with centers and ORA to develop the bioresearch monitoring (BIMO) program alignment within FDA Engaged with UK and EU health authorities to share information, and conduct good clinical practice and pharmacovigilance inspections (joint and observational) Refined the use of the Clinical Investigator Site Selection Tool (CISST), which utilizes a multi-attribute algorithm to score clinical site/investigator risk and supports prioritization of clinical sites for inspection 5
Office of Scientific Investigations FY17 Activities BIMO Warning Letters issued from FY14-FY17 18 16 14 12 Postmarketing Adverse Drug Experience Sponsor Investigator 10 Good Laboratory Practice 8 6 4 2 Institutional Review Board Sponsor Clinical Investigator 0 FY14 FY15 FY16 FY17* * As of 8/2017 6 6
Office of Unapproved Drugs and Labeling Compliance FY17 Activities Homeopathic teething tablets warnings and recalls In September 2016, FDA first warned consumers not to use homeopathic teething tablets and gels based on serious adverse event reports. In January 2017, FDA released its laboratory finding that the belladonna alkaloid content in teething tablets marketed by CVS and Hyland s was not uniform and far exceeded the labeled amount. The manufacturers of the CVS and Hyland s teething tablets (Raritan Pharmaceuticals and Standard Homeopathic Company, respectively) voluntarily recalled their products. Standard Homeopathic Company recalled their products after receiving an FDA-requested recall letter from the Associate Commissioner for Regulatory Affairs. In August 2017, FDA issued a warning letter to a manufacturer of homeopathic in-process powder blend mixtures that contained belladonna. Violations include release of powder blends prior to validation of the manufacturing processes, and failure to perform identify testing. 7 7
Office of Unapproved Drugs and Labeling Compliance FY17 Activities Cancer Fraud Enforcement Initiative Multi-center collaborative enforcement effort with CDER, CFSAN, CDRH, CVM, and ORA 14 Warning Letters to firms illegally selling more than 65 products that claim to prevent, diagnose, treat, mitigate or cure cancer Four Online Advisory Letters posted Consumer Education Press Release, FDA Voice Blog, Consumer Update article 8 8
Office of Unapproved Drugs and Labeling Compliance FY17 Activities Through mid August 2017: Conducted more than 120 compounding inspections 48 warning letters have issued to compounders 40 state referral letters have issued Over 170 complaints and adverse event reports associated with compounded products or compounding facilities have been investigated Conducted more than 20 for-cause inspections to follow up on the complaints and adverse event reports associate with compounded products 9
Office of Unapproved Drugs and Labeling Compliance FY17 Activities Developed or contributed to the development and publication of compounding documents. Following are recent examples: Final rule, Additions and Modifications to the List of Drug Products That Have Been Withdrawn or Removed From the Market for Reasons of Safety or Effectiveness Final guidance, Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act Final guidance, Electronic Drug Product Reporting for Human Drug Compounding Outsourcing Facilities Under Section 503B of the Federal Food, Drug, and Cosmetic Act Final guidance, Repackaging of Certain Human Drug Products by State-Licensed Pharmacies and Outsourcing Facilities 10 10
Office of Drug Security, Integrity and Response FY17 Activities Implementing the Drug Supply Chain Security Act (DSCSA) Worked with CBP to modernize business processes through implementation of the Automated Commercial Environment/International Trade Data System (ACE/ITDS) Coordinated the following drug recalls Mylan recall of Epi-Pen Coordinated 30 compounding related recall events Recall and critical shortage coordination of Hospira/Pfizer products 11
Drug Supply Chain Security Act Goals Develop an electronic, interoperable system by 2023 to identify and trace certain prescription drugs as they move through the U.S. supply chain to: Facilitate the exchange of information by trading partners at the individual package level Improve efficiency of recalls Enable prompt response to suspect and illegitimate products when found Create transparency and accountability in the drug supply chain Establish national standards for licensure for wholesale distributors and third-party logistics providers 12
http://www.nifds.go.kr/apec/supplychain/apec_supplychaintoolkit_170317.pdf
CDER Recalls All Classes FY13-FY16 2000 1800 1600 1400 1200 1000 800 Events Products 600 400 200 0 FY13 FY14 FY15 FY16 www.fda.gov 14
Major Reasons for Recalls FY13-17* 2013 Lack of Assurance of Sterility Impurities/Degradation Products Presence of Particulate Matter 2014 Marketed Without an Approved NDA/ANDA Presence of Particulate Matter Lack of Assurance of Sterility 2015 Lack of Assurance of Sterility Presence of Particulate Matter Impurities/Degradation Products 2016 Lack of Assurance of Sterility Impurities/Degradation Products Marketed Without an Approved NDA/ANDA CGMP Deviations www.fda.gov 2017 Lack of Assurance of Sterility Impurities/Degradation Products CGMP Deviations Failed USP Dissolution Test Requirements Major Reasons by Recall Event. * = Q3 15
Office of Manufacturing Quality OMQ warning letters CY17 Warning Letters 60 50 40 30 20 Other India China US 10 0 2015 2016 2017* Year www.fda.gov *Through August 15, 2017. Compounding warning letters are not included. 16
Improvement in CGMP Warning Letter Timeframes When compared to 2017, there has been a 55% improvement since 2015; and 44% improvement since 2016. 2015 2016 2017 (Jan-19Jul) Inspection Report Received by CDER to WL Issued Inspection Report Received by CDER to WL Issued Inspection Report Received by CDER to WL Issued 11 months on average 9 months on average 5 months on average www.fda.gov 17
Warning Letter and Import Alert Trends Recurring themes in OMQ warning letters Delay/Deny/Limit FDA inspections Contract manufacturing/quality Agreements Supply chain information/pedigree Sterility assurance Rudimentary CGMP (No QC testing) Data integrity issues www.fda.gov 18
Office of Manufacturing Quality FY17 Activities Contract Manufacturing: From Bad to Worse Drugs Made for You by Firm B You have engaged Firm B to manufacture Firm A Perox-A-Mint, (b)(4). These products [ ]are adulterated as enumerated in the preceding violations. They are also adulterated for the reasons set forth in Warning Letter 515029, issued by FDA to Firm B on June 29, 2017. Among other things, Firm B manufactured your oral solution drugs using the same equipment in which Firm B manufactured toxic industrial-grade car washes and waxes. You are responsible for ensuring that all of your products are manufactured in accordance with CGMP, including oversight of the manufacturing operations conducted by your contractor, Firm B, on your behalf. Contractors are extensions of the manufacturer, and you are required to ensure that your drugs are made in accordance with section 501(a)(2)(B) of the FD&C Act to ensure safety, identity, strength, quality, and purity -WL July 2017 19
Office of Manufacturing Quality FY17 Activities Final Guidance on Quality Agreements: Quality agreements can be used to define expectations and responsibilities in a contract manufacturing arrangement up front. https://www.fda.gov/downloads/drugs/guida ncecomplianceregulatoryinformation/guidanc es/ucm353925.pdf 20
Rudimentary CGMP What FDA found on inspection: www.fda.gov 21
Sand Filter Rudimentary CGMP What FDA found on inspection: www.fda.gov Storage Tank Blue sand filter removes mud and sediment from water flowing into open underground storage tank. Two buffalo roaming perimeter of the facility. White pipe in tank connects to pump behind black container, leads to the production area. 22
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