Week of July 1st 2018 | FDA Sent These Warning Letters to Pharma Companies

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Week of July 1st 2018 | FDA Sent These Warning Letters to Pharma Companies

FDA posted 6 warning letters this week, including 1 to a finished pharma firm, 1 to an API manufacturer, and 1 to a compounding pharmacy. We cover these 3 below:

DRUGS:

  • Foshan Jinxiong Technology Co., Ltd. (Guangdong, China) received a warning letter on June 26th 2018 based on the outcome of an inspection ending August 18th 2017. The firm is identified as a contract manufacturer of OTC drugs. FDA suggests the firm hire qualified consultant(s) to assist them in coming into GMP compliance and to read the FDA guidance on Quality Systems. FDA placed the firm on Import Alert on February 14th 2018. Deficiencies include but are not limited to:
    • The firm released drug products without data to support that they conform to specifications, specifically identity and strength of active ingredient. They state that their customers, to who they release products to, may perform additional testing. FDA requests that they provide the following:
      • All chemical and microbial test methods and specifications used to analyze each lot of your OTC drug products prior to a lot disposition decision; and
      • A summary of test results obtained from testing retain samples of all OTC drug products within expiry that have been distributed in the United States. These test results should include identity and strength of active ingredients, and all other appropriate chemical and microbial quality attributes.”
    • The firm failed to test incoming components and relied on certificates of analysis from unqualified suppliers. FDA requests they provide the following:
      • “Quality control release specifications for all incoming components, and the tests you perform for each lot;
      • A summary of test results obtained from full testing of all your incoming components to validate the COA from each raw material manufacturer;
      • A summary of your procedures for qualifying and overseeing the adequacy of contract facilities that test the OTC drug products you manufacture; and
      • A comprehensive, independent review of your material system to determine whether all containers, closures, and ingredients from each supplier are adequately qualified, assigned appropriate expiration or retest dates, and incoming material lot controls are adequate to prevent use of unsuitable containers, closures, and components.”
    • The firm did not have adequate stability data to support expiry testing. FDA asks them to provide:
      • “A revised ongoing stability SOP, including but not limited to adding a test for active ingredient content at each stability station; and
      • stability test results of all drug products distributed in the United States within expiry using stability-indicating methods to determine if results meet specifications. If you obtain out-of-specification results, indicate the corrective actions you will take.”
    • The firm lacked specific identification for each lot of component and did not have unique lot or control numbers for distributed product.

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  • Sichuan Friendly Pharmaceutical Co., Ltd (Sichuan, China) received a warning letter on June 22nd 2018 based on the outcome of an inspection ending October 27th 2017. The firm manufactures APIs and was placed on Import Alert on March 22nd 2018. FDA recommends they hire a consultant(s) to assist them in coming into GMP compliance. Deficiencies include but are not limited to:
    • The firm failed to test APIs for residual solvents. The equipment is multi-product, and one of the APIs uses a class 2 solvent. FDA suggested the firm read ICH Q3C Impurities:  Residual Solvents. FDA asks the firm to provide:
      • “A comprehensive risk assessment of all (b)(4) USP distributed within the United States that did not undergo residual solvent testing. Summarize your retention sample test results for the batches distributed to the U.S. Specify the actions you will take if any batch is found to contain residual solvent limits above appropriate specifications, including notifying customers or conducting recalls.
      • A completed analytical method validation, and updated test methods and specifications in accordance with USP for your (b)(4)
      • A list of all residual solvents used in your facility and your risk-based plans to strictly limit (or discontinue use of) any class 1 or 2 solvents. Includes specification for all residual solvents used in API manufacturing and cleaning operations.”
    • The firm does not have adequate cleaning validation. Only 1 API is used as a challenge product and this is not used to establish validated cleaning within all equipment. Cleaning validation did not address carryover of residual solvents used in the equipment. FDA requests the firm provide:
      • “Your updated cleaning validation for all multi-use equipment at your facility. Include a summary report of cleaning validation with quantification of any drug carryover, residual solvents or other impurities detected; acceptable limits for each impurity; justification for the drugs you choose as worst-case candidates for the study; your rationale for selecting cleaning agents; and the effectiveness of your cleaning procedures.
      • A comprehensive risk assessment to determine the impact of inadequate cleaning validation on batches of (b)(4) USP, within expiry released for distribution to the United States.”
    • The firm was unable to provide stability data supporting the expiry dating of the API. FDA asks the firm to provide;
      • “Retention sample test data for all batches of (b)(4) distributed to the U. S. market within expiry using stability-indicating methods.
      • An updated stability program, including stability-indicating methods, and methods that detect changes in the physical appearance of the API which could indicate degradation.”
    • The firm used invalidated Excel spreadsheets to calculate assay results for products release and testing. During the inspection, the manager noted the calculations were incorrect. The spreadsheet lacked password protection and contained unlocked calculation formulas which were incorrect. When results were recalculated with the correct formula, multiple results were OOS. The firm did not adequately address the situation. FDA asked them to provide:
      • “A comprehensive assessment of your data review system used throughout your manufacturing and laboratory operations to determine where else it is deficient. Include a detailed corrective action and preventive action (CAPA) plan with systemic remediation to address deficient data review, including quality unit oversight. The CAPA should include, but not be limited to, revised procedures, training, and systemic actions implemented to assure the integrity of all CGMP records.
      • An assessment of all Excel spreadsheets used to support CGMP operations to identify and investigate the extent of inaccuracies, such as incorrect formulas and other deficiencies. Include a detailed CAPA plan to address the noted deficiencies and to prevent recurrence.
      • A retrospective review and risk assessment of all test data for API within expiry and distributed in the United States using computerized systems that lack sufficient control to prevent modifications and deletions. If you obtain OOS results based on this assessment, indicate your action plan, such as notifying customers and/or initiating recalls.
      • A comprehensive independent assessment of your overall system for investigations of deviations, atypical events, complaints, OOS results, and failures. Your CAPA should include, but not be limited to, improvements in investigation competencies, root cause analysis, written procedures, and quality unit oversight.” 

COMPOUNDING PHARMACY:

  • Jacobs Pills, Inc (Elmsford, NY) received a warning letter on May 31st 2018 based on the outcome of an inspection ending February 28th 2017 (yes, 2017). The firm did not receive valid prescriptions for each patient and compounded melatonin which is not a compound eligible for exemptions under 503A(a).

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About the Author

Barbara W. Unger

Barbara W. Unger formed Unger Consulting, Inc. in December 2014 to provide GMP Quality consulting services to the pharmaceutical and biopharmaceutical industry. At Amgen, she led the segment of the Corporate GMP Audit group at Amgen focused on API manufacturers, Quality Systems and Computers. She developed, implemented and maintained the GMP Regulatory Intelligence program for 8 years at Amgen Inc. This included surveillance, analysis and communication of GMP related legislation, regulations, guidance and industry compliance enforcement trends. This was an essential service and tool within the Corporate Audit function.

Unger Consulting Inc. | www.ungerconsulting.net | 805.217.9360

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