Week of September 9th 2018 | FDA Sent These Warning Letters to Pharma/Device Companies

FDA posted 7 warning letters this week including:

Also, this week the “U.S. Food and Drug Administration today announced a series of critical and historic enforcement actions related to the sale and marketing of e-cigarettes to kids. In the largest coordinated enforcement effort in the FDA’s history, the agency issued more than 1,300 warning letters and civil money penalty complaints (fines) to retailers who illegally sold JUUL and other e-cigarette products to minors during a nationwide, undercover blitz of brick-and-mortar and online stores this summer.”


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  • FDA issued 2 warning letters to Medtronic, 1 to a site in Juncos, Puerto Rico based on an inspection ending May 15th 2018 and a 2nd regarding a site in Mounds View, MN based on the outcome of an inspection ending May 14th 2018. Both warning letters were issued to the Chairman and CEO of Medtronic, Inc.
    • Deficiencies in Puerto Rico include but are not limited to failure to validate processes for the Blackwell implantable cardiac defibrillators and failure to document activities in the device history record.
    • Deficiencies in MN include but are not limited to failure to have adequate procedures for design transfer for the Blackwell implantable cardiac defibrillators and failure to establish adequate procedures for changes in the production process.


  • Longood Medicine (Beijing) Co., Ltd (Beijing, China) received a warning letter dated August 27th 2018 based on the outcome of an inspection ending September 29th 2017. The firm manufactures over the counter drug products. FDA suggests the firm hire qualified consultant(s) to assist them in coming into GMP compliance. They also were cited for distributing unapproved new drugs. GMP deficiencies include but are not limited to:
    • Uncontrolled and unofficial production and laboratory records were identified. These included duplicate records with incomplete fields and strike throughs. In response to this warning letter the firm is to provide:
      • “Comprehensive, independent assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are deficient. Include a detailed CAPA plan that systemically remediates deficient documentation practices, and ensures you retain complete and accurate records.
      • A comprehensive CAPA for your training program to ensure all staff at your facility are fully trained in CGMP. Provide a fully remediated training program for your entire operation. Place special emphasis on assuring that all staff involved in any CGMP function are trained and competent in acceptable recordkeeping practices, such as retaining all records, completing records contemporaneously, documenting any error in records, and ensuring that all procedures are approved by quality unit.”
    • The firm fails to perform adequate oversight of their contractor and fails to ensure they use a validated terminal sterilization process. The firm is asked to provide:
      • “Your qualification procedures for assessing the suitability and competence of potential contractors before outsourcing, and for ongoing monitoring and review of the performance of the contract facility to identifying and implement any needed improvements;
      • A detailed plan for ensuring that the process your contractor uses to terminally sterilize all products, including Chlora-Cleanze Proprep applicators, is adequately validated;
      • Complete sterilization records from your contractor for Chlora-Cleanze Proprep applicators, lot 20170601. If you do not have sufficient evidence that the lot in question or any lot intended for the U.S. market was adequately sterilized, indicate the corrective actions you will take, such as customer notifications and product recalls.
      • A corrective action and preventive action (CAPA) plan to fully remediate your review and release procedures for finished drug products. Your procedures should require that third-party contractors provide sufficient production and control records to demonstrate compliance with established, approved written procedures and specifications before a lot is released or distributed by your quality unit.”
    • The firm failed to have an ongoing program for monitoring process controls to make sure the process maintains in a state of control. In response to this letter the firm is asked to:
      • Detail your validation plan for ensuring a state of control throughout the product lifecycle.
      • Include a timeline for performing appropriate process performance qualification (PPQ) for your Chlora-Cleanze Proprep applicator manufacturing process, and describe your program for vigilantly monitoring batch-to-batch variation to ensure an ongoing state of control for all of your products. Also include your PPQ protocol.”
  • Lernapharm (Loris) Inc (Quebec, Canada) received a warning letter on September 4th 2018 based on the outcome of an inspection ending December 12th 2017. The firm was placed on import alert 66-40 on April 24th 2018. FDA also recommends the firm hire qualified consultant(s) to assist them in coming into GMP compliance. Deficiencies include but are not limited to:
    • The firm failed to adequately validate the sterilization process and did not test sterility of the finished product but relied on use of the BI organisms’ strip. The FDA reminds the firm that parametric release is appropriate only for robust sterilization methods. In response, the firm is asked to provide:
      • “Describe corrections to your manufacturing operation that will establish a high level of sterility assurance. If you intend to implement a terminal sterilization process, provide a robust sterilization method and rigorous validation protocol that assures the new method achieves a sterility assurance level of 10-6 or more (e.g., provide (b)(4) and (b)(4) data for any (b)(4) sterilization method), and uses an appropriate resistant biological indicator that represents the worst-case resistance of microbes that could be found in your environment and product. Regarding the latter, include (b)(4) determinations for each biological indicator lot to demonstrate its resistance to the specific sterilization method proposed for use by your firm.  
      • If you plan to continue use of your current (b)(4) step at the conclusion of processing, describe the facility and process improvements that will ensure that units subjected to that step are first produced by aseptic processing.
      • Also include the microbiological testing procedures that you will be using in your process validation studies for in-process and finished product testing. Regarding (b)(4) sterility testing, provide your test method, validation protocol, and validation report.
      • In addition, provide sterility testing results for all batches of your purportedly sterile (b)(4) batches that have been released and are within expiry. If such testing reveals substandard quality drug products, provide your corrective actions, including notifying customers and product recalls.
    • The firm failed to adequately investigate customer complaints including ones for leaking seals due to debris that accumulated on the sealing element of the packaging machine. In response to the letter the firm is to provide:
      • “Your comprehensive investigations into the additional 18 batches potentially affected by debris on the sealing (b)(4), including your CAPA and a plan to ensure its effectiveness. If these investigations reveal any substandard quality drug products, provide actions that you will take such as notifying customers and product recalls.
      • An update on your root-cause evaluations and related CAPA for all complaints you received relating to non-integral containers (e.g., leaking containers, dried contents), with special emphasis on further mitigation of human factors associated with the manufacturing process, in-process checks, and final inspection.
      • An improved process for risk assessment.
      • Your updated assessment of patient hazards associated with loss of package integrity.
      • A comprehensive, independent assessment of your overall system for investigations of deviations, atypical events, complaints, out-of-specification results, and failures. Your CAPA should include but not be limited to improvements in investigation competencies, root-cause analysis, remediation, written procedures, and quality unit oversight. Also, include your process for evaluating CAPA effectiveness.”
    • The firm does not have stability data to support the labeled expiry of the drug products. Stability studies did not include sterility or container closure testing at expiry. In response to the letter, the firm is to provide:
      • “A full summary of stability data results for all batches tested, with each time interval, attributes tested, the testing methods used, and the written stability protocol that was followed. Include testing of all microbiological and chemical attributes, and any updated test data to determine whether the integrity of your container-closure systems (and products are sterile, as applicable) is maintained throughout the entire shelf life.
      • A comprehensive assessment and CAPA to ensure the adequacy of your stability program. Your CAPA should include, but should not be limited to a remediated standard operating procedure (SOP) describing your stability program; stability-indicating methods; stability studies to support each drug product in its container-closure system before distribution is permitted; an ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid; and specific attributes to be tested at each station.”
    • Manufacturing areas do not have adequate control and air classification. In response to the letter, the firm is to provide:
      • “A protocol to review your (b)(4) filling and sealing zone, and support room environments, to determine whether they meet appropriate air classification standards, and any associated plans for facility upgrades.
      • A comprehensive identification of all contamination hazards in your manufacturing operations and an independent risk assessment that includes, among other things, your manufacturing processes, equipment, and facilities to ensure their suitability for sterile production; and
      • A detailed CAPA plan that describes all actions to be taken relating to facilities, equipment, manufacturing methods, controls, people, and raw materials to assure sterility.”
    • The firm does not have an adequate environmental monitoring program to ensure the appropriate microbiological quality of the area. In response to the warning letter, the firm is to provide:
      • “Provide your environmental monitoring procedures. These procedures should include appropriate:
        • Frequency, location, and duration of sampling; sample size; and specific sampling
        • Action and alert limits for each location, and a description of its function and ISO classification;
        • Instructions regarding investigations of out-of-limit (OOL) environmental monitoring results; and
        • Identification of microorganisms detected in environmental monitoring samples. For example, all microorganisms recovered in the filling room should be routinely identified.
      • Also provide environmental monitoring and bioburden monitoring data including:
        • A list of all lots of sterile (b)(4) produced by your firm since January 2015 and all bioburden tests performed. Annotate which lots were tested for bioburden and timing of each sample ((b)(4) sterilization or earlier in the process). Include all microbial count test results and state whether microbial identification was performed. If so, provide the identity of each microbe.
        • A list of all environmental monitoring tests done for sterile (b)(4) production since January 2015, date of the sample, location sampled, and the identity of all isolated organisms.
        • Your bioburden monitoring and testing procedures.
        • A list of any out-of-specification results from bioburden or environmental monitoring testing and all original results and related investigations (if any result was re-tested or invalidated).”


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About the Author

Barbara W. Unger is Govzilla’s Quality Expert and Editor-in-Chief of GMP Regulatory Intelligence.  She 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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