Week of May 13th 2018 | FDA Sent These Warning Letters to Pharma Companies

FDA published 4 warning letters this week:

  • 2 were issued for unapproved new drugs
  • 2 were issued to drug firms addressed below


  • Ei LLC (Kannapolis, NC) received a warning letter on April 16th 2018 based on the outcome of an inspection ending October 6th 2017. Based on the nature of manufacturing and the identified deficiencies, it is interesting that FDA makes no mention of placing the firm on Import Alert.  Deficiencies include but are not limited to:
    • The firm manufactures human drugs in the same facility where pesticides are produced.  They also share the same equipment.
    • Equipment cleaning procedures were not validated, see above. The firm is to provide the following:
      • “A comprehensive risk evaluation that addresses the potential for each of your human drugs to be cross-contaminated with any other products, including human drugs and any other drugs, cosmetics, pesticides, or other products you manufacture in your facility.
      • Your detailed plan for performing adequate cleaning validation of production equipment for all drugs you manufacture. Include summary reports of cleaning validations with corresponding acceptable limits of any residual drugs or other impurities; effectiveness of your cleaning procedures and agents; and analytical methods to prevent cross-contamination of your drugs.
    • Investigations into possible cross contamination are inadequate, including identification of unknown impurities in product. The firm is to provide the following.
      • “An assessment of the quality and safety of your products still in distribution and within expiry based on the outcome of your retrospective review of investigations. Explain your inclusion and exclusion parameters for the retrospective review of investigations.
      • Your plan to assure the adequacy of investigations in conjunction with your global approach to preventing cross-contamination and assuring product quality.”

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  • Reine Lifescience (India) received a warning letter on May 9th 2018 based on the outcome of an inspection ending November 3rd 2017. The firm manufactures APIs. The warning letter focuses heavily on inadequate controls over electronic data. FDA placed the firm on Import Alert 66-40 on March 30th 2018 and suggests they employ a qualified consultant(s) to assist them in coming into GMP compliance. Deficiencies include but are not limited to:
    • The firm lacked documentation for method verification/validation. In addition, data were located in a folder named “PD Trial.” While it was stated this was for product development, the investigator found batch data from APIs. These results differed from the recorded test results. The firm is requested to provide:
      • “a summary of method validation and verification studies for all analytical methods used for product release;
      • a summary of the impact assessment for released batches;
      • improved procedures regarding validation/verification requirements and updated analytical methods;
      • a comprehensive, independent review of your laboratory practices, methods, equipment, and analyst competencies. Based on this review, provide a detailed corrective action and preventive action (CAPA) plan to fully remediate your laboratory system.
      • a global CAPA plan as requested below under ‘Data Integrity Remediation.’” 
    • Audit trails were disabled on instruments used in testing of APIs and lacked controls to prevent users from deleting or altering electronic data. One of the analysts had ‘administrator’ privileges within the system. The firm is to provide the following in response to the warning letter:
      • “provide a summary of your interim controls to prevent deletion and modification of data;
      • define the roles and responsibilities of personnel who have access to analytical instruments and data;
      • provide a standard operating procedure (SOP) that ensures that all quality control tests are performed by an analyst and receive second-tier review (e.g., by a manager) from a separate individual; 
      • detail the associated user privileges for each analytical system;
      • provide a detailed summary of your procedural updates and associated training for user role assignment and controls; and
      • provide detailed procedures for your review of audit trail data.”
    • Multi-product equipment was used to manufacture APIs released to the US prior to cleaning validation. The firm is to provide the following to FDA in response to the warning letter:
      • “Scientific rationale for API, rinse, and swab sample specifications prior to performing cleaning validation;
      • a summary of updates to your cleaning validation protocol to better incorporate conditions identified as worst case. This should include evaluating drugs that are of highest toxicity, drugs that are lowest solubility in their cleaning solvents, and swabbing of various equipment locations that are most difficult to clean.
      • a summary of SOP that have been updated to ensure an appropriate program for verification and validation of cleaning procedures for new products, processes, and equipment.”

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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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