A very busy week on the warning letter front! Six warning letters to API/pharma firms and 1 to a GLP firm for non-clinical studies. We cover all below:

GLP:

  • North American Science Associated (NMSA) (Minneapolis, MN) received a warning letter on March 23rd, 2018 based on the outcome of a BIMO inspection ending November 17th, 2017. The letter references devices that were the subject of non-clinical studies evaluated during the inspection. Deficiencies include:
    • The study director did not ensure that experimental data including unanticipated responses of the test system were accurately recorded and verified. This deficiency included failure to ensure that data were recorded contemporaneously with their observation and failure to ensure that raw data is consistent with requirements of the protocol.
    • Specimen containers were not appropriately identified with study, type, and date of collection. Further, samples were unaccounted for or were missing.
    • Failure to secure and archive specimens. No index of materials.
    • Reagents in the laboratory were not labeled with concentrations, storage requirements, and expiry date.

DRUGS:

  • Yicheng Goto Pharmaceuticals CO., Ltd (Hubei Province, China) received a warning letter on July 26th, 2018 based on the outcome of an inspection ending September 14th, 2017. The firm manufactures APIs and was placed on import alert 66-40 on January 10th, 2018. The firm is encouraged to hire qualified consultant(s) to assist them in coming into GMP compliance. Further, FDA identifies that similar observations were identified during inspections in 2011 and 2014. Deficiencies include but are not limited to:
    • The firm failed to conduct cleaning validation for most of the critical non-dedicated production equipment. In response to the letter, the firm is asked to provide:
      • “Your updated cleaning validation protocol and report for all equipment you use to manufacture drugs including all results and established acceptance criteria. Also, include updated procedures for equipment cleaning and maintenance, with provisions including but not limited to documentation of all cleaning operations.
      • A risk assessment to determine the effect of inadequate cleaning practices on all potentially affected lots of intermediates and API distributed to the U.S. market. This assessment should include but not be limited to an analysis of retains of all lots at risk for potential cross-contamination.
      • Your proposed market action plan including customer notifications, retain testing protocol, enhanced complaint monitoring, and recalls, if appropriate, to address all potentially affected lots of intermediates and API in the U.S. supply chain at risk for potential cross-contamination.
      • Provide your interim action plan to ensure adequate cleaning before you complete your validation studies, including but not limited to performing cleaning verification testing before change-over to a different API or intermediate to ensure cleaning effectiveness. Also include your acceptance criteria for each API and intermediate.
      • A comprehensive, independent review to identify risks of cross-contamination between drugs (API and intermediates) manufactured at your facility. Assess the suitability of your facility and process design to prevent cross-contamination, and include an evaluation of your equipment, material, personnel, and waste flows. Include a detailed corrective action and preventive action (CAPA) plan with systemic remediation and timelines.”
    • The firm failed to perform system suitability tests and use standards. In addition, analysts performed manual integration on chromatograms without a written procedure. The firm is asked to provide:
      • “An assessment of all test methods used by your firm to ensure they have appropriate instructions, method suitability criteria, and have been appropriately validated to determine whether they are fit for purpose.
      • A reanalysis plan for all batches within retest date that were analyzed using methods lacking system suitability or standards.
      • A comprehensive review of all instances of chromatographic manual integration. Provide scientific justification for the manual integration parameters you used for analysis. For integrations that lacked scientific justification, provide your plan for reintegration with appropriate reintegration parameters. Assess whether reintegration results comply with your established API acceptance criteria. If you identify out-of-specification (OOS) results, describe actions, such as customer notification and recalls, you have taken or will take to ensure the quality of marketed products and to protect patients.
      • Provide a comprehensive, independent review of your laboratory practices, methods, equipment, and analyst competencies. Based on this review, provide a detailed CAPA plan to fully remediate your laboratory system. Elements of your CAPA should include, but not be limited to, measures you will take to strengthen quality assurance oversight of review and approval of method validation and test results. Your plan should also include your process for evaluating the effectiveness of the implemented CAPA.”
    • The firm does not have stability data to support the retest date nor do they have annual stability monitoring of the API. The firm is asked to provide: “In response to this letter, provide your plan of action with timelines to develop and implement a complete drug stability program for API manufactured for the U.S. market. Your program should be designed to support all assigned retest dates and process hold times for each API. Assess the stability of all API currently distributed to the U.S. market.”
    • The firm failed to validate the manufacturing process for several APIs and does not have an ongoing program for monitoring process controls. In response to the warning letter, the firm is asked to “…provide your validation protocols and reports. Also provide an update on the status of process performance qualification for your manufacturing processes for all API distributed to the U.S. market and your program for ensuring an ongoing state of control of your manufacturing processes.”
  • JT Cosmetics & Chemicals Pvt Ltd. (Gujarat, India) received a warning letter on July 27th, 2018 based on the outcome of an inspection ending February 28th, 2018. The firm manufactures OTC products. In addition to GMP deficiencies, the firm was cited for distribution of unapproved drugs and misbranding. The firm was placed on import alert 66-40 on June 11th, 2018. GMP deficiencies include but are not limited to:
    • The firm released products without testing for identity and strength of the active ingredient. In addition, the microbiological test results on the CoA were falsified and testing was not performed. FDA asks the firm to provide the following in their response to the warning letter:
      • “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. Include test results for identity and strength of active ingredients, and all other appropriate chemical and microbial quality attributes.”
    • The firm did not test incoming raw materials, nor were suppliers qualified. In response to the warning letter, the firm is requested to provide:
      • “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;
      • A comprehensive, independent review of your material system to determine whether all containers, closures, and ingredients from each supplier are adequately qualified, and assigned appropriate expiration or retest dates; and whether incoming material lot controls are adequate to prevent use of unsuitable containers, closures, and components.”
    • The master and batch production records don’t include many of the basic requirements including manufacturing instructions, identification of major equipment, and sampling information. In response, the firm is asked to provide: “…a risk assessment of products released to the U.S. market without adequate and approved production and control documentation. Also provide procedures you have implemented or revised to assure production records are completed as required and reviewed by your quality unit prior to release of products for distribution.”
    • The firm lacks an adequate quality unit and does not have adequate procedures for basic GMP functions. “In response to this letter, provide a comprehensive assessment and a corrective action and preventive action (CAPA) plan to ensure that you establish an effective quality unit with appropriate authority, responsibilities and resources. Your response should also include a detailed procedure describing your remediated quality unit’s responsibilities.”
    • The firm is also instructed regarding Data Integrity Remediation in FDA’s standard boiler plate request.
  • Signature Formulations LLC (Phoenix, AZ) received a warning letter on July 31st, 2018 based on the outcome of an inspection ending November 9th, 2017. The firm manufactures a variety of OTC drug products. FDA also cited the firm for distribution of unapproved new drugs and misbranding violations. The GMP deficiencies include but are not limited to the following:
    • The firm releases products without testing to determine the products meet specifications. The firm is asked to provide:
      • “The quality control test methods and specifications you rely upon to analyze each of your finished OTC drug products before making batch release decisions;
      • An action plan and timelines for testing retained samples of all finished OTC drug products distributed and within expiry to determine the identity and strength of active ingredients. If such testing reveals that you released drug products that did not meet specifications for identity or strength of active ingredients, indicate what corrective actions you have taken or will take, such as notifying customers or recalling products.”
    • The quality unit released drug products when they had no assurance that products met specifications or were manufactured under adequate controls. They also failed to ensure that basic GMP requirements were met. In response to the letter, the firm is required to “…provide your plan for establishing adequate quality systems. Include your approved written procedures and drug product specifications.”
    • The firm did not test incoming components but rather relied on the vendor CoA without establishing validity of the data. Further, an identity test was not performed. In response to the letter, the firm is to provide:
      • “A retrospective review for all drug product lots, within expiry and in distribution, manufactured using components that were not adequately tested and controlled. Based on your review, indicate any corrective actions and preventive actions you have taken, including a recall of affected products, if appropriate.
      • Your procedure to test incoming components.
      • A detailed description of how you plan to test each component for conformity with all appropriate written specifications for identity, purity, strength, and quality. Explain how you intend to perform at least one identity test for all incoming components used in your drug product. If you accept your suppliers’ COA in lieu of testing components for purity, strength, and quality, specify how you plan to establish the reliability of your suppliers’ test results through validation at appropriate intervals.”
    • The firm does not have cleaning procedures. In response they are asked to provide:
      • “Your equipment cleaning procedures and cleaning validation report to demonstrate the adequacy of your cleaning procedures.
      • Your evaluation of all drug product lots, within expiry and in distribution, identifying the effects of any cross-contamination that may have occurred.”
    • The firm does not have stability data to support the expiration date. “In response to this letter, you should provide an adequate written stability testing program and results to support your assigned expiration dates.”
  • Bill Beauty and Health Products Ltd (Ontario, Canada) received a warning letter on August 1st, 2018 based on the outcome of an inspection ending March 16th, 2018. The firm manufactures OTC drug products. The firm is advised to hire a GMP consultant(s) to assist them in coming into GMP compliance. As part of the form 483 response the firm “acknowledged the significance of the inspectional observations, and indicated that you [the firm] will “not be exporting these or any other products that may be regarded as drugs in [the] USA.” Your response provided limited corrective actions and lacked detail regarding specific corrective actions and preventive actions to bring your facility into CGMP compliance.” Deficiencies include but are not limited to:
    • The firm released products without testing the identity and strength of the active ingredient — nor were they tested for microbiological count or the presence of objectionable organisms.
    • The firm did not perform an identity test on purchased APIs. They also accepted other components without testing and accepted products on the basis of the vendor’s CoA.
    • The firm did not validate manufacturing processes and did not have an ongoing process control monitoring process.
  • Paramesh Banerji Life Sciences, LLC (New Brunswick, NJ) received a warning letter on August 7th, 2018 based on the outcome of an inspection ending December 7th, 2017. The firm manufactures homeopathic drug products. Deficiencies include but are not limited to:
    • The firm failed to validate the manufacturing process. This has safety impact because products contain Belladonna and others include Nux vomica which contains strychnine. “In response to this letter, provide your validation plans for both the current manufacturing processes and the proposed manufacturing processes for crude substances. Include your timeline for performing process performance qualification for your drug products, as well as your approach for monitoring batch-to-batch variations on an ongoing basis. In addition, provide a risk assessment for distributed drug products you manufactured using unvalidated processes.”
    • The firm did not test incoming raw materials but, rather, accepteded them on the basis of the vendor’s CoA. The validity of the CoA data was not established through appropriate validation. The firm maintains “there are no known methods specified ‘in any documentation’ for testing (b)(4) to verify identity, strength, quality and purity. You explained that, as a result, you have not performed any testing.” FDA did not accept that answer and asks the following to be provided in response to the warning letter.
      • “Your procedure for testing each incoming active pharmaceutical ingredient.
      • Your plan to test each component for conformity with all appropriate written specifications for identity, purity, strength and quality.
      • Your plan for performing at least one identity test for all incoming components used in your drug products labeled as homeopathic.
      • Your description, in detail, of how you plan to establish the reliability of your supplier’s test results through periodic validation, if you accept your supplier’s COA in lieu of testing components for purity, strength, or quality.
      • A risk assessment for any drug products manufactured using components which were not adequately tested and controlled.”
    • The firm lacked an adequate quality unit to cover operations at the site. They are requested to provide the following in response to the warning letter.
      • “Your plan to establish an adequate quality control unit with appropriate authority and sufficient resources to carry out its responsibilities and consistently ensure drug quality.
      • Your updated procedures, covering all aspects of your facility and operations that may affect the identity, strength, quality, and purity of your drug product.
      • Your corrective action plan to ensure that you create and maintain documentation to demonstrate acceptability of all operations”
  • Apotex Research Private Limited (Bangalore, India) received a warning letter on August 9th, 2018 based on the outcome of an inspection ending November 17th, 2017. The firm was placed on import alert 66-40 on April 12th, 2018. FDA states the firm’s quality systems are inadequate and refers them to ICH guidance on Pharmaceutical Development (Q8), Quality Risk Management (Q9), and Quality Systems (Q10). FDA identities that the deficiencies are repeats of problems at other sites including in warning letters issued to two other sites in India on June 2014 and January 2015. Both of these sites were placed on import alert 66-40.
    • In addition, the Apotex site in Toronto received a warning letter on February 2013. In light of the repeated deficiencies at multiple sites, FDA states that ‘These repeated failures at multiple sites demonstrate that management oversight and control over the manufacture of drugs is inadequate.’
    • Finally, FDA recommends the firm hire GMP consultants to assist them in coming into GMP compliance. The MHRA identified deficiencies at this plant on November 17th, 2017 and issued a report of GMP non-compliance. The nature of the non-compliance was identified as “…failures in the cross-contamination controls applied by the manufacturer resulting in a risk of cross contamination above Permitted Daily Exposure (PDE) from some products.” Deficiencies identified in the warning letter include but are not limited to:
      • The firm does not adequately investigate OOS events and support them with scientifically justified conclusions. FDA provides multiple detailed examples. They request the firm provide the following in response to the warning letter.
        • “Explain why (b)(4) mg capsule batch (b)(4) was shipped and used for your bioequivalence studies before testing and investigational activities were completed. Also, describe whether your procedures require all testing and investigations to be completed prior to batch release.
        • Perform a three-year retrospective review to determine whether outlier tests have been used in previous OOS investigations, and determine whether you used them to improperly invalidate OOS results.
        • Provide the report and associated CAPAs for your retrospective review of all VIRs and VICs initiated since January 1, 2015. Include a third-party assessment of each of the VIRs and VICs, and of your firm’s final report.
        • Assess the procedures you use to evaluate (b)(4) uniformity, including collecting and testing samples and evaluating results.
        • Provide a comprehensive, independent assessment of your overall system for investigations of laboratory and manufacturing-related deviations, discrepancies, complaints, OOS results, and failures. Your CAPA plan should include but not be limited to improvements in investigation competencies, root cause analysis, written procedures, and quality unit oversight. Also, include an improved process for evaluating CAPA effectiveness.”
      • The firm failed to establish adequate in process specification. “In response to this letter, remediate your current procedures to ensure that (b)(4) are tested for appropriate quality attributes (b)(4). Provide us with any updates made to your procedures. Provide a list of all products manufactured in a similar manner and include an assessment of the effects on any batches produced in this manner which are within expiry.”