FDA posted 22 warning letters, most of them from the Center for Tobacco Products. Among the group were four warning letters for pharma companies and one to a device manufacturer, we cover these five below.

DRUGS

  • Mylan Pharmaceuticals (Morgantown, West Virginia) received a warning letter dated November 9, 2018, based on the outcome of an inspection ending April 12, 2018. Rather than issuing the letter to the site head, FDA chose to send a message by issuing the letter to the Mylan CEO.
    • This is not the first time Mylan has run afoul of the FDA. In 2015 a single warning letter addressed three Mylan sites, and in April 2017 another site received a warning letter. FDA suggests the firm employ a consultant to assist them in coming into GMP compliance. FDA questions the authority given to and exercised by the Mylan quality unit:
      • “Your inspectional history and significant findings in this letter indicate that your quality unit is not fully exercising its authority and responsibilities. For example, your quality unit failed to ensure that cleaning operations are adequate to prevent cross-contamination; manufacturing changes are appropriately evaluated; manufacturing processes are robust and capable of consistently delivering quality product, and investigations are effective. Your firm must provide the quality unit with the appropriate authority, sufficient resources, and staff to carry out its responsibilities and consistently ensure drug quality.”  FDA also states “Your firm’s quality systems are inadequate. For guidance on establishing and following CGMP compliant quality systems to establish and maintain an ongoing state of control, see FDA’s guidances:…”
    • RAPS Regulatory Focus reports that Mylan is discontinuing and transferring product manufactured at the site in the wake of the warning letter. Further, Mylan continues to recall valsartan-containing drugs in the US.  Also the EDQM has suspended the certificate of suitability for Mylan’s facility in Hyderabad and has initiated recalls of Mylan’s valsartan products in the EU. Deficiencies identified in the warning letter include but are not limited to:
      • Cleaning validation/verification is inadequate to prevent cross-contamination. Visible drug residues were observed on equipment that was deemed to be clean. The firm continued to experience swab failures related to detergent residue across numerous non-dedicated equipment. Cleaning program was, in general, inadequate. The firm is asked to provide the following in response to the letter:
        • Provide evidence of a validated program in which cleaning procedures used to remove active ingredients and detergents from production equipment can consistently meet predetermined and scientifically sound specifications.
        • Justify the number, location, timing, and frequency of cleaning swabs on equipment, and the selection of products and equipment types for your cleaning matrix validation/verification activities.
        • Assess all equipment ((b) (4)) in which drug product residues were discovered during manufacturing or cleaning operations at your facility.
        • Provide a retrospective investigation into all cleaning swab failures and identify the root cause of the failures. Specify any swab failures for which the corrective action was to re-clean without investigating the root cause of the failure. Provide your corrective action and preventive action (CAPA) plan that details improvements to procedures for cleaning and equipment inspection that will be implemented as a result of your investigation.
        • Describe your updated cleaning training program for your production and quality assurance employees. Include any objective competency and proficiency results to assess training effectiveness.
      • OOS management and investigations into process deviations were inadequate. The identified root cause did not consistently include scientifically supported conclusions. In response to the warning letter the firm is asked to provide:
        • A retrospective, independent review of all OOS (raw materials, in-process testing, and finished testing) results obtained for drug products currently within expiry. Assess whether the scientific justification and evidence were conclusive for each invalidated OOS result. For investigations that establish laboratory root cause conclusively, determine effectiveness of the CAPA and ensure that all laboratory methods vulnerable to the same root cause are identified for remediation. For any OOS results with inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of manufacturing steps, raw materials, process capability, deviation history, batch failure history). Provide a CAPA plan that identifies manufacturing root causes and specifies meaningful improvements.
        • A retrospective, independent evaluation of the adequacy of major manufacturing investigations (e.g., deviations, rejects) performed for products currently within expiry.
        • 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. Also, include your process for evaluating CAPA effectiveness.
      • During the inspection, major changes were identified that were not adequately managed. FDA stated: “Changes in blend size, formulation, and manufacture of your drug products were not evaluated consistently, appropriately, or thoroughly before execution. In many cases, you failed to use your change management system for significant changes. Furthermore, numerous batches with major process changes were not included in your stability program.” Further, the firm lacks an ongoing process monitoring program to ensure that the manufacturing process remains in a state of control. The firm is asked to provide the following in response to the warning letter:
        • A comprehensive, independent evaluation of your change management system. This review should include, but not be limited to, a review of your procedure(s) to ensure that changes are sufficiently justified, adequately reviewed, and approved by your quality unit. The change management program should include such elements as adding lots to the stability program when there is a significant manufacturing change; provisions for qualification and validation; and a process for determining change effectiveness.
        • An independent, retrospective review of any changes that may have significantly increased variation in manufacturing for all batches within expiry. This would include, but not be limited to, changes to your equipment, facility, materials, measurements, and process. Provide explanations and conclusions regarding how changes may have affected the identity, strength, quality, or purity of your drug products. This retrospective review should afford particular attention to all drug products (b) (4).
        • An assessment of the reliability of your manufacturing operations, with an emphasis on variation introduced by (b) (4). Describe your plans to improve equipment and facility design (b) (4), and to mitigate or eliminate human error.
        • Detail your validation plan for ensuring a state of control throughout the product life cycle. This should include, but not be limited to, a description of your program for vigilant monitoring of intra-batch and inter-batch variation to ensure an ongoing state of control.
  • Surmasis Pharmaceutical (Des Moines, Iowa) received a warning letter on November 6, 2018, based on the outcome of an inspection ending on March 1, 2018. Deficiencies include but are not limited to:
    • The firm invalidated OOS results on the basis of “outlier tests.” The FDA requests that the firm provide the following as part of their response to the warning letter:
      • Provide a retrospective review of all invalidated OOS results obtained for products on the U.S. market. Assess whether the scientific justification and evidence were conclusive. For investigations that established the laboratory root cause conclusively, determine the adequacy of the corrective action and preventive action (CAPA) plan, and ensure that the other laboratory methods vulnerable to the same root cause have been identified for remediation. For any OOS results that had an inconclusive root cause or no root cause identified in the laboratory, include a thorough review of production, such as batch manufacturing records, adequacy of manufacturing steps, raw materials, process capability, deviation history, and batch failure history. Provide a CAPA plan that identifies the potential manufacturing root causes for all such investigations. Include appropriate process improvements.
      • Evaluate all instances in which a statistical “outlier” test was used to invalidate OOS results. Assess batch quality in each instance and take appropriate action on any batch for which quality is not assured.
      • Assess your overall system for investigating OOS results. Provide a CAPA plan to improve the quality of OOS investigations. Your CAPA plan should ensure that your revised OOS investigations procedure includes enhanced quality unit oversight of laboratory investigations, identification of adverse laboratory control trends, and investigation of potential manufacturing causes when a laboratory cause cannot be conclusively identified.
      • Provide a comprehensive, independent assessment of your overall system for investigations of deviations, atypical events, 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 your process for evaluating CAPA effectiveness.
    • The firm did not maintain electronic data logs of alarms for in-process equipment such as for the coating machine, the checkweigher and packager. The firm did not investigate alarms for the impact they may have on product quality. FDA requests the firm to provide the following in response to the warning letter.
      • Provide a complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates documentation practices and ensures that you retain complete and accurate records. This review should afford special focus to your electronic record retention and should ensure that electronic data are retained and deviations relevant to manufacturing are captured in your batch records for all manufacturing equipment with automated alarm functions.
      • Provide a retrospective review to determine whether potential breaches of your manufacturing parameters had any effect on the quality of products released to the market.
    • The firm did not ensure that laboratory records included complete data. Audit trails showed multiple instances of repeat tests that were not reported. FDA included the long version of their data-integrity-remediation activities.
  • Product Packaging West, Inc (North Hollywood, CA) received a warning letter on November 2, 2018, based on the outcome of an inspection ending March 13, 2018. FDA suggests they hire a consultant to help bring them into GMP compliance. The deficiencies include but are not limited to:
    • The firm did not test incoming raw materials or components but rather relied on the supplier’s CoA. This was all the more critical because the firm receives glycerin and they failed to determine whether it was potentially contaminated with Diethylene glycol or ethylene glycol. In response to the warning letter the firm is to provide:
      • Describe in detail how you plan to test each incoming component lot for conformity with all appropriate written specifications for purity, strength, and quality. If you accept your suppliers’ COA in lieu of testing each component lot for purity, strength, and quality, describe how you plan to establish the reliability of your suppliers’ test results for these attributes at regular intervals, and include a commitment to test at minimum every incoming component lot (both active and inactive ingredients) for USP identity requirements. Also, provide your revised procedure remediating these deficiencies.
      • Provide your revised SOP for testing all incoming lots of glycerin to ensure that they are not contaminated with DEG and EG.
    • The firm has not performed process validation for OTC drug products. They are required to provide the following:
      • Your validation plans for your manufacturing processes, including your timeline for performing process performance qualification for all your drug products, and a detailed summary of your approach for routinely monitoring (b)(4) and (b)(4) variations on an ongoing basis.
      • A risk assessment and retest results (including both microbial and chemical tests) for all distributed drug product batches within expiry that were manufactured using unvalidated processes.
    • The firm does not follow their procedures to operate a sanitary water system. In response to the warning letter, they must provide:
      • A comprehensive evaluation of the water system design, conducted by a qualified consultant, and a thorough Corrective Actions and Preventive Action (CAPA) plan to appropriately modify your water system and validate it.
      • Validation outcome for the (b)(4) water system, obtained after all identified design issues have been fully corrected and maintenance repairs have been completed. Include the system validation protocol, the complete test results, and the final validation report.
      • An effective written program for validation, ongoing control, maintenance, and monitoring that ensures the remediated system consistently produces water that meets (b)(4) Water, USP monograph specifications and appropriate microbial limits.
      • Your total count limit for (b)(4) water. This limit should ensure that water quality is appropriate in view of the intended use of the products produced by your firm.
      • A water system monitoring SOP that specifies routine microbial testing of (b)(4) water to ensure its acceptability for use in each batch of drug products produced by your firm.
    • The firm lacks records for cleaning, sanitizing and inspecting the water system and are to provide:
      • New or revised SOP(s) that establish appropriate manufacturing equipment records.
      • Copies of the logs documenting any cleaning, maintenance, and repairs performed on all major manufacturing equipment since the FDA inspection.
    • The firm does not describe the responsibilities of the quality unit, and their quality systems are inadequate. They are asked to provide:
      • A CAPA to ensure that the roles and responsibilities of your quality unit are clearly defined and established, and to ensure that the quality unit has the appropriate authority and resources needed to carry out its responsibilities.
      • Your SOPs for the quality unit, including the procedures for ensuring that all decisions on manufacturing and quality are appropriate throughout your operations.
  • I. Shay Cosmetics Inc (Carson, CA) received a warning letter on October 29, 2018, based on the outcome of an inspection ending December 7, 2017. They also manufacture product under contract. Based on the nature of the deficiencies in this letter, it calls into question what if any oversight was performed by those who contracted the services of this firm. FDA recommends they employ a qualified consultant to assist them in coming into GMP compliance. Further, they identify repeat violations and observations at the facility from 2008, 2010, 2012 and 2013.  Deficiencies include but are not limited to:
    • The firm does not adequately address OOS events. In response to the warning letter, the FDA requests:
      • 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. Also, include your process for evaluating CAPA effectiveness.
      • A retrospective assessment of all drug product lots within expiry to determine whether they meet their purported quality standards. For each lot that does not meet its purported quality standards, provide your plan to take appropriate action(s) (e.g., notifying customers or product recalls). For instance, regarding water quality, you should assess how failures of tests such as total dissolved solids and the use of an unvalidated water system affected the quality of finished products within expiry.
      • A comprehensive, independent evaluation of the water system design, including a thorough CAPA plan to remediate and validate a suitable water system.
      • An effective program for ongoing control, maintenance, and monitoring that ensures the remediated system consistently produces water that meets Purified Water, USP monograph specifications, and appropriate microbial limits. Regarding the latter, a total count limit significantly tighter than (b)(4) CFU/ml would be appropriate for products produced by your firm.
      • Detailed procedures for validating, maintaining, controlling, and monitoring your water system.
      • The executed protocol, all test results, and the final report supporting validation of your water system.
    • At the instruction of the CEO, the firm’s quality unit released product with failing results yet adjusted the CoA to indicate passing results. In response to the letter they are asked to provide:
      • Your plan to ensure personnel functioning in the quality control unit are qualified to perform its duties and will have the authority to execute them.
      • Your plan to ensure all procedures, including those applicable to the quality control unit, comply with CGMP, are established, and are followed.
    • The stability program is inadequate because the firm assigned a 2 year expiry to product which failed to meet specifications during that timeframe. In a very interesting comment, the warning letter states “During the inspection, the CEO indicated failing testing results are not necessarily indicative of product stability.”  FDA asks them to provide:
      • A list of all OOS stability test results for products manufactured in the past five years. Include the product name, active pharmaceutical ingredients (API), quality attributes, specifications, results, stability study conditions (e.g., temperature and humidity), test points (e.g., 1-month, 2-month), dates of test points, date(s) of manufacture, and lot release dates.
      • Your investigation into each stability failure for all products within expiry to ensure that all products will meet their quality attributes throughout their labeled shelf life.
      • 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 used to determine whether the integrity of your container-closure systems (and the sterility of products, as applicable) is maintained throughout their shelf life.
      • A comprehensive assessment and CAPA to ensure the adequacy of your stability program. Your CAPA should include, but not be limited to a remediated SOP 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.
    • The firm does not perform a specific identity test upon receipt of each component. This includes failure to test purchased APIs. Their procedure permits them to qualify vendors without establishing the reliability of their test data. In addition, “According to your procedure, the strength of hydrogen peroxide API will be ‘extrapolated’ from finished product testing. However, you do not perform assay testing for 3% hydrogen peroxide finished products.” FDA states that the firm “allowed negligence to occur” when the quality unit failed to detect the comparison of two identical samples for the identification of the API. They are asked to provide:
      • Investigate the root cause for personnel not following written procedures to test components, and implement CAPA to prevent recurrence. Explain how you will ensure CAPA effectiveness.
      • Provide your revised procedures for ongoing receipt and disposition of all component lots, including but not limited to API, to ensure they possess their purported identity, purity, strength, and other appropriate specifications.
      • Provide a comprehensive, independent review of your material system to determine whether all containers, closures, and ingredients from each supplier are adequately qualified; whether they are assigned appropriate expiration or retest dates; and whether incoming material controls are adequate to prevent the use of unsuitable containers, closures, and components.
    • The firm does not perform release testing for drug product to ensure it meets specifications, particularly for identity and strength. They are to provide:
      • Your plan to ensure complete finished product testing.
      • A list of all finished products for which the identity and strength of each active drug substance were not determined before release. Include an assessment of product quality and potential impact on patients for each lot of finished product within expiry and identified as untested for active drug substance identity and strength before release.
      • Your plan to promptly test all distributed drug products within expiry that were not fully tested before their release.
      • Substance identity and strength testing before release, identify the actions you will take going forward to prevent adverse impact to patients, and the time frames in which these actions will be taken.

DEVICE

  • American Contract Systems (Bloomington, MN) received a warning letter on November 6, 2018, based on the outcome of an inspection ending October 2, 2018. This is unusually quick on the issuance of the warning letter! The firm is a device manufacturer and contract sterilizer for various surgical trays/kits for hospital use. Deficiencies include but are not limited to:
    • The sterilization operations have not been adequately validated. The firm could not demonstrate that certain packaging configurations were included in the most recent validation. Nor could they demonstrate that specific products were represented by the product families in the most recent validation report and finally the validation report did not adequately assess actual use conditions.
    • The firm does not have any procedures for monitoring and controlling critical process parameters.
    • The firm failed to develop, conduct, control and monitor production to ensure the device conforms to specifications.
    • There are no procedures for changes to a specification, method, process or procedure.
    • The firm does not have an adequate organizational structure including the assignment of an individual responsible for day-to-day quality operations.