The FDA posted 6 warning letters this week, 3 of which address human drug manufacturers. Two of these 3 manufacture OTC drug products. We continue to provide the information that FDA requests firms to provide because this provides a roadmap for FDA expectations — invaluable information for those firms that may find themselves with similar challenges.

DRUGS:

  • Jalco Cosmetic Pty Limited (Australia) received a warning letter on May 18th, 2018 based on the outcome of an inspection ending December 13th, 2017. The warning letter addresses OTC products. The firm is a contract manufacturer and FDA reminds them of their responsibility in this area. Overall, FDA states that their quality unit is inadequate, and they recommend that the firm employ qualified consultant(s) to assist in coming into GMP compliance. They were placed on Import Alert 66-40 on March 8th, 2018. Deficiencies include but are not limited to:
    • Drug products are released without testing for the presence and strength of active ingredients. They commit to testing for active ingredients “if a test method is available.” The FDA requests the following be submitted in response to the warning letter:
      • “Appropriate specifications for each chemical and microbial attribute of your products.
      • Protocols and timelines for the establishment and validation of all methods that you will use to test each batch of your U.S. drug products for identity, strength, quality and purity. Also include your test methods.
      • Your procedure to assure that any future test methods contracted to a third-party laboratory are properly transferred and validated prior to use. Also include your procedures for assuring oversight of the adequacy of laboratory analyses performed on your behalf by a third-party laboratory, and any related investigations regarding these analyses.
      • The actions you have taken to determine the quality of your U.S. drug products within expiry which were previously released without adequate testing, including identity and strength of active ingredients.”
    • The firm failed to test incoming active ingredients/components and, instead, relied on the vendor CoA. FDA asks the firm to provide the following:
      • “…a detailed description of how you plan to test each component for conformance with all appropriate written specifications for identity, strength, quality and purity. If you plan to rely on your suppliers’ COA test results (with the exception of identity) in lieu of testing, describe in detail how you plan to establish the reliability of your suppliers’ test results prior to use of a supplier’s ingredient in production, as well as through periodic validation. Lastly, provide a risk assessment for all drugs within expiry and distributed within the United States that were manufactured from inadequately-tested and controlled components.”
    • The firm has not qualified the filling machine nor have they validated the manufacturing process. The firm is asked to provide:
      • “…provide analysis of retain samples for your drug products currently in U.S. distribution. Include your updated stability testing program. Describe stability-indicating methods and acceptance criteria for each chemical and microbiological test to support the labeled storage conditions and expiry dates for your drug products.”
    • The site of manufacturing, equipment, raw materials, and container closure system were changed upon initiating manufacturing at this firm. Stability studies were not initiated to support the previous expiry data. Previously, the 24 and 36 month time points were sub potent and failed viscosity respectively. The firm is asked to provide:
      • “analysis of retain samples for your drug products currently in U.S. distribution. Include your updated stability testing program. Describe stability-indicating methods and acceptance criteria for each chemical and microbiological test to support the labeled storage conditions and expiry dates for your drug products.”
  • Europharma Concepts Limited (Ireland) received a warning letter on May 16th, 2018 based on the outcome of an inspection ending November 3rd, 2017. This firm is an OTC manufacturer and a contract manufacturer. They were placed on Import Alert 66-40 on February 22nd, 2018, and FDA recommended they employ qualified consultant(s) to assist in coming into GMP compliance. Deficiencies include but are not limited to:
    • The firm fails to test the glycerin that they purchase as an ingredient for the present of diethylene glycol. This is an immediate safety issue. The firm also fails to test incoming raw materials. The firm states they are now “…collecting and evaluating test methods for these materials.” In response to this warning letter, the firm is requested to:
      • “Provide written procedures for how you will qualify your suppliers, both initially and on an ongoing basis. Describe whether you intend to test each lot of incoming components for all attributes. Alternatively, if you intend to rely on the supplier’s certificate of analysis, provide specifics on how you will verify each suppliers’ test results at regular intervals and include a commitment to test every incoming component lot for identity, at minimum.
      • Provide a detailed risk assessment for drug products that contain glycerin and are within expiry in the U.S. market. Test retain samples of all lots for DEG and EG. If you find that you released any batch for which results are out-of-specification, indicate the corrective actions you will take, such as customer notifications and product recalls.
      • Provide a comprehensive, independent review of your laboratory practices, methods, equipment, and analyst competencies. Based on this review, provide a detailed corrective action and preventative action plan to fully remediate your laboratory system.”
    • The firm failed to validate the manufacturing process and demonstrate that it is reproducible and controlled. Regarding the product identified in the observation the firm said: “It is not viable either contractually or commercially to incorporate it into extensive validation activities.” The firm is requested to provide the following:
      • “…provide improved procedures regarding validation/verification requirements, updated analytical methods, and your validation plans if you intend to resume manufacturing products for the U.S. market.”
  • Jilin Shulan Synthetic Pharmaceutical Co Ltd (Jilin Province, China) received a warning letter on May 14th, 2018 based on the outcome of an inspection ending November 10th, 2017. The firm manufactures APIs, one of which is caffeine. The firm was place on Import Alert 66-40 on March 1st, 2018. The 3 deficiencies identified in this letter focus on failures in data integrity and data governance. Deficiencies include but are not limited to the following:
    • The firm does not investigate manufacturing deviations including OOS events. In the instance where the operator did not follow the procedure, the individual was fined 50 yuan but an investigation was not opened. The firm also maintains dual sets of laboratory records, and the quality department admitted this was the practice.
    • Audit trails were not enabled on HPLC, GC, and IR systems. No alternative method was in place to record and monitor changes to data that are collected on these instruments.
    • Operators had full system permissions to modify and delete data. The investigator identified files in the recycle bin.
    • Activities are not documented in records at the time they are performed. Batch records were pre-signed, partially completed, and completed in pencil. The investigator also found 2 batch records for a single lot being completed by 2 different operators.
  • The FDA also included the ‘long version’ of their data integrity remediation statement.