Week of Feb 11th 2018 | FDA Sent These Warning Letters to Device & Pharma Companies

The FDA posted 6 warning letters this week, and we cover 5 of them below. One went to a device firm, and 4 went to finished pharmaceuticals sites, all located outside the US.

Medical Devices

  • Curasan AG (Frankfurt Germany) site received a warning letter on August 23, 2017, based on the outcome of an inspection ending May 11, 2017. The firm manufactures dental devices. Deficiencies include but are not limited to:
    • For at least one product the firm did not conduct design validation, although their SOPs require this.
    • The firm has not established a manufacturing procedure for one of their products.
    • Complaints are not reviewed to determine whether an MDR needs to be submitted. The FDA comments on the deficiencies in the MDR procedure that the firm developed in response to the inspection.


  • Cosmecca Korea Co., Ltd (South Korea) received a warning letter dated February 2, 2018, based on the outcome of an inspection ending September 22, 2017. The firm manufactures OTC products. Cosmecca Korea Co. Ltd. is yet another South Korean OTC manufacturer who has been subject to enforcement action in the past few months. The FDA placed the firm on Import Alert 66-40 on January 8, 2018. Almost all deficiencies are in the area of data integrity. Deficiencies include but are not limited to:
    • The firm released products in the absence of data to support that they met specifications. The firm could not provide analytical data to support release.
    • The investigator documented examples of record falsification. For example: “Your quality control laboratory employee stated that he fabricated laboratory data for untested finished drug products by manipulating electronic laboratory records. For example, he changed the file names for test results of previously tested drugs so that the file names appeared to reflect the results of other lots of product. Your firm used this falsified laboratory data to determine the strength of your OTC (b)(4) drug products. Your response stated that your quality assurance manager instructed laboratory analysts to manipulate, falsify, or fabricate data..”
    • Inaccurate data from batch records were used to calculate potency.
    • Analysts shared usernames and passwords, and all users had administrator rights to laboratory computer systems.
    • Specifications for incoming raw materials exceed USP limits.

(RELATED: Want to see the complete list of enforcement documents — including recalls, alerts, and import alerts from this week? Start your FREE trial of the GMP Regulatory Newsletter today.)

  • Jiangmen Nowadays Daily Goods Co., Ltd (Guangdong, China) received a warning letter on September 12, 2017, based on the outcome of an inspection ending March 9, 2017. This firm also manufactures OTC drug products and was placed on Import Alert 66-40 on June 7, 2017.  Deficiencies include but are not limited to:
    • OTC products are released without testing for conformance to specifications, including identity and strength.
    • The firm failed to test incoming APIs and components but relied on the vendors CoA.
    • Products are not supported by process validation nor does the firm have an ongoing process monitoring program.
  • Guangzhou Baiyunshan Pharmaceutical Co. Ltd (Guangdong, China) received a warning letter on November 1, 2017, based on the outcome of an inspection ending May 25, 2017. The FDA placed the firm on Import Alert 66-40 on October 25, 2017. This is yet another OTC manufacturer.
    • Equipment labeled as clean contained visible material and product residue.
    • Although included in the validation protocol, the batch records do not include time limits for a step identified to be critical.
    • The firm was unable to identify the manufacturer of a critical raw material batch that was on site. Also, the firm lacks systems to appropriately qualify raw materials and their suppliers.
    • Release stickers were stored, uncontrolled, behind pallets of raw materials.
    • Product labels do not include all ingredients.
  • Bayer Pharma AG (Leverkusen, Germany) received a warning letter on November 14, 2017, based on the outcome of an inspection ending January 20, 2017. Justin Boyd was the single investigator for this inspection. The 9-page form 483 is available for purchase at the FDAzilla Store. Among the more interesting observations that didn’t make it into the warning letters was observation four that statesA document control system has not been established.”  This observation identifies a variety of data integrity examples as do observations 9, 10, and 11. Boyd has expertise in the evaluation of data governance and data integrity and is among the group of inspectors who frequently identify serious deficiencies in this area. The inspection addressed the twin areas of aseptic processing and data integrity where shortcomings often lead to additional enforcement actions. Deficiencies in the warning letter include but are not limited to:
    • Cleaning processes for shared equipment are not adequate. Equipment in three different rooms, labeled as ‘clean,’ was observed with residue on exterior surfaces After the inspection, the firm tested tablets manufactured in the same equipment to assess the potential for cross-contamination.  The testing confirmed cross-contamination of products manufactured under contract for an unidentified customer.  The firm recalled several lots of tablets.  FDA requests the following “in response to this letter, provide:
      • Your retrospective review supporting the safety and purity of each batch of product manufactured with your (b)(4) that remain within expiry in the U.S. market. Include a summary report of analytical testing results supporting your conclusions. Provide scientific justification if you to propose to exclude any batch that remains within expiry from this retrospective testing.
      • A comprehensive plan to assess cleaning procedures, practices, and validations for each piece of manufacturing equipment used to manufacture more than one product. Also include your plans to ensure that powder residues are removed from room surfaces as part of product changeovers.”
    • Investigations into customer complaints of ‘leakage’ did not identify a root cause even though their supplier informed them of a defect that Bayer did not address in the investigation. Further, the firm failed to evaluate retain samples or review past complaints to identify instances of bag integrity defects.  FDA requests they address six specific items in their response to the warning letter.
    • Investigators identified discarded original personnel training records that were required to be retained by the firm’s SOP. Investigators also identified discarded forms used to document and set inspection parameters for the automated tablet visual inspection machinery.  “In your response, you noted that you documented and approved final set-up parameters, “but historically the calculations generated in support of those parameters have not been preserved.” You indicate that programming the visual inspection machine to detect defects may not be a CGMP activity.”  FDA informed the firm that this was, in fact, a cGMP. The FDA asks the firm to address the following in response to the warning letter “In response to this letter:
      • Reassess any systems or activities associated with drug manufacturing or testing equipment that you consider “non-GMP.” Provide your reassessment and describe improvements in your procedures for document handling, retention, and destruction.
      • Review your training program’s effectiveness, including but not limited to evaluating the reason(s) that some individuals failed to follow standard operating procedures. Summarize your CAPA.” 
    • When reviewing audit trails, the investigator noted unreported data from in-process tablet weight checks. The firm programmed the weight checker not to report values that varied more than a specific (redacted) percentage of the target weight.  In a retrospective analysis of tablet weight assessments, limited to all rejected measurements, the firm identified about 8,000 rejected measurements.  FDA raises the question of how these data impact conclusions about equipment qualification and process validation. The firm is asked to provide a summary listing of the equipment and process documents they reviewed.  FDA seems to suggest that perhaps the equipment and process validation are not operating in a state of control.
    • “Data Integrity Remediation 
      • FDA acknowledges that, before our inspection, you began a data integrity remediation program. Our investigator documented that, as part of your data integrity remediation program, you discontinued the practice of performing “test” injections as a result of an internal assessment in June 2016. However, we noted that you only reviewed chromatographic data for (b)(4) and (b)(4) generated between January 1, 2015, and June 23, 2016.
      • Your action plans submitted on May 11, 2017, and August 10, 2017, did not include an assessment of other products manufactured and tested at your facility. Additionally, the retrospective review did not include data generated before January 1, 2015, used in support of drug applications submitted to FDA. Further, your retrospective review only focused on the laboratory. You did not investigate potential data integrity lapses in other manufacturing systems.
      • In response to this letter, provide your revised action plan. In your summary report, include other products manufactured and tested at your facility and identify any data generated before January 1, 2015, that was used to support drug applications submitted to FDA. Also, include your protocol and methodology. Summarize all laboratories, manufacturing operations, and systems covered by the assessment. Specify whether a qualified independent consultant performed interviews to ensure that the nature and scope of the problem was fully determined. Discuss the role of the independent consultant in auditing the integrity of your data and assisting with CAPA. Justify why you excluded any part of your operations or systems.”

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