FDA Issues Warning Letter to Bayer for Finished-Products Manufacturing Plant

By Akia Thorpe -

February 16, 2018

The FDA has issued a Warning Letter to Bayer for good manufacturing practices (GMP) violations for finished pharmaceuticals based on an inspection of the company’s manufacturing facility in Leverkusen, Germany. The Letter was in response to a FDA inspection from January 12–20, 2017. The Letter was issued in November 2017 and posted on the FDA website in February 2018. 

The FDA cited the company for several issues, including for failing to establish and follow adequate written procedures for cleaning and maintenance of equipment. It noted that the company’s cleaning practices for non-dedicated equipment were inadequate, and the agency observed residue on the company’s manufacturing equipment. The agency said the company did not sufficiently access whether US shipped products manufactured with the materials of concern were cross-contaminated.

The FDA also said that the company’s investigations into product-quality complaints were inadequate. It said that the company did not determine a root cause for a container-closure defect. The agency noted that the company’s supplier informed the company of the defect, but the agency said that the company did not address it in its investigation. The FDA also said that the investigation failed to include an examination of retain samples or review past complaints to identify other instances of bag-integrity defects.

The agency also noted that company’s quality-control unit did not sufficiently oversee adequacy of procedures at its facility to assure drug-product quality, which included instances of discarded training records and discarded automated visual-inspection machine parameters.

The agency also noted that in reviewing audit trails, its investigator observed unreported data from in-process tablet weight checks. The agency also noted that the company, as part of data-integrity remediation plan, did not include an assessment of other products manufactured and tested at its facility and investigate potential data-integrity lapses in other manufacturing systems.

The FDA outlined several actions for the company to take to address the issues cited in the Warning Letter. The FDA requested that the company provide a retrospective review supporting the safety and purity of each batch of product manufactured concerning the product(s) of concern that remain within expiry in the US market. The agency asked that Bayer include a summary report of analytical testing results supporting its conclusions and provide scientific justification for any batch that it proposes to include and that remains within expiry from the retrospective testing. The agency also asked for a comprehensive plan to assess cleaning procedures, practices, and validations for each piece of manufacturing equipment used to manufacture more than one product. It also asked that the company include its plans to ensure that powder residues are removed from room surfaces as part of product changeovers.

With respect to issues relating to investigating failure of a batch or its components, including issues of bag integrity, the FDA requested that the company provide the following:

  • A list of all complaints received from 2014 to the present that indicate potential bag non-integrity, with detailed descriptions including complaint dates, product names, batch numbers, description of complaint, exact breach locations, root causes, and corrective action and preventive action (CAPA). The agency also asked that the company include its final, updated investigations into issues observed in the batches of interest.
  • A retrospective review of all investigations relating to complaints that could impact the quality of products within expiry in the US market, including an assessment of the depth of investigation, identification of potential root causes, review of related trends, and CAPA;
  • A full assessment and remediation of the company’s systems for investigating complaints, failures, and deviations to ensure they are thorough, scientifically sound, and culminate in appropriate and effective CAPA;
  • Procedures requiring more thorough examination or testing of retention samples during investigations, including both the complaint batch and other potentially affected batches;
  • Procedures that ensure each complaint of a critical defect is carefully evaluated to determine whether marketed products may be impacted; and
  • Improvements in the company’s ongoing monitoring of vendor or contractor acceptability and an explanation for how it will ensure that vendors notify it about significant deviations or potential defects in materials (e.g., by modifying quality agreements).

With respect to quality-control issues, the FDA asked that the company reassess any systems or activities associated with drug manufacturing or testing equipment that it considers “non-GMP.” It also requested that Bayer provide its reassessment and describe improvements in its procedures for document handling, retention, and destruction. In addition, the agency asked the company to review its training program’s effectiveness, including but not limited to evaluating the reason(s) that some individuals failed to follow standard operating procedures.

As part of Bayer’s retrospective tablet-weight assessment, the agency asked that Bayer explain whether its findings impact data supporting tablet-manufacturing equipment qualification and manufacturing process validation studies. It also asked that the company provide a summary listing of equipment qualification and process-validation documents that it reviewed.

Source: FDA