The U.S. Food and Drug Administration (FDA) has warned Mylan Pharmaceuticals, Inc. over “significant violations of current good manufacturing practice (cGMP) regulations for finished pharmaceuticals” at its Mylan Laboratories Limited facility in Nashik, Maharashtra, India during the period from September 5 to 14, 2016.
The warning letter, dated April 3 and released by the FDA yesterday, stated: “Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to cGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).”
The warning letter was sent to Rajiv Malik, president of Mylan Pharmaceuticals, Inc. in Canonsburg, PA. The company commented in press reports that it is working to address the issues raised by the FDA in the letter.
The FDA acknowledged receipt of Mylan’s October 5, 2016 and subsequent correspondence saying that the agency reviewed them “in detail.”
During the September inspection, the FDA investigator observed several specific violations, including:
- Failure to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192). The agency termed Mylan’s response as “inadequate” because the company “failed to implement a corrective action and preventive action (CAPA) plan to mitigate errors that you attribute to laboratory process.”
- Failure to establish an adequate quality control unit with the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated (21 CFR 211.22(a)). The FDA said the company response was inadequate partly because it had not identified and investigated each instance in which data acquisition was interrupted.
Regarding data integrity remediation, the FDA wrote that the facility’s quality system “does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture.”
FDA asked Mylan to provide a comprehensive investigation into the extent of the inaccuracies in data records and reporting, including:
- A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of the operation that the company proposes to exclude.
- An assessment of the extent of data integrity deficiencies at the facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of the facility’s operations in which the company discovered data integrity lapses.
- A comprehensive retrospective evaluation of the nature of the testing data integrity deficiencies.
The FDA letter also requests a current risk assessment of the potential effects of the observed failures on the quality of drugs, including analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity, and risks posed by ongoing operations, and a management strategy that includes the details of the company’s global corrective action and preventive action plan.
That strategy, according to the FDA, should include:
- A detailed corrective action plan that describes how Mylan intends to ensure the reliability and completeness of all of the data generated, including analytical data, manufacturing records, and all data submitted to FDA.
- A comprehensive description of the root causes of the data integrity lapses, including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment.
In conclusion, the FDA noted in its letter that the violations cited are not intended as an all-inclusive list, adding that “until you correct all violations completely and we confirm your compliance with cGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer.”
The agency requested a written response to its warning letter within 15 working days of receipt.