Sun Pharma Receives FDA Warning Letter for Data-Integrity Issues

FDA has issued a Warning Letter to Sun Pharmaceutical Industries for data-integrity issues and related cGMP violations at the company’s active pharmaceutical ingredient (API) and finished product manufacturing operations at the company’s facility in Vadodara, Gujarat, India. FDA issued the letter in response to an inspection of the pharmaceutical manufacturing facility made on November 13 to November 16, 2013. FDA said the firm’s initial response lacked sufficient corrective actions.

At the firm’s API facility, FDA said that the firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards. It said that the firm was missing fundamental raw data and information necessary to document its analyses. For example, these analyses lack the following critical data: identification of the samples tested, including name and source, batch number or other distinctive code, and date of the sample; the complete record of all raw data generated during each test, including graphs and electronic files from laboratory instrumentation; the test method used; sample preparation as prescribed by the method, preparation and testing of standards, reagents, and standard solutions; records of all calculations performed in connection with the test; test results; and the signature of the person who performed each test and the date the tests were performed as well as the date and signature of a second person showing that the original records had been reviewed for accuracy, completeness, and compliance with prescribed acceptance criteria.

In addition, FDA said the company frequently performs “unofficial testing” of samples, disregards the results, and reports results from additional tests. For example, during stability testing, the firm tested a batch sample six times and subsequently deleted this data. FDA further cited data-handling issues in the company’s high-performance liquid chromatography (HPLC) and gas chromatography (GS) analyses. The inspection revealed numerous examples of deleted GC electronic raw data files on the computer controlling the GC instruments that were replaced with identical “official” chromatogram file names. The identically named GC data files that were deleted had been created at different times and contained disparate data. Also, it appeared that data were not consistently archived to the central server.   

“Your response is inadequate in that you did not conduct an adequate investigation into the pervasive practice of deleting files,” said FDA in its letter. “In the reports provided in your response, you did not identify what criteria you used to designate each type of HPLC and GC data files (e.g. blanks, standards, samples, and system suitability runs). The response does not identify any impurity standards used in your procedures and does not provide the procedures that your firm was using to conduct the ‘trial’ and ‘unofficial’ runs. In addition, your investigation found 47 instances of apparent trial injections of samples for which the results were out-of–specification, and some of these batches were distributed to the US market. The investigation failed to adequately examine why your analysts hid or deleted these runs. Your response only explains that your firm chose to retest samples from the implicated lots, but does not address the causes of the original out-of-specification results or justify the basis of your decision to invalidate the original failing result and accept the passing retest result.”
FDA said that these examples suggest “a general lack of reliability and accuracy of data generated by your firm’s laboratory, which is a serious CGMP deficiency that raises concerns about the integrity of all data generated by your firm. We are concerned that your laboratory allowed the practice of “trial” injections and deletion of both GC and HPLC files to persist without implementation of controls to prevent data manipulation until at least September 2013.” The firm was also cited for failure to assign and identify raw materials with a distinctive code, batch, or receipt number, and to identify the disposition of materials. For example, FDA said it observed numerous partially unidentified filled bags.

At the company’s finished drug product manufacturing operations, FDA cited the firm for failure to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records. FDA said its investigator identified numerous deleted raw data files on computers used for the company’s GC instruments in its quality control laboratory and a basic lack of audit trail and data security for analytical files. It also cited the firm for failure to maintain written production, control, or distribution records specifically associated with a batch of a drug product for at least one year after the expiration date of the batch. During the inspection, the investigators found approximately 10 waste bags containing torn or partially destroyed raw data CGMP records related to a variety of manufacturing activities. 

FDA said the company’s response was inadequate in that the investigation was primarily limited to the discarded CGMP records cited in the Form FDA-483. The investigation did not include a comprehensive review of all records in the waste area or a thorough review of the firm's practice of destroying CGMP records. FDA also noted that the company did not train contract employees in CGMP or in job-specific procedures. In addition, the agency said that CGMP documents, including procedures and batch records, could not be fully comprehended by many of the contract employees.

Source: FDA

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