Ipca Laboratories received a warning letter dated January 29, 2016 for three inspections conducted in 2014. This included one API site (‘Ratlam facility’) inspected July 14-18, 2014 and two drug product facilities (‘Pithampur facility’ and ‘Piparia Silvassa facility’) inspected on October 13-17, 2014 and December 1-19, 2014 respectively. The substantial delay between inspection and warning letter enforcement actions continues a trend that began at least in 2015. Reference is made to a previous blog entry that identifies these increasing lag times. The firm ceased shipping product to the US and three sites were also placed on import alert on January 22, 2015 (Ratlam) and March 24, 2015 (Piparia Silvasa and Pithampur). HERE is the notification Ipca Laboratories sent to the Bombay stock exchange in March of 2015. FDA concludes the letter with actions that the firm must take to correct “systemic data manipulation” at the three sites in addition to addressing the deficiencies identified in the warning letter. These requirements have been used in at least seven other warning letters issued in 2015 where data integrity faults were identified and look very similar to consent decree agreement requirements. Reference is made to a previous blog entry that identifies the firms who received requests for such information. The remediation for Ipca Laboratories will not be quick or inexpensive. This warning letter seems to identify a particularly egregious set of practices of data manipulation that were known to and supported by management. Details follow:
Ratlam Facility (FEI 3002807297) an API facility. Deficiencies include but are not limited to:
- A ‘lack of basic laboratory controls’ to maintain the security of electronic data. Data were integrated inappropriately to yield a passing result and when integrated using proper integration parameters the results were OOS. In another instance, the date – time stamp was reset to appear to show a passing result was obtained prior to the date when the analysis, using inappropriate integration conditions, was actually conducted at the FDA investigators request. Analysts could change the date-time stamp because they had PC Administrator access. Further, aborted runs did not include an explanation and the data were not retained. Several examples were provided and in addition staff confirmed the common practice of “…if we find a failure, we set back the date/time setting and re-integrate to achieve passing results…” The analyst explained that deleting, overwriting, changing integration parameters, and altering PC date and time settings were done for raw materials, in-process testing, and finished API drugs.”
- Further, the firm failed to adequately investigate and resolve critical deviation. The examples provided are associated with the lack of controls over the computer systems that did not prevent manipulation of data. FDA provides a detailed explanation.
- Failure to document activities at the time they were performed was identified in the microbiology laboratory. The investigator found that the daily temperature record in the 2-8C refrigerator was changed and data were backdated. After questioning, the analyst’s supervisor indicated that the analyst was directed to fill out the logbook “after the fact.”
- Media growth promotion plates were missing and at least one was re-created to make it appear as if the samples were complete.
- FDA states repeatedly states that the firm “…used these incomplete results to evaluate the quality of this drug.”
- The warning letter notes that an anonymous email was sent to management on August 5, 2013 identifying lack of control in the QC labs and falsification of data. FDA deemed the investigation that resulted was inadequate and incomplete. It would be interesting to know whether this same email was sent to FDA and perhaps prompted the focus of these inspections.
Pithampur (FEI: 3007574780), Drug product manufacturing site. The deficiencies included multiple examples where data had been overwritten and deleted without justification. Also, test injections were made prior to official sample testing and these data were overwritten by subsequent testing. The firm responded that they will focus on revie of data print outs and revising the governing SOP. This clearly does not meet regulatory agency expectation that raw data will be reviewed in the format in which it is collected. FDA stated: “Because your quality unit did not review the original electronic raw data, you were unable to detect rewritten, deleted, or overwritten files. Without this information, you have no way to ensure that the tests you use to evaluate the quality of incoming raw materials are accurate or reliable.” The form 483 associated with this inspection states “Due to the apparent laboratory practice of directing raw data “trial” chromatogram paths randomly throughout your firm’s hard drive in no apparent organized fashion, in what appears to be an attempt to hide results from review…”
Piparia Silvassa (FEI3005977675), drug product manufacturer. Deficiencies include performing sample test injections and then ignoring the results. These data were not considered along with the official test run results when making lot release decisions. FDA states that “Your quality unit must review all analytical data when making batch release decisions.”
Taken together, it appears the firm has wide spread purposeful manipulation and falsification of data with management involvement in the apparent deception. These deficiencies represent more than bad practices or inadequate procedures and call into question all data generated by the sites. Other Ipca Laboratories sites might well be expected to share similar deficiencies and practices.
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