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Regulators Again Find Data Integrity Problems at Indian Manufacturing Site

Posted 17 June 2014 | By Alexander Gaffney, RAC

Regulators Again Find Data Integrity Problems at Indian Manufacturing Site

Nearly three months after Canadian generics firm Apotex was put on import alert by the US Food and Drug Administration (FDA), the agency has released the text of a Warning Letter issued to the company, highlighting alleged practices that led to some of the firm's products being banned from the US.


Apotex has been the recipient of three FDA Warning Letters, which indicate major deficiencies and threaten further action by regulators, since 2009. All three letters, sent in June 2009, March 2010 and February 2013, highlighted alleged current good manufacturing practice (CGMP) deficiencies at the sites.

The 2013 letter to Apotex was seen as being particularly bad, as the letter hit the company for deficiencies at not one but two facilities in the same letter. In one purported instance, FDA said it tested the microbiological activity of an environmental monitoring plate which Apotex staff had claimed showed "zero" microbiological activity. FDA conducted its own testing on the plate and determined that at least one colony forming unit (CFU) was present.

In many cases, discrepancies had gone uninvestigated, FDA said, raising concerns that problems were not being properly addressed. "The evidence suggests that Apotex has failed to implement adequate global and sustainable corrective and preventive actions, and that it continues to manufacture and distribute pharmaceutical product without upholding its legal obligation to comply with CGMP," FDA said, using unusually blunt language.

"FDA's inspections continue to find repeated deficiencies in your quality systems," regulators continued. "We highly recommend that appropriate resources be used to conduct a thorough retrospective evaluation of past deficiencies and that appropriate permanent changes be implemented to ensure that your corporation manufactures pharmaceutical products using a sustainable quality platform in all your facilities.”

Apotex's 2014 and 2010 letters have both been issued "Closeout" letters by FDA, indicating that they have resolved their problems.

Problems in Bangalore

But until now, Apotex's problems were confined to Canada, and specifically several of its facilities in Ontario.

Now the company is facing a problem in a different country altogether: India.

In a 16 June 2014 letter to the company—and, unusually, released to the public the same day—FDA recounted a series of major deficiencies it allegedly found during a January 2014 inspection of the company's manufacturing facility in Bangalore, India.

Like letters sent to at least 10 other India pharmaceutical manufacturers, Apotex was chided by FDA for a lack of control over its data. In at least one case, electronic records for one batch test revealed out-of-specification results regarding residual solvents. That test result was then discarded in favor of a later test, FDA found.

In another case, another out-of-specification result was found to have been replaced with the outcome of another sample tested an hour after the initial sample failed, FDA wrote.

FDA said interviews with Apotex facility staff determined this was a "common practice," and that employees regularly only recorded data results if the outcome was favorable. "If the results obtained were atypical, a fresh sample was to be prepared and analyzed," FDA claimed. "The original sample testing was not recorded."

Regulators said the testing practices "demonstrate a general lack of reliability and accuracy of data generated by [Apotex]"—something it called a "serious CGMP deficiency that raises concerns about the integrity of all data generated by [the] firm."

FDA inspectors also found that Apotex staff had "used 'finished product reports review data' worksheets to document critical laboratory information days after the actual testing was performed," instead of at the time the testing was performed. These reports were sometimes filled out almost a month after the testing was conducted, FDA found. Regulators appear concerned that the results could have been inaccurate or "selectively" falsified, compromising the integrity of all collected data.

Regulators called on the company to institute a wide range of corrective controls at the facility, including a full investigation into past problems and the development of a comprehensive improvement plan.

The Bangalore site has been subject to an import alert covering all drugs and antibiotics (except for Riluzole tablets, used to treat AML) since 1 April 2014. FDA's Warning Letter indicated that it will remain in effect until "all corrections have been completed" and confirmed by regulators.


FDA Warning Letter to Apotex

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