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FDA cites cGMP violations and data-integrity issues and raises concerns over the company's ability to implement a robust and sustainable quality system.
FDA issued a Warning Letter to Wockhardt on Nov. 25, 2013, which raised concerns over the company's corrective actions taken in response to GMP violations cited by the agency for earlier inspections of the company's facilities in Waluj and Chikalthana, Maharashtra, India as well as the ability of the company to implement a robust and sustainable quality system. FDA also asked the company to conduct a global assessment of its plants and to provide a corrective action plan to demonstrate commitment, procedures, actions, and controls for ensuring data integrity.
In its Warning Letter, FDA noted that the company did not provide sufficient corrective actions to GMP violations cited by the agency during its inspection of July 22–31, 2013. The agency noted that the firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards. For example, its investigators identified the company's practice of performing “trial” sample analysis for high-performance liquid chromatography (HPLC) analyses at its Chikalthana and Waluj facilities prior to acquiring the “official” analytical data for release and stability testing. At the Chikalthana facility, FDA investigators observed the practice of performing “trial” injections for HPLC analyses used to test content uniformity, assay, and dissolution for release and stability for at least four different products.
In addition, FDA noted that it discovered that some of the “trial” injection data was not kept on the HPLC hard drives because the firm had deleted it and that the firm’s management confirmed that the files were deleted as part of an internal audit conducted as a result of the March 2013 FDA inspection at the Wockhardt facility located in Waluj. FDA noted that its investigators also found similar instances of the use of “trial” injections stored in default folders on the HPLC hard drive for at least four drug products.
"The lack of reliability and accuracy of data generated by your firm's laboratory is a serious cGMP deficiency that raises concerns about the integrity of all data generated by your firm," said FDA in its Warning Letter. "We are also concerned that your quality unit allowed the practices of 'trial' injections…and deletion of HPLC files to persist without implementation of sufficient controls to prevent data manipulation. Moreover, your firm’s second response to the FDA 483 dated October 2, 2013 essentially confirms that actual samples were used as 'trial' injections.It appears that QC [quality control] analysts attempted to mask the practice of performing sample 'trial' injections by labeling them as standards rather than by the actual batch numbers or other identifying information."
FDA said it was "particularly concerned" about the company's ability to implement a robust and sustainable quality system. FDA said the findings from its current inspections include repeat citations from FDA’s inspection of the Wockhardt Waluj, Aurangabad, India facility conducted in March 2013. "These repeated observations and citations indicate that your quality unit is not exercising its responsibilities and may not have the appropriate authority or ability to carry out its responsibilities," said FDA. FDA also said the firm failed 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 is asking Wockhardt to provide evaluation of all laboratory equipment that may be affected by the lack of adequate controls to prevent data manipulation.It is further requiring the company to address the root cause of the quality unit's failure to control and detect the manipulation or alteration of laboratory documents and describe actions to prevent recurrence. It is also asking the company to provide procedures to manage all computerized data and how the data will be used, retained, and stored to ensure its integrity.
Wockhardt was also cited for a failure to follow written procedures for production and process control designed to assure that its drug products that it manufactured have the identity, strength, quality, and purity they purport or are represented to possess and to provide for proper documentation. At the Chikalthana site, investigators observed poor documentation practices during in-process testing. FDA said the company's response to this matter indicate whether this poor documentation practice is an isolated case or is a matter of widespread behavior in this facility. FDA also noted that the firm failed to follow a written testing program designed to assess the stability characteristics of drug products. FDA is requesting the company provide an action plan to ensure improvements in its stability program, including explaining how the stability scheduler software will ensure the stability sample accountability is carried out as is established in the approved stability protocol.
"It is apparent that Wockhardt is not implementing global and sustainable corrective actions. It is essential that your firm implement a robust quality system," said FDA in its letter. "FDA strongly recommends that Wockhardt’s executive management immediately undertake a comprehensive and global assessment of your manufacturing operations to ensure that your systems and processes, and ultimately, the drug products you manufacture, conform to FDA requirements for safety, efficacy, and quality."FDA further is requiring Wockhardt to describe its corrective action plan that describes its commitment, procedures, actions, and controls to ensure data integrity. This plan should include the corrective actions implemented to ensure that all managers, supervisors, and quality-unit personnel are properly trained in detecting data-integrity and manipulation issues. FDA is also recommending that the company hire a third-party auditor, with experience in detecting data-integrity problems to assist with this evaluation and to assist with overall cGMP compliance.
Until all corrections have been completed and FDA has confirmed corrections of the violations and the firm’s compliance with cGMP, FDA said it may withhold approval of any new applications or supplements listing Wockhardt as a drug product manufacturer and that failure to correct these violations may result in FDA refusing admission of articles manufactured at Wockhardt facilities in Chikalthana and Waluj.