The US Food and Drug Administration (FDA) has posted a Warning Letter, dated June 10, 2014, on its website for Tianjin Zhongan Pharmaceutical Co. Ltd. for cGMP violations at the company’s active pharmaceutical ingredient manufacturing facility in Tianjin, China, based on an inspection of the facility from September 23-27, 2013.

FDA cited the firm for failing to adequately complete and follow written procedures for cleaning equipment and its release for use in API manufacture and for failing to maintain adequate records of major equipment usage.The agency also noted that the company’s production operation supervisors and quality unit failed to detect and correct these deficient cleaning practices. FDA is advising the firm to prepare and implement a corrective action plan sufficient to  address and prevent the recurrence of these deficiencies. The corrective action plan should detail the systemic improvements to be made, including, but not limited to, improved management oversight of cleaning operations, commitment to maintain individual equipment records (e.g., equipment logs), and training all relevant personnel in cleaning procedures

FDA also cited the company for failing to conduct adequate change control to evaluate all changes that could affect the production and control of intermediates or APIs. The agency noted that the company failed to identify, document, evaluate, and approve several changes in production. Specifically, it cited the company for using different equipment than was referenced in a drug master file and for not evaluating the impact on product quality for this change or validating the effectiveness of change implementation. FDA also noted that the firm did not conduct a change-control investigation or did not document the changes in its manufacturing processes as required by its standard operating procedures (SOPs). FDA is advising the firm to conduct a retrospective assessment of all changes it has made to equipment and procedures used in the manufacture of given APIs and the impact on product quality and to correct its change-management system.

FDA also cited the firm for failure to adequately review and investigate product deviations. The agency said that during its inspection, the company’s manufacturing workshop contained significant particulate material, fluid, and a plastic tube (apparently from a pen) and subsequent sample collection of the residues were insufficient to allow for an adequate investigation. FDA is advising that the company provide an assessment of its deviations system and related corrective action plan, which includes hiring qualified personnel to perform investigations, improving the training program, maintaining a sufficient number of staff, conducting timely remediation, and improving deviation investigation procedures.

FDA also noted that the firm did not adequately control its certificates of analysis (COAs), citing that the company’s employees in its foreign trade office generated and issued COAs for products and that the company’s quality unit did not control or retain records of all such COAs. FDA also noted that nadequate qualification of critical production equipment was a concern, citing the company for a failure to maintain current technical drawings of a production equipment used in API manufacturing and a failure of qualification documents for not including important installation verification parameters, such as material of construction, the volume capacity, configuration/location, or material.

In its letter, FDA said it “strongly recommends that your executive management immediately undertake a comprehensive evaluation of global manufacturing operations to ensure compliance with cGMP regulations. As part of these efforts, it is imperative that you build a robust quality system, and assure proper management oversight of operations and quality. Your inability to detect and prevent the above deficient practices, as well as other deficiencies found during the inspection, indicate that your current quality system is ineffective at achieving overall compliance with cGMP.” FDA recommended that the company engage with a third-party consultant to ensure GMP compliance. The company has 15 days following receipt of the Warning Letter to specify the steps it has taken to prevent and address the deviations.

Source: FDA