Chinese API Manufacturer Zhejiang Hisun Receives Warning Letter

On Dec. 31, 2015, FDA issued a warning letter to Zhejiang Hisun Pharmaceutical Co., Ltd., as a result of inspections that took place on March 2–7, 2015 at the Taizhou City, Zhejiang Province, API manufacturing facility. The company was cited for deviations from cGMP including data integrity issues and failure to conduct appropriate microbiological testing on API batches where microbial quality is specified. The company was placed on import alert in September 2015.

Data integrity issues noted by FDA included “failure to prevent unauthorized access or changes to data, and to provide adequate controls to prevent manipulation and omission of data.” FDA said, “Your firm relied on incomplete records to evaluate the quality of your drugs and to determine whether your drugs conformed with established specifications and standards.”  

FDA investigators also found that the company routinely re-tested samples without justification and deleted analytical data.  “We observed systemic data manipulation across your facility, including actions taken by multiple analysts, on multiple pieces of testing equipment, and for multiple drugs,” wrote FDA in the warning letter. “Our concerns about deletion of data are heightened by the significant number of customer complaints for subpotency and out-of-specification (OOS) impurity levels from 2012–2014. We observed data deletion in your laboratory related to assay and impurity levels during this time period. During the inspection, we asked to review your lab’s raw analytical data of the lots associated with four of the 61 complaints. However, you were unable to provide the raw data because it had been deleted. Without raw test data for the lots associated with these complaints, your firm could not adequately investigate the complaints, nor could you expand your investigation to determine whether other lots were affected by the same problems or take corrective actions, such as recalling drugs if appropriate.”

FDA acknowledged the company’s commitment to hire a third-party consultant, set up user access restrictions, and upgrade computerized systems with audit trails, but said that these actions were insufficient to correct the broad data manipulation and deletion problems observed at the facility and to prevent their recurrence. FDA asked the company to provide a comprehensive investigation and evaluation of data integrity deficiencies and their root causes, a risk assessment, a management strategy that includes a detailed global corrective action and preventive action plan, and other information about planned actions to correct problems.

In addition to data integrity issues, FDA inspectors noted a “failure to conduct appropriate microbiological testing on API batches where microbial quality is specified.” Inspectors observed dried and cracked culture media plates. FDA noted in the warning letter that “From 2012 to 2014, several of your customers complained that microbial results were OOS when they tested your API upon receipt. In your response, you concluded that the percentage of customer complaints reporting OOS microbial test results was insignificant. You attributed the customers’ OOS microbial results to test methods that differ from your own.

Your response lacks your findings and corrective actions from your recent investigation of dried out and cracked culture media plates. For example, you did not retest the batches that received OOS microbial complaints, even after we pointed out this deficiency. You lack scientific justification to conclude that your customers’ OOS findings are inaccurate or insignificant.”

FDA requested “An accelerated timeline for completing retroactive microbial testing of all potentially-compromised batches via an independent laboratory, and a commitment to respond with all results promptly” among other actions.

A final problem noted in the warning letter was with access to information during inspection.

Source: FDA