Warning letter due to inadequate document management and GMP non-compliant analytical software

Templates for product release forms in GMP-controlled environments are sensitive documents. Their GMP-compliant handling requires strict control of their release, use, forwarding and accounting. What FDA inspectors found during their visit at the site of the Chinese API manufacturer Henan Lihua Pharmaceutical, however, was far behind the minimal standards for document management as it can be expected at a GMP-regulated facility. Apart from the fact that release documents were freely available, the inspectors also criticised the use of analytical software for in-process and quality control that had not been configured in a GMP-compliant manner.

The warning letter issued six months later included the following details:

  • Numerous blank records and stamps had been freely available in the office of the production area, the lock of which had been defective. The forms were already marked with a "Permitted to Leave Factory" stamp even though they were still blank.
    Company's response: stamping the forms in advance facilitates the release process. The employee responsible for documentation was not aware that the broken lock posed a risk. SOP will be adjusted and personnel trained again.
  • The analysis instrument used for stability testing (what analytical method was used is not mentioned in the warning letter) had been used directly after the in-process analysis stability testing. After reviewing the audit trail, the inspector observed that the software was configured to continuously use the "preview run" function. Thereby, the data from the preceding analysis run was overwritten each time and only the data from the last analysis saved. The period between the individual (overwritten) runs equalled the exact time it took to prepare a run (sample, blank sample, standard). Such a procedure, where raw data is deleted, is a fraud attempt in the eyes of the FDA inspectors.
    Company's response: the requirement to save data from previous analysis runs has not been known. Analyses instruments with new software will be procured.

For the FDA, such responses are inadequate since they don't concentrate on the actual problem, which lies in the quality culture. There was no evidence for the inspectors that the personnel had been trained appropriately and that GMP-compliant workflows had been established - especially in the quality control unit. It is not enough to replace hardware and software. Rather, suitable control procedures should be established, after which raw data is to be saved and audit trails are to be reviewed.

Please also see the FDA's warning letter to Henan Lihua Pharmaceutical - the company has been placed on Import Alert by the FDA.

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