Data integrity still in the focus of FDA: new warning letter to Japanese API manufacturer

For the past 3-4 years, the topics data and data integrity have been moving into the focus of FDA inspections. Recently, Japanese API manufacturer Yuki Gosei Kogyo Co. Ltd. received a warning letter referring to this. The inspection took place between 13 and 17 November, 2017; the warning letter was published on 17 July, 2018.

Criticism in the warning letter

While warning letters on medicinal products usually reference the corresponding chapters of 21 CFR Part 211, API warning letters usually reference ICH Q7; in this specific case, the chapter VI "Documentation and Records",  Subchapter F "Laboratory Control Records" - "Failure to maintain complete data derived from laboratory tests conducted to ensure your API complies with established specifications and standards".

Problem at Yuki Gosei Kogyo

The company does not ensure that complete data from testing of the API are included in the batch record and reviewed by the quality unit. In one case, one substance passed all tests on one day. However, the inspector found further analysis data from the same batch of the substance, including OOS results. These samples had been taken earlier on the same day and on the day after. The error was that the quality unit had not reviewed and evaluated this data before batch release. The inspector observed the same issue for several other products not intended for the US market.

FDA reaction to the company's response regarding the deficiencies

The company declared these not reviewed analyses as "trial analyses". These were performed on a sample solution for conditioning the HPLC column. The FDA's feedback - why were these "trial analyses" performed using a sample instead of a standard solution and why was this extra analysis run in addition to the system suitability test.

The company also explained that a review after the inspection found further electronical data which had not been mentioned in the batch records. The FDA's feedback here - it is not sufficient only to review the laboratory data. All other GMP areas where information is generated and maintained also need to be reviewed. Furthermore, the FDA found the review criteria and methods lacking.

The consequences

The FDA criticised an insufficient system for maintaining data integrity. Until the correction of all deviations has been confirmed, the FDA may withhold approval of any new applications or supplements listing the company as drug manufacturer.

Source: FDA Warning Letter to Yuki Gosei Kogyo Co. Ltd. from 17 July, 2018