The US Food and Drug Administration (FDA) this week released three warning letters sent to medical device manufacturers, including Florida-based UVLrx Therapeutics, Inc., Germany-based DRG Instruments GmbH and France-based ELITech Group SAS, as well as one to the Vapi, India-based active pharmaceutical ingredient (API) manufacturer Vital Laboratories.
The inspection conducted at UVLrx from 27 March 2017 to 4 April 2017 to assess a clinical study the company was conducting found that among other violations, UVLrx received institutional review board (IRB) approval to enroll 1,000 subjects for one trial protocol but 3,063 subjects were actually enrolled. FDA also found that at least 10 clinical investigators were not approved for a study, though they received investigational devices and began treating subjects.
About five investigators participating in one of the studies were shipped devices "after the site had been administratively closed by the IRB," FDA said.
UVLrx did not monitor its studies or maintain documentation, FDA added, noting the firm failed to apply proper device labeling or to include the investigational device caution statement.
FDA’s inspection of the Marburg, Germany-based site in October 2016 found that the manufacturer of enzyme-linked immunosorbent assays (ELISA) failed to establish and maintain process control procedures and failed to identify the actions needed to correct and prevent recurrence of nonconforming product and other quality problems, among other issues.
In one example, FDA notes that the manufacturing errors that led to many low patient results with a lot of the company’s Estradiol Salivary ELISA were caused by a failure to update the manufacturing procedures or standard matrices after a design change.
"Although you identified the cause of the issue within the [corrective and preventive action] CAPA report, you did not identify the actions needed to correct the failure of communicating approved manufacturing changes and did not have procedures to verify the effectiveness of such action," FDA said. "You were not able to provide any written procedures to communicate approved manufacturing changes to the manufacturing employees in a timely manner. A documentation change control system has not been established."
During a three-day inspection last March at the French company’s Spankeren, The Netherlands-based site, FDA found the company failed to adequately establish and maintain procedures for CAPAs and did not have documented instructions covering the practice of postponing CAPAs.
FDA noted that the company did not investigate some complaints, including one of "rusty residue" and others related to leaking units.
During a three-day inspection last April, FDA uncovered "significant deviations from current good manufacturing practice" for APIs. The agency found that the firm did not review all production records to determine if certain steps were "occasionally performed, without any rationale," or if master batch record formulas for some drugs were incorrect.
Reporting errors for multiple products were also found to be repeat deviations from FDA’s 2013 inspection of this site.
"These repeated failures at multiple sites demonstrate that your company’s oversight and control over the manufacture of drugs is inadequate," the agency said.
FDA is seeking the results of a review of the firm’s production records to identify instances of production deviations for all drugs distributed in the US within expiry, the results of a retrospective investigation of batch records for all of API distributed to the US within expiry and an investigation report and risk analysis for all drugs tested on certain gas chromatography equipment since 2015, among other information.
UVLRX Therapeutics Inc 9/25/17
DRG Instruments GmbH 9/19/17
ELITech Group B.V. 9/20/17
Laboratories Pvt Ltd Plant II 10/10/17