FDA Issues Warning Letter to India Facility

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The agency cites Apotex’s Bangalore facility with quality system failures.


FDA issued a Warning Letter on Jan. 30, 2015 to Apotex Research Private Limited for cGMP violations. The Bangalore, India facility was cited for a variety of procedural problems related to data control, written procedures, and computer systems.

In the letter, FDA states the company failed to include complete data derived from all necessary tests in compliance with 21 Code of Federal Regulations (CFR) 211.194(a). The inspection revealed that the company did not report data from “trial” testing of samples and only reported results from additional tests conducted. FDA says the company failed to perform the proper corrective and preventive actions, and the company’s response to the agency’s concerns only raised more questions.

The investigator also pointed out a failure to properly control computer systems and that the company allowed unauthorized personnel to make changes to master production and control records. The letter states:

“QC personnel created unauthorized folders on laboratory computerized systems without appropriate oversight. Our review of the HPLC Empower III data collected in 2013–2014 in the commercial QC laboratory found a data folder entitled ‘WASH.’ According to your management, the folder was intended for column wash injections using blank solvent prior to and following sample runs, although you have no standard operating procedure (SOP) detailing this process. One of your laboratory analysts stated that this folder does not contain any standard or sample injection results. However, our investigator found that this folder contained a total of 3,353 injection results, some of which appeared to be samples.

“Your analyst confirmed that the single injection titled ‘19’ in the ‘WASH’ folder represented a trial sample injection performed prior to the official analysis of (b)(4) Tablets on December 19, 2013. From this chromatogram in the ‘WASH’ folder, our investigator documented an unidentified impurity at relative retention time (RRT) (b)(4) calculated at a concentration of (b)(4)%. However, the specification for any unidentified impurity is (b)(4)%.  You neither investigated nor reported this out-of-specification (OOS) result.


“Your firm acknowledged that the analysts involved in performing single injections failed to follow good laboratory practices described in the SOP ‘General Laboratory Working,’ and that the analysts conducting the injections in question made decisions to perform unauthorized, unapproved injections. Your response indicates that, during an interview of the laboratory analyst conducted approximately six months after the incident, you determined that he may inadvertently have used an old sample vial from the LC tray for the single injection made for the purpose of a column wash.  We question your conclusion about the likely cause without having any supporting documentation or record, and based only on memory of what may have happened six months earlier.”

According to FDA, the company also failed to establish appropriate procedures to prevent objectionable microorganisms in drug products. “During the inspection of the QC Microbiology Laboratory, our investigators observed missing in-progress microbiological test plates for various finished drug products, in-process products, water, and media growth promotion samples. … The FDA investigator noted other instances of missing samples/plates for in-process drug products, potable water, and growth promotion, even though records indicated that they were in the incubator.”

Apotex’s quality control unit also failed “to review and approve all drug product production and control records to determine compliance with all established, approved written procedures before a batch is released or distributed (21 CFR 211.192). … Your quality unit is responsible for assuring that your firm is operating in a sustainable state of control throughout the manufacture and lifecycle of all drugs produced at your facility. Your quality unit has the overall responsibility for oversight and approval of quality related activities. As part of your corrective action and preventive action plan, please describe how your quality unit will provide consistent, adequate review and approval of investigations and production batch records.” 

In the letter’s conclusion, FDA stated, “The foregoing examples are of serious cGMP violations demonstrating that your quality system does not adequately ensure the accuracy and integrity of the data generated at your facility to ensure the safety, effectiveness, and quality of the drug products you manufacture.” 

Source: FDA.gov