During a June 23, 2014 through July 1, 2014, inspection of the Apotex Research Private Limited (ARPL) manufacturing facilities located at Plot #1 & 2, Bommasandra Ind. Area, 4th Phase, Jigani Link Road, Bangalore, India, investigators from the U.S. Food and Drug Administration (FDA) identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations caused their drug products to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 351(a)(2)(B), in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding did not conform to, or are not operated or administered in conformity with, CGMP.
The FDA conducted a detailed review of the firm’s response dated July 22, 2014 and noted that it lacks sufficient corrective actions. They also acknowledged receipt of the firm’s additional correspondence dated August 11, 2014, August 29, 2014, September 30, 2014, October 31, 2014, December 5, 2014 and January 9, 2015.
The investigators observed specific violations during the inspection, including, but not limited to, the following:
- Your firm failed to establish and follow appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile (21 CFR 211.113(a)).
“On June 23, 2014, 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. For example:
- Finished drug product (b)(4) Tablets (b)(4)mg batches (b)(4) and (b)(4) microbial sample plates/tubes were placed in the incubators on June 19-20, 2014, as documented in your LIMS computer system. The plates should have been incubated for (b)(4) days, per your procedures. On June 23, 2014, no plates/tubes for this batch were observed in any of the incubation chambers.
- Finished drug product (b)(4) Tablets (b)(4) mg Exhibit Batch (b)(4) sample for microbial testing was prepared on June 13, 2014. Your firm failed to provide the FDA investigator with the worksheet to document the incubation times and media used for the analysis. Your analyst described that the entire microbial test for this batch had already been completed the previous week but that the analyst had “forgotten” to document the details on the worksheet.
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.
As a result of the above observation, your firm initiated an investigation and reported that 290 (b)(4) plates and 36 media tubes under testing were missing, affecting 45 product sample batches, 12 growth promotion test batches, and 37 negative control plates. Your firm also found discrepancies between the documentation and location of samples/plates and you indicated that the majority of the missing plates were found in the decontamination area for disposal.
In your response, you refer to an investigation and indicate that “…two analysts momentarily panicked (upon (1) learning that FDA Investigators were approaching the microbiology Lab and (2) seeing used petri plates from the weekend scattered throughout the laboratory)[sic] and directed the lab technician to immediately remove the petri plates from the microbiology lab … in an utterly misguided and ill-conceived attempt to clean up the microbiology lab prior to the start of the FDA inspection.”
Your response lacks a comprehensive risk assessment of your failure to follow procedures, your inadequate documentation system and your inadequate practices related to microbiological control. Your response failed to evaluate the effect of these violations on product quality, and did not include an assessment as to whether any other batches have been compromised.
ARPL’s inability to prevent and detect poor recordkeeping practices raises serious concerns regarding the quality system in place at the time of the inspection. Appropriate controls are essential to assure that the information used for making decisions is trustworthy, accurate, and reliable.”
When a firm fails with its procedures and recordkeeping practices, the Agency will consider these issues part of a larger problem to include Quality System issues. It is somewhat difficult to believe that the technician and the analysts panicked to such a degree that plates would be removed from the laboratory because the FDA Investigators were arriving. One would think that the entire facility would be aware of the FDA’s presence and continually maintain the facilities in a pristine condition. The failure to follow procedures, have good documentation practices and maintain microbiological control suggests a lack of training and proper internal management skills.
In addition, the dates of the incubation vs. the arrival of the FDA did not “hold water”. The FDA could readily review the dates of incubation to determine when plates and tubes would complete their incubation period based upon the Company’s SOPs and USP<61>. These forms of fabrication only cause the FDA to review the laboratory’s data in additional detail.