Warning Letter Posted on Troubled Cadila Drug Facilities
FDA has posted a Warning Letter (see earlier story) to India’s Cadila Healthcare that cites numerous GMP deviations following two 2014 inspections its Moraiya formulation facility and Ahmedabad active pharmaceutical ingredient (API) facility. Company officials have reportedly initiated steps to transfer some products to other manufacturing sites.
At the Moraiya facility, the agency says its investigators found that the firm did not adequately investigate out-of-specification laboratory test results involving potency and content uniformity specifications for warfarin sodium. After the inspection, the firm suspended warfarin production for two months while it corrected the findings. However, in a 2015 meeting with FDA officials, the firm acknowledged that additional lots had failed since it resumed manufacturing, according to the Warning Letter.
FDA says this recurring quality problem was also identified in a 2013 inspection, which revealed inadequate process controls and complaint and failure investigations related to warfarin tablets. It notes that a recall was also conducted that year for warfarin 2 mg tablets because of a failed assay and oversized tablets.
“The recurrence of these failures is apparently due to inadequate identification of root causes and lack of action to resolve this manufacturing problem,” the letter says. “These persistent failures indicate that your manufacturing process is not in a state of control. Nevertheless, at this time, drugs from this facility are being released to the market.”
At the API facility, the Warning Letter says the inspection found that the firm obtained failing results for related compound analysis in four undisclosed API batches. “You did not identify the root cause of these failures, and reprocessed the failed batches without scientific justification,” the letter says.
The API inspection also raised data integrity concerns. The Warning Letter says the firm failed to exercise sufficient controls over computerized systems to prevent unauthorized access or changes to data. For example, it says the firm “failed to adequately control the use of computerized systems in the quality control laboratory. Our inspection team found that the laboratory manager had the ability to delete data from the Karl Fischer Tiamo software. During our limited review of your Karl Fischer data, we found that one file had been deleted. However, because the audit trail function for the Karl Fischer Tiamo software was not activated, and because eight different analysts share a single username and password, you were unable to demonstrate who performed each operation on this instrument system. You do not have a record of the acquisition of all data, nor do you have records of changes to or modifications of such data.”
The agency says the facility also failed to ensure that all quality-related activities are recorded at the time they are performed. FDA investigators found that employees use “rough or unofficial notebooks” to document various GMP activities. One “unofficial” notebook entry stated that Pseudomonas was present in the water system, but the firm could not provide the investigators with any documentation regarding this and any subsequent investigation, according to the Warning Letter.
Additionally, FDA investigators found several plastic bags filled with paperwork and other scrapped items in the scrap yard. One item was a torn notebook of deficiencies recorded during a review of the facilities batch manufacturing records. “In your response of 12/26/2014, you stated that these were personal notebooks intended only for meeting and other discussion notes,” the Warning Letter says. “Your response did not explain why your production personnel used unofficial paper for documenting GMP relevant data. Your response also did not explain whether the lower-yield event was investigated. Your batch records should include complete information related to the manufacture of each batch, including notation of any deviation, its evaluation, and investigation.”
The Warning Letter asks that the firm conduct a “comprehensive investigation and evaluation into the failures underlying these violations. Describe your methodology, including the role of an independent third party if you choose to engage one. Include detailed conclusions about the extent of your data integrity deficiencies and their root causes, which may involve lack of record control, non-contemporaneous recording, deletion of data, and other problems with the integrity of data.”