FDA cites repeated, fundamental cGMP issues in its warning letter to Torrent Pharmaceuticals

October 17, 2019
Agnes Shanley

Agnes Shanley is senior editor of Pharmaceutical Technology.

Emphasizing the need for senior management to take cGMP compliance seriously, the agency pointed to “improvisational” validation procedures, lack of compliance with written procedures, as well as inadequate process control, root cause analysis, and corrective and preventive action (CAPA) in its warning letter.

On October 8, 2019, the FDA issued a warning letter to Torrent Pharmaceuticals, based in Gujarat, India for current good manufacturing practice (cGMP) compliance problems that inspectors found during an inspection of the company’s facility in Indrad in early April 2019. In what is becoming a familiar theme, the warning letter mentions that these problems had previously been found in a previous inspection of the facility in April 2017.

According to FDA, the company failed to follow written procedures for production and process control. One major problem was the fact that written process validation protocol was not followed. Official protocol required that three consecutive batches of any alternative API used in manufacturing meet specific quality specifications.  

Instead, the warning letter states, operators and technicians opted for an undocumented approach.  After the first of three process validation batches failed dissolution tests, the letter says, they tested a fourth batch (which also wound up failing dissolution tests).  That fourth batch had never been specified in the company’s validation protocol. After out-of-specification (OOS) investigations were launched, all four batches were rejected. 

The company developed an “interim” protocol to support use of the alternate API, FDA’s letter said, even though it had data showing that the process cold not produce material of adequate quality.  As a result, a number of out-of-spec Losartan potassium tablets (both USP 50- and 100-mg) were shipped to the United States (where they were later recalled for unacceptably high levels of nitrosamine impurities).

In its previous response to an FDA 483 triggered by a facility inspection, the company had even stated that the change in API had no impact on the product’s manufacturing and quality, the letter stated.  Torrent had not investigated the root causes of the batch failures, or provided justification for changing the API it used in the manufacturing process, according to FDA. 

After outlining the specific examples of noncompliance, the letter then defined the philosophy behind process validation and process qualification studies. FDA has asked for a detailed summary of the company’s validation program, and how it will ensure a state of control throughout the product lifecycle. FDA also requested clarification of how the company will perform monitoring of variation within and between different batches of product to demonstrate control, and also asked for a timeline for performing process performance qualification of each of its products. 

Lack of insight into reasons for out-of-specification (OOS) results

The agency found multiple instances where initial OOS results were invalidated without sufficient investigation.  Between January 2017 and March 2019, FDA’s letter stated, the facility had invalidated between 60 and 70% of initial OOS test results and had not followed up to find root cause. In its response to FDA last Spring, the company stated that OOS results had fallen from 77% to 41% between January 2017 to March 2019.

Pointing out the connection between OOS investigations and CAPA, FDA noted that the company had been criticized for these deficiencies previously, in inspections at its Indrad facility in April 2017 and at its Dahej plant in March 2019.

“Repeated failures at multiple sites demonstrate that executive management oversight and control over the manufacture of drugs is inadequate,” the letter said, emphasizing the fact that senior managers bear the final responsibility for ensuring cGMP compliance. It asked for:

  • an independent, third-party review of all invalidated OOS (including in-process and release/stability testing) results for products currently in the US market.

  • a report explaining whether laboratory error was at the root of the problem, or, if that was not the cause, a full review of production including batch manufacturing records, variability of raw materials, process capability, deviation, complaint, and batch failure histories.

  •  Summaries of potential root causes for each investigation, and a comprehensive review and remediation plan for systems used to investigate OOS results.

FDA’s letter states that it may withhold approval of any new drugs that the company may have under review at the agency, and refuse to allow products made at the facility to be sold in the US, it asked for a written response within 15 days.

Source: FDA Warning Letter to Torrent Pharmaceuticals, October 8, 2019.