After an inspection of the drug manufacturing plant of Dr Reddy’s Laboratories (DRL) at Srikakulam in Andhra Pradesh that spanned nine days, inspectors of the United States Food and Drug Administration (USFDA) issued two adverse observations on April 4, 2017. Shortly before the close-out meeting that day, two senior employees of DRL in an unusual move “requested” one of the inspector to “remove the observations” claiming that they were “not significant”.
In the report, one of the USFDA inspectors wrote: “Mr Toshniwal and Mr Reddy Kallam requested that I remove the observations from the FDA-483. They indicated that the observations were not significant. I explained that the deficiencies were significant because they demonstrate conditions whereby laboratory data could be manipulated.” K S Toshniwal works as a vice-president at DRL. Sanjeeva Reddy Kallam works as director, central quality team. FDA-483 is the form through which adverse observations are issued.
For the 2017 inspection — from March 27 to June 4 —, the USFDA issued the establishment inspection report (EIR) to DRL in February this year. However, in the EIR, the regulator maintained the OAI (Official Action Indicated) status, which means the inspection is not yet closed.
The inspectors also noted in the report that “inspection delays were caused by the firm” as they had to repeatedly request for documents “which were not being provided as requested”.
The USFDA had issued a warning letter to the unit — designated “CTO VI” — at Srikakulam on November 5, 2015. This unit manufactures active pharmaceutical ingredients, which is raw material to manufacture medicines. Until DRL corrects outstanding issues to USFDA’s satisfaction, the regulator has the power to withhold approval of new products and new drug applications of the company, refuse admission of products manufactured at the facility into the US and issue an import alert. An import alert on a unit means that drugs can’t be exported to US from that unit till the alert is removed. DRL earned about half of its revenues in 2016-17 from the US market.
The USFDA inspector added: “I also indicated that I disagreed with removing the details in Observation 2, pertaining to the multiple templates that could be used to report and review the chromatographic data. I stated that I thought the 483 observations were fair. I stated that with a little more time, I would be including deficiencies pertaining to process validation.”
The inspector added: “I indicated that a comprehensive review of all changes including equipment, process, and corrections and validations… was requested multiple times; however was not provided in a manner which could be assessed during the span of the inspection. I stated that since the product quality reviews performed by the firm in response to the Warning Letter were limited to just (specific number) of the firm’s drugs, that each of the drugs should undergo a product quality review.”
On May 22, 2018, during the earnings conference call with market analysts, G V Prasad, CEO, DRL, stated: “So on Srikakulam, we are not yet clear whether it will require a re-inspection because the inspection, which happened was fairly straight forward. The FDA has asked us to do some additional work with respect to last year of working on the investigations and data. We are doing that. And, we expect to fulfill the request that FDA made with us in the next month or month and half. And after that, we will have to ask the FDA what next step should be.”
In response to the specific queries by The Indian Express, the DRL spokesperson stated: “Apart from official statements we put out to the stock exchanges and during our quarterly earnings calls, we do not comment on specific aspects related to any regulatory process or actions, as a matter of company policy.”
Many adverse observations were given verbally. The EIR stated: “Verbal discussions included the lack of appropriate follow-up and documentation for investigations, batch record instructions are not always complete or have sufficient detail to prevent batch to batch variability, and process validations are not always complete.”