New Delhi: The US Food and Drug Administration (FDA) has sent a warning letter to the Indian pharmaceutical company Lupin Limited after deeming its efforts to address violations of various good manufacturing practices at its facility in Tarapur, Maharashtra “inadequate”.
The FDA sends a ‘warning letter’ to a manufacturer if it has “significantly violated” the agency’s regulations. Violations may be poor manufacturing practices, problems with claims for what a product can do, or incorrect directions for use. The manufacturer is directed to correct the problem within a specific timeframe.
A warning letter comes after a Form 483 is issued, which the US drug regulator hands out after the inspection of a company’s plant and finds any aberrations on site which constitute violations of the US’s Federal Food, Drug, and Cosmetic (FD&C) Act and other related Acts.
The US FDA’s warning letter says the company’s active pharmaceutical ingredients or APIs that are used in making drugs were found to be adulterated and in violation of its Current Good Manufacturing Practice (CGMP).
Lupin, a transnational company, produces a range of pharmaceutical products, including generic medicines, branded medicines, APIs, biosimilars (drugs similar to approved drugs) and has 15 plants in India, the US, Brazil and Mexico.
According to the company’s website, the Tarapur plant – where the alleged violations occurred – produces “both fermentation-based and synthetic APIs”.
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Lupin Ltd, while disclosing the receipt of the Form 483 in April, had said that it was confident of addressing the concerns raised by the US FDA. However, the regulator was not satisfied with the response and issued the warning letter in September but posted it online only last week – after the necessary redactions mentioned as ‘(b)(4)’.
The warning letter says, “Your response is inadequate because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP.”
The warning letter, which was issued on September 27, 2022, asked the company to respond within 15 days – or before October 11. “If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion,” it said.
The Wire wrote to the company asking if it had responded to the warning letter. While the email went unanswered, the company spokesperson said over the phone, “We would have submitted the response within the stipulated timeline.”
The spokesperson refused to give additional details regarding the response and also asked that their name is not mentioned because they were not the “official spokesperson for the company to talk about regulatory matters” and only handled media enquiries.
In response to an email that The Wire sent, the US FDA also refused to share details since it was an “ongoing compliance matter”.
US FDA. Photo: Reuters
Why was the warning issued?
The warning letter cites three specific concerns – all related to what is known as ‘genotoxic impurities’ that were found in drugs and APIs. Genotoxic impurities may alter the structure of DNA in a human cell and may cause cancer, depending on the type of impurity.
But the letter adds that the “deviations” cited in the letter are not intended to be an all-inclusive list of deviations that were found at the facility. “You are responsible for investigating and determining the causes of any deviations and for preventing their recurrence or the occurrence of other deviations,” it says.
The first concern that the FDA listed is about the cleanliness of the equipment that was used in manufacturing the drugs. The names of the drugs have been redacted in the letter. It states that the company performed multiple investigations to assess whether the existing cleaning procedures of the equipment eliminated or reduced genotoxic impurities, “after certain impurities were detected in API”.
The company also performed tests to assess if cross-contamination of the equipment (used in the manufacture of the drugs in question) was prevented from the equipment which was not in use. The letter stated the response given by the company lacked sufficient data to establish that the cleaning procedures were robust in doing both these jobs.
“The identification of genotoxic impurities in quantities near their established limits suggests excursions are possible,” the letter stated.
“All intermediates and API manufactured on non-dedicated equipment [equipment which was not ideally dedicated to manufacturing the API in question and was yet used] to manufacture [the drugs in question] should be subject to validated sampling and analytical testing to ensure they are not contaminated with unacceptable levels of genotoxic impurities,” the warning letter stated.
It also accused the company of rejecting the “unfavourable data” that its studies generated on this subject “without appropriate scientific justification.” To address this concern, the FDA had asked the company to do an “independent retrospective assessment of cleaning effectiveness to evaluate the scope of cross-contamination hazards.”
The second concern that the FDA raised is about the company’s refusal to properly assess the effectiveness of the processing steps which theoretically reduce the genotoxic impurities. The letter said the company performed a slew of ‘benchtop studies’ and found that “impurities are purged out effectively and there was no additional need for in-process monitoring.” But the commercial studies of the same batches of the API showed that the purging steps did not remove all “genotoxic impurities to a consistent level”. And yet, the company did not further investigate and declared that “the manufacturing process [was] capable of effectively purging this impurity”.
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The third concern is the failure to investigate all critical deviations. The letter said the report submitted by the company missed the ‘out-of specification’ results despite them being clearly available for a particular batch of the drug.
Meanwhile, the company has suspended the production of drugs from the Maharashtra facility for the US market and the FDA has asked it to notify its office in case it planned to resume supply. The letter also asked the company to correct deviations ‘promptly’.
“[The] FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any deviations are completely addressed and we confirm your compliance with CGMP,” the letter stated.
Another plant of Lupin, based in Pune, is also under the FDA’s scanner. The US regulator has issued another Form 483 for 17 adverse observations about the site and the company has once again responded that it would ‘expeditiously’ adhere to the concerns. The Pune facility is involved in the development and commercialisation of biosimilars for global markets, the company’s website says, adding that it has “state-of-the-art facilities for production of biologics using microbial and mammalian platform technology”.