The FDA told FE that it had given as many as 403 intimations of violations of its manufacturing norms to Indian plants in the period from 2011 to November 2013. That these were indeed minor violations, customarily to mention in the inspection report (formerly called Form 483) is evident from the fact that in the six financial years to FY14, only 21 warning letters were issued to Indian plants.
It is not obvious, therefore, that Indian companies should be subjected to such stiff and fractious scrutiny. What could give further credence to the notion that the FDA may be a bit more suspicious of Indian plants than those elsewhere is
that close to a fourth of USFDA inspections for Good Manufacturing Practices (GMP) outside the US are conducted in India. Of course, India has 526 US-FDA units, (second only to China, which has 960 such units), but even China attracts only 10% of the FDA inspections outside the US.
Most top-notch Indian drug companies have the larger chunk of their revenue coming from the US and the rest of North America. According to a JPMorgan report, Indian companies produce approximately 40% of generic drugs and over-the-counter products and 10% of finished dosages in the US.
When it comes to FDA’s serious crackdown (such as bans/import alerts), at the receiving end has mostly been plants in Mexico, Canada and the UK, showing that GMP negligence is found more in those countries than in India or China. While 74% of Mexican drug-making sites registered with FDA are under a ban, around 30% of Canadian and British manufacturing facilities approved by the FDA to supply medicines have been issued an import alert. The FDA data show that 403 Form 483s were issued to Indian facilities since January 2011 to November 2013, with the highest number of 155 in 2012. The data include adverse reports issued to drug manufacturers, food product makers and bio-research monitoring individuals.
“Observations are made when in the investigator’s judgment, conditions or practices observed would indicate that any food, drug, device or cosmetic has been adulterated or is being prepared, packed, or held under conditions whereby it may become adulterated or rendered injurious to health,” the USFDA guidelines state.
The USFDA does not make public the details or issuance of a Form 483 while companies have seldom disclosed the receipt of this document. No details of the alleged violations were provided to FE.
A Form 483, theoretically, is a precursor to a warning letter, if the issues identified during an investigation remain unresolved. A warning letter may lead to an import alert if the violations continue to remain serious and the regulator anticipates them to pose a significant risk to US citizens.
Sun Pharmaceuticals Industries, India’s largest drug firm by sales, received five Form 483 in the period mentioned above, four of them in 2012. Sun Pharma’s Karkhadi facility located in Gujarat, inspected in November 2013, was the latest Sun facility to get a warning letter.
“The issuance of a Form 483, or a list of observations, is a usual practice after the USFDA completes its inspection of a plant. This includes all types of observations as may be appropriate for the facility. As a company with a long-term interest in the US pharmaceutical market, we remain compliant at all times and close out the 483s as soon as possible, either internally or along with an external consultant as may be appropriate,” Sun Pharmaceutical said, when asked about whether the issues identified in its facilities were resolved as on date.
Sun Pharma’s Caraco facility in Detroit had received a warning letter in 2008 which was lifted in August 2012. Its New Jersey unit was also the recipient of a warning letter in 2010 which was later resolved in October 2011.
Mumbai’s Glenmark Pharmaceuticals’ subsidiary Glenmark Generics received two Form 483s in 2013 and two in 2011. The company’s Colvale Bardez facility in Goa received negative observations in 2011 and again when it was inspected in July 2013. The other two units to receive the Form were its Ankleshwar and Indore units.
“We have been inspected several times over the last few years and we believe that we are compliant on all our manufacturing facilities. We believe that we have no outstanding issues with the FDA at this point in time,” Glenmark said.
Mumbai-based Lupin received three Form 483s, of which one was issued against Lupin Bioresearch Center in Pune. The other two facilities were its Madideep unit located in Madhya Pradesh and its unit in Indore. The company has not responded to queries regarding whether the facilities are now cleared by the FDA. Three of Dr Reddy’s Laboratories’ manufacturing facilities were inspected in 2012 – while one was checked in 2011. The Hyderabad-based company said that all 483s were resolved to the satisfaction of the regulator. The company’s Mexico facility received a warning letter in June 2011 which was cleared in July 2012.
“Regulatory headwinds remain one of the key risks to the Indian pharmaceutical sector especially in light of the increasing scrutiny by the USFDA to ensure quality and compliance. While the volume of warning letters issued by USFDA has increased over the last four years, there has been a higher impact on Indian companies recently from the increasing activities of the US regulator (import alerts, warning letters, Form 483s),” a JPMorgan report dated Sept 2013 said.
Eight Indian companies received US-FDA warning letters in FY2013, all of which are still being resolved.
Wockhardt Ltd and Aurobindo are some of the Indian companies that have faced the short end of the regulatory straw in the last two years. While Aurobindo has resolved the import alert issued against its unit-VI cephalosporin facility in Hyderabad facility in March 2013, Wockhardt and Ranbaxy are still struggling to get USFDA nod for its units.
Wockhardt, whose Waluj and Chikalthana units are already facing an import ban for deviations from current good manufacturing practices, received six visits from the USFDA during 2013, of which five resulted in Form 483s. The latest of the five was for the Mumbai-based company’s Baddi unit located in Himachal Pradesh – which was inspected in September, 2013. Gurgaon-based Ranbaxy has three of its units under an import ban, located in Mohali, Dewas and Paonta Sahib. The company’s units were investigated eight times in 2011 and 2012, with no inspection conducted in 2013.
Yusuf Hamied-led Cipla has received eight Form 483s after inspections were conducted in 2011, 2012 and 2013. Its units located in Dhar in Madhya Pradesh and Goa were checked in March and May, 2013. Cipla did not reply to an email inquiring about the status of clearance of the Form 483s.
Other BSE-listed companies which have received Form 483s in 2013 are Torrent Pharmaceuticals, Cadila Healthcare, Ipca Laboratories, Indoco Remedies, Jubilant Lifesciences, Divi’s Laboratories, RPG Lifesciences, Piramal Enterprises and Alembic Pharmaceuticals.
Torrent said observations made by the US-FDA against its plants were minor in nature while Hyderabad-based Granules India said: “There were no major observations, we have, in fact, received an Establishment Inspection Report (EIR) stating that everything is good and the inspection is closed.”
“Response was provided to USFDA for the 483’s received during audit. FDA reviewed our responses and found satisfactory. Establishment Inspection Report was issued by the US-FDA classifying both the facilities as acceptable with respect to cGMP compliance,” Jubilant Lifesciences said.
Other companies named above did not respond to FE queries.
Indian companies are not the only ones facing the brunt of increased scrutiny. The world’s second largest drugmaker by revenue Mylan Inc’s Indian subsidiary Mylan Laboratories has received seven Form 483s since 2011 with two of them in 2013. In October 2013, its Hyderabad facility and in November 2013, its unit in Visakhapatnam got adverse reports.
Bangalore-based Strides Arcolabs’ unit, Agila Specialities – which was bought by Mylan for $1.6 billion in the biggest deal in the pharmaceutical space in 2013 – had said in September that its Sterile Manufacturing Facility 2 (SFF) in Bangalore received a warning letter after an inspection conducted by the overseas regulator in June 2013.
“We take any FDA observation very seriously, and we are fully committed to drug quality and see every observation as an opportunity for the industry to continue to improve. We have either already addressed the agency’s observations or are working diligently to address the observations as quickly as possible, and we are confident in being able to resolve them satisfactorily,” Pennsylvania-based Mylan Inc President Rajiv Malik said.
“(US) FDA measures you against a cGMP – current good manufacturing practices – and standards keep on evolving, so what was current yesterday may not be current today. FDA also does not have a very standardised tool to measure cGMP compliance. It means that different inspectors have their own subjectivity towards some of the things and there may be differences of interpretation of the same data by different inspectors,” a senior executive at a multinational drug-maker said on condition of anonymity.