Marksans, whose product portfolio includes therapeutic segments of cardiovascular, central nervous system, antidiabetic, pain management, gastroenterology and anti-allergy drugs and whose market capitalisation stood at Rs 5,299.75 crore in August last year, has said that it is working closely with the US FDA to resolve the issue and is committed to address the observations “comprehensively”.
It also maintained that the observations do not include data integrity issues — considered more serious violations — that may lead to warning letters, considered serious escalation of form 483 when the FDA is not satisfied by the responses and action taken by the companies, and sometimes follows it with suspension of import by the defaulting companies.
Prior to the US drug regulator issuing this form to Marksans this week, a similar procedure was followed for three other Indian companies, Alkem Laboratories and Cipla, both headquartered in Mumbai, and another Indian pharma giant Zydus, in quick succession over the last three weeks.
ThePrint has seen copies of the forms issued to these firms. Alkem did not respond to email queries sent on action taken following the development. This report will be updated if and when a response is received.
Cipla said it takes all regulatory inspectional observations seriously and is committed to addressing any issues holistically and expeditiously.
With reference to the outcome of the recently concluded GMP inspection by the US FDA at Cipla’s Patalganga facility, the company said, it is important to note that the observations cited are procedural in nature.
“Additionally, the company would like to clarify that an observation pertaining to cleaning of equipment is related to two specific equipment — one of which was non-operational, and the other was under maintenance and repair at the time of the inspection,” it said. It added that none of the issues stated by US FDA have an impact on the quality of any products supplied from the facility or the site’s ability to continue manufacturing.
A Zydus spokesperson responded by saying that for the inspection which concluded in March 2024, the company is responding to the observations with effective corrective and preventive actions and is confident of addressing them.
Unending saga of quality lapses
Worryingly, these developments, which bring bad repute to the companies involved and stand to dent India’s standing as the “pharmacy to the world” are not isolated cases.
This tag had already taken a beating after a number of Indian pharma companies were linked with serious adverse reactions, including deaths, over the last two years, following supply of adulterated drugs and cough syrups to Gambia and Uzbekistan, among others .
But if smaller companies are accused of taking advantage of India’s lax regulatory norms in manufacturing substandard drugs for developing and underdeveloped countries in Africa and Asia with poor regulatory oversight, do those who export crucial generics to developed nations such as the US fare better? The answer, sadly, may not be in the affirmative.
The latest developments closely follow other episodes, which unravelled over the last six weeks — when at least three other Indian pharma giants namely Natco Pharma, Lupin and Glenmark — had to recall certain batches of three different drugs following US FDA enforcement reports.
These enforcement reports, seen by ThePrint, underlined violations in current good manufacturing practices at the drug manufacturing units of these companies in India.
Worse still, on 28 March and 8 April, warning letters were issued to Mumbai-based Kilitch Healthcare and Hyderabad-headquartered Natco Pharma respectively. These companies, too, did not respond to queries by ThePrint on what they are doing to address the observations made by the US FDA following inspections of their drug manufacturing units.
Pharmaceutical analysts say that while US FDA’s actions against Indian companies are not new, there is more limelight on the issue now, especially after one such action led to a serious shortage of cancer drugs in the US last year and forced it to turn to China.
In June last year the FDA ordered the halt of the import of life-saving cancer drugs by Gujarat-based Intas pharma — a key supplier of chemotherapy drugs such as cisplatin and carboplatin to the US — following gross GMP violations, including data integrity issues.
Intas Pharma did not respond to a query by ThePrint on what it was doing in response to an alert by the US FDA forbidding entry of future shipments of drugs originating from its facility in Gujarat’s Sanand into the US.
However, in response to email query from ThePrint on the status of this alert, the US FDA said that “in order for FDA to consider removing a product and/or firm from import alert or DWPE (Detention Without Physical Examination), FDA must have evidence that the conditions that gave rise to the apparent violation have been resolved and that gives FDA confidence that future entries will be in compliance with FDA laws and regulations”.
Pharmaceutical expert Salil Kallianpur termed this string of episodes “sad”.
“That’s because in the post pandemic world, where most countries around the world were shifting to a China + 1 approach, Indian companies have/could have benefited greatly, especially in the pharma sector where exports to the US are a very important part of growth plans for drug companies,” he told ThePrint.
Indian Pharmaceutical Alliance (IPA), a network of 25 research-based Indian drugmakers, most of whom are suppliers of generic drugs to the US, underlined that in recent years, bilateral trade between India and the US has been consolidating.
“The Covid-19 pandemic and the changing geo-political landscape has highlighted the significance of close India-US cooperation, particularly in the pharmaceutical sector,” said IPA secretary general Sudarshan Jain.
Jain also pointed out that the country had the largest number of USFDA-approved plants (603) outside of the US as of 2023.
According to him, the average of official action indicated (OAI) by the US FDA against Indian companies is not worse than the global average and it should be seen as an indication that, barring some lapses here and there, Indian pharma companies are at par with the best in the world.
“Importantly, the global average of OAI by the FDA in 2023 was 13 percent — out of 814 inspections undertaken — and it was the same 13 percent for 133 inspections conducted at its approved plants in India,” Jain insisted.
According to him, form 483 issued by the US FDA should be seen in context. “Such actions by the FDA are higher in number for drug making units globally, including the ones in the US because the regulator has gold standards in measuring CGMP requirements for a plant,” he said.
Figures shared by the IPA show that India’s pharmaceutical product exports to the US reached $7.55 billion in FY 2023, marking a 6.18 percent increase from the previous fiscal year ($7.11 billion in FY 2022).
For the period of April to October 2023, the export to the US was approximately $4.47 billion, reflecting an 11.98 percent growth compared to the same period last year, which was $3.99 billion, it showed.
But Kallianpur maintained that Indian companies must get their act together to be able to produce high quality generics for the US market and elsewhere.
A quality control analyst with a Hyderabad-based drugmaker who did not wish to be named conceded that most pharma companies, indeed, were battling an image crisis. “Internally these discussions and measures on how to strengthen the quality culture in our plants are being taken more seriously now. We understand that regulators in developed countries and even consumers are looking at us sceptically,” he said.
‘Regulation must keep pace with growth’
In response to queries by ThePrint, US FDA said that while the volume of drug manufacturing activity in India stands out in terms of its scope and scale, manufacturing and quality challenges encountered by investigators are “largely similar to those seen around the world in manufacturing”.
“Protecting patients is the highest priority of the FDA and the agency remains committed to using all available tools to oversee the safety, effectiveness, and quality of FDA-regulated products,” it said.
It maintained that drugs intended for the US market manufactured outside the country must meet the same standards as drugs made in the US. “As drug manufacturing has globalised over the years, we have modernised our programs to help ensure that companies–regardless of where they are located–continue to meet the FDA’s strict standards for producing medicines for US patients that are high quality, safe and effective,” it said.
According to the regulator, “some inspections” of facilities in India found deficient manufacturing practices that do not meet US product quality standards.
The FDA communicates these violations to pharmaceutical manufacturers and urges them to take actions to address these issues to protect the health and safety of US patients, it said.
The regulator also said it has identified significant data integrity issues at some facilities in India, and takes such data integrity lapses “very seriously”.
“In response to significant data integrity problems, we have taken appropriate actions, including issuing import alerts and warning letters. Additionally, the FDA and our international regulatory counterparts regularly exchange information about quality and data integrity violations observed in different facilities around the world,” it informed ThePrint.
Highlighting that it is collaborating closely with industry and governments to support access to safe, effective, and high-quality medications manufactured in India, the FDA said “it is critical that India’s regulatory infrastructure keeps pace with the growth of the drug manufacturing industry in India to ensure that relevant quality and safety standards are met”.
Data shared by the regulator shows it carried out 672 drug quality assurance inspections in India over the last five years. Of these, the highest (200) were carried out in 2019 followed by 146 inspections in 2023.
ThePrint reached Rajeev Singh Raghuvanshi, the Drugs Controller General of India, who heads the Central Drugs Standard Control Organisation (CDSCO), over calls for his perspective on the comments shared by the US FDA but received no response by the time of publication. This report will be updated if and when a response is received.
Looking at alternatives?
After the US FDA stopped importing drugs like cisplatin from Intas last year, the US started evaluating Chinese companies such as Qilu Pharma, to fill in the gap.
But a senior official in the Department of Pharmaceuticals under the Ministry of Chemicals and Fertilisers stressed that this was only a temporary measure and not one that could hit Indian pharma exports in the long run.
Though the US FDA did not categorically answer ThePrint’s query on whether the US is looking at alternatives for suppliers of generic drugs to the country, Dinesh Thakur, a public health expert focused on improving health policy in the US and India, said that the US already seems to be looking for alternatives to the Indian supply chain because of sustained problems with Indian companies.
“Unfortunately, China is no better. They have had their own problems and the geopolitical nature of the US-China relationship is not conducive to moving the supply chain to China. I see two things happening, time will tell which one is sustainable,” Thakur said.
“Manufacturing is coming back to the US — example is Civica Rx — they are manufacturing many old generics in the US today. Second, Vietnam is emerging as a strong alternative to India. They are doing everything right when it comes to manufacturing quality and building capacity to take over our business,” he said.
Civica Rx, a non-profit generic drug company, was founded in 2018 by leading philanthropists for the purpose of preventing and mitigating drug shortages in the country.
Thakur, co-author of the book The Truth Pill: The Myth of Drug Regulation in India, also suggested that Europe is also actively disengaging from supply chains based in India. “In fact it is taking various measures to become self-sustainable and not be dependent on the vagaries of the Indian drug manufacturing sector,” he opined.
But figures shared by Uday Bhaskar, president of the Pharmaceuticals Export Promotion Council of India (Pharmexcil), an agency under the Union Ministry of Commerce and Industry, do not support this claim.
Statistics shared by the organisation show that India supplied drugs worth $2513.32 million to the US in February 2024, as opposed to drugs worth $2055.97 in February 2023.
“This is a robust growth of over 22 percent,” Bhaskar told ThePrint.
Pharmexcil figures also show that India exported pharmaceutical products worth $25.4 billion in 2022-23 of which the largest share ($8327.24 million) was supplied to countries which fall under the North American Free Trade Agreement (NAFTA) region, namely the US, Canada and Mexico. These figures also show that nearly 30 percent of all Indian pharma exports are meant for the US.
Thakur, had a counter argument. “The figures indeed look promising but if they (Indian pharma companies) look at three years ahead, do they think they will have similar growth? That is the question. It’s not about what they are draining right now, it’s about how sustainable this market is for them in a few years,” he said.
When it comes to sterile projects such as injectables, which command a higher price compared to solid oral dosage like tablets and capsules, can they provide a break-up for the last three years, he asked.
IPA’s Jain said the group had no such break-up readily available of drugs supplied to the US but insisted that Indian pharma companies will continue to do well. His argument was supported by a pharma analyst associated with a US-based asset management company.
“In my view, Indian firms are mitigating risk by filing from alternate facilities and as long as there is no data integrity issue, they should be able to address the compliance issues over a 1-1.5 year cycle,” said the analyst, who did not want to be named.
Kallianpur said after China, India is the only other large market with manufacturing scale to meet US requirements and it must continue to expand its export portfolio on the back of high quality products — which is non-negotiable.
With China facing deflationary conditions and inflationary conditions easing in the US and the European Union, demand for low-cost, high quality medicines will only increase. India must capitalise on this long-term trend and not compromise for short-term profit, he said.
(Edited by Amrtansh Arora)
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