BackWhy regulating nitrosamines in India will prove challenging
Unlike the US drug regulator, however, the Indian drug regulator, CDSCO, does not yet require the pharma industry to control for nitrosamines. This means that firms that supply to the Indian market are currently left to their own devices
PremiumNote: This is an accompanying piece to the story ‘The toxic drug impurity imperilling Indians’.
In April 2021, quality-control professionals from several Indian pharmaceutical firms attended a panel discussion on nitrosamine contamination in drugs. The firms, all of which supply to the US market, had recently been hit by the US drug regulator’s stringent new nitrosamine-control regulations. During the hour-long discussion, organised by the United States Pharmacopoeia—the body that sets drug quality standards for USA—they spoke about the difficulties in adhering to these rules. Rajiv Desai, the global quality head of the Mumbai-based Lupin Limited, talked about the challenges posed by the fact that nitrosamines could be formed anywhere in the pharma value chain: in reagents, solvents and excipients, or during storage. “It's just churned around the entire industry," Desai said, “Not a single area of the manufacturing process has been left untouched by this impurity".
Unlike the US drug regulator, however, the Indian drug regulator, CDSCO, does not yet require the pharma industry to control for nitrosamines. This means that firms that supply to the Indian market are currently left to their own devices; this includes the Indian arms of multinational firms that supply to the USA. But the panel discussion showed that the Indian industry won’t have it easy if the CDSCO changes its stance. The industry will then have to take a close look at its manufacturing processes, rejig some of them, and invest substantially in both equipment and training.
Trace and control
Nitrosamines are typically formed when nitrosating agents react with amines. So, to ensure drug safety, the USFDA has asked firms to evaluate if any part of their value chain, from raw materials to storage conditions in pharmacies, can create such nitrosamine building-blocks.
This evaluation isn’t easy. For a large drug maker, it means reaching out to hundreds of raw-material suppliers. These suppliers, who make active pharmaceutical ingredients, reagents, solvents, excipients or inks, will then have to assess whether their products contain impurities such as nitrites (nitrites are nitrosating agents). Being small firms, these suppliers often lack the in-depth understanding of their products to make this assessment, Kacharu Toshniwal, a business unit head at Ahmedabad-based Zydus Cadila, said during the April panel discussion. “That is a very big pressure point."
And the same time, such risk-evaluations cannot be done away with. The other option would be blanket nitrosamine testing for every drug, which isn’t straightforward either. Nitrosamines are dangerous to humans even at levels of a few parts per billion, and a chemist cannot detect such ultra-trace levels by blanket testing alone, says Edwin Gump, vice president of the small molecules department at the United States Pharmacopoeia. The chemist must know exactly which nitrosamine they are looking for—whether NDMA, NDEA or NMBA—and must then design a suitable method to detect it. This is where a risk evaluation comes in, because it can help predict which nitrosamine can possibly form.
The equipment
In July this year, the US Pharmacopoeia published a set of methods to detect seven types of nitrosamines in blood pressure drugs called sartans. These methods use four types of instruments, known as Liquid Chromatography-High Resolution Mass Spectroscopy (LC-HRMS), Liquid Chromatography – Tandem Mass Spectroscopy (LC-MS-MS), Gas Chromatography- Tandem Mass Spectroscopy (GC-MS-MS) and headspace Gas Chromatography- Mass Spectroscopy (Headspace GC-MS). All of these are highly sensitive instruments that can detect chemicals at parts per billion levels.
The problem is that these instruments are currently not widely available in the pharmaceutical industry. In 2019, when the CDSCO asked pharma companies to test for nitrosamines, many small- and mid- scale manufacturers in Maharashtra approached the state regulator to say they didn’t have the required instruments, says DR Gahane, the joint commissioner of Maharashtra Food and Drug Administration. The CDSCO’s own drug laboratories lack the instruments mentioned in the US Pharmacopoeia methods as well, as do several state drug laboratories.
And these instruments don’t come cheap either—an LC-HRMS or an LC-MS-MS system can cost upto ₹2 crore, several sources told Mint. Even large drug makers, who currently have such instruments, may not have them in the sufficient numbers to meet their testing needs, says Muralee Krishna Unguturu, chief scientific officer at the Hyderabad based contract research firm, Vimta Labs. Faced with the requirement of meeting the USFDA’s regulations, many Indian firms are now buying new instruments, or turning to contract researchers like Vimta.
But buying the instruments isn’t the end of the story, because these instruments aren’t plug-and-play devices. Pharma firms require skilled personnel to run them and to develop the right testing methods. The methods published by USP in July this year have been shown to work only for some sartan drugs, and cannot be used, unmodified, for others. “No one method is perfect for (every) product. Even for a (single) product, at times, you may have to check multiple methods to ensure that what you're reporting is the correct nitrosamine," Rita Santhakumar, head of analytical research at the Mumbai-based Sun Pharma, said during the April panel discussion.
Unfortunately, as on today, quite a few small firms lack either the infrastructure or the skills to test for nitrosamines, said Rajender Kumar Potlapally, senior director, synthetics, at US Pharmacopoeia’s Hyderabad office. “Neither do they have the knowledge, nor the capabilities, nor the instrumentation."
Missing guidance
The two agencies that will play a major role in ensuring nitrosamine-free drugs for Indian consumers are the CDSCO and the Indian Pharmacopoeia Commission (IPC), the Indian equivalent of the US Pharmacopoeia. While it is CDSCO’s responsibility to regulate nitrosamines, it is the IPC’s job to develop testing methods for the Indian context. But both agencies are lagging behind on this task.
The reason the IPC must develop methods for the Indian market, instead of relying on the US Pharmacopoeia’s methods, is that the latter body is focused on drugs sold in the USA. On the other hand, several drugs available in India today are unavailable in the USA; ranitidine is one current example.
Another key responsibility of the IPC is to sell so-called “reference standards"—authentic samples of nitrosamines that chemists must use as a comparison while testing for nitrosamines. For instance, in order to detect NDMA in the anti-diabetes drug metformin, a drug maker will need an NDMA reference standard.
However, IPC hasn’t published any testing methods yet; nor is it selling nitrosamine reference standards. In an email interview with Mint, Rajeev Raghuvanshi, scientific director of the IPC, said the agency had begun work on testing methods, but only planned to publish them by 2022. As for reference standards, he said that Indian entities could use reference standards from the US Pharmacopoeia, if those standards weren’t yet available with the IPC.
The problem is that while Indian pharma companies may be able to buy reference standards from the US Pharmacopoeia, this solution will not work for state drug laboratories. Scientists at several state drug labs told Mint that, being government set ups, they did not have the option of buying reference standards from the US Pharmacopoeia, because their prices are often higher than Indian Pharmacopoeia prices. And government labs are required to buy at the lowest price.
This means that if CDSCO ever regulates nitrosamines, enforcing these regulations is going to be tough for both CDSCO and state labs, because they neither have the equipment, nor the standards, to do so.
Priyanka Pulla is a Bangalore-based reporter covering health. Her reporting on Covid-19 is supported by a grant from the Thakur Family Foundation. The Foundation exerts no editorial influence on her work.
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