India and the nitrosamine saga

In my recent article published in Mint (behind a metered paywall reset every month), I wrote about how India was dealing with the issue of nitrosamines – carcinogenic compounds that can contaminate drugs. Several wealthy countries, like the US, European Union countries, and Australia, are taking nitrosamine contamination very seriously. India, on the other hand, has been dragging its feet. Neither the central Indian drug regulator, CDSCO, nor state drug regulators, have undertaken nitrosamine testing; nor have they mandated that pharmaceutical firms keep nitrosamines within safe limits.

Soon after I wrote this article, I received feedback from several sources in a Clubhouse discussion and through other forums. I am summarising some of the feedback and questions raised here:

  1. When we talk about regulating nitrosamine impurities, we also need to talk about far more basic problems with the Indian drug supply

Nitrosamine impurities are a bit of a ‘cutting-edge’ problem, whereas the India regulator and the Indian Pharmacopoeia are yet to fix basic drug-quality problems like the enforcement of Good Manufacturing Practices or the use of up-to-date technologies to test for other, arguably more toxic, impurities.

Think of the diethylene glycol (DEG) poisoning that killed atleast 20 children in Jammu and Himachal Pradesh in 2020. DEG is a deadly chemical, which destroys the kidneys, and the children had consumed a cough syrup contaminated with it. DEG is an extremely well known pharmaceutical adulterant, there are suitable methods available to test for it, and Indian law has safeguards to prevent such poisoning. In other words, DEG is not like nitrosamines – it’s a far older story.

And yet, more than eighty years after the first recorded case of drug contamination with DEG in the USA, in which over 100 people died, India is still seeing children die from DEG-contaminated medicine. We already know that many very basic GMP failures occurred in the Jammu-Himachal-DEG case (look out for my article on this topic, coming soon). When we aren’t ensuring such basic quality checks yet (i.e pharma companies testing their raw materials for well-known toxins like DEG), can we really expect pharma companies to respond to the nitrosamine problem?

What’s more, nitrosamines are not the only area in which the CDSCO and the Indian Pharmacopoeia Commission (IPC) are lagging behind. The Indian Pharmacopoeia is frequently slow in keeping up with global scientific and regulatory changes, a pharma expert who runs an API/formulations firm told me. They cited the example of so-called elemental impurities. Elemental impurities, as the name suggests, are a range of elements that shouldn’t be present in medicines, because they are toxic and not of much therapeutic use. The most toxic among them are heavy metals like lead and arsenic, which can creep into medicines through mined excipients like talc and titanium dioxide.

Until very recently, most global pharmacopoeias used a now obsolete, 100+ year old test for these impurities. This test was neither particularly sensitive or specific – it couldn’t differentiate heavy metals from each other. To conduct it, a chemist must visually compare the colour of a solution containing the elemental impurity with the colour of a lead sulphide solution. If the colour of the test solution is lighter than the lead sulphide solution, it means total amount of heavy metals is within limits. One can imagine how crude this test would be; the expert told me that its results vary widely, depending on the lab lighting, glassware quality or even the eyesight of the person performing the test!

This is why the world is moving to better technologies and methods for elemental impurities. In a process that began almost a decade ago, and culminated in March 2019, the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) adopted new guidelines for measuring them. These guidelines set far more stringent upper limits for 24 elemental impurities, including many that cannot be detected in the color test. The colour test cannot detect the low levels prescribed by ICH anyway; if a pharma company wants to adhere to these limits, it must adopt more modern methods such as Inductively Coupled Plasma – Mass Spectroscopy (ICP-MS). Moreover, the ICH-Q3D, as the ICH’s elemental impurity guidelines are called, recommend a risk-based approach to testing. Instead of testing every product for every element, whether nickel, cadmium or arsenic, a manufacturer is advised to follow a more sophisticated approach: they must first assess the risk that the impurity is present, and then device a testing strategy for it.

Soon after, and in some instances, before, the ICH-Q3D was adopted, ICH members, like Europe, Brazil, the US and Japan have adopted these guidelines and updated their pharmacopoeias. The US subsequently knocked out the 110-year old color test for heavy metals. But India, as usual, is lagging behind. It continues to use the outdated color test, which also makes life hard for manufacturers who supply to US or Europe. Even though they may have conducted risk assessments for their medicines, and tested the medicines using ICP-MS, they still have to perform the obsolete color test to satisfy Indian regulators. “Liters of lead solutions used needlessly. Not good for the environment also,” the expert told me.

This is not the only example. There are many more monographs in the Indian Pharmacopoeia that have failed to keep up with global changes. Nitrosamines are just the latest in this line. More than one expert told me that given the costs and complexity of controlling for nitrosamines, the IPC and the drug regulator may drag their feet on bringing in new regulation, because many small Indian firms may not be able to keep up.

Still, there is some movement on the elemental-impurity front. The IPC website has published a general chapter on elemental impurities, along the lines of the ICH-Q3D, for comments from stakeholders. It’s hard to say if this general chapter will become official soon though, because complying with it would require small and medium manufacturers to conduct risk assessments, and perhaps invest in new infrastructure, like ICP-MS systems. All that is not necessarily easy.

2. How much will it cost Indian manufacturers to keep nitrosamine contamination in check?

When it comes to quality in the Indian market, the issue of cost is never far behind. If India adopts the FDA’s and EMA’s approach to nitrosamine contamination, all pharma companies will need to assess the risk that *any* of their products can potentially contain nitrosamines. This will, no doubt, cost small and medium firms a pretty penny. And India is a price sensitive market, with government programs like Jan Aushadhi trying to drive prices down further, without necessarily keeping an eye on quality.

Here is a look at why controlling for nitrosamines is neither easy, nor cheap for manufacturers. Consider a pharma firm, say ABC, which manufactures some 100 formulations and 50 APIs. For every formulation, this company will need to contact its API supplier and its excipient supplier, to understand the risk that these raw materials contain either nitrosamines, or the building blocks of nitrosamines (nitrites, amines etc). These building blocks could be present in the API or the excipient, or they could be impurities in the API or excipient.

Recall that this is how NDMA ended up in Zhejiang Huawei’s valsartan – a chemical (sodium nitrite) used to quench leftover sodium azide reacted with an impurity in the solvent dimethylformamide. In other words, NDMA was formed in a side reaction of the manufacturing process. To predict this kind side reaction, a manufacturer must have in-depth knowledge of their synthetic route, and every possible impurity that can arise from it. And I am told that many manufacturers, especially small firms who don’t invest in research, don’t have such knowledge.

Once manufacturer ABC completes its risk assessment and finds that one of its drugs has a high chance of being contaminated by, say, NDMA, they must test a few batches of the drug to show that the total NDMA levels are a small percentage of the limit allowed by regulators. If this testing reveals that NDMA is approaching the upper limit in multiple batches, ABC must start testing every batch of the final product, routinely.

To do this, it must invest in expensive apparatus – maybe a liquid chromatography-high resolution mass spectroscopy system (LC-HRMS), that costs upto Rs 2 crore. Then it must find a skilled professional to operate it, and that skilled professional must develop an appropriate method to test for NDMA in the drug. This is because a pharma company cannot directly copy publicly available testing methods: each drug and formulation requires a custom-test.

ABC must repeat this process for all of its 100 formulations and 50 APIs. As I reported in Mint, even large pharma companies like Sun Pharma and Zydus Cadila, are struggling with this challenge. How will small and medium firms deal with it?

Which brings us to the issue of price. Any pharma company that does all this, and invests in new skills and infrastructure to control nitrosamines, may want to raise prices. Will Indian consumers accept this increased cost? Will government schemes like Jan Aushadhi pay for it?

I think the answer to this question will determine whether Indians will ever get nitrosamine-free drugs.