The nitrosamine saga
Bengaluru: On February 18, 2020, V.G. Somani sent a letter to Bhagoji Khanapure, the drug controller of Karnataka. One of India’s 36 regional drug-controllers, Khanapure oversees the safety of all medicines sold in Karnataka. Somani is the head of India’s apex drug regulatory agency, the Central Drug Standards Control Organisation (CDSCO). In his role, Somani must track emerging drug-safety concerns in the rest of the world and take a call on how India should react to them.
The February 2020 letter, marked to all 36 drug controllers, was about one such safety concern that had rocked the global pharmaceutical industry. A few of CDSCO’s international counterparts, including the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), had discovered a class of probable carcinogens, called nitrosamines, in commonly used medicines. These medicines included the acidity blocker ranitidine and blood-pressure drugs known as sartans.
Nitrosamines are drug ‘impurities’, a term for chemicals that are not supposed to be in drugs. They are also ‘mutagens’, which can react with human DNA and potentially cause cancer. There is ample evidence that some nitrosamines, like N-Nitrosodimethylamine (NDMA) – which international regulators had found in both ranitidine and sartans – are highly likely to cause cancer in humans. With other compounds, such evidence doesn’t yet exist, although their mutagenic nature is enough to trigger alarm.
However, vague wording in Somani’s letter belied the urgency of these global developments. Somani merely asked Khanapure to tell manufacturers in the state to “take appropriate measures to ensure patient safety.” It was a recommendation, not an order. The letter didn’t contain any deadlines.
Given the weak wording in the letter, Khanapure looked for other cues to decide how he could respond. Traditionally, the CDSCO has banked on the decisions of another national agency – the New-Delhi-based Indian Pharmacopoeia Commission – to take a call on how CDSCO should control drug impurities.The Indian Pharmacopoeia Commission publishes a text called the Indian Pharmacopoeia every four years. It lists mandatory quality standards for all drugs sold in the country, including the concentrations of impurities allowed in drugs. The CDSCO is responsible for enforcing these standards on drug manufacturers.
But as Khanapure told The Wire Science in March 2022, the Indian Pharmacopoeia’s latest edition – published in 2018 – and all its amendments, made no mention of nitrosamines.
Khanapure concluded that neither the CDSCO nor the Indian Pharmacopoeia Commission had decided to legally restrict the concentrations of nitrosamines in drugs. So he simply forwarded Somani’s letter to all drug-manufacturing associations in Karnataka, and dropped the matter.
Across the country in February 2020, several state drug controllers reacted to Somani’s letter in similar fashion. They passed on the letter to manufacturers but didn’t follow up on whether the manufacturers were implementing the recommendations.
In all, there was no enforcement.
The lack of concrete orders from the CDSCO and the Indian Pharmacopoeia Commission on the nitrosamine issue in 2020 was in sharp contrast with the situation elsewhere in the world. In particular, drug regulators belonging to a global standards-setting consortium called the International Council of Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) responded decisively to the problem.
Since 2014, several ICH regulators have been imposing a standard called ICH M7, which requires manufacturers in these regions to limit the concentration of mutagens like nitrosamines in their medicines, so that a person isn’t exposed to more than a safe maximum dose of these substances per day.
It was against this background that the European drug regulator, a member of ICH, first discovered NDMA in the blood pressure drug valsartan from a Chinese drugmaker in July 2018.
In response, the regulator used ICH M7 principles to conclude that the concentration of NDMA in valsartan was high enough to expose patients to more than the safe maximum dose of the chemical, thus posing a risk to patients’ health. (See Box 1)
When the European regulator published this information, multiple countries pulled the Chinese drugmaker’s valsartan from their shelves.
How manufacturers calculate concentration from safe maximum dose
Every drug has a maximum daily dose, which is the most a patient is allowed to take in a day. Now if animal toxicity data, or human toxicity data indicates that the safe maximum dose of the impurity is 2 mg a day, and the maximum daily dose of the drug is 2,000 mg a day, then the concentration of the impurity can be calculated by dividing the safe maximum dose of the impurity by the maximum daily dose of the drug. In this case, the concentration would be 2 mg divided by 2,000 mg = 1 / 1000 = 0.1% of the drug.Box 1
Concerned that nitrosamines could be tainting other drugs, too, other ICH members – including the US FDA and Health Canada – began actively looking for nitrosamines in more products. The exercise revealed that the nitrosamine problem was more widespread than thought. These toxic compounds were also present in drugs related to valsartan, such as losartan and irbesartan. The antacid ranitidine, the tuberculosis drug rifampicin and the diabetes drug metformin were affected as well.
By the end of 2020, several ICH regulators had used M7 principles to calculate safe maximum doses for six nitrosamines, including NDMA. They published these numbers so that manufacturers could calculate the maximum concentration of nitrosamines that could safely be present in their drugs (See Box 1). ICH regulators also installed tough measures for drugs other than the ones that they had already found to be contaminated. For instance, the US FDA asked all manufacturers to assess all their drugs for the risk of nitrosamine contamination.
The CDSCO, on the other hand, wasn’t a member of the ICH then and isn’t today. It is merely an “observer” at the consortium, which means it can participate in ICH meetings , but has no obligation to implement these standards within its jurisdiction.
Moreover, India’s regulatory apparatus has historically resisted adopting ICH standards voluntarily. Faced with the nitrosamine alarm, CDSCO and the Indian Pharmacopoeia Commission continued the trend of charting a different path. Unlike ICH countries, they didn’t ask manufacturers to recall contaminated drugs immediately, didn’t publish safe maximum doses for nitrosamines, and didn’t demand risk assessments from manufacturers.
As this article went to press – four years after the nitrosamine contamination in valsartan was identified – the CDSCO and the Indian Pharmacopoeia Commission still hadn’t taken any of these actions. Nor was it clear exactly what action they would take in the coming days. (See section: Nitrosamines: India’s road ahead)
In effect, Indian drug manufacturers are today being allowed a double standard with respect to nitrosamines: the medicines they export to ICH countries are required to be nitrosamine-free – while there is no such rule for the medicines they make for Indian consumers.
Disturbing as this sounds, the tardiness of India’s drug regulators in keeping up with ICH standards for mutagenic drug impurities is not an isolated phenomenon. For a complex set of reasons, both the CDSCO and the Indian Pharmacopoeia Commission have historically taken a more lenient stance on all kinds of drug impurities.
These double standards raise many ethical questions. If impurities pose a health risk to Indians, then why shouldn’t Indians get drugs with low levels of impurities just like their counterparts in ICH countries do? If they don’t pose a health risk, then why do ICH regulators limit impurities so stringently?
The answers to these questions are complicated, and require a deep dive into the history of ICH, the Indian regulatory agencies and the science of drug impurities.
What a double standard means
Drug impurities can be classified broadly into three groups: organic impurities, elemental impurities and residual solvents. Any of these three types of impurities can be mutagenic. (See Box 2)
Unlike the active ingredient and the excipient in the drug, these impurities aren’t of any use to patients. On the contrary, they can be harmful – either by being outright toxic or by breaking down the active ingredient. But since it’s hard for manufacturers to eliminate these impurities altogether, drug regulators allow impurities to be present at concentrations considered safe for humans.
This is where ICH standards come in: they require manufacturers to extensively evaluate their manufacturing process and identify all possible impurities that can arise from them. Next, they guide manufacturers on how to determine the doses and concentrations at which these impurities are safe, based on in vitro, animal and human toxicity data. Since 1990, when the ICH was first formed, the body has published standards for all four impurity groups.
In 1995, the ICH consortium finalised Q3A, a standard that provided a blueprint of how one could control organic impurities in active ingredients. Then, in 1996, it finalised Q3B, which did the same for organic impurities in drug formulations. Q3C, Q3D and M7, finalised in 1997, 2014 and 2014, tackled residual solvents, elemental impurities and mutagens, respectively. (See Box 2)
What are the types of drug impurities?
There are three broad types of drug impurities. The first is organic impurities – substances that have carbon-hydrogen bonds. These can be formed when the active ingredient in the drug degrades due to heat or light, or by reacting with excipients .
The second group is inorganic impurities, which includes heavy metals such as lead, arsenic and chromium. Chromium can leach into the drug from the equipment used to synthesise the drug, while arsenic can contaminate excipients such as talc.
The third group is residual solvents. Manufacturers use solvents as a medium in which to synthesise drugs, although they are typically removed from the final product. But when they get left behind, they are called residual solvents. Examples include highly toxic solvents such as acetonitrile and benign ones like acetic acid.
Mutagens can be organic, inorganic or solvents. Nitrosamines are an example of organic impurities.Box 2
ICH standards enjoy acceptability even among non-ICH countries and global public health agencies for many reasons. First, the consortium was originally founded by the European, US and Japanese regulators, who are among the most experienced regulators in the world. (Today, 11 more regulators have joined the ICH). The experience of these three entities comes from the fact that most drugs available in the world today were first developed by manufacturers in these three regions. So it was the European, US and Japanese regulators that first evaluated the efficacy, safety and quality of these drugs.
Other countries typically use the drugs first developed in ICH regions or copycat versions of them, known as generics. In approving these generic drugs, regulators in other countries who may lack the experience and resources that ICH regulators have, rely heavily on the judgement of the latter. It’s not a stretch to imagine, then, that non-ICH regulators will rely on ICH judgement for the quality standards for these drugs, too.
Indeed, many non-ICH countries and international public health bodies give a lot of weight to ICH standards.
The WHO’s prequalification programme – which certifies the quality of drugs from select manufacturers across the world – requires manufacturers to comply with Q3A, Q3B, Q3C, Q3D, M7 and other ICH standards.
And apart from ICH member-regulators today, who are obliged to follow the consortium’s standards, many other countries voluntarily comply with them. For example, the East African Community, a regional economic bloc consisting of seven countries, requires medicines sold locally to follow ICH quality standards even though the bloc is only an ICH observer.
Given its wide influence, the ICH benchmarks are among the few truly international standards today – a situation that is also self-perpetuating. “To date, ICH standards and WHO prequalification are the only internationally recognised ways of assessing the quality of medicinal products,” said David Reddy, CEO at the Medicines for Malaria Venture, a Switzerland-based not-for-profit that develops new malaria therapies.
Indian regulators, however, have historically taken a contrarian stance. They have resisted becoming either ICH members or adopting the consortium’s standards voluntarily. The current edition of the Indian Pharmacopoeia, published in 2018, is more lenient vis-à-vis impurities in drugs than Q3A, Q3B and Q3D are. And it has no specific requirement for mutagens along the lines of M7.
The reason for this stand of India is twofold. First, despite its reputation as being the ‘pharmacy of the world’, the vast majority of India’s manufacturers, which are small- and mid-sized, lack the technology and skills required to meet ICH standards. Only a few large firms, which also export to the US, Europe and other ICH countries, follow these standards when making drugs for export.
Second, India has historically been distrustful of the ICH. Three Indian stakeholder groups – the small- and mid-sized industry, patient advocacy groups and regulators – strongly believed that the ICH’s impurity limits weren’t driven entirely by drug-safety considerations, but also by protectionism and technological advancements.
Together, these factors prompted Indian regulators to reject several ICH impurity standards published between 1996 and 2014.
This situation is changing slowly, however. Today, at least one government agency, the Indian Pharmacopoeia Commission, has a different position than it did earlier. Its scientific director, Rajeev Raghuvanshi, said in a January 2022 interview with The Wire Science that it was time for Indian industry to catch up with the ICH.
The CDSCO’s stance remains unknown, however. CDSCO head Somani declined all interview requests.
Raghuvanshi also rejects his predecessors’ arguments, that ICH standards are protectionist or excessively technology driven. Instead, he believes they represent a global scientific consensus on safe and efficacious medicines. He also believes that 2022 is a different time, that Indian industry has evolved greatly from a decade ago and is in a far better position today to adapt to ICH requirements. “I think the time has come for India to bring changes more aggressively, and harmonise with the ICH,” he said.
But how aggressive these changes will be is anyone’s guess. There are indications that an upcoming edition of the Indian Pharmacopoeia, due out on July 1, 2022, may be more in line with ICH standards. But there is continuing opposition from the small-and mid-sized pharma industry against adopting ICH standards even today. This means changes in the Indian Pharmacopoeia’s 2022 edition could represent only baby steps towards complying with international standards, and not giant leaps.
The story of ICH Q3A and Q3B
ICH was founded in 1990 by regulators and associations of drugmakers belonging to three high-income regions: the US, Europe and Japan. These regions were pharmaceutical powerhouses at the time, developing most new drugs globally and conducting 90% of all pharmaceutical research. It is these new drugs that drugmakers from other countries, like India, subsequently made generic versions of.
At its core, the ICH’s goal was simple. In the 1980s, the regulators of the US, Europe and Japan were imposing differing standards for drug quality, efficacy and safety. Even the format in which each regulator sought information from manufacturers differed greatly. This meant that the maker of a drug registered in one country often had to redo expensive tests and reformat information extensively to meet the standards in another country, thus increasing both the cost and the time required to register new drugs in new regions.
Against this background, the idea of the ICH was for regulators and the industry from the three regions to draw up common standards – or to ‘harmonise’ their standards – using scientific principles. The expectation was that such harmonisation would allow drugmakers to register their products more easily in new countries, keep costs down and bring medicines faster to patients.
Among the many standards the ICH targeted for harmonisation were impurity limits. Impurities can enter drugs in multiple ways: the active ingredient of the drug can break down; the equipment used to make the drug can leach unwanted chemicals; reagents and solvents used to synthesise the drug can get left behind in the final product; or the excipients can become contaminated. Because these impurities can potentially be toxic, regulators ask manufacturers to ensure that their concentrations remain at safe levels.
But the regulators of all three regions had no common policy in place to calculate these safe concentrations. And even the differing policies they had were in need of an overhaul.
At the time, regulators deemed the concentration of impurities in drugs that were tested in safety and efficacy trials, before being sold to patients, to be safe. So regulators typically required a drugmaker to ensure that the concentrations in the commercialised drug stayed below the concentrations in the drug they had tested in pre-market trials. To meet this quality standard, drugmakers used methods like thin layer chromatography, which separates a mixture into its components, and allows a crude assessment of the concentration of each component.
This safety net wasn’t always enough, however. The clinical trials conducted by drugmakers were often too small to capture adverse events linked to impurities. Such adverse events can be rare – which means only very large trials can detect them.
Infographic: Drug impurities
Tetracycline impurity causes kidney damage.
Cefotaxime impurity causes anaphylaxis.
Aluminium in dialysis fluid can cause dementia.
Nickel in injectable drugs can damage the heart.
Dimethylformamide in a dye used by eye-specialists can also cause anaphylaxis.
Hydrazine, a contaminant in the tuberculosis drug, isoniazid, could cause cancer.
Nitrosamines in Valsartan.
For instance, in 1961, the British firm Beecham Research Laboratories rolled out the antibiotic ampicillin, after in vitro studies, animal studies and a human study. The human study included just 18 children and found that the antibiotic worked against urinary tract and intestinal infections.
Once the drug hit the market and more patients began using it, however, some began to report a severe skin rash. Eventually, Beecham scientists linked this skin rash to a protein impurity in the antibiotic.
In a 1990 review, Anthony C. Cartwright, then an official in the British regulatory system, described dozens of similar examples where scientists had identified toxic impurities in drugs, often after the drug had already been commercialised. Among inorganic impurities, scientists had found that aluminium in dialysis fluid could cause dementia in vulnerable patients, and nickel in injectable drugs could damage the heart. Among organic impurities, an impurity in degraded tetracycline could damage a part of the kidney while another impurity in the antibiotic cefotaxime could cause anaphylaxis. The solvent dimethylformamide, if left over in a dye used to diagnose eye disorders, could also cause life-threatening anaphylaxis. And the mutagenic chemical hydrazine, a contaminant in the tuberculosis drug isoniazid, could cause cancer.
None of these are minor side-effects.
Cartwright, who until 1996 worked for the UK Medicines Control Agency, the predecessor of UK’s Medicines and Healthcare products Regulatory Agency today, said his review made ICH regulators realise they needed a better system to set limits on impurities. “This review was a major step forward,” Cartwright wrote in an email to The Wire Science. This was the genesis of ICH’s Q3A and Q3B standards.
The ICH working groups who wrote the Q3A and the Q3B standards attempted to tackle the impurity problem by determining a common safe dose or a concentration for most of the impurities that could potentially be formed during drug synthesis. The idea was that testing the toxicity of each individual impurity was infeasible, because thousands of them could form during the synthesis of the many drugs that people use. And to determine a single impurity’s toxicity, a manufacturer would have to identify its chemical structure and conduct safety trials by feeding the impurity to rodents – an expensive and time-consuming proposition.
Earlier work by toxicologists had shown that it was possible to derive common safe doses for most chemicals except for the really toxic ones. In 1986, a US FDA scientist named Alan M. Rulis studied multiple databases of toxicity studies for chemicals to conclude that if one excluded particularly potent compounds like pesticides – which are selected for toxicity – the rest were likely to be safe to rodents at a dose of 1 mg per kg per day. This translated to a safe dose for humans of about 1-10 micrograms (µg) per kg of body weight a day.
So Cartwright, who represented Europe in the ICH, and his colleagues from other ICH regions set out to identify a similar limit for impurities. To do this, they turned to the databases of the US FDA. These databases included information on the concentrations of impurities for all drugs that had been licensed for sale in the country until then – and adverse-events reported through the country’s pharmacovigilance system. The numbers indicated that most impurities weren’t toxic below a dose of 1 mg/day, Cartwright said. The analysis excluded potent impurities with known toxicity, such as some residual solvents, mutagens or elemental impurities like lead.
Separately, Cartwright said, he also asked other regulators if they had any experience implementing such a common safety limit already. Health Canada answered in the affirmative. The limit they had been applying was a concentration, rather than a dose, of 0.1%. And after applying this limit, the regulator hadn’t encountered any unexpected safety issues.
“The Canadian authorities had applied a general limit of 0.1% for some years without any apparent problems, so I invited someone from Health Canada to the working party meeting to review their experience, which he did.” Cartwright recalled.
Eventually, the ICH working group selected both the 0.1% concentration and the 1 mg dose as empirical safe limits for impurities in active ingredients under ICH Q3A. The consortium also identified similar safe thresholds for drug formulations under ICH Q3B.
Several independent researchers later used other publicly available chemical databases to confirm the suitability of the 1 mg safe dose that the ICH had identified. In a 2012 paper, for example, UK-based toxicologist David Snodin and his colleague Sean D. McCrossen analysed a database of over 600 compounds from industrial, agricultural and food sources.
This database, first prepared in 1996, lists the maximum doses of chemicals that animals can safely consume daily without experiencing adverse events. Extrapolating this data to humans – a common way of setting safety limits for substances with little human data – Snodin and his colleagues arrived at the 1 mg per day value.
In 2017, another group of scientists from the pharma companies GlaxoSmithkline, Pfizer, AstraZeneca and Janssen confirmed the validity of the 1 mg/day threshold, again using multiple databases.
How ICH Q3A and Q3B work
ICH Q3A and Q3B start with asking drugmakers to list out all impurities that can potentially be formed, given the chemical reactions that go into synthesising the drug (potential impurities). Next, manufacturers must also list out the impurities they can actually detect using analytical technologies like chromatography (actual impurities).
To evaluate actual impurities, the standards introduce three concepts: the reporting threshold, the identification threshold and the qualification threshold. If the concentration of an actual impurity is higher than the reporting threshold, the ICH Q3A and Q3B require the manufacturer to report the impurity’s presence to the regulator while applying for a licence to market the drug.
If the concentration exceeds the identification threshold, the ICH Q3A and Q3B require the manufacturer to map-out the impurity’s chemical structure, an exercise that gives an idea of whether the impurity is toxic to humans. If they are unable to identify it, the manufacturer must tinker with their manufacturing process to reduce the concentration below the threshold.
Finally, if the impurity exceeds the qualification threshold, the manufacturer must go one step beyond identification. They must conduct a range of studies, including computer modelling, in vitro studies and animal trials, to show that the impurity is not toxic at this concentration – or find such studies in existing literature. Otherwise, they must reduce the concentration below the threshold.
In ICH Q3A, the reporting threshold is 0.05% of the quantity of the active ingredient – when the daily dose of the active ingredient is less than 2 gm.
Meanwhile, the identification threshold is 0.1% or 1 mg, depending on which is lower. These numbers reflect the safe concentrations and safe doses suggested by Health Canada’s and FDA’s data, respectively.
Finally, the qualification threshold in Q3A for a drug with a dose lower than 2 gm is 0.15% or 1 mg, whichever is lower. These numbers were again derived from data available to ICH regulators. ICH Q3B follows a similar system of reporting, identification and qualification thresholds. (See Box 3)
ICH standards versus WHO and the Indian Pharmacopoeia
Select standards to compare: Q3AQ3BQ3CQ3DM7
When AI < 2 gm:
1. Reporting threshold = 0.05%.
>2. Identification threshold = 0.1% or 1 mg, whichever is lower.
3. Qualification threshold = 0.15% or 1 mg, whichever is lower.
When AI > 2 gm:
1. Reporting threshold = 0.03%.
2. Identification threshold = 0.05%.
33. Qualification threshod = 0.05%
WHO prequalification program:
Same as ICH.
WHO recommendations for member countries:
Recommend adoption of Q3A.
Indian Pharmacopoeia Commission
General chapter 5.5:
1. No reporting threshold.
2. Identification threshold = 0.3%
3. Qualification threshold = 0.5%
1. When AI ≤ 1 gm = 0.1%.
2. When AI > 1 gm = 0.05%.
1. When AI <1 mg =1% or 5 µg whichever is lower.
2. When AI is 1 mg - 10 mg = 0.5% or 20 µg, whichever is lower.
3. When AI > 10 mg - 2 gm = 0.2% or 2 mg, whichever is lower.
4. When AI > 2 gm = 0.1%
1. When AI < 10 mg = 1% or 50 µg, whichever is lower.
2. When AI is 10 mg - 100 mg = 0.5% or 200 µg, whichever is lower.
3. When AI is 100 mg - 2 gm = 0.2% or 3 mg, whichever is lower.
4. When AI > 2 gm = 0.15%
WHO prequalification program:
Same as ICH.
WHO recommendations for member countries:
Recommend adoption of Q3B.
Indian Pharmacopoeia Commission
General chapter 5.5:
1. No reporting threshold.
2. Identification threshold = 0.5%
3. Qualification threshold = 1%
Safe maximum dose to be calculated individually for each solvent.
WHO prequalification program:
Same as ICH.
WHO recommendations for member countries:
Recommend adoption of Q3C.
Indian Pharmacopoeia Commission
General chapter 5.5:
Same as Q3C.
Safe maximum dose to be calculated individually for each elemental impurity, by route of inhalation.
WHO prequalification program:
Same as ICH.
WHO recommendations for member countries:
Leave decision of adoption of Q3D to member country.
Indian Pharmacopoeia Commission
General chapter 2.3.13:
Old heavy metal test.
1. Threshold of toxicity for most mutagens = 1.5 µg/day.
2. For very potent mutagens, like nitrosamines, the 1.5 µg/day doesn't apply. Instead, a safe maximum dose must be calculated seperately, based on animal and human studies
WHO prequalification program:
Same as ICH.
WHO recommendations for member countries:
Recommend adoption of M7.
Indian Pharmacopoeia Commission
No guidelines for mutagenic impurities.
One consequence of these two new impurity standards was that manufacturers had to upgrade the technology they were using to detect and measure impurities, said Cartwright. The identification thresholds in both Q3A and Q3B were far lower than the impurity limits specified by the European, US or Japanese pharmacopoeias until then.
This in turn meant manufacturers could no longer use techniques like thin layer chromatography, which couldn’t detect or quantify such low concentrations of chemicals. Instead, they began to adopt more modern methods like high-performance liquid chromatography (HPLC).
In fact, the reporting threshold of 0.05% in Q3A reflected this necessary shift, according to Cartwright. 0.05% was the ‘limit of quantification’ for HPLC instruments at the time. Like thin layer chromatography, this technique also separates impurities from the active ingredient. And it is often used together with an ultraviolet detector, which measures the concentration of each impurity. Together, they are called HPLC-UV instruments.
A limit of quantification of 0.05% means that HPLC-UV instruments in the 1990s could measure the concentration of individual chemicals in a mixture accurately only when they occurred in more than 0.05% of the mixture. This is why ICH Q3A demanded that every impurity occurring above this level be documented.
One of the key problems with Q3A and Q3B, however, was that neither standard explained the rationale behind the reporting thresholds, identification thresholds and qualification thresholds. This rationale was only known to the representatives of ICH countries who wrote these standards. This opacity led to questions later on why the Q3A and Q3B chose the thresholds that they did.
The story of Q3C, Q3D and M7
While Q3A and Q3B proposed thresholds for all impurities, they didn’t elaborate much on special subsets of impurities – namely, residual solvents, elemental impurities and mutagens (See Box 2). Deriving safe doses for these solvents involved different considerations than most organic impurities needed.
For many residual solvents, both animal and human toxicity data was already available, obviating the need for an empirically-derived common safe dose – like the 1 mg threshold in Q3A. In other words, safe doses for each residual solvent could be calculated separately.
Meanwhile, determining safe doses for elemental impurities is a different ball game compared to organic impurities, said David Snodin, the UK-based toxicologist. When ingested orally, many of these elements can form complexes with a class of acids in the body called uronic acids. This can make some elements less toxic, even though they may be more harmful when injected or inhaled, according to Snodin.
For this reason, a simple calculation of one common safe dose for all routes of ingestion, as Q3A and Q3B provided, wasn’t enough for elemental impurities. Instead, safe doses for elemental impurities had to be calculated separately according to the route of ingestion, whether oral, parenteral or inhalation.
Finally, mutagens can be damaging at doses far lower than the identification thresholds set under Q3A and Q3B. In fact, scientists had previously identified a safe maximum dose, or a ‘threshold of toxicological concern’, for most mutagens at 1.5 µg a day – which is thousand-times lower than the Q3A’s identification threshold of 1 mg. Moreover, some mutagens, like nitrosamines, are considered even more potent: the safe dose for NDMA for example is 96 nanograms a day – another thousand-times lower.
Given these differences, ICH published special standards for residual solvents, elemental impurities and mutagens in 1997, 2014 and 2014, respectively.
Instead of a common safe dose for all impurities, the Q3C used actual toxicity data for dozens of commonly used solvents, such as acetonitrile and formic acid. These solvents were classified into three groups – with the most toxic, like benzene, being limited at extremely low concentrations and the least toxic being allowed in higher concentrations. ICH Q3D adopted a similar approach, setting safe doses for 20 individual elements based on the route of ingestion and preparing a blueprint to evaluate the toxicity of the remaining elements.
As for M7: given the low doses at which mutagens are toxic, and the difficulty of detecting them using analytical instruments like HPLC, this standard requires manufacturers to assess whether potential impurities could be mutagens. If the manufacturer expects mutagens to form, M7 asks them to develop special analytical methods to detect them.
If Q3A and Q3B forced manufacturers to upgrade their analytical methods once, Q3D and M7 set off a veritable hamster-wheel of technological upgrades. The low safe maximum doses suggested by Q3D required manufacturers to deploy technologies such as induction-coupled plasma mass spectroscopy, which can detect these trace metals in substances. HPLC instruments can’t pull this off.
In fact, until Q3D came about, most pharmacopoeias recommended a far more primitive method to detect elements, like heavy metals, in drugs. This method could only confirm if the sum of all heavy metals in the drug was below a certain safe limit; it couldn’t measure the concentrations of each metal. Many individual metals can be toxic at levels this method couldn’t flag. Q3D solved this problem by setting limits on individual metals and invoking more advanced techniques.
Meanwhile, to detect the low doses at which mutagens became toxic, manufacturers couldn’t rely anymore on HPLC-UV. Instead, HPLC had to be combined with more advanced detectors, such as high resolution mass-spectroscopy (HRMS) or tandem mass-spectroscopy (MS-MS). These HPLC-HRMS and HPLC-MS-MS instruments were both expensive and required skilled personnel to operate. In India they can cost up to Rs 2 crore each today.
Criticism of ICH standards
Within years of ICH Q3A, Q3B and Q3C becoming official, the first murmurs of disagreement arose from the regulators of non-ICH countries, including India.
Although the ICH began as a cooperative between three regions in 1990, its influence had grown worldwide within a decade. Given the heavyweight status of the US, European and Japanese regulators, their counterparts in other countries perceived their standards to be the best, leading to many non-ICH regions voluntarily adopting them.
At the same time, the ICH was also doing its bit to proselytise. In 1999, soon after Q3A and Q3B had been finalised, the ICH launched an initiative called the ‘Global Cooperation Group’: one of its goals was to encourage the adoption of ICH standards outside the three ICH regions. But even though it was doing all it could to spread the word, the ICH remained a closed group: countries outside the US, Europe and Japan couldn’t become members nor influence the standards.
Perhaps as a natural consequence, non-ICH countries were sceptical of ICH standards. A 2001 report of a meeting of seven global drug regulators, mostly from non-ICH regions, recorded some of their concerns. Among them, representatives from India’s CDSCO, China, Poland, South Africa, Sweden and Thailand pointed out that the Q3A and Q3B documents hadn’t explained the rationale for their thresholds. This stoked questions about whether these thresholds were based on safety considerations.
ICH regulators had also incorrectly assumed that using advanced technology (such as HPLC instruments) to detect impurities would lead to safer drugs, the report said. This wasn’t necessarily true – because “the additional benefits from these rigorous safety standards had not been demonstrated, but the costs incurred by manufacturers in meeting the requirements are significant,” the report argued.
In conclusion, the report asked the WHO to not enforce ICH standards on its member countries without performing a benefit-cost analysis of implementing these standards.
WHO heeded the advice. In a 2003 report, the WHO’s Expert Committee on Specifications for Pharmaceutical Preparations, an advisory group to the WHO, agreed with the concerns of the international regulators. This committee’s recommendations heavily influence the International Pharmacopoeia, a book of quality standards for essential drugs that the WHO publishes. Many countries adopt monographs from the International Pharmacopoeia into their own local pharmacopoeias. The committee’s recommendations also influence which quality standards the WHO’s prequalification programme follows.
Despite their scepticism, however, the WHO’s Expert Committee made a seemingly contrary recommendation to the WHO that year. It advised that any new monographs in the International Pharmacopoeia from that year on should follow the Q3A, Q3B and Q3C standards. Since then, the WHO prequalification programme has been following Q3A, Q3B and Q3C as well. The WHO also began to recommend that member countries adopt these standards.
The reason behind the WHO Expert Committee’s decision was somewhat nuanced, and wasn’t quite a whole-hearted endorsement of ICH standards.
Even though the committee didn’t believe that Q3A, Q3B and Q3C enhanced patient safety, it postulated that the act of harmonisation would in itself help member countries. That is, if all member countries followed the same quality standards, their drug manufacturers would be able to introduce new life-saving drugs more quickly, thus benefiting their peoples.
“Knowing that harmonisation of compendial requirements can improve access to essential medicines, [the WHO Expert Committee] supported the alignment of new monographs with decisions of regulatory authorities which follow ICH,” Luther Gwaza, who leads a WHO team that works on pharmaceutical norms and standards, wrote to The Wire Science in an email.
Later on, when the ICH introduced Q3D for elemental impurities and M7 for mutagens, the WHO began using both for its prequalification program. As for recommending this standard to member countries, however, the WHO made an exception for Q3D: given the high cost of complying with it, the WHO left the decision to adopt this standard to the national drug regulators of each country. (See Box 3)
Note here that it wasn’t just non-ICH countries that were critical of ICH standards. Several independent commentators as well as pharmaceutical industry experts in ICH countries have said that these standards are far from perfect.
For example, Snodin, the UK-based toxicologist who authored a paper confirming the suitability of the 1 mg identification threshold in Q3A, has pointed out several other flaws with Q3A. Among them, he said, it is unclear why Q3A chose both a concentration and a dose for its identification threshold and qualification threshold.
Snodin is referring to the fact that Q3A guidelines require manufacturers to identify an impurity if it exceeds 0.1% of the active ingredient or 1 mg, whichever is lower. Similarly, Q3A requires manufacturers to qualify an impurity if it exceeds 0.15% of the active ingredient or 1 mg, whichever is lower. These requirements create “glaring inconsistencies” in the standard, Snodin said in an email.
In a 2012 paper, Snodin explained these inconsistencies with an example. The maximum dose of an impurity a patient will receive in a day can be calculated from the concentration of the impurity, multiplied by the maximum daily dose of the drug. So if an impurity is present at 0.10% in an active ingredient with a maximum daily dose of 1 g, Snodin wrote, the maximum dose of the impurity would be 1 mg – lower than the qualification threshold of 0.15% proposed in Q3A.
In other words, ICH Q3A was treating a 1 mg dose of the impurity as safe and not in need of qualification.
But if the same impurity was present at 0.2% in a different active ingredient, with a much lower maximum daily dose of 5 mg, the maximum dose of the impurity would be 10 µg. This would exceed the qualification threshold of 0.15% – which would be 7.5 µg/day for the second drug.
That is, ICH Q3A was treating the same impurity as safe at the 1 mg level but possibly as toxic and in need of qualification at the much lower level of 10 µg!
Fabienne Benoist, the head of regulatory affairs at the Drugs for Neglected Diseases Initiative (DNDi), a Switzerland-based non-profit, pointed out another problem with Q3A and Q3B. The safety thresholds set in both standards are based on the assumption, she said, that a patient will consume the drug continuously, through their entire lifetime. For example, the 1 mg identification threshold is based on the toxicity of an impurity consumed throughout one’s life.
But this assumption doesn’t apply to many drugs, Benoist said. “Some industry experts have questioned recently whether these limits are too conservative for shorter duration therapies. Treatments for neglected tropical diseases frequently fall into this category, and DNDi would welcome scientific review of these guidelines,” she wrote in an email. DNDi currently follows ICH guidelines when developing drugs.
Given that the Q3A and the Q3B standards are over 30 years old today, it is high time both are reviewed, both Benoist and Snodin said. But Snodin also added that more-recent guidelines, like M7, don’t have the same flaws. M7 for instance allows higher concentrations of mutagens in drugs that are consumed for shorter periods of time.
Asked whether the ICH plans to review its standards, the consortium’s secretariat wrote in an email: “ICH is open to revising existing ICH guidelines or adopting new topics for harmonisation … based on proposals from its members or observers”. The secretariat also added that as an observer at ICH today, the CDSCO could submit such proposals as well.
India’s first stab at controlling impurities
The Indian government set up the Indian Pharmacopoeia Commission in 2005. Until then, a different body, called the Indian Pharmacopoeia Committee, was responsible for specifying the country’s drug-quality standards. But this committee was failing to keep up with the needs of India’s rapidly expanding pharmaceutical industry. Among its shortcomings, the committee was publishing the Indian Pharmacopoeia at 10-year intervals even though the pace of developments in the field merited more frequent updates.
The Indian Pharmacopoeia Commission was meant to tackle this problem by publishing more frequent editions and keeping up with the science.
Among the first topics the newly formed commission dealt with was the control of impurities. In 2005, neither the Indian Pharmacopoeia (the last edition of which was published in 1996) nor CDSCO had a general policy to limit the levels of impurities in drugs, along the lines of Q3A and Q3B. What’s more, of the pharmacopoeia’s 1,253 monographs for active ingredients, drug formulations, excipients, etc., only 448 had any tests for impurities. The rest had no impurity tests even though all drugs contain some impurities.
So India sorely needed a general policy to control impurities in all active ingredients and drugs – as the dangers of these contaminants had grown abundantly clear by then. Such a general policy would help on two counts.
First, the pharmacopoeia had no monographs for many drugs sold in the country – either because they had just been licensed or because the pharmacopoeia hadn’t gotten around to setting quality standards for them. The general policy would guide the CDSCO on setting limits on these ‘non-pharmacopoeial’ drugs. Second, even the impurity limits in pharmacopoeial drugs needed to be driven by a consistent policy, based ideally on the toxicology of impurities. The commission could then apply this policy to all new drugs that would enter the Indian Pharmacopoeia from then.
Yet adopting Q3A and Q3B was out of the question, multiple former commission members told The Wire Science. Not only was the industry not ready, even the Union and state drug regulators didn’t have the instruments required to measure such low levels of impurities, said J.L. Sipahimalani, who was a member of the scientific body of the commission in 2007. Incidentally, this situation persists to this day: several state drug regulatory labs, such as those in Jammu & Kashmir and Himachal Pradesh, continue to suffer a shortage of HPLC machines.
The drug manufacturing industry was in an equally bad situation. Of the 6,000 licensed drugmakers in India in 2007, only around a 100 were exporting to ICH regions at the time, according to one report that cited numbers from the Federation of Indian Chambers of Commerce & Industry. This meant that only those 100 could meet the stringent ICH standards that had been in place since the mid-1990s. The difference between the top 100 companies and the remaining firms was vast.
In a presentation he made in 2007, Saranjit Singh, a member of the scientific body of the Indian Pharmacopoeia Commission at the time, noted that export-oriented companies, such as Ranbaxy and Cipla, could have upto 600 HPLC machines, giving them sufficient infrastructure to test for impurities. But the smallest of all manufacturers had none.
Here, Singh made a key argument that arguably shaped Indian impurity standards in the coming years. He contended that despite their inability to meet international standards, India’s small- and medium-sized manufacturers were crucial to the country. Numbering in excess of 1.2 billion – 32% of whom subsisted on less than a dollar a day and 80% of whom bore healthcare expenses out of their own pockets – Indian citizens couldn’t afford expensive drugs, Singh wrote.
To top it all, he added, the stringent impurity standards of the US and Europe were likely driven by protectionist tendencies and technological advancements rather than by safety considerations. Singh was repeating the same argument that multiple global regulators had made in 2001 at the WHO meeting: that the availability of advanced instruments (like HPLCs) in ICH regions had led to standards being based on technologies rather than on toxicity considerations surrounding impurities.
Singh wasn’t the only one who accused the ICH of protectionism. A lobby group for India’s small- and mid-sized pharma industry, called the Indian Drug Manufacturers’ Association (IDMA), has repeatedly directed similar claims at the ICH. Summarising IDMA’s historical objections to the ICH, Gopakumar G. Nair, a former president of the IDMA, told The Wire Science in a 2022 interview that ICH impurity limits were frequently motivated by the commercial interests of Big Pharma. Meeting such stringent limits raised costs for manufacturers but wasn’t always required for public health, Nair said.
A third group of vocal ICH critics were health activists. In particular, the People’s Health Movement, a global network of activists, was concerned that imposing the ICH’s stringent standards on Indian companies would raise their production costs, thus putting drugs out of reach of millions of Indians. The People's Health Movement has also repeated the assertion that ICH standards aren’t entirely driven by patient safety.
In a 2014 statement to the World Health Assembly, the policymaking body of the WHO, the People’s Health Movement strongly protested a WHO proposal to ask all member countries to adopt ICH standards. The statement read:
“The ICH compromises the neutrality of the process of setting regulatory norms and standards. … It seeks to raise the bar on acceptable manufacturing standards, and to globalise these. However, higher standards, beyond a point, do not add to medicines quality and public health outcomes. It adds to costs of manufacturing and is a barrier to entry of generics in [low- and middle-income countries].”
One source of the belief that ICH was indulging in protectionism was the composition of the consortium. The ICH’s founding members included not just the regulators of Japan, the US and Europe but also industry associations representing pharmaceutical innovator-firms from these three regions. These firms, which included multinationals like Merck and Pfizer, were known for developing new drugs instead of generics. Indian companies, on the other hand, have always specialised in generics. Innovator firms and generics firms have a long history of competing with each other.
Expectedly, then, dominance of innovator firms in the ICH fostered scepticism among Indians. The global consortium, Indians believed, was too heavily influenced by these firms – firms that were protecting their turf from their generics competitors. Using the ICH to arbitrarily raise global impurity standards, so that generics firms couldn’t meet them, was just one such protectionist tactic. The opacity surrounding the thresholds in early ICH guidelines, like Q3A and Q3B, worsened this distrust.
Against the background of these arguments, Singh’s presentation in 2007 concluded that India needed its drug-quality standards to be “rational, practical and simple” – which is code for more lenient. This would allow small- and mid-sized manufacturers to keep producing medicines, thus keeping the medicines accessible to the poorer sections of society.
This line of reasoning led to the rejection of ICH limits for many years afterwards. “We had to keep the availability of drugs in mind. So we decided not to blindly follow the standards of anyone else,” G.N. Singh, who headed the Indian Pharmacopoeia Commission until 2012, told The Wire Science in a 2022 interview.
Concerns about Indian impurity standards
Even though India rejected ICH standards, based on the claim that they weren’t driven by safety, the standards India eventually adopted aren’t driven by safety considerations either. In fact, Indian standards ended up becoming what Indian regulators were accusing the ICH of: a strategy to protect the local industry, rather than to limit toxicity based on scientific data.
For example, in the 2007 edition of the Indian Pharmacopoeia, the first to be published by the newly-minted Indian Pharmacopoeia Commission, the identification and qualification thresholds for organic impurities were set at a seemingly arbitrary multiple of the thresholds in Q3A and Q3B.
These limits are outlined in a so-called “general chapter”, numbered 5.5, which explains the Indian Pharmacopoeia’s overarching philosophy on impurities. The 1 mg identification limit in Q3A, supported by several chemical databases, doesn’t appear anywhere. Instead, the identification threshold for impurities in active ingredients is 0.3% of the quantity of the active ingredient – three-times the ICH’s threshold of 0.1% in Q3A. The qualification threshold is 0.5%, again roughly three-times the ICH threshold of 0.15%. And the chapter doesn’t offer any reporting threshold, as Q3A does. (See Box 3)
Asked about the basis of the 0.3% and 0.5% thresholds, a former member of the Indian Pharmacopoeia Commission’s scientific body, who didn’t wish to be named, said the thresholds were designed to ensure most Indian manufacturers could comply with them. “So if we thought that only a small number of manufacturers could comply with 0.1%, we widened the circle by raising the number to 0.3%.”
Could India have prepared more rational safety standards, based on the toxicity data of impurities, rather than on considerations of what manufacturers could comply with? It was certainly unlikely in 2007 – when the CDSCO, the Indian Pharmacopoeia Commission and the industry were all still new to the problem of impurities. Further, both the CDSCO and the commission lacked the infrastructure and resources to carry out this complex exercise, several experts told The Wire Science.
India had no national pharmacovigilance system then – the Indian Pharmacopoeia Commission started a national pharmacovigilance program only in 2010 – which would have thrown up toxicity data on impurities, allowing empirical limits to be defined, like in Q3A and Q3B. Another option would have been for a national Indian agency to help the small-and mid-sized industry with toxicity studies for organic impurities. But this would again have required tremendous skill, investments and will.
This said, the former Pharmacopoeia Commission member defended India’s impurity strategy in 2007. Even an identification limit of 0.3% was a big leap forward at the time, the member said. Given that the Indian Pharmacopoeia had no general policy on limits, and most monographs lacked impurity tests, he argued, this meant impurities could be present in vast and dangerous amounts in many drugs, with the drug still not being considered substandard.
Most pharmacopoeias worldwide allow the concentration of the active ingredient of many drugs to vary between 90% and 110% because the active ingredient can degrade, and some loss of active ingredient doesn’t impact efficacy. But in the absence of any general policy on impurities, and the lack of impurity tests in many drug monographs, the pharmacopoeia effectively allowed an impurity to make up up to 10% of drugs that lacked monographs – an extremely high threshold.
Against this background, the thresholds in the 2007 pharmacopoeia were a major advancement, the member said. “Perhaps we couldn’t impose international standards in India. But at least we brought in some limits and got the industry started. This needs to be appreciated.”
However, the 2007 edition of the Indian Pharmacopoeia did accept ICH Q3C – the ICH standard on residual solvents. In its “general chapter” number 5.4, the pharmacopoeia listed safe concentrations for 59 well-known solvents, all of which match with those listed in ICH Q3C.
The reason why the Indian Pharmacopoeia Commission adopted ICH standards on residual solvents, even though it didn’t accept ICH’s Q3A and Q3B, was practical: Indian companies had already been limiting the use of some of the most toxic solvents identified in Q3C, like benzene. So adopting this standard would not be as challenging as adopting Q3A and Q3B. “Q3C was already being applied by the industry, and the use of Class 1 [the most toxic] solvents was already forbidden. So it was logical to apply this standard,” the former Indian Pharmacopoeia Commission member said.
Later on, in 2014, the ICH developed the M7 and the Q3D, further raising the technological demands on manufacturers. Experts in the Indian Pharmacopoeia Commission were clearly unhappy with the trend of tightening impurity limits further and further.
A presentation by Saranjit Singh in 2012, when M7 and Q3D were being prepared, captures his consternation. By this time, Singh was no longer a member of the commission’s scientific body, although he later became the member of an advisory body on impurity standards to the commission.
In the presentation, Singh spoke about seemingly insurmountable challenges that controlling mutagens presented. In 2008, the US FDA had discovered a mutagen and carcinogen called ethyl methanesulfonate in Pfizer’s HIV drug, Viracept. That year, both the US FDA and the European Medicines Agency began requiring that this impurity be limited below the threshold of toxicological concern for mutagens – which is 1.5 µgrams per day. Singh estimated that to meet this criterion, given the maximum daily dose of Viracept was 50 gm a day, each tablet couldn’t have more than 0.000003% of ethyl methanesulfonate. Detecting and measuring an impurity at this level was an “analyst’s nightmare”, he wrote.
This trend of tightening impurity standards year after year posed a real danger to the availability of medicines, Singh argued.
“The issue of impurities is getting more and more complicated, with danger of getting out of hand. The cost of testing, combined with input of costly reference standards, is set to increase the cost of even older products.”
Perhaps it is these concerns that eventually led to the Indian Pharmacopoeia adopting no specific guidelines on mutagens. As for heavy metals: the Pharmacopoeia continues to use the older test, which ICH countries began phasing out after Q3D came about (in 2014).
But this decision had its costs. The rejection of Q3A, Q3B, M7 and Q3D may have kept Indian drug prices among the lowest in the world – but it also created a blind spot in the Indian regulatory system for exceptionally toxic impurities like mutagens. Even if controlling the levels of mutagens is expensive, the toxicity of many of them, like nitrosamines or ethyl methanesulfonate, merit such controls. By not adopting any guidelines on mutagens, India may have thrown the baby out with the bathwater in its quest to keep costs low.
Pressure to keep up with the ICH
A lot has changed in the Indian pharma industry since 2007, when the Indian Pharmacopoeia Commission prepared a general philosophy on impurities for the first time. In particular, the Indian pharmaceutical industry’s ambitions have grown, making the adoption of ICH standards an attractive prospect.
Today, contrary to the situation in 2007 or even in 2014, parts of the Indian industry don’t just want to voluntarily adopt ICH guidelines but want India itself to become a member of the ICH. This would entail meeting impurity standards as well as the ICH’s 60 other drug standards on the conduct of clinical trials, good manufacturing practices, pharmacovigilance and so forth.
In early 2022, the Indian government called for a consultation with the pharmaceutical industry to prepare a blueprint for the country at 100 years of independence, in 2047. As part of this consultation, the industry set revenue targets of $130 billion by 2030 and $600 billion by 2047.
To meet these targets, many say, becoming a member of the ICH is necessary. Doing so will ease the way for Indian manufacturers’ products into ICH countries and cut down on duplication of research. India will also find it easier to strike mutual recognition agreements with ICH countries – in which the regulators of these countries accept the quality assessments of Indian drug regulators, said Dinesh Dua, chairman of Pharmexcil, an agency set up by the Indian government to promote drug exports. If India joins ICH, “the respect and recognition for us will be enhanced 100-times,” Dua said.
Predictably, the stakeholder groups pushing the most for India to join the ICH are the large, research-focused pharma companies which already export to ICH countries. Among them is a lobby group called the Indian Pharmaceutical Alliance – which counts companies like Dr Reddy’s Labs, Glenmark Pharma and Lupin, Ltd. among its 24 members. The alliance has argued that for Indian industry to reach its 2047 revenue goal, ICH membership is inevitable. Sudarshan Jain, secretary general of the alliance, told The Wire Science that India should aim to become a member within three to five years. “All of the industry needs to agree on this and work towards it,” he said.
A recent development that supports the Indian Pharmaceutical Alliance’s and Pharmexcil’s stance is that the ICH is no longer the closed organisation it was over 30 years ago. In 2010, the consortium initiated reforms to tackle long-standing criticisms of how it functioned. The goal of these reforms included cutting the influence of innovator-firms on the ICH while bringing in the generics industry and regulators from new geographical regions as members.
After these reforms were completed in 2015, a few middle-income countries became members of the ICH, including China, Brazil and Mexico. An association of generics industries, called the International Generic and Biosimilar Medicines Association, also joined. This is around the time, in 2016, that India also became an observer at the ICH.
China’s decision to become a member of the ICH has created some pressure on India to do so as well. Both countries are competitors in the global generics market – and an ICH membership gives China a leg-up over India, by increasing the acceptability of its products. Some say that if middle-income countries like China can afford the cost of compliance with ICH standards, India also probably can. (India is classified as a ‘lower-middle-income’ country by the World Bank while China is an ‘upper-middle income’ country.) Pharmexcil’s Dua pointed out that an ICH membership will offer India an opportunity to actively influence ICH guidelines it doesn’t agree with – an attractive proposition.
But the small- and mid-sized industry, particularly the IDMA, is still not on board with this aggressive plan. At the same time its position is more nuanced than it has been. IDMA’s current president, Viranchi Shah, is no longer making the same arguments that past presidents, like Gopakumar Nair, did: that ICH standards are protectionist and don’t serve patient interests. On the contrary, in a representation the IDMA made to India’s commerce ministry in January 2022, Shah said that “aligning with global standards”, like those set out by the ICH, would be an important strategy to meet the country’s 2047 goals.
Nevertheless, IDMA’s proposed timeline for either aligning with or joining the ICH is dramatically different from that of the Indian Pharmaceutical Alliance. Shah said joining isn’t possible for at least another 10 years. The reason: many small- and medium-sized pharma firms still can’t keep up with ICH standards.
Impurities are a particularly tricky proposition for the small- and mid-sized sector, according to Shah. If Indian regulators imposed Q3A, Q3B or any other ICH guideline today, the industry would struggle to identify impurities and conduct the expensive animal tests to qualify them at the low levels required by the ICH. Given these challenges, forcing such standards “will just lead to a situation where the regulation will be there on paper but will be very difficult to enforce,” Shah said.
The strong opposition from the small- and mid-sized sector to ICH standards means that the Indian Pharmacopoeia is unlikely to get a makeover overnight, despite the pro-ICH stance of its current scientific director, Rajeev Raghuvanshi.
In 2021, the Indian Pharmacopoeia Commission published two draft general chapters on impurities on its website, representing baby steps by India towards meeting ICH impurity standards. The first, an amendment to general chapter 5.5 on impurities, brings the chapter in line with Q3A and Q3B. It also refers to ICH M7 in requiring manufacturers to adopt the mutagen standard for active ingredients (but not drug formulations).
The second – a new general chapter numbered 5.10 – echoes ICH Q3D for elemental impurities. This new chapter would mean that manufacturers must upgrade from the primitive test they are currently using to control heavy metals.
By publishing these two draft chapters in 2021, the Indian Pharmacopoeia Commission was seeking feedback from the pharma industry. This is the typical process the commission follows before adding or amending chapters before launching a new edition of the Indian Pharmacopoeia. The amendments in 5.5 and the addition of 5.10 are aimed at the 2022 edition of the Pharmacopoeia, due to be published on July 1.
By all indications, the 2022 edition will also have a chapter on nitrosamines. In May 2022, the Indian Pharmacopoeia Commission published a document listing all changes that will appear in the 2022 edition. This document announces a new general chapter, numbered 5.11, on nitrosamines, although no draft chapter on this has been published yet.
But many key questions remain about these upcoming chapters. It is unclear whether general chapter 5.5 will apply to all drugs currently sold in India or only to new drugs licensed in the country from 2022 onwards. The same holds true for general chapter 5.10 on elemental impurities and 5.11 on nitrosamines.
In the first scenario – i.e. if ch. 5.5, 5.10 and 5.11 will apply only to new drugs: the new pharmacopoeia edition won’t make a serious dent on the quality of the majority of Indian drugs or on patient safety, because new drugs licensed each year constitute only a miniscule proportion of the drugs already in circulation. In the second scenario, if ch. 5.5, 5.10 and 5.11 will apply to extant drugs as well: the Indian industry will be forced to undergo a sea-change, complying with more stringent limits than they have ever before. Lobby groups like IDMA want the Indian Pharmacopoeia Commission to adopt the former approach, introducing ICH standards only for new drugs first, and expanding to currently sold drugs only later.
As this story went to print, it remained unclear which approach the Indian Pharmacopoeia Commission would finally take for the 2022 edition. Raghuvanshi refused to comment on the scope of the three chapters, saying he couldn’t commit to anything until the pharmacopoeia was published.
The nitrosamine saga: the road ahead
Regardless of what the Indian Pharmacopoeia 2022 eventually says about nitrosamines, the fact remains that neither the CDSCO nor the Indian Pharmacopoeia enforced any safe limits on nitrosamines for four years since the valsartan contamination incident in July 2018. Indian consumers are already paying the price of this delay.
These mutagens pose a particularly high cancer risk to those who take contaminated medicines for a long time, like hypertensive and diabetic patients. One American study estimated that if 100,000 people took the highest dose of NDMA-tainted valsartan manufactured by Zhejiang Huawei – the Chinese firm whose product triggered the entire nitrosamine saga – for six years, between 40 and 126 of them would develop cancer. The risk would be higher for patients who took multiple nitrosamine-contaminated drugs and for those who took them for longer than six years, the study noted.
Millions of Indians take medicines at risk of nitrosamine contamination, often for decades together, and alongside other at-risk medicines. Market research firm IQVIA’s data for 2018 showed that Indians consumed at least 3,078 million pills belonging to the sartan class of drugs that year. The number could be higher if combination pills containing sartans are included.
Meanwhile, another drug at risk of nitrosamine contamination is a slow-release version of metformin hydrochloride. Metformin hydrochloride itself is among the most widely used in India given the country’s large diabetic population.
With so many Indians taking possibly tainted drugs on a daily basis, a drug-induced cancer epidemic is a real possibility.
In every one of these cases, Indian companies have had to recall millions of doses from shelves in ICH countries due to the presence of nitrosamines. Such recalls have rarely occurred in India, however.
For example, on January 7, 2022, the US FDA announced that a New-Jersey-based company was recalling 23 lots of an extended-release version of metformin hydrochloride tablets due to NDMA contamination. These tablets had been manufactured by Gujarat-based Zydus Cadila. Questions sent to the Gujarat state drug controller, CDSCO and Zydus Cadila on whether Zydus recalled the product in India went unanswered.
Some experts who believe that ICH standards represent a global consensus on drug quality, safety and efficacy see the current situation in India as unethical. If Indian companies can manufacture drugs to comply with the standards in ICH countries, why can’t they do so for India, asked Ganadhish Kamat, who retired as the global head of quality at Dr Reddy’s Labs in 2021.
“We are supplying high quality drugs to the entire world. Indian people do not deserve anything less.” Kamat added that when he was with Dr Reddy’s, the company’s policy was to make the same quality of drug for all markets.
The idea of any double standard being unethical is also driving greater acceptance of ICH standards elsewhere in the world. The African Medicines Regulatory Harmonisation initiative, for instance, aims to harmonise drug-quality standards across the African continent. And it plans to eventually adopt ICH standards or WHO standards – “to avoid any speculation about the promotion of double standards,” said Margareth Ndomondo-Sigonda, the head of the initiative, in an email.
For India, too, making the transition to ICH standards is possible – provided the small- and mid-scale sector receives help from the government, many say. The former pharmacopoeia member suggested that a network of national laboratories could be assigned the task of helping drug-makers test the toxicity of organic impurities, thus arriving at safe maximum doses for them. This would enable manufacturers to adhere to these standards without bearing the burden of qualifying each impurity. Another strategy that would help India is to seek ICH membership, which will help the country push for standards better suited to middle-income countries.
Whatever the solution, it is clear that India’s impurity problem is a complex one. It is also clear that the Indian regulatory system is not trying hard enough to find the solution. This is evidenced by the fact that most Indian state drug regulatory labs are currently not even enforcing India’s existing impurity standards, which were created keeping the challenges of the industry in mind.
Against this backdrop, for India to adopt stringent international standards like those of the ICH, and to successfully enforce them, may be a long shot.
The reporting for this article was supported by a grant from the Thakur Family Foundation. The foundation did not exercise any editorial control over the contents of the article.
The description of the Indian Pharmacopoeia Commission was changed from “regulatory” to “government” agency at 11:31 am on June 27, 2022.
Research, reporting and writing: Priyanka Pulla
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