This entire article is like a masterclass on #scicomm#SciWriting, technical writing
Clear definitions of technical terms for drug impurity, historical explanation on standards established for their limits, consequences for violating them & the difficulties in upholding them
Inside the Fight To Decide How Pure India’s Drugs Need To Be By Priyanka Pulla
"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"
"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"
"A drug formulation contains two components, the active ingredient and the excipient. The active ingredient treats the illness, while the excipient provides bulk, shape, flavour and form to the formulation. Anything apart from these two components is an impurity"
"Impurities can be 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"
Companies that have a monopoly on manufacturing machines/equipment and the parts for making spectrometers, chromatographs needed to identify impurities in drugs with high precision have influence over the policy making of drug standards for low and middle income countries
Yaar "decolonization" karna hai na toh ispe karo, make it possible to manufacture everything in your country locally for cheap but with the HIGHEST STANDARDS AND QUALITY to increase self-sufficiency, autonomy.
"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"
"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"
Sometimes I think what we have in the name of govt and govt agencies is simply a shell of the real thing, like theatre. Like as if the roles, rules, protocols, guidelines, laws are just there to give a "look" of legitimacy, enough to pretend for the outside world
"When EU regulator published this information, multiple countries pulled Chinese drugmaker’s valsartan from their shelves
Concerned that nitrosamines could be tainting other drugs too other ICH members FDA & Health Canada began actively looking for nitrosamines in more products"
"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 no so that manufacturers could calculate maximum concentration of nitrosamines that could safely be present in their drugs"
"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"
"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"
What can be done to remove this kamchalau/kamchori culture in govt agencies?
"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?"
"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"
"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"
"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"
"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"
"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"
"Impurities can be 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"
"ICH Q3A (for organic impurities in active ingredients) and Q3B (organic impurities in drug formulations) 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"
"Reporting threshold : If an impurity is present in a drug at a concentration/dose above the threshold, the ICH Q3A & Q3B standards require the presence of this impurity to be reported to the drug regulator"
"Identification threshold : If an impurity is present in a drug at a concentration/dose above this threshold, the ICH Q3A and Q3B standards require the impurity's chemical structure to be identified"
"Qualification threshold : If an impurity is present in a drug at a concentration/dose above this threshold, the ICH Q3A and Q3B standards require the manufacturer to conduct computer modelling, in-vitro studies and rodent studies to determine how toxic the impurity is"
"Alternatively, the manufacturer can look for existing toxicity data that answers this question"
"If concentration of actual impurity is higher than reporting threshold, ICH Q3A (organic impurities in active ingredients) & Q3B (organic impurities in drug formulations) require manufacturer to report the impurity’s presence to regulator while applying for a licence"
"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 qualification threshold, manufacturer must go one step beyond identification. They must conduct a range of studies, including computer modelling, in vitro studies & 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, 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 & qualification thresholds"
"If concentration of actual impurity is higher than reporting threshold, ICH Q3A (organic impurities in active ingredients) & Q3B (organic impurities in drug formulations) require manufacturer to report the impurity’s presence to regulator while applying for a licence"
"ICH standards versus WHO and the Indian Pharmacopoeia
Wah Wah Indian Pharmacopoeia has no reporting thresholds 😑🥲
"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"
"While Q3A & Q3B proposed thresholds for all impurities, they didn’t elaborate much on special subsets of impurities – residual solvents, elemental impurities & mutagens. 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"
"Simple calculation of 1 common safe dose for all routes of ingestion as Q3A & Q3B provided wasn’t enough for elemental impurities. Instead safe doses for elemental impurities had to be calculated separately according to 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 (Q3C) , elemental impurities (Q3D) and mutagens (M7) in 1997, 2014 and 2014, respectively"
"Instead of a common safe dose for all impurities, the Q3C (residual solvents) 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 (elemental/inorganic impurities i.e heavy metals) 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 (mutagens): 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 Q3A (organic impurities in active ingredients) & Q3B (organic impurities in drug formulations) forced manufacturers to upgrade their analytical methods once, Q3D (elemental/inorganic impurities i.e heavy metals) & M7 (mutagenic) set off a hamster-wheel of tech upgrades"
The low safe maximum doses suggested by Q3D (elemental/inorganic impurities i.e heavy metals) 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 of
"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"
Globally i.e even in EU, US, Japan people were consuming drugs that didn't have a cap on heavy metal impurities coz there were no guidelines to identify, test, isolate & remove them
"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"
"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, ICH was also doing its bit to proselytise. In 1999, soon after Q3A & 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 & Thailand pointed out that the Q3A & 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 “additional benefits from these rigorous safety standards had not been demonstrated, but costs incurred by manufacturers in meeting the requirements are significant,” 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"
"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"
What if WHO hadn't heeded though? What if WHO had enforced Q3A, Q3B & Q3C standards for all it's member countries.
Or perhaps struck a deal with orgs to supply HPLC-UV instruments at a cheaper rate to member countries who couldn't afford it or make the tech open source
"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"
"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 (organic impurities in active ingredient)
"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 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"
"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"
"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"
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"
"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.
"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"
"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"
What if right from it's conception ICH had involved lower and middle income countries?
"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"
"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"
Idiots. Your decision on going lenient quite possibly has led to people getting chronic diseases from the impurities in the drugs you made available for them.
Increased access ghanta hai if the drugs are of substandard quality.
"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"
Identification threshold for impurities in active ingredients is 0.3% of quantity of active ingredient, 3x ICH’s threshold of 0.1% in Q3A
Qualification threshold is 0.5%, 3x ICH's threshold of 0.15%
"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%”
"Again, why not any advocacy on making HPLC-UV, ICP-MS, MS-MS, HRMS instruments cheaper to buy or manufacture locally?"
"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?"
"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"
"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"
This reads as — We know we were screwing the Indian population with dangerous levels of toxic impurities for decades in the name of "access", atleast now we decided to screw a bit less
Idiots. Your decision on going lenient quite possibly has led to people getting chronic diseases from the impurities in the drugs you made available for them.
Increased access ghanta hai if the drugs are of substandard quality.
"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"
"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"
Eh? Countries complying with Q3D and M7 ke liye nightmare nahi tha kya fir?
"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"
"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"
"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"
By not adopting any guidelines on mutagens, India may have thrown the baby out with the bathwater in its quest to keep costs low
"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
"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.
Recent development that supports 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 influence of innovator-firms on 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"
Also considering how china is such a manufacturing hub for electronic equipment it shouldn't find it hard making machines/equipment and the parts for spectrometers, chromatographs needed to identify impurities in drugs with high precision, locally
Some say that if middle-income countries like China can afford the cost of compliance with ICH standards, India also probably can.
"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"
Shut shop then. People's health is not something to played "tricks" with.
"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"
Oh this is key, hope it's the former.
"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"
I asked the writer later, it only applies to the new drugs
"Raghuvanshi refused to comment on the scope of the three chapters, saying he couldn’t commit to anything until the pharmacopoeia was published"
"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"
Oh damn totally forgot when the article mentioned in the beginning that this NDMA tainted drug was from a chinese firm, even more surprising considering china became an ICH member
"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"
"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"
Wah Wah
So the Indian Pharmacopoeia Commission is finally doing it's job well, ICH is becoming more transparent and reforming including middle income countries, generics associations but the regulatory body is still stuck to it's old ways
"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"
"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"
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