Bengaluru: On February 2, 2021, a chemist at the Nagpur lab of the Maharashtra Food and Drugs Administration set out to test a strip of tablets of metronidazole, an antibiotic. The tests were part of the Maharashtra state drug regulator’s surveillance programme, in which its labs evaluate random samples for quality.
The batch of metronidazole the chemist had received was manufactured by a company called Quest Laboratories in Madhya Pradesh, and subsequently selected for testing by a drug inspector at a pharmacy in Bhandara.
The tests didn’t proceed as planned. To confirm the drug’s quality, a government lab is supposed to conduct all tests listed in an official text called the Indian Pharmacopoeia. It is written by an agency called the Indian Pharmacopoeia Commission and sets the minimum standards for drugs sold in the country.
For metronidazole tablets, the pharmacopoeia requires the following:
- The tablet must contain metronidazole – ascertained by an identity test
- It must contain as many milligrams of metronidazole as the label claims – content test
- It must dissolve within a certain amount of time, thus releasing the antibiotic into the patient’s body – dissolution test
- It must not have excessive amounts of unwanted chemicals – or impurities – impurity test
The pharmacopoeia requires similar tests for most drug tablets.
But the Nagpur lab, which conducted the first three tests for metronidazole, skipped the impurity test. It wasn’t the first time: a chemist from the lab, who didn’t want to be named, told The Wire Science that they have often skipped impurity tests before, simply because the lab couldn’t find the materials needed to conduct them.
The lab itself wasn’t the only one, in fact. Through information obtained under the Right to Information (RTI) Act and interviews, The Wire has learnt that government drug labs in at least seven states – Kerala, Karnataka, Gujarat, Andhra Pradesh, Himachal Pradesh and Goa – and one union territory, Jammu and Kashmir, have either not conducted impurity tests ever, or haven’t performed them as a matter of routine.
This means the Indian government’s surveillance of medicine quality has a big and critical blindspot. Impurity testing is a core-pillar of quality, Ganadhish Kamat, previously global head of quality at the Hyderabad-based Dr Reddy’s Laboratories, said. Some drug impurities are toxic, which means that not controlling their levels would directly put patient health at risk, he added.
The reasons why impurity tests have taken a backseat across India differ from state to state – but they all point to a system that has neglected this aspect of drug quality for many years. Officials at some labs revealed that they didn’t have the equipment to conduct impurity tests, while those at other labs alleged financial and logistical obstacles to finding the materials required for impurity tests.
And even though these obstacles have existed almost as long as impurity tests have existed in the Indian Pharmacopoeia, few state regulators have been able to surmount them.
Why impurity tests matter
Drugmakers need to control impurities tightly for several reasons. Every medicine is supposed to have only two parts. The first is the active ingredient, which actually treats the patient. In a metronidazole tablet, it is the metronidazole antibiotic itself. The second is the so-called excipient, which gives the tablet its form, colour and flavour. Some common excipients are lactose, dextrin and tartrazine.
Anything apart from these two is not only unnecessary but could even be toxic, said Ed Gump, vice-president of the small molecules department at the US Pharmacopoeia, the American standard-setting agency for drugs.
“Impurities can run the gamut from being relatively benign, and having very low safety concerns, to things that might be carcinogenic or have a specific type of toxicity that needs to be controlled,” he said.
One class of impurities that recently grabbed headlines is the carcinogenic nitrosamines. Since 2018, regulators around the world have found nitrosamines in several drugs, including blood pressure medicines and acid blockers, setting them scrambling to find the source of the problem and fix it quickly. Indian state labs have thus far refrained from large-scale nitrosamine tests for drugs sold in the country – mainly because these labs don’t have the equipment needed for such an exercise.
Other toxic drug impurities include 4-aminophenol, which occurs in the common painkiller paracetamol, and 2-methyl-5-nitroimidazole, which occurs in metronidazole.
But toxicity isn’t the only reason. Any superfluous substance in a medicine can potentially react with the active ingredient or the excipient, causing the drug to break down, according to Koduru V. Surendranath, a drug quality expert at the US Pharmacopoeia’s Hyderabad offices. In fact, even excess water in a drug can react with the active ingredient in a way that makes the drug ineffective, he said.
All this means that when drug regulators skip impurity tests, they endanger patient health. Furthermore, their systematic neglect of impurity tests has also distorted official estimates of the rates of substandard drugs in India – a key measure of drug quality.
For example, in a 2018 Lok Sabha answer, the Union Ministry of Chemicals and Fertilisers reported that of 82,599 samples tested by states and union territories in India in 2018, only 2783 – or 3.36% – were found to be substandard. Now we know this figure doesn’t capture impurity failures, simply because several government labs aren’t even conducting these tests.
A shortage of materials
The neglect of impurity testing by state regulators has historical roots. Even though the Drugs and Cosmetics Act 1940 allows regulators to prosecute manufacturers for every substandard drug, regulators have traditionally done so only for shortfalls in drug content. The other three parameters – dissolution, disintegration and impurities – are equally important vis-à-vis the integrity of tablets and capsules, but have been sidelined, mainly for expediency.
This said, impurity tests are also harder to perform than dissolution and disintegration tests, which is why labs don’t conduct them routinely. The biggest challenge these labs face is in finding the right materials. For the tests, a chemist typically uses a technique called chromatography, for which they need either a placebo, a dummy sample of the drug that has only the excipients – or an impurity standard, a pure sample of the known impurities in the drug
Box: How do drug labs test for impurities?
To test a drug for impurities, an analytical chemist typically uses a technique called chromatography.
In one of its most common versions, called high-performance liquid chromatography, the drug is dissolved in a solvent and passed through a column of a material with a specific chemical property – such as silica, which is highly adsorbent. On this journey, the active ingredient, the impurities and the excipients are unequally attracted to the silica and become separated from each other.
The speed at which they travel is, to the chemist, the signature of each component.
The chemist then performs two kinds of tests for impurities, depending on what the Pharmacopoeia prescribes.
One is for impurities already known to occur in a specific drug. An example is 2-methyl-5-nitroimidazole in metronidazole. To test for this, the chemist will compare the signatures of all the drug components with the signature of a pure sample of 2-methyl-5-nitroimidazole. This pure sample is the impurity standard.
When the signature of one of the components of the drug sample matches with that of the impurity standard, the chemist can identify and quantify the impurity.
Pharmacopoeias also prescribe tests for unknown impurities. To conduct them, chemists compare the signatures in the drug sample with that of a placebo – a dummy version of the drug that has the excipients but no active ingredients.
This comparison allows the chemist to ‘subtract’ the signature of the excipients from the signatures of the drug components, leaving only the signatures of the impurities and the active ingredients.
Herein lies the rub. State drug labs have been unable to procure placebos because only the drug manufacturer can give it to them. And even though manufacturers are required by law to cooperate with testing, they often decline to do so.
This is especially true when the manufacturer is located in a different state from the lab. The placebo then has to be shipped across a state border, and this often doesn’t happen, Paresh Parmar, senior scientific assistant at the Gujarat regulator’s lab, told The Wire Science. “We are able to get placebos from manufacturers in Gujarat, but for those in other states, it is difficult.”
This is why Kerala, which imports most of its drugs, has struggled to get its share of placebos for tests, according to an official from the state’s drug control department. The state doesn’t penalise manufacturers for not cooperating either, because impurity testing is not a big-enough priority.
When labs do manage to get hold of placebos, their next challenge is to find impurity standards – another key ingredient of impurity tests.
(See box: ‘How do drug labs test for impurities?‘)
A drug lab can either get its impurity standards at no cost from the manufacturer – or buy them from a third-party supplier. Both pose a problem.
Some government labs, including those of the Maharashtra Food and Drugs Administration (FDA), depend on manufacturers for lack of funds to buy impurities. According to Sangita Thakur, assistant director at the Maharashtra FDA, the administration hasn’t been allocated any money to buy impurity standards. And as with placebos, manufacturers often drag their feet with supplying standards, she said.
Other government labs, like those in Gujarat, Karnataka and Kerala, do have the required funds – but still have trouble. For them, the choice of supplier is between the Indian Pharmacopoeia Commission, the official supplier of impurity standards in India, the Pharmacopoeias of other countries, such as the US and British ones, and private suppliers, such as the US-based Millipore Sigma and the UK-based LGC Standards.
Most labs prefer dealing with the Indian Pharmacopoeia Commission for cost reasons. In fact, according to Sudha Swamy, chief scientific officer at the Karnataka drug control department, buying from other suppliers isn’t even an option because the price difference is so large. For instance, the Indian Pharmacopoeia Commission sells 20 mg of an impurity for the anticonvulsant drug carbamazepine for Rs 12,500 to government labs – while the US Pharmacopoeia’s price for 25 mg for the same substance is $798 (Rs 59,850).
“If we want to buy impurities from the British Pharmacopoeia and the US Pharmacopoeia, we have to shell out lakhs,” Swamy said.
This leads to another obstacle in the way of impurity tests: the Indian Pharmacopoeia Commission doesn’t sell enough. Of the thousands of standards required to test drugs listed in the Indian Pharmacopoeia, only 197 are currently available from the commission. And even these aren’t always in stock, according to Swamy.
The Karnataka, Kerala and Maharashtra lab officials couldn’t provide estimates of how many times they had skipped impurity tests as a result. But Parmar of Gujarat said it could be up to 50% of the time. Officials from Goa didn’t respond to questions, although documents obtained through RTI applications showed impurity tests to be frequently missing from routine surveillance.
Some states have never done an impurity test
While the Karnataka, Maharashtra, Kerala and Goa labs ‘simply’ avoided impurity tests at times, those in Jammu and Kashmir, Himachal Pradesh and Andhra Pradesh have never tested for impurities. Even though these labs cater to major populations, they have suffered drastic funding, infrastructure and skill shortages for decades – typifying the general dysfunction of India’s drug regulatory system.
The skeletal resources available to these organisations have meant that impurity tests have been the first to go.
Consider the nearly 40-year-old Composite Testing Laboratory in Kandaghat, Himachal Pradesh. It’s the only lab dedicated to the state and receives more than 2,000 samples every year. A central lab, called the Regional Drugs Testing Laboratory, in Chandigarh, helps out with surveillance in Himachal – but also serves other states.
But in spite of its heavy workload, the Kandaghat lab has only one high-performance liquid chromatography (HPLC) system, and no gas chromatography system – two of the most common forms of chromatography used for impurity tests.
(See box: ‘How do drug labs test for impurities?’)
With the single instrument, the lab can test around 365 samples a year, Aravind Sharma, a senior scientist at the lab, estimated. So the lab has jettisoned impurity tests in favour of focusing on content, dissolution and disintegration tests.
Similar problems plague the two labs in Jammu and Kashmir. Despite having been around for decades, both only had one HPLC unit each until two years ago, Purnima Kabu, an assistant drug analyst at the Central Food and Drugs Lab in Jammu, told The Wire Science.
In 2019, both labs purchased three more HPLCs each, and are only now considering starting impurity tests.
“We didn’t have staff. We didn’t have funds. So it was better to do assays [identification and content tests] than to do impurities,” Kabu said.
Andhra Pradesh (from which Telangana split seven years ago) is in a similar rut. According to Govinda Krishna Kinthada, joint director of the Drugs Control Laboratory in Vijayawada, the lab receives 4,000 samples a year from across the state – but lacks both the infrastructure and funds to conduct any impurity tests.
Significantly, both Andhra Pradesh and Himachal Pradesh are major manufacturing and export hubs – and the complete absence of impurity tests here bodes poorly for India as well as the whole world.
According to one estimate, Himachal meets 35% of Asia’s drug demand. London-based analytics firm Globaldata has estimated that Andhra Pradesh has one of the largest concentrations of contract manufacturing units in India. This means local regulatory deficiencies can quickly telescope into problems in other states and countries.
Addressing the impurity-test gap needs a multi-pronged approach. First, state regulatory agencies must stop treating impurity tests as optional. These tests are required under the Drugs and Cosmetics Act, and are also critical to patient well-being.
In a post he wrote earlier this year, Kamat pointed out a troubling consequence of skipping impurity tests. Most global pharmacopoeias allow the quantity of the active ingredient of a drug to vary from 90% to 110%. This means, Kamat argued, that up to 10% of the active ingredient could degrade into an impurity – except most pharmacopoeias also limit degradation impurities in drugs to 2%.
So when a drugmaker or a regulatory lab skips an impurity test, they risk selling a drug that has five-times the legal amount of potential toxins.
Next, and once regulators stop treating impurity tests as optional, state governments must give them sufficient funds to purchase impurity standards, so that they aren’t at the mercy of manufacturers. Regulators also need to start demanding placebos from manufacturers whenever they need it.
Finally, the Indian Pharmacopoeia Commission must start making enough impurity standards. The shortfall of standards from the commission affects government labs but also small- and medium-scale manufacturers that can’t afford the prices of suppliers like Millipore Sigma.
Rajeev Raghuvanshi, who took over as scientific director of the commission this year, said his team has been working to expand the repertoire of impurities. But there are challenges here, too, according to him.
Impurity standards are not readily available for sale, and a handful of suppliers synthesise them on request. Since the commission lacks the manufacturing capacity to make such standards, it has to float tenders, find suppliers and strike deals with them. Once a pipeline is set up, standards have to be tested and characterised before being sold to the commission’s customers.
According to Raghuvanshi, this process wasn’t taken up in earnest until recently. He plans to change this, he added. He said the commission has already floated tenders for 200+ impurity standards, apart from what they already have, and will be able to provide upto 50% of the impurities listed in the Indian Pharmacopoeia by next year.
Once this happens, the commission will aim to establish its own manufacturing facility for impurities. “That is the plan in phase 2, maybe a couple of years from now,” Raghuvanshi said.
Only if the commission holds up its end of the bargain, state regulators take impurities more seriously and state governments fund drug labs adequately can Indian patients finally expect safe and effective drugs one day.
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.
Priyanka Pulla is a science writer.