Hard questions remain about quality

Last week, Dr Cyriac Abby Philips, better known by his social media, moniker @liverdoc, caused quite the stir on social media by revealing the results of a crowdfunded study that he had conducted on the quality of generic drugs sourced from various outlets, especially government funded pharmacies or schemes like the Jan Aushadi programme, rebranded as the Pradhan Mantri Bharatiya Janaushadhi Pariyojana by the present government.

While the peer-reviewed publication of the study is still awaited, the big takeaway from @liverdoc’s Twitter thread is that each and every of the 131 generic drugs he tested, including those from government supplied pharmacies passed every quality parameter laid down by the Indian Pharmacopeia Commission in its official publication, the Indian Pharmacopeia.

These results, especially the ones pertaining to government-funded pharmacies are quite incredible since historically the government’s own data has revealed chronic problems with generic drugs sold through these outlets.

For example, in 2017, a government-funded survey of drug quality in India involving 47,954 samples from various sources revealed that 10% of drugs sampled from government pharmacies failed testing in government laboratories. For the rest of the market, the rate of failure of drugs was approximately 3.16%.

The survey did not include fixed-dose combination drugs that contain two or more active pharmaceutical ingredients. These constitute the majority of the nation’s drug supply. There are other reports like one by Comptroller and Auditor General from 2012 which claimed that 25% of locally sourced drugs by the Armed Forces Medical Services Depot failed quality tests.

Similarly with the Jan Aushadhi programme, there have long been complaints from patients and doctors of poor quality outcomes from taking these drugs. In the last Parliamentary session, in December, the government disclosed that between 2020 and 2025, a total of 206 prosecutions were filed by state drug controllers against pharmaceutical manufacturers because samples of their drugs drawn from the Jan Aushadhi programME failed testing in their laboratories.

Given that state drug controllers prosecute only the worst cases of quality failures, the actual number of Not of Standard Quality drugs are likely much higher.

For example, if a drug has only 75% of the active ingredient, the prosecution guidelines laid down by the government prohibit criminal prosecution. Only if that number falls below 70% are state drug controllers required to prosecute. So the figure of 206 prosecutions disclosed in the Parliament represents only serious cases of Not of Standard Quality drugs, not every drug which failed quality testing.

Previous tests

There is then also regular news in the press of other drugs, drawn from private pharmacies and hospitals failing testing in government laboratories. In 2024, over 3,000 samples failed testing in government laboratories. In February 2025, the state government of Himachal Pradesh informed the state legislature that 1,683 samples of drugs manufactured within the state had reportedly had failed quality testing in the previous two years.

Given this weight of history, the results published by Philips are astounding and we look forward to the peer-reviewed publication of this study that hopefully provides more details on the design of the study and actual test results.

For example, were the samples which were sent for testing adequately “blinded”? This is crucial in today’s India because private laboratories are aware of the possibility of government backlash if they were to report a large number of drugs from the government’s flagship scheme failing quality testing.

In 2014, the government of India threatened to sue a group of American academics who had concluded on the basis of testing “made in India” generic drugs that the Indian pharmaceutical industry was more likely to sell poor quality generics in Africa. That study did not even mention the names of any Indian companies and yet it attracted a threatening legal action.

Blinding the lab to the source of the drugs was therefore a crucial requirement.

Similarly, the statistical model for the sample size of 131 samples included in the study. If one were to model based on the government’s own Not of Standard Quality data, the number of samples from Jan Aushadhi stores would have to be more than twice that of the sample size to give a 90% confidence to an assertion that all samples sourced pass quality test.

Lastly, there has to be some disclosure on how exactly the laboratory procured “reference samples” from the Indian Pharmacopeia Commission. These “reference samples” are basically small quantities of the pure active ingredient against which the sample is tested in order to establish purity of the assay.

We raise this issue because there have been several complaints from state run laboratories regarding long delays by the Indian Pharmacopeia Commission. in supplying reference samples.

A couple of drugs mentioned in the doctor’s Twitter thread, (rifaximin and febuxostar) do not feature in the list of available reference standards published on the Indian Pharmacopeia Commission’s own website. An explanation of how the lab procured reference standards from Indian Pharmacopeia would go a long way in establishing the credibility of the study.

Critical issues

In addition to the above, we feel it is necessary to clarify some critical issues pertaining to the claim that pharmacopeial testing is all that matters for the purposes of establishing quality.

This is not completely true. In the 1960s, when the first antibiotics were going off patent in the United States, the country’s regulator was faced with the question of how exactly to validate the quality of generics. Repeating clinical trials was an expensive proposition and also unethical since some patients would have to be given a placebo.

The other option was to rely on pharmacopeial testing in the laboratory. However, this option was not considered a reliable indicator of the ability of a drug to dissolve in the stomach and permeate the intestinal lining of a patient in order to enter a patient’s bloodstream.

This is important because although both the innovator and generic use the same active ingredient, the other excipients such as the binding agents may differ from one another, affecting the ability of the generic to dissolve at the same rate as the innovator.

For this reason, the US Food and Drug Administration made it mandatory for generics to conduct bioequivalence testing – the generic drug would be given to healthy volunteers and the rate at which the drug became bioavailable in the human body would be measured in the volunteers’ blood and urine. If the dissolution curve matched the curve of the innovator drug, it was considered bioequivalent to the innovator and hence interchangeable.

The World Health Organisation released a technical recommendation regarding bioequivalence testing in 1996. India made it mandatory only in 2017, except that the rules were so vaguely formulated that we still do not know if the requirement extended to previously authorised generics. We also do not know the parameters of the waiver provided to generics that are highly soluble and permeable.

As a result, we do not know which generics in India are bioequivalent. In other countries such as the United States, the regulator publishes an “Orange Book” that allows patients and doctors to check the generics which have been rated to be “bioequivalent”. India does not do this.

We have been asking the government for quite sometime now to at least force the manufacturers to indicate on their labelling whether their drugs have been declared bioequivalent.

To return to Philips’ study, doctors should recognise that even if the drugs in question have all passed pharmacopeial testing, there is no guarantee these drugs will have the same effect in patients unless these drugs have also been established to be bioequivalent.

This is especially true for Narrow Therapeutic Index drugs. These are drugs where even a small change in bioavailability can have a significant effect in treatment outcomes. Examples of such drugs include Tacrolim, which is used to suppress the immune system after organ transplantation surgeries and drugs such as Levothyroxine, which is used to treat thyroid deficiencies. There are many documented studies of how generic Levothyroxine has caused poor treatment outcomes in patients due to bioavailability issues.

That the Indian pharmaceutical industry has had an issue with bioequivalence is not a secret. In fact, faked bioequivalence studies was one of the starting points of the scandal at Ranbaxy. Similar allegations were made against GVK Bio by international regulators.

There are also studies conducted by doctors at PGIMER which demonstrated with clinical trials that bioavailability of generic Tacrolimus and generic Itraconazole varied significantly from the innovator brands. For the second study, these brave government doctors were rumoured to have received backlash from the powers that be in Delhi.

Batch-to-batch consistency

Two more issues before we conclude.

The first is that surveys based on drug samples drawn from the market have limited value for the simple reason that such surveys rarely capture batch-to-batch consistency issues: the toughest part of pharmaceutical manufacturing is ensuring batch-to-batch consistency. In addition, testing of limited samples fails to capture contamination problems that are not consistent across batches.

It is precisely for this reason that regulatory practices in the West focus more on compliance with Good Manufacturing Practices – adherence to processes is the surest guarantee of quality. On this count, we have a huge mountain of evidence in American and European drug inspection reports of Indian facilities failing to comply with Good Manufacturing Practices standards. The rigour expected of the pharmaceutical industry in India is simply missing.

The second is that bulk procurement conducted by public agencies or private hospitals tend to deal with larger companies. They also have their own testing requirements before the release of drugs into the market. As a result, most of the drugs sampled as part of the Philips study had already cleared one round of testing that likely weeded out many poor quality manufacturers as evident from “blacklists” published by government agencies.

We suspect that results may have been very different if samples tested were procured from the smaller private pharmacies and government hospitals that follow a localised procurement strategy rather than a centralised bulk strategy. The former attracts more smaller manufacturers.

To conclude, while we are surprised by the results presented by Philips on Twitter, he has started an important public debate on the quality of generic drugs.

A peer-reviewed publication must now follow to establish the study’s credibility and hopefully, we will see more such studies in the future along with the necessary caveats. At stake are important issues of public health and the cost of access to medicine.

The writers are co-authors of The Truth Pill: The Myth of Drug Regulation In India.