A petition to relook the legal framework governing stability testing of drugs in India

We recently sent a petition requesting it to reexamine the entire legal framework surrounding stability testing of generic drugs in India to the Ministry of Health.

The issue of stability testing is critical in guaranteeing that only medicines of standard quality reach patients. This is because most drugs, which are combination of chemical substances (and in the case of biosimilars, proteins and peptides) are inherently unstable over long durations of time. It takes a feat of chemical engineering to ensure the stability of a drug over a period of several months and in varying conditions over a supply chain that may cross continents. If the manufacturing process is anything less than precise, there is a high possibility that the resulting drug will degrade in a manner that affects its therapeutic efficacy. This could have an adverse impact on patients, especially if the drug qualifies as a life-saving drug.

The most common environmental factors influencing stability of drugs are temperature, humidity and sunlight. These three factors could severely degrade drugs during their transport and storage. For this reason, almost every country requires all drugs to undergo stability testing for their entire life-cycle. Such stability testing requires exposing a sample of every batch manufactured to external elements such as heat, humidity and light in special chambers designed for such testing. If the sample fails initial stability testing, it is usually mandated that the batch from where it is drawn to be destroyed entirely. Presuming the batch clears its initial stability testing, most countries require the manufacturer to test retained samples from that batch which is shipped to the market at regular intervals until the lifecycle of the drugs expires. If at any stage, the samples so retained fail stability testing, the manufacturer is required to affect a recall across the supply chain. It is possible for a drug to be stable for a few months of its lifecycle and degrade thereafter due to poor manufacturing practices or exposure to high heat and humidity conditions. Since recalls are expensive and deeply damaging to reputations of companies, there is a great incentive for pharmaceutical companies to fabricate testing data, especially since most countries require such testing to be done internally with records being maintained for inspections by external regulators. It is no surprise then that multiple Indian companies, starting with Ranbaxy, have been caught fabricating stability data by the USFDA.

Returning to the subject of our petition, we make a case for reviewing the Indian legal framework governing stability testing of pharmaceutical drugs. Put briefly, India did not have a stability testing for generics entering the market after they lost their ‘new drug’ status under Indian law. Under Indian law a drug is considered ‘new’ for the first four years after it is approved by the DCGI. During this period all approvals go through the DCGI’s office. Manufacturers entering the market after the first 4 years are only required to get approvals from state licensing authorities. For the longest time, India has had two different regulatory frameworks for ‘new drugs’ and those that are no longer ‘new drugs’. In context of stability testing, ‘new drugs’ were always required to undergo ‘stability testing’ – the requirements were laid down in Appendix IX to Schedule Y of the Drugs & Cosmetics Rules, 1945 and which was subsequently replaced by the New Drugs and Clinical Trial Rules, 2019. For reasons that are not clear, the same system did not extend to drugs being approved by state licensing authorities after the expiry of the ‘4 year’ period. From a scientific viewpoint – this makes absolutely no sense.

Indian regulators have been aware of this legal status for a long time now but have dragged their feet when it came to taking corrective action. In 2013, both the Drugs Consultative Committee (DCC) and the Drugs Technical Advisory Board (DTAB) did deliberate on the issue before making recommendations to the Government to make stability testing compulsory. In fact the DCC stated that the lack of a mandatory stability testing requirement was a “serious lacunae” and that “that it is necessary that evidence and data of the stability of the drug products proposed to be manufactured by the licensee are required to be submitted to the regulatory authorities so as to ensure the stability of the drug formulations licensed in the country by the State Licensing Authorities.”

Thereafter one set of amendments to the Drugs & Cosmetics Rules, 1945 was published for comments in 2015. These amendments never became law – for reasons that were never disclosed. In 2018, another, a significantly watered down version was made the law. All generic drugs, even those approved after the first 4 years would be required to submit stability data for approval. But unlike the draft amendments of 2015 which specifically required stability data to be generated as per the requirements of Appendix IX, the version in 2018 did not lay down any specifics on the kind of data that was required to be generated, the sample size for testing and the manner in which the stability data had to be documented. Given that India has approximately 36 different state licensing authorities, it makes no sense to not mention these requirements in the law. Such ambiguity enables wide interpretations of the law by the state licensing authorities resulting in substandard drug products in our drug supply.

After filing applications under the Right to Information Act, 2005 the Ministry of Health did provide us with some barebones guidelines that lacked the force of law and which were not published anywhere in the public domain. Even these guidelines were likely a result of an earlier petition that we had filed with the Ministry of Health.   

In any event it is clear that this entire framework requires deep deliberation and study. To this end, our petition to the Ministry of Health requests for the setting up of an expert committee to examine the following issues:

  • Do the New Drugs and Clinical Trial Rules, 2019 provide clear and cogent guidance on stability testing when compared to the WHO and USFDA regulations on the same point?
  • How can the Drugs & Cosmetics (Third Amendment) Rules, 2018 be amended to provide sufficient clarity on the parameters for stability testing of generic medicines?
  • What should be the mandatory documentation that companies should be required to generate and store with regard to their internal stability testing?
  • Should the criteria for stability testing be different for “new drugs” and “generic drugs”?
  • Should Indian law be amended to mandatorily require stability testing of every batch of drugs by the Indian pharmaceutical industry?
  • Should Indian law be amended to mandatorily require government laboratories to test samples drawn from the market, for impurities?
  • Should Indian law on packaging of drugs be amended to require the publication of more accurate storage conditions?   
  • Should the failure to conduct stability testing for a batch of drugs before they are released in the market be equated to the sale of adulterated drugs?
  • How best can the law deter the fabrication or manipulation of data related to stability testing?

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