Amid US Cough Syrup Findings, Regulators Feel India Needs To Work On Perceptions But Also Make Improvements
Executive Summary
In wake of the furore caused by OTC cough syrups made by two small Indian companies, former and current US FDA and MHRA officials say quality-related issues are not specific to India. However, while image management needs some work, manufacturers in the country also need to make further improvements to ensure quality.
India is among the nations with the largest number of US Food and Drug Administration (FDA)-compliant plants - the 2020-21 annual report by the Indian government claiming the second-highest number of such facilities outside the US.
However, a furore over deaths in Asia and Africa last year reportedly caused by over-the-counter (OTC) cough syrups manufactured by a few small companies in India and Indonesia - as determined by the World Health Organization (WHO) – led to its reputation being tarnished.
At a recent event in India, panellists including current and former officials of the US FDA and the UK’s Medicines and Healthcare products Regulatory Agency (MHRA), when asked to respond to these incidents, said quality-related incidents are not restricted to India, but that manufacturers should be more proactive in ensuring quality standards are met.
Carmelo Rosa, director, Division of International Drug Quality at the FDA's Center for Drug Evaluation and Research (CDER), said quality aberrations are not exclusively an “India issue.”
In the US, illness in infants was reported in late 2021 and early 2022 from multiple strains of Cronobacter bacteria linked to powdered infant formula made at Abbott’s facility in Sturgis, MI. Later, the FDA found quality control problems at facilities operated by multiple businesses.
FDA Commissioner Robert Califf has announced a reorganization and other changes to elevate and improve the foods program, saying it is long overdue to become a priority. (Also see "Will Califf’s Attention To Foods Come At Expense Of US FDA’s Drugs Program?" - Pink Sheet, 23 Feb, 2023.)
Perception Vs Reality
At the BioAsia 2023 discussion on "India for India and India for the world – where does quality stand," former good manufacturing and distribution practice inspector at the MHRA, Ian White, said “I've been inspecting for seven years…traveling within this region for that time, I have to say, I think some of the best facilities worldwide are in India.”
“Unfortunately, that's not always recognized in the perception of the industry within India, outside of India…I grew up in the UK industry, hearing horror stories [of] manufacturing…So, it was quite surprising to me as I started traveling to actually see some of the facilities you have in India and certainly in the context of knowledge that you have, which in my opinion is quite exceptional,” he pointed out.
As moderator, CNBC-TV18 anchor and associate editor research Ekta Batra asked the panellists if regulators’ perception of an Indian company changes when they see separate manufacturing set-ups within the same facility for different markets.
“Even in facilities that make products in the US, it's not uncommon to have other areas that are manufacturing at less than US quality standards - they might be aligned for rest of the world [or] other semi-regulated markets. So, to the extent that we keep advocating that there should be one global quality policy and standard, for us there shouldn't be multiple quality standards,” said Sarah McMullen, FDA’s country director for India.
Companies that can manufacture products to meet the standards of stringent regulatory authorities (SRAs) like the FDA shouldn’t ideally offer “any less” to other countries, she observed.
Pavan Kumar Mocherla, BD’s EVP and president Greater Asia, agreed that different quality standards for different markets are unacceptable. “There is a mindset there. And this is driven by the cost factor” and unless the underlying mindset changes, he doesn’t see a change in this approach.
The Cough Syrup Saga
In the incidents related to cough syrups, Gambia, one of the countries which reported the deaths, roped in the US Centers for Disease Control and Prevention (CDC) to investigate the cause. Early this month, CDC’s report said the investigation “strongly suggests that medications contaminated with diethylene glycol or ethylene glycol imported into The Gambia led to this acute kidney injury cluster among children.” (Also see "The Quality Lowdown: The Effort Required To Stem Substandard, Illegitimate, Unapproved Drugs" - Pink Sheet, 13 Feb, 2023.)
Earlier, the WHO had issued an alert after it found "unacceptable levels" of toxins in cough syrups made by six companies - PT Yarindo Farmatama, PT Universal Pharmaceutical, PT Konimex and PT AFI Farma from Indonesia and Maiden Pharmaceuticals Ltd. and Marion Biotech Pvt. Ltd. from India. Maiden’s syrups were purported to be linked to the incidents in Gambia and Marion’s to Uzbekistan, respectively.
India’s Central Drugs Standard Control Organisation said when it collected control samples from Maiden Pharma’s batch that was exported to The Gambia it found no contamination. However, samples from Marion were found to be substandard. Marion’s production license has been suspended and several company officials arrested, while an Indian court has recently sentenced two officials of Maiden Pharma to imprisonment over exporting substandard cough syrups to Vietnam in a probe that began in 2014.
Meanwhile, as part of its efforts to improve quality and regulatory oversight, India now requires bar codes on packaging for active pharmaceutical ingredients and will soon implement the measure for finished dosages.
Pre-COVID Deficiencies Being Repeated
However, CDER’s Rosa pointed out that regulators like the FDA “don't necessarily operate and focus on perception. Our approach is what we find when we go to a facility.”
Pointing to 20 import alerts post-COVID and 60 Official Action Indicated classifications issued to Indian companies between November 2019 to November 2022, Batra asked if Indian manufacturers had become less cautious or there was an increase in the incidences of inspection and hence negative outcomes. (Also see "US Pricing Pressure Spotlights Regulatory Compliance As Key To Indian Companies’ Performance" - Scrip, 28 Oct, 2022.)
“We were very surprised that after COVID, [when] we visited some of the facilities, we found some similar problems and deficiencies that were occurring before COVID came to life,” Rosa said.
Some of the findings have been “pretty consistent…we're talking about issues with cleaning, issues with quality systems, not understanding what happened, not defining roles and responsibilities. But again, it's not only about India,” said Rosa, who is also chair of The Pharmaceutical Inspection Co-operation Scheme (PIC/S) Active Pharmaceutical Ingredient Expert Circle. (Also see "PIC/S Resumes Assessment Of Countries Seeking To Join Inspection Scheme; Russian Application Frozen For Now" - Pink Sheet, 9 Jun, 2022.)
However, “it may be more notable here [India] because of the number of inspections. But I don't have that data to show that because of inspections there is a direct correlation to the increase [in negative inspection outcomes] that we're seeing.”
Biosimilars – A Different Cup Of Tea?
Sarfaraz K Niazi, adjunct professor of pharmaceutical sciences at the University of Illinois pointed out that every biosimilar developer from Amgen down to Pfizer has received a complete response letter as “this is a newer science….and they're really not ready to see what FDA considers to be most critical.”
Niazi has been advocating the US Congress remove the interchangeability clause from the Biological Price and Competition Act to enable faster acceptance of biosimilars. (Also see "MPP's Guide To Cutting Biosimilar Approval Times, Costs By Third Or More" - Scrip, 16 Dec, 2022.)
Asked if companies face tougher scrutiny for biosimilars, Biocon, Ltd. unit Biocon Biologics’ chief quality officer Michael Cutter acknowledged that Indian companies “have definitely seen this difference, coming from FDA inspections and from other inspections. I don't know the drivers for this - whether it's preconceptions or not, I couldn't say. We've had discussions with many of the health authorities to try and understand this."
At the same time, “we can't cry into our coffee that we had a difficult inspection. It's not the inspector’s job to manage our quality. And, from my perspective, the worst reason for improving your quality is just because you had a bad inspection." It's much better for patients and business, which has many other stakeholders, if companies have a robust quality control system, he added,
Differences In Enforcement
Referring to increased efforts by SRAs to harmonize standards and extend mutual recognition agreements, Cutter felt "the way that we are trying to move towards having common requirements is a good step ahead.”
McMullen concurred, but in response to Batra’s question if there would only be “one regulator and one compliance” for companies in the future, FDA’s McMullen pointed out that they are two different things. “So, we have the standard and we have the enforcement. Those are different and when it gets to mutual recognition, the enforcement has to be commensurate.”
The FDA’s associate commissioner for global policy and strategy, Mark Abdoo, observed “We use the PIC/S indicators when we do our mutual recognition assessment, but the enforcement needs to be consistent. We need to have an assurance that our partner is capable of conducting an inspection that will meet our requirements, and that it will provide us the information that we need in order to take risk-based decisions.”
A regulator could “run into a lot of problems where there's uneven enforcement or compliance or where there are multiple layers of regulatory oversight responsibility that divert and then allow regulators to point the fingers at each other and say 'No, that's not mine' that there's like a central versus a state dynamic...,” he added.