India’s Cleanroom Highs and Woes

India. A continent of extremes. To some, it’s an enchanted land where outrageous wealth lives alongside extraordinary poverty. One in which breathtaking natural beauty co-exists with massive urban decay. India is a nation where a deep-rooted mystical tradition does little to slow the drumbeat of technological advancement. Home to the largest supplier of generic pharmaceuticals and to a space program operating on a shoe-string budget, the country seems adept at leveraging the best cleanroom technology in its pursuit of a better seat at the global table. But does that pursuit also entail short-cuts that could compromise safety? Let’s take a closer look…

Just a few days ago, India’s Chandrayaan-2 blasted off from the Sriharikota space station, a rocket launch site operated by the Indian Space Research Organization based in Andhra Pradesh. To date, only three other countries have successfully landed on the lunar surface – the United States, the then Soviet Union, and China – and the craft’s journey largely echoes that of Israel’s lunar attempt with Beresheet. After an initially aborted launch attempt, Chandrayaan-2 entered Earth’s orbit where it will remain for 23 days before setting itself on the path to the Moon. And, assuming that this mission is successful, Chandrayaan-2 will be doing something other missions have not yet achieved: mapping the satellite’s little-explored South Pole.

In a historic ‘first,’ the expedition is led by two female engineers, Ritu Karidhal and Muthayya  Vanitha whose launch success inspired messages of congratulation from across the country.

In a tweet by iconic film star and producer Anushka Sharma, the mission directors were described as ‘nothing short of superheroes’ and Prime Minister Narendra Modi also commented on the venture being ‘Indian at heart, Indian in spirit!’ So, assuming the craft lives up to its name – ‘Chandrayaan’ means ‘moon craft’ in ancient Sanskrit and Hindi – what will it do if it, unlike Beresheet before it, successfully touches down on the lunar surface?

Standing 144 ft in height (roughly equivalent to a 14-story building) the launch vehicle has three parts: an orbiter, a lander, and a rover. This last part, the rover, will pick up where India’s first mission to explore the Moon left off in 2008. Although Chandrayaan-1 did not actually touch down, it succeeded in mapping the surface using visible, near infrared, low-energy X-rays, and high energy X-rays to prepare a three dimensional representation of both the near and far sides of the Earth’s best known satellite. Chandrayaan-2, with its shoestring budget of just $140 million, will continue the work by searching for both water deposits and the presence of hydroxyl – a compound formed by the bonding of one atom of oxygen to one of hydrogen. In India’s earlier mission, a Moon Mineralogy Manager, an instrument developed by NASA, gave scientists hope  that water may actually be present on the lunar surface. And this hypothesis was later confirmed by a re-examination of data from the 1999 Cassini probe and by the 2005 flyby of the Deep Impact spacecraft on its way to connect with comet Tempel 1.

Furthermore the excitement about what Chandrayaan-2’s rover might find on its rocky travels   does not stop there. According to an interview published by NPR, the perhaps aptly-named Jessica Sunshine of the University of Maryland-College Park, described lunar water as being surprisingly different from the element we recognize here on our own small blue planet. According to Sunshine it is ‘a very thin film of molecules stuck to the surface. […] “It’s not liquid water, it’s not frozen water and it’s not gaseous water, OK? It’s none of those things.”(1)

Moreover, it is scarce. Sunshine estimates that removing the water molecules from an area the size of a football field would yield less than a quart of the element, and even that small amount depends on the time of day it is recovered. ‘The water seems to appear and disappear during the course of a lunar day, as temperatures rise and fall,’ claims correspondent Nell Greenfieldboyce on NPR’s program All Things Considered.(2)

All of which further complicates an already complex operation. For the mission directors of the Chandrayaan-2 project the pressure is most definitely on. For Muthayya  Vanitha, for instance, managing the data transmission between Mission Control and the craft and orbital logistics is a demanding role. Her counterpart, Ritu Karidhal, is overseeing all aspects of navigation and has the pressure of living up to her moniker, India’s ‘rocket woman.’ They are also responsible for directing a project crew which is 30% female and, in a country like India where ‘women in many fields don’t have a level playing field to work on,’ the burden of responsibility for ensuring success is weighty indeed. As writer Stuti Bhattacharya writes in iDiva, India’s largest lifestyle online portal for women, ‘It is a win for women, who are not given the same opportunities as men by a society which wants us to get married, have children, and make rotis, not guide rocket ships to the Moon.’(3)

Which perhaps tangentially brings us to the second piece of cleanroom-related news from India: blood pressure medications.

According to an article in Business Insider, the Federal Food and Drug Administration (FDA) recently issued a recall of all drugs that contain a chemical identified as N-Nitroso-N-methyl-4-aminobutyric acid (NMBA). This toxin was an impurity detected in some common medications used to treat elevated blood pressure and in heart failure prevention. Among the more than 30 recalls is a batch manufactured by Hetero Labs based in Hyderabad, southeastern India. According to the company’s website, Hetero is that country’s largest producer of generic drugs and has ‘around 18 state-of-the-art manufacturing facilities, which are cGMP compliant and have been approved by various Ministries of Health and regulatory authorities like US FDA, WHO, MCC – South Africa, MHRA-UK, TGA – Australia, PMDA – Japan, KFDA (Korea) among others. The company has a rich manufacturing product portfolio of over 200 products across a wide range of therapeutic categories. Hetero has a strong global presence in over 120 countries and has been offering API’s and generic formulations to partners across the globe.’(4)

What the website does not state, however, is that the company has been the subject of investigations by the FDA in 2016 and 2017. Nor does it account for why Hetero’s employees allegedly shredded a number of company documents ahead of an FDA inspection without even keeping a log of what was destroyed. Likewise information on the website fails to explain the warning issued on account of a failure to sanitize equipment and an apparent disinterest in batch discrepancies.(5)

And lastly, it also fails to note that the impurity introduced into its products – NMBA – is a probable carcinogen that was once used in the manufacture of liquid rocket fuel. In a separate incident, Chinese manufacturer Huahai was also found to have introduced NMBA into a blood pressure medication, Valsartan also known as Diovan. An antihypertensive, Valsartan is an angiotensin II receptor antagonist, meaning that it prevents blood vessels from narrowing and therefore elevating blood pressure. It is recommended for patients as young as six years of age.

As Sandy Walsh of the FDA stated: ‘“while surveillance inspections declined slightly in China from 2017-18, inspections in India have increased substantially.

Clearly a greater degree of oversight in the manufacturing processes of both countries needs to be undertaken to prevent future instances of similar contamination. The FDA, whilst subjecting certain international manufacturers to enhanced scrutiny, can only do so much founded upon a ‘risk-based inspection strategy.’ As Sandy Walsh of the FDA stated: ‘“while surveillance inspections declined slightly in China from 2017-18, inspections in India have increased substantially. Among other things, the number of inspections in any given country reflects our risk-based prioritization of our inspections and improvements in our targeting; our increasing ability to leverage inspectional work done by trusted partners, especially in Europe; and a higher number of pre-approval inspections.”(6)

In a memo by the European Medicines Agency (EMA) regulator it was noted that the NMBA may have been created accidentally by the ‘combined use of the solvent dimethylformamide and sodium nitrite,’ a theory that resonates with the FDA.(7) Moreover, since the toxin is thought to be a by-product, it is not something for which a product is routinely tested. Detection of NMBA would require analysis via gas chromatography accompanied by mass spectrometry and, as a spokesperson for the European Directorate for the Quality of Medicines (EDQM) acknowledged in the Business Insider interview: ‘“These techniques are not normally used routinely to test pharmaceutical products.”’(8)

But when the life-saving pharmaceutical has been contaminated by a carcinogen also found in liquid rocket fuel the danger to human health must surely be worth the cost of a couple of additional tests.

But perhaps they should be? As Anders Fuglsang notes in the Business Insider story, ‘“We need to ask ourselves how it is possible – despite pharmacopoeias and agency guidelines, inspection programs with coordination across continents, a system of public quality control, and companies complying with all rules – that a nasty carcinogen can find its way into our drugs and be there for years without anyone noticing.”’(9) A salient question indeed. And perhaps safeguarding the purity of a drug with global sales of 10.4 billion pills in 2017 might actually be worth the investment of time and technology necessary for increased scrutiny. For those prescribed antihypertensives or those at risk for heart failure, the 1 or 2 pills per day (respectively) are critical to survival. But when the life-saving pharmaceutical has been contaminated by a carcinogen also found in liquid rocket fuel the danger to human health must surely be worth the cost of a couple of additional tests.

What do you think? Are you troubled by the potential of contamination in pharmaceuticals manufactured in India? Do you trust that bodies such as the FDA, EMA, and EDQM are regulating the industry sufficiently? And what about the latest in India’s space program developments? We’d love to know your thoughts…

References:

1. https://www.npr.org/templates/story/story.php?storyId=113159860
2. ibid
3. https://www.idiva.com/the-daily-agenda/indian-news/the-iconic-indian-women-leading-the-isro-mission-chandrayaan-2-to-the-moon/18001582
4. http://camberpharma.com/about-us/hetero
5. https://www.businessinsider.com/why-blood-pressure-medicine-keeps-getting-recalled-losartan-2019-3
6. ibid
7. https://www.businessinsider.com/r-toxin-at-heart-of-drug-recall-shows-holes-in-medical-safety-net-2018-8
8. ibid
9. ibid