Greening the pill

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There is an urgent need for concerted measures and renewed commitment from pharma companies and policy makers to halt the advance of drug pollution and its disastrous impact on the environment

India is the global host for 2018 World Environment Day, to be observed on June 5, as part of the UN’s endeavour to spread awareness and draw attention towards pressing environmental concerns. As part of this year’s theme, ‘Beat plastic pollution’, India joins global leaders in tackling the huge menace of plastic waste and seeking solutions to this mammoth challenge.

But, even as we train our focus towards this pertinent issue, it’s time we recognised and addressed another environmental concern of the same magnitude – drug pollution.

Yes, ironically, the pharma industry, entrusted with the role of saving and improving lives, is allegedly one of the major contributors to environmental pollution. And, the Indian pharma industry, often called the ‘Pharmacy of the World’ has been named as a chief perpetrator of this transgression.

Drugging the environment

It has been accused that in the march towards fulfilling its ambitions of becoming a global pharma powerhouse, India’s pharma sector is responsible for fuelling the creation of an environmental crisis with its poor wastewater management and effluent treatment methods as well as negligence in monitoring and reducing levels of greenhouse gas emissions. Several global studies highlight and caution against the rising drug pollution in India. (See Box: Drug Pollution: A mammoth issue)

Drug manufacturers deny these allegations, refute the findings of the reports and attribute vested interests to the global organisations who have funded these reports. But, India’s Environment Ministry itself classifies pharma manufacturing as a “red category” activity due to the production of hazardous waste.


Box 1: Drug pollution: A mammoth issue

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The findings of a major study undertaken in 2016 by Changing Markets Foundation, a non-profit organisation, on behalf of Nordea Bank, a Sweden-based financial institution highlighted that Hyderabad is facing uncontrolled pollution due to the toxic waste generated from the city’s drug manufacturing facilities. The city is home to several major pharma players including Aurobindo Pharma, Hetero Drugs, Dr Reddy’s Laboratories, Mylan, and MSN Laboratories, amongst others; and is one of the world’s largest bulk drug manufacturing hubs, exporting a huge amount of medicines to markets across the globe, including the European Union and United States every year.

What’s more, a follow-up investigation titled, ‘Hyderabad’s pharmaceutical pollution crisis: Heavy metal and solvent contamination at factories in a major Indian drug manufacturing hub’, which included field tests conducted in April and September 2017, claims that the measures taken to control pollution have not had the desired effect. In fact, the report cautions, “with plans afoot to expand the city’s pharma production capacity over the coming years and the lack of credible regulation and measures to control manufacturing emissions, the future looks grim for the area’s inhabitants.”

A report published in the Journal of the Geological Society of India in October 2017 also revealed that groundwater in Hyderabad’s Nalgonda district contain toxic substances including lead, cadmium, vanadium and arsenic “in concentrations that are thousands of times higher than the maximum levels prescribed for drinking water quality by the World Health Organisation (WHO) and Bureau of Indian Standards (BIS).” It also discloses that the adverse impact of this pollution on human health and ecosystems include near eradication of some species, feminisation of fish and rise in antimicrobial resistance (AMR).


Getting to green

Pharma companies are morally bound to develop effective alternatives to products and processes which might be harmful to the environment in a bid to tackle the crisis of drug pollution. It has become imperative for the industry to look at adopting more sustainable drug discovery routes and development practices.

But, how should the industry go about achieving this objective?

Renowned pharma scientist, Dr Himadri Sen, Chairman, STEERLIFE India recommends that going green is possible through designing of pharma products and processes which prevent or reduce the use and generation of hazardous substances. He also opines that continuous manufacturing provides cleaner, flexible, efficient options of running pharma processes through implementation of PAT and thereby reduces carbon footprint.

Avoiding the use of Class I and II solvents in both, API manufacturing and pharma product manufacturing; recycling of other solvents etc. are some of the other measures that he recommends to improve the environmental credentials of pharma companies.

Similarly, Dr Sajeev Chandran, Associate Director, Advanced Drug Delivery Research & IVIVC/ Biopharmaceutics, Pharmaceutical R&D, Lupin, refers to the adoption of ‘benign syntheses as an environment-friendly measure. He clarifies that it may mean using less of organic solvents (methanol, dichloromethane, toluene, dimethyl formamide and acetonitrile), using less hazardous reagents, decreasing number of steps in the synthesis process of the molecule and also developing bio-friendly catalysts.”

Dr Rakeshwar Bandichhor, Associate Director, API, R&D, Dr Reddy’s Laboratories apprises, “A myriad of opportunities are there with the generic industries to reduce the E-factor and develop cost effective and green synthetic routes of medicines.” He says, “Given the opportunity, the philosophy of green chemistry, which is best defined as the utilisation of a set of principles that reduces or eliminates the use or generation of hazardous substances in the design, manufacture, and applications of chemical products, can be adopted.


Box 2: Did you know?

Interestingly, drug pollution is a long identified problem. In fact, Parcelsus, a renowned Swiss physician and alchemist of the 16th century, credited with the introduction of chemistry in medicine, had cautioned that ‘the dose makes the poison’. As one of the basic tenets of toxicology, it means ‘a substance can produce harmful effect associated with its toxic properties if it reaches a susceptible biological system within the body in a high enough concentration.’ (Source: Wikipedia). This adage also provides the basis for public health standards and highlights the need to ensure that only acceptable levels of contaminants are found in food, drinking water and the environment.

It can be said that negligence in understanding the gravity and significance of these teachings and taking effective measures to put them into practice have led to today’s crisis of drug pollution and its magnitude.


He explains, “Staying with green chemistry fundamentals, right route selection/ processes amenable to scale up with minimum PMI etc. would make pharma products less burdensome environmentally. For more than a decade, we have witnessed a lot of technological advancements and sophisticated tools are now available to realise green chemistry and engineering at higher scale e.g. continuous manufacturing, bio-catalysis etc. These enablers have the potential to make medicines without adversely affecting the environment.”

So, what has been the progress on this front? Are many drug companies making conscious efforts towards inculcating more environment-friendly practices in their drug development processes?

These questions elicit a mixed response from the industry experts and veterans.

Dr Bandichhor explains, “Over the past few years, the importance of green chemistry gained momentum and significant amount of research have been directed towards the development of new technologies and methodologies for environmentally benign processes at the innovator companies. Apart from technological green paradigm shift, improvements in the process conditions, economics, ever-increasing environmental controls and social pressure, incorporating green chemistry into the syntheses of medicines and intermediates have been steadily gaining priority in the pharma industry.”

However, he also points out, “Consideration of green principles into synthetic route design has evolved into an institutionalised practice among major pharma companies, but still has a long way to go.”

Dr Sen feels that though Indian pharma companies are familiar with these concepts, a sincere effort to implement them is lacking due to limited availability of options, regulatory framework and lack of financial rewards.

Cecilia Van Cauwenberghe, Associate Fellow and Senior Industry Analyst, TechVision and Vandana Iyer, Senior Research Analyst, TechVision, Frost & Sullivan informs, “There is a growing awareness about sustainable drug discovery and development methods across the global pharma industry, as evidenced by the shift towards the adoption of green chemistry practices by large pharma concerns such as Abbott, Amgen, Merck, Roche and Johnson & Johnson.”

Barriers to sustainability

Experts endorse the adoption of greener products and processes, but also make us aware that making the shift from the current practices to more sustainable approaches such as adoption of green chemistry would be no child’s play.

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Van Cauwenberghe and Iyer explain, “Drug discovery and development is in itself a challenging and time – consuming process which is associated with high attrition rates. Hence, redesigning an established process using a more sustainable approach is usually perceived as a difficult process from a business and technological standpoint. Most chemists would face challenges in incorporating green practices throughout the drug discovery and development process.”

Nitesh H Mehta, Co-Founder Director, Newreka Green-Synth Technologies and Krishna B Padia, Executive Director, Green ChemisTree Foundation, in an earlier article shared with Express Pharma, had listed down and elaborated on the myriad that impede the implementation of green chemistry. Here are some excerpts from that article.

  • Lack of availability of green chemistry-based technologies: The green chemistry tool box (set of platform technologies based on the principles of green chemistry and engineering, alternatives to conventional synthetic chemistry-based processes/ chemistries) is still quite empty. We still don’t have viable green chemistry-based solutions for many processes like nitration, sulphonation, friedel-craft, etc.
  • Challenges in scale-up and commercialisation of green chemistry-based technologies: There are many inventions/ innovations that have already been developed by various academic and research institutes and these are potential solutions for some of the environmental challenges faced by the industry. However, for whatever reasons, these solutions haven’t been pursued after lab scale development. Academic/research institutes need to make extra effort to customise the solutions and demonstrate their technical and commercial viability at a reasonable scale, to gain the industry’s confidence. The industry needs to stretch themselves to take the risks that are associated with scale-up and commercialisation of new solutions.
  • Lack of connect between green chemistry solution providers to industry: One of the key barriers is the communication gap between the industry and green chemistry solution providers. This could be because the industry is in one part of the world and the solution providers is in other part of the world. This could also be due to insufficient marketing of the potential solution by the solution provider (usually the case with academic/ research institutes who don’t proactively market their solutions to the industry). This could also be due to industry not putting enough efforts to search and look around for solutions.
  • Lack of knowledge and information about green chemistry: Chemists and chemical engineers working on designing new products and processes have limited knowledge about the basic principles of green chemistry and engineering. It’s critical to ensure that teams working on drug discovery and development have workable knowledge about these principles. It’s also important to introduce green chemistry in our curriculum so that the next generation of chemists and chemical engineers are shaped to think ‘green.’
  • Myths about green chemistry: Certain myths prevailing about green chemistry are also a barrier in its implementation in the industry. Myths like green chemistry is good theory but not practically feasible, it is difficult and complex, not viable for small and medium size organisations, it requires huge resources, etc., should be busted.
  • Regulatory barriers: In pharma and other industries, any change in processes (when a green chemistry-based process is replacing a conventional process), has to go through validation trials, changes in documentations and filings, as well as require series of approvals from internal regulatory affairs team, customers and finally, from external regulatory agencies like FDA. Besides the time invested for tedious process of making these changes in DMF filings, this also involves significant cost/ financial resources. Hence, green chemistry-based solutions need to offer returns that justify the investment of time and money.

Ways to catalyse progress

It is said that for every problem there is a solution. It stands true in this case as well. Industry experts inform that though it would require strategic planning, concerted efforts and long term commitment, there are ways and means to encourage greener practices. Let’s examine some of the major ones.

  • Building a business case for going green: Van Cauwenberghe and Iyer expound, “Focusing on green chemistry practices that improve the efficiency of drug development methods will help derive more value through lower material consumption. Using fewer materials for drug synthesis can help reduce waste and production costs and can help improve the total yield of the product. This will surely aid in making a very strong business case for green drugs.”
    Dr Bandichhor points that there is a strong business case for greener products in pharma.  “Since cost effective, green chemistry which is involved in production of medicines does not allow generation of significant amount of waste and reduces environmental burden, it can fetch more profit than the regular products because of two reasons: In-built cost effectiveness and products can be marketed at a higher price with special emphasis in the leaflet information that the product has been developed by using green technologies,” he elaborates.
  • Incentivising green practices: Van Cauwenberghe and Iyer recommend this and say, “It will help drive new innovations in pharma production methods, while also promoting awareness about sustainable drug discovery and development pathways. Lastly, it will be extremely important for organisations to have a transparent and unbiased reporting structure for encouraging green drug discovery practices at every stage of development. This will help enable optimal outreach and support for creating sustainable pharma solutions.”
  • Regulatory support: Dr Sen recommends, “The government and regulatory authorities should encourage pharma industries to develop product and process which are energy efficient, less toxic to the environment and use recyclable solvents and packing materials. The government should provide tax benefits and extend exclusivity. The regulatory agencies should consider facilitated reviews for the implementation of green and efficient process and products. It should also ban or tighten the limit for materials which has potential environmental hazards.

Dr Bandichhor recommends, “Quality products, those are being developed using green technologies, can be approved at a faster pace by regulatory agencies and sold at a higher price due to the fact that the development requires intensive R&D toward simplification or finding complicated chemistry/ process alternatives.”

Agreeing with these views, Dr Chandran apprises that governments and regulatory agencies in the US, EU and Japan have been very aggressively encouraging and incentivising pharma industry to adopt greener practices.

Citing an example, he says, “In 1995, the US Environmental Protection Agency (EPA) instituted an annual awards programme, highlighting scientific innovations in academia and industry that advanced green chemistry. This was under the patronage of the President of USA. Many states in the US now have legislative restrictions on using toxic solvents/ chemicals in synthesis of pharma and household goods.”

He also informs that in 2005, three scientists – Yves Chauvin of France, and Robert Grubbs and Richard Schrock of the US – won the Nobel Prize in chemistry for simplifying the process of synthesising carbon compounds.

India too should look at encouraging individuals and organisations involved in researching, developing and implementing green solutions.

  • Industry-academia collaboration to encourage green chemistry: Van Cauwenberghe and Iyer say, “There is still a rising need for improving the dialogue between the industry and academia for encouraging the adoption of greener approaches for drug discovery and development applications.” “Industry and academic experts should be willing to support green chemistry approaches by providing the appropriate academic and laboratory environment as needed, even if it requires greater time and investment,” they say further.

They further opine, “Academic initiatives that engage closely with industrial establishments will help address green chemistry challenges effectively, while also enabling the increased adoption of sustainable drug development practices. Initiatives such as the American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable should be encouraged and nurtured to help drive green pharma innovations and set global standards for sustainable pharma practices.”

Dr Bandichhor also highlights, “Lack of education at fundamental level has posed a great challenge toward mandating and implementing green chemistry in general.”

He further informs, “In the recent past, both industry and academia have started playing a pivotal role in invigorating green chemistry and engineering to have processes which are more sustainable and robust. But, the bigger challenge that we have today is to bring green chemistry to a level where it becomes an unavoidable and obvious choice during product development.  Collaborative green education must start from the academic course that can teach us about significance of green approaches in pharma material production.”

Thus, there are various steps that can be taken if there is  serious commitment towards the environment.

Benign by Design: The panacea to our problem?

‘Benign by Design’ is another interesting concept that comes to fore as we look for more sustainable approaches. Over the past few years, this term has gained a lot of traction. In the context of the pharma industry, it is often used to refer to drugs which are intentionally designed to be eco-friendly as they are easily biodegradable in the
environment.

Explaining the concept further, Dr Chandran elaborates, “Benign by design involves molecules being designed in such a way that it only survives as long as it is required to provide its necessary function and not beyond. And thereby preventing long-lasting drug molecules that leave our bodies undigested (metabolised) or unchanged, and escape into the environment. The proponents of green chemistry call it ‘Holy Grail’ of drug design: triggered instability. It means that we should be able to find a method to stabilise a compound when we want it and destabilise it when the intended purpose is over.”

He further informs, “It is known that almost 15-20 per cent of commercially available drugs are already bio-degradable but by chance so in a sense can be considered ‘green drugs’. The question is, can it be done intentionally?”

Globally, there are a few proponents of this concept. For instance, Klaus Kümmerer, Environmental Chemist from Leuphana University in Lüneburg, Germany and John Warner, Co-founder, Warner Babcock Institute for Green Chemistry in Wilmington, US are researchers pursuing strategies to develop biodegradable drugs. They have met with a limited amount of success as well.


Box 3: Case studies: Going Green

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Case 1: Amgen moved to using enzymes instead of transition metals for catalysing small molecule synthesis. This helped reduce the manufacturing time by 80 per cent. The process change also doubled the yield, lowered the cost of starting material by over 99 per cent and eliminated the need for organic solvents used in chromatographic small molecule purification.

Case 2: Researchers at North Carolina State University developed a green chemistry method that improves pharma manufacturing efficiency, while minimising the cost of processing time. The development consists of a microsphere-packed, tubular reactor which is used in a pseudo-homogeneous catalysis technique. The elastic silicone-based microspheres were developed using a microfluidic technique and are loaded with palladium catalyst. This microfluidic system generates elastomeric microspheres with a narrow size distribution to make them suitable for loading in a tubular reactor without clogging. Apart from providing enhanced efficiency, this pseudo-homogeneous technique encourages a green approach by using nontoxic solvents such as water and ethanol.

Case 3: When Pfizer was gearing up for commercial production of Viagra (sildenafil citrate), their chemists designed a new reaction strategy that radically reduced the amount of solvent required, cut out the reagents tin chloride (an environmental pollutant) and hydrogen peroxide (a fire and transportation hazard), and produced just a quarter of the waste of the original process.

Case 4: Another leading drug for treating high cholesterol, Zocor (simvastatin), traditionally used a multistep method involving large amounts of hazardous reagents that produced a large amount of toxic waste. A new method for synthesizing the drug uses an engineered enzyme and a low-cost feedstock that was optimised by Codexis, a biocatalysis company

Case 5: Codexis again collaborated with Merck to develop a greener route for synthesizing sitagliptin, the active ingredient in Januvia, a treatment for type 2 diabetes. This collaboration led to an enzymatic process that reduces waste, improves yield and safety, and eliminates the need for a metal catalyst

Case 6: STEERLife has developed a continuous wet granulation process using Twin screw processing technology. This single step process perform Granulation, drying and sizing in a single pot thereby improves the processing efficiency and is a much cleaner process. STEERLife has collaborated with  Prof. Muzzio Fernando, Rutgers University, US. Under C-SOPS programme to develop a true continuous process for tablet manufacturing.


But, the current belief that stable compounds are the best, when it comes to ensuring efficacy and effectiveness of drugs, is one major impediment to the adoption of concept. However, its advocates claim that “making compounds stable under all circumstances is the wrong goal.”(http://www.chemistryworld.com/earth/environmentally-benign-by-design/3007842.article)

Dr Chandran also enlightens, “Greener pharma formulations which use excipients to stabilise the drug till the intended purpose of use can be designed. In today’s approved drugs list, there are many examples wherein drugs are stabilised by way of physical or hydrogen bonding with excipients. More companies are starting to see the business opportunity in intentionally designing drugs that disintegrate harmlessly in the environment. Such companies want to be prepared if more consumers ask for better drugs without unwanted side effects.”

But he believes that one of the biggest challenges in its way would be getting regulators on-board. He says, “There has to be a fundamental shift in the industry perspective as to how we perceive stability of a drug molecule. Another important initiative will be introduction of this concept in mainstream university curriculum.” But, do we have any takers for it in India? There is a lack of clarity on this front.

As Dr Chandran explains, “Not many Indian companies as on date are involved in NCE research and till now, no entirely new molecule has been approved out of their research programs. So, it is difficult to comment how much of this design concept has been implemented at their end.”

However, as the old adage goes, ‘Where there’s will, there’s a way’. And, as India ventures on a journey of innovation, if it takes strategic measures and invest time, resources and money in adopting the concept of ‘benign by design’, the country could negate allegations against it of polluting the environment and emerge as a true global power house through sustainable approaches.

What does the future hold?

Drug pollution has huge adverse impact and implications to our survival itself. We are on the brink of a huge existential crisis, spawned and spurred by our negligence and misuse of our ecological resources. Therefore, it is time to realise that we will soon be staring our own extinction in the face unless unless initiate strong measures to reverse the harm done to the environment. It is time for the Indian pharma industry to find ways of healing the patients without harming the environment, to safeguard our future.

References:
– Dunn, P.J, Galvin, S. and Hettenbach, K. “The development of an environmentally benign synthesis of sildenafil citrate (Viagra™) and its assessment by Green Chemistry metrics.” Green Chem. 2004, 6, 43-48. DOI: 10.1039/B312329D
– U.S. Environmental Protection Agency. “Presidential Green Chemistry Challenge Awards: 1997 Greener Synthetic Pathways Award.” http://www2.epa.gov/green-chemistry/1997-greener-synthetic-pathways-award (accessed June 30, 2015).
– U.S. Environmental Protection Agency. “Presidential Green Chemistry Challenge Awards: 2012 Greener Synthetic Pathways Award.” http://www2.epa.gov/green-chemistry/2012- greener-synthetic-pathways-award (accessed June 30, 2015).
– U.S. Environmental Protection Agency. “Presidential Green Chemistry Challenge Awards: 2010 Greener Reaction Conditions Award.” http://www2.epa.gov/green-chemistry/2010-greener-reaction-conditions-award (accessed June 30, 2015).
– Leahy, D. K. et al. Org. Process Res. Dev. 17, 1099–1109 (2013)
– http://doi.org/10.1002/aic.16119

lakshmipriya.nair@expressindia.com