Besides being patient friendly, pharmaceutical drugs and their manufacturing processes are expected to be eco-friendly as well. However, the pharma industry has its own share of problems in doing so. By Sachin Jagdale
Role of catalysts
Use of a catalyst is considered unavoidable in the drug manufacturing process. However, catalysts like palladium are not only expensive for the company but also harmful for the environment. So, is there a need to find an alternative to catalysts as a step towards making drug development eco-friendly? According to experts, contrary to popular belief, catalysts are not polluting agents apart from few exceptions. In fact, catalysts can aid in reducing environment pollution.
Pravin Herlekar, Chairman, Omkar Chemicals, says, “Use of catalysts is a must in many drug manufacturing processes. There are alternate processes without the use of a catalyst. However, they would lead to more complex issues related to effluents. Catalysts are primarily used to improvise on the yields of the desired product, minimise by-products, expedite kinetics of the reactions and minimise effluents. There are new generation catalysts such as chiral catalysts and nanotech-based catalysts which make use of common metals such as cobalt, nickel, copper, etc. as against costly materials like palladium. However, they are process specific and cannot be applied in general. But one must say that use of a catalyst helps in reducing environmental issues.”
A chemical research scientist, speaking in his personal capacity, echoes Herlekar’s views. According to him use of catalysts is a must. He says, “As of now catalysts are unavoidable. Catalysts avoid all routes that other chemicals would take as reagents. Use of a proper catalyst is very important. Different types of catalysts can be used for one reaction. However, yield and selectivity of the desired product will change with the catalyst. Catalyst with the best yield and selectivity must be used. Next step is the optimisation of process parameters. In the pharma industry, optimisation is mostly avoided due to urgency or lack of time in product development, very rapid product changes, unawareness or negligence. Catalysts are unavoidable, but must be used wisely. I do not think there is any research to avoid catalyst. In fact, catalysts are the best candidates to do the job with maximum yield selectivity and minimal waste.”
Replacing stoichiometric methods with catalyst would be a good eco-friendly option, opines a spokesperson from BASF. “The key to more eco-friendly processes in fine chemicals manufacturing is the substitution of classical organic syntheses employing stoichiometric amounts of inorganic reagents with cleaner, catalytic alternatives. The E factors (by waste per kg product) of chemical processes increase dramatically on going downstream from bulk to fine chemicals and pharma products, mainly owing to the use of stoichiometric methods,” informs BASF’s spokesperson. He adds, “The concept of atom efficiency is a useful tool for rapid evaluation of the amount of waste generated by alternative processes. To make processes more atom-efficient and decrease the E factor, catalysts are key to success. For example, the Presidential Green Chemistry Awards show examples of catalysts being used for making processes more eco-friendly. A good starting point for the use and impact of E-factor calculations and the role catalysts can make in this is: Pure and Applied Chemistry, 2009, 72 (7), p.1233-1246 by R.A. Sheldon.”
Though changing drug design is an option mulled over by scientists, developing ‘benign by design’ drug is hardly possible. Understandably, why would a company think about sacrificing drug qualities that keep it active and stable for the sake of environment?
BASF spokesperson says, “If this is referring to the production process of a specific drug we can state the following: a trend is observed towards replacing stoichiometric reagents by catalysts to make processes more cost efficient and eco-friendly. If the statement is referring to changing the chemical structure of a pharma compound, making a statement by BASF is more difficult and better answered by pharma companies. However, it is known that changing the design of a pharma compound has an impact on the pharmacological effect and typically cannot be considered for existing pharma products.”
Herlekar opines, “The drug required for a particular disease is designed after considering its efficacy, extent of side effects, affordability, etc. Once the drug is designed, we have to select the most cost effective process for manufacturing the same. This can be done by adopting the best available processes of synthesis, while keeping in mind the final targeted cost of drug. A suitable route of synthesis should be chosen to address the issues relating to the environment.”
Dealing with effluents
Water is the largest receptor of pharma effluents. Drug residues excreted by the pharma manufacturing plants linger in water bodies for months or even years. The challenging part is that the effects of these residues are hard to isolate and sometimes poorly understood. According to reports, anti-depressants like Prozac might disrupt frog development. Consumption of fish containing harmful chemical may prove fatal to human life as well. So effluents remain one of the biggest hurdles in making drugs eco-friendly.
Vijay Ramanavarapu, Corporate Development, General Manager, Granules India, says, “Companies can treat effluents more effectively to ensure that they are properly disposed of. Proactive companies can install zero-liquid discharge (ZLD) systems to ensure that all water is treated on-site and can be safely used for other applications such as garden water. While many Indian companies aren’t being proactive right now, we feel that in the future, successful companies will focus on how to minimise their environmental impact due to increasing emphasis on sustainability. Many companies, in particular, Western-based customers, are increasingly using environmental sustainability as a selection criteria when picking a new supplier.” He adds, “While researching new methodologies, pharma companies need to ensure the end product is still the same and the impurity profile of the product doesn’t change. Any major changes including different raw materials will require regulatory approvals from agencies such as the US FDA which will take time for a company to receive. At Granules India, our R&D has actively been working on green technologies that will reduce our carbon footprint. We believe this will not only give us a cost advantage but also improve our overall sustainability efforts.”
While developing pharma processes, chemists hardly make prior discussions with chemical engineers, complains a chemical engineering expert. He explains, “Chemist’s target is to get the product, yield does not matter to them. Process engineering and intensification must be done. The use of statistical techniques like design of experiments in process development and optimisation is also lacking. Effluents will be produced, but E-factor can be very low if process (reaction and workup) is well optimised.”
The most cost effective processes may lead to serious environmental issues while the most eco-friendly processes may lead to high cost of production. “We have to strike a balance wherein we optimise both these factors,” stresses Herlekar.
He adds, “Pharma effluents may certainly be chemical-free and there are ways and means to do so. Such effluents can be treated by making them neutral, followed by adjusting their levels of biological oxygen demand (BOD), chemical oxygen demand (COD), etc. They can be further processed in multiple effect evaporators, RO plants, incinerators, etc. and the water obtained can be recycled back into the process. However, all these operations add to the cost of the product and the market must accept and sustain the same.”
There are many research activities which are still at the conceptual stages. For e.g. Developing drugs with photodegradable properties. These drugs would be light sensitive and would decompose once exposed to light in the waste treatment plant. Possibilities of adding temporary stabilisers to the drug which would break off only after arriving inside the body are also being explored.
As mentioned earlier, becoming eco-friendly is an expensive option and pharma companies would require a hefty balance sheet to invest in the same. Under tight market conditions, raising additional money is seen as a business eroding step by the pharma industry. Unless going green coincides with some other profit-making measures, convincing drug manufacturers to implement eco-friendly methods looks difficult.
“In India, most the drug manufacturing is being done in the SME sector and these units do not have the requisite financial strength as well as the space required for exhaustive treatment facilities. One way to come out of this situation is to have government support in promoting larger CETPs in the industrial areas wherein the government can subsidise the cost of processing effluents,” says Herlekar.
Becoming eco-friendly should be the joint venture between the pharma industry and the government. Financially strong MNCs can afford to invest extra money for new developments, however, for majority of the Indian drug manufacturers, government’s subsidy would prove helpful. Subsidy could be on buying machinery to treat effluents or to provide lands for effluent treatment at nominal costs. Government can also reward a company with the most eco-friendly record.
The way forward
Eco-friendly drugs is a possible yet difficult to achieve dream. Any successful drug is a result of years of effort, research and investment. Changing these drugs, their manufacturing/research set up overnight, is obviously not very practical for pharma companies as they offer solutions that suits their financial requirements. Moreover, treating human beings first gains priority over caring for the environment. However, both humans and the eco-system are part of a cycle where they are interdependent. Damage to one of the entities would surely affect the other.