NET ZERO for Active Pharmaceutical Ingredient & Fine/Specialty Chemicals: Nondestructive Creation

Achieving NET ZERO ⁽¹⁾ has become the latest new and loud chant for the processes that produce Fine/Specialty and Active Pharmaceutical Ingredients (API). Pharmaceutical industry is known for its high emissions per kilo ⁽²⁾. Many do not want to acknowledge this. It is very possible to reduce/minimize the solvent use for every chemical synthesis process from the onset. Pathway to lower/reduce the solvent use for each product is “Nondestructive Creation” ⁽³⁾ i.e. commercialization of alternate processing method for each product from the onset. This will significantly lower the “Net Zero” number for each product from the onset ^{(4, 5, 6)} and can be applied to existing products. Creativity and imagination of everyone is welcome.  

 

It takes a whole village for an innovation to be developed, launched, and adopted.

— Edmund (Ned) Phelps, Nobel Laureate ⁽³⁾

 

Implementation of methods to achieve “Net Zero” requires effort of “THE WHOLE VILLAGE” ^{(4, 5, 6, 7)} (chemists and chemical engineers, marketing, financial analysts, supply chain professionals, quality control, regulators, maintenance, and manufacturing personnel) and has to become their religion and way of life. It is very likely that the effort might involve changes to how the chemistry is commercially practiced in the alternate equipment. Process will definitely involve reconfiguration of manufacturing/process technology and its execution. Done correctly the desired molecule and its performance will not change. I am sharing my perspective for the effort and is not influenced by any “for profit and non-profit” organization. 

 

Act of solvent reduction for every chemical process begins from the day of chemistry inception/conception as there is no tomorrow. Tomorrow never arrives as it will come tomorrow.

 

Each company can develop its own pathways. Based on my experience the simplest is to reduce the solvent use at every reaction step. That is easier said than done. It can be achieved by taking advantage of combination of physical properties e.g. melting point, boiling point and freezing point, mutual solubilities in different solvents, their mutual social behavior and chemical kinetics ⁽⁸⁾coined as sociochemicology ⁽⁹⁾. Their exploitation does simplify manufacturing processes.  

 

It is not only necessary but critical that for the long term benefit, intellectual property which involves how the processes are modified and practiced be internalized and protected at each company. Some new learning about how the unit processes ⁽¹⁰⁾ and unit operations ⁽¹¹⁾ are practiced might be necessary. Fine tuning of the existing processes/methods most likely will be necessary. For experienced chemists and chemical engineers it is very likely that the new learning to get to “Net Zero” will be minimal. 

 

It is expected and very likely that no new chemistries might have to be developed for the existing products. Current commercial  chemistries most likely will have to be executed differently in smaller/alternate equipment. In this effort interaction/mutual behavior, physical and chemical properties and reaction kinetics ⁽⁸⁾ of each chemical used and produced would have to be capitalized to simplify the processes. “Creativity and Imagination” of each member of the “THE WHOLE VILLAGE” ^{(4, 5, 6, 7)} team will be of utmost value. Process development chemist, engineer and members of the scale up team will play critical role in the effort. This will minimize implementation time. Following steps can be used to get to “Net Zero” and they are reviewed. 

 

1.     Sociochemicology ⁽⁹⁾ of chemicals

2.     Process centric designs 

3.     Creativity and imagination of the WHOLE VILLAGE ⁽³⁾

 

Each chemist and chemical engineer is familiar the above two aspects. Third is individual and collective experience dependent.  

 

Every chemical synthesis patent be, it a fine/specialty chemical or API walk us through the reaction mechanism. It is up to “The Whole Village” to harness it to create a minimum solvent use process. We are also taught all of the tools to do that unit operations ⁽¹¹⁾. Some are examples are discussed ^{(4, 5, 6, 7)}.  

 

Sociochemicology of Chemicals:

 

Sociochemicology ⁽⁹⁾ encompasses physical and chemical properties of each chemical and how they interact with each other. Mutual behavior of chemicals and processing equipment used in the process influence manufacturing methods and their execution. Each physical and chemical property needs to be exploited differently to create and simplify processes. This is emphasized as it has value for every process design.  

 

API and fine/specialty chemical industry is living with the tradition of using larger sized equipment to produce the end products. It is due to the fact that the equipment is available and can do the needed job.  

 

Round bottom flask and associated laboratory equipment does not allow exploitation of physical and chemical properties of the chemicals. Intent in the lab is to prove feasibility of the reaction chemistry. Scale up using larger available equipment is done, a tradition of SEVENTY PLUS YEARS ^{(4, 5, 6, 7)}. Laboratory does not have the provisions to experiment and demonstrate interaction of physical and chemical properties. They may be able to show feasibility but it is up to the chemist and chemical engineer “how to use them and simplify the processes”. 

 

We do not need to review the details of traditions as every chemist and chemical engineer knows them well. However, a brief of process development and commercialization would help. Generally a process engineer takes the information developed in the lab, proves its feasibility in a pilot plant and designs a process in a large reactor, a tradition of 70+ years. Since the commercial processes are “lab centric processes” and speed to market dictates commercialization, generally there is no or minimal attempt to minimize  the solvent use by evaluating and/or creating an alternate process. In pharma due to regulations after the fact does not happen. 

 

Process Centric Designs and Creativity and imagination:

 

Since most of the chemists and chemical engineers might not have the feel for the mutual behavior of chemicals ⁽⁸⁾ it can be a challenge to incorporate their nuances in actual designs. It will be necessary that due to non-availability of mutual behavior and other properties data might have to be generated internally. “Skunk works” ⁽¹²⁾ will be needed. It can be a place to experiment with alternate equipment and designs ^{(12, 13, 14)}.

 

My experience is that “process centric” designs will and do minimize solvent use. Creativity and imagination with process centric designs go hand and glove to reduce solvent use. Downsizing equipment will/should not change process chemistry but can change how the chemistry would be practiced. Such equipment is being used in chemical and other manufacturing industries ^{(12, 13, 14)}. They do lower the volume of solvent used per kilo from the current conventional agitated reactor designs. It is very possible that many could say that it cannot be done. Unless we try and consider such outlier/nondestructive creative designs ^{(4, 5, 6)}, “Net Zero” will not happen. 

 

Best is to share some examples. Most solid raw materials are generally fed in a reactor that has large excess of solvent (as much as 50%) that is used in the process. However, if the solid can be metered to the reaction system via an eductor ⁽¹²⁾ using the solvent used in the reaction, one can reduce the total solvent used in the reaction. This is especially true if a back mix flow process design ⁽¹⁵⁾ can be used. Such reaction designs along with an inline heater/heat exchanger ^{(12, 13, 14)} can reduce solvent use. Plate and frame heat exchangers ⁽¹¹⁾ have been used as reactors. It is critical that the chemists and chemical engineers have a complete understanding and command of the reaction kinetics ⁽⁸⁾. Depending on melting point and solubility of chemicals we are presented with many opportunities to reduce solvent use ^(4,5,6). 

 

As stated earlier mutual insolubilities and density differences ^{(8, 11)} can be used in many ways to facilitate and simplify processes. Some of the examples where solvent use can be significantly reduced/eliminated are reviewed ^{(4, 5, 6, 7, 16, 17, 18, 19, 20)}. There are many other examples are available in literature. One of the reasons for not incorporating many of such nuances in process design, my understanding, is the time pressure to get the product to the market. 

 

As indicated earlier almost every chemical synthesis patent shows us the pathway (reaction mechanism) to minimize solvent use i.e. direct how one can achieve “Net Zero”. Laboratory processes are fitted in the existing equipment that is available on the site, square plug in a round hole ⁽²⁰⁾. This happens as the chemical industry is tuned to using jacketed reactors for chemical synthesis, a 100 years old tradition. Most overlook how to exploit the reaction sequencing, kinetics ⁽⁸⁾ and sociochemicalogy ⁽⁹⁾  of the chemicals used and produced. Result is opportunity to lower the solvent use per kilo of the product is lost. 

 

Equipment used in other industries ^{(13, 14)} and some used differently in the chemical industry ⁽¹¹⁾ can reduce solvent use and facilitate the processes. To minimize solvent use “what if” comparison analysis is necessary to select the best equipment ^{(4, 5, 6, 12)}. At times best equipment may not be the normal agitated reactors. Inline heaters are all electric heaters and they not only minimize investment in external heat sources (boilers or hot oil heaters) but facilitate capitalizing on mutual solubilities ^{(4, 5, 6)} and reaction kinetics ⁽⁸⁾, thereby reducing solvent use for every reaction step. This value needs to capitalized on. It is time we do if we want to reduce solvent use. 

 

For example compared to conventional jacketed reactors inline electrically heated heat exchangers ⁽¹³⁾ offer much higher heat input (flux) per unit surface area (2.5 to 7.5 sq. ft./gal.) compared to conventional reactors (0.10-0.23 sq. ft./gal.). High heat input per sq. ft. improves reaction time. Their use as chemical reaction equipment is not advertised and is seldom considered. Some have and are used stealthily in the chemical synthesis for more than 60 years with excellent results ^{(4, 5, 6, 12)}. Generally they will be used in a back flow mix reactor ⁽¹⁵⁾ configuration. Most likely capital investment for electrically heated heat exchangers would lower compared to Dowtherm or hot oil based heaters.   

 

Such designs ^{(4, 5, 6)} are intellectual property of each company and need to be protected. Process designers will be challenged as at time information is not available from the vendors. They want to control their equipment use and that is tantamount to sharing proprietary information to improve their sales even when confidentiality agreements are signed. Lack of information form equipment and chemical supplier vendors has become an obstacle ⁽²¹⁾ and can interfere in “what if” analysis to select the optimum equipment for least solvent use. All factors, lack of equipment and physical properties information is and can be an interference in manufacturing technology innovation.  

 

Modular process designs ^{(4, 5, 6, 13)} can be very valuable alternate process design to current practices. They can reduce capital investment, improve profitability and add process flexibility to meet fluctuating product demands. It is possible that use of such configurations might be considered a cumbersome venture as the chemical/pharmaceutical industry is not tuned to out of the box thinking. However, we need to understand their value in reducing solvent use for every chemical synthesis process. They can be a competitive advantage and improve speed to market. 

 

Hedging on use of non-traditional equipment is an impediment to manufacturing technology innovation. All of the above are the low hanging fruits. All has to come from within each company as they know every process detail and nuance. Outsiders may be and that is big “may be” able to help but grassroot thinking has to be internal. 

 

Nondestructive Creativity Pathway:

 

Current established practice, from the laboratory to commercial scale where excess solvent per kilo is used is due to need to fit the process in an existing equipment, a case of fitting a square plug in a round hole ⁽²⁰⁾. To achieve “NET ZERO” every bit of “nondestructive creativity” and understanding of chemistry and chemical engineering by every chemical engineer and chemist will be needed and may have to be tested. They will have to think out of the box using suggested methods ^{(4, 5, 6, 7)} or any of their chosen methods. They have the creativity and imagination to excel. There will be initial apprehension but when conventional unit processes ⁽¹⁰⁾ and unit operations ⁽¹¹⁾ are applied they will see the benefits.  They could going forward become addicts. Applying out of the box ideas and concepts should not be any concern as they will be based on their education and training.

 

With all said and done underlying question would be “Is API manufacturing and fine/specialty chemicals ready to venture out to “NET ZERO”? Answer is “IT DEPNDS”. 

 

Yes there will be financial and business model implications as many of the APIs do not have sufficient product volume and can be produced on a campaign basis. Business models at companies might have to be reconfigured and there could be resistance. Upside will be significantly lower equipment idle time ⁽²²⁾ which has marred API manufacturing and can be attributed as a cause of high emissions. With alternate processes companies could respond quickly to any drug shortages. All of the above are the low hanging fruits. Again, all of the innovations have to come from within each company as they know every process detail and nuance. Outsiders may be able to help and that is big “may be”. Grassroot thinking, innovation, has to be internal.  

Since there is no mandate to achieve “Net Zero” for the existing products each company will have to justify their effort. There are financial implications for every business. They will think twice as hard to take their products to “Net Zero”. Significant amounts of monies ^{(23, 24)} are postulated to be spent from every business’s pocket with unknown return, unless there is a governmental mandate, likelihood of companies moving to solvent reduction per kilo of product i.e. REAL “Net Zero” for the existing products are extremely low. Companies could change their model as the suggested technologies and methods can lead to consolidation and higher profits. How much regulatory approval might be needed would have to be defined. Achieving “Net Zero” for the Brand and New Generics should not be a question. It is a must.  

Task at hand is not easy but if things were easy we would not have many of the technology innovations. Everything would have been done long time ago. Question going forward for us is “Are we willing and able to take up the challenge of reducing emissions?” We have a choice. Let’s make the right choice to achieve “Net Zero” in Active Pharmaceutical Ingredient & Fine/Specialty Chemical manufacturing. We owe it to the coming generations.  

Girish Malhotra, PE

 

President

 

EPCOT International

 

References:

 

1.     Net Zero: A Short history Accessed October 24, 2024

2.     Sheldon R.A. The E factor 25 years on: the rise of green chemistry and sustainability, Green Chemistry  Accessed February 17, 2021 

3.     Hubbard, G. Nondestructive Construction, TECH & INNOVATION Strategy+ Business, May 29, 2007 Accessed January 26, 2021.

4.     Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability, John Wiley & Sons, February 2011 

5. Malhotra, Girish: Chapter 4 “Simplified Process Development and Commercialization” in “ Quality by Design-Putting Theory into Practice” co-published by Parenteral Drug Association and DHI Publishing© February 2011
6. Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter April 2022
7. Malhotra, Girish: Profitability through Simplicity
8. Levenspiel, O. Chemical Reaction Engineering, John Wiley & Sons Inc, 1972, Second Edition, Accessed December 20, 2020
9. Malhotra, Girish: Sociochemicology May 30, 2013 Accessed January 13, 2023
10. Shreve, R. Norris: Unit Process In Chemical Processing, Ind. Eng. Chem., 1954, 46 (4), pp. 672–672
11. Unit Operation, https://en.wikipedia.org/wiki/Unit_operation,  Accessed July 11, 2017
12. Malhotra, Girish: Quick Review of Chemicals Related Process Development, Design and Scale up Considerations, Profitability through Simplicity, November 7, 2018
13. Process Technology
14. Wattco   
15. Malhotra, Girish: Capitalizing on Mutual Behavior and Chemical Reactivity of Chemicals, Profitability through Simplicity, May 29, 2023
16. Malhotra, Girish: Review of Continuous Process for Modafinil, Continuous Processing in the Chemical and Pharmaceutical Industry II, 2009 Annual Meeting, November 10, 2009,Nashville, TN
17. Malhotra, Girish: Analysis of API (Omeprazole): My perspective, Poster Session: Pharmaceutical Engineering, 2009 AIChE Annual Meeting, November 11, 2009, Nashville, TN
18. Malhotra, Girish: Art and Science of Chemical Process Development & Manufacturing Simplification, AIChE May 17, 2023
19. Malhotra, Girish: Considerations to Simplify Organic Molecule (API) Manufacturing Processes: My perspective, Profitability through Simplicity,  April 20, 2019.
20. Malhotra, Girish: Square Plug In A Round Hole: Does This Scenario Exist Pharmaceuticals?, Profitability through Simplicity, August 17, 2010
21. Malhotra, Girish: Information Challenges for Product, Process Development and Process Design: A Reality Check, Profitability through Simplicity, April 10, 2011 
22. Schrader, Ulf: Operations can launch the next blockbuster in pharma, McKinsey & Co.,  February 21, 2021 
23. What is Net Zero? McKinsey & Company , October 25, 2024  
24. Malhotra, Girish: ENVIRONMENTAL CONSERVATION (GREEN CHEMISTRY, NET ZERO, DECARBONIZING) IN ACTIVE PHARMACEUTICAL INGREDIENTS (APIS) & FINE/SPECIALTY CHEMICAL MANUFACTURING, Profitability through Simplicity, October 2, 2024