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

 

ENVIRONMENTAL CONSERVATION (GREEN CHEMISTRY, NET ZERO, DECARBONIZING) IN ACTIVE PHARMACEUTICAL INGREDIENTS (APIS) & FINE/SPECIALTY CHEMICAL MANUFACTURING:

I am sure most of us have heard and/or read about “Green Chemistry (1998) ” ⁽¹⁾, “Net Zero (2009)” ⁽²⁾ and then Decarbonizing” ⁽³⁾. Before we can tackle them we need to understand what do these mean and how they came about in chemical manufacturing processes needs to be understood. Before these words became in vogue environmental conservation has been the basic necessity of each process design and manufacture of every chemical but did not have high emphasis. Protecting our environment has been chemist and chemical engineer’s  legacy but the degree has varied. 

It is speculated that an investment of ~$9 trillion dollars ⁽⁴⁾ per year would be needed has to achieve 90% Net Zero or Decarbonization by 2050. What is the basis of this money, how it is going to be spent and how much of these monies are allocated to pharmaceuticals is an unknown. What methods and/or technologies will lead to decarbonization of API have not been proposed or even conjectured ⁽⁵⁾. The proposed yearly (~$9 trillion per year) amount is so large that It is beyond anyone’s imagination. I hope someone from McKinsey & Co. can shed some light on the numbers their breakdown and the technologies that will lead to decarbonizing of pharma APIs.

I am presenting my perspective and is not influenced by any “for profit or nonprofit” organization. It is also worth refreshing how did the industry arrive at the current situation. I have been involved in various capacities with environmental conservation in organic chemical (includes fine/specialty chemicals, additives, coatings and pharmaceutical and petrochemical industries since 1968. I believe there are simple ways to get to Net Zero in API manufacturing and their formulations but effort is needed. A concerted effort would need diligent application of principles of chemistry and chemical engineering. I am sure companies can achieve the target/s with lower spending. I am sharing methods that I have practiced and work. I have respectfully repeated myself to drive the point home. We have an excellent opportunity to reduce pharma’s carbon footprint. 

HOW DID PHARMA GET TO THE CURRENT SITUATION? 

Most of the chemical synthesis innovation started with the manufacture of dyes and colorants in Europe ⁽⁶⁾. Wood vats were used as they were available. These reaction vessels were open top or had wood lids. With time metallurgy developed. Processing equipment developed and mechanical agitators became the norm. As the mechanical engineering and metallurgy developed agitated vessels/reactors reaction vessels had lids and jackets that were necessary to heat and or cool the reactions other processing equipment ^{(6, 7, 8)} came about. With time process controls methodologies developed and have greatly assisted manufacturing processes. 

Dye and colorant manufacturing companies ⁽⁶⁾ in Europe discovered many of the chemicals had disease curing value, they became the titans of pharma landscape ⁽⁶⁾. Companies also discovered that same organic chemistries applied to dye chemicals and disease curing chemicals. By changing the solvent amount used in the recipe their manufacturing processes could be fitted in the existing equipment. Cleaning of the equipment in between processes and products minimized cross contamination. This led to minimum new investment for the API (disease curing) synthesis chemicals. These practices have since continued.  

While the chemicals were being developed, knowledge of chemistry and how manufacturing practices of the chemicals was being standardized. There were simultaneous developments in chemistry unit processes ⁽⁹⁾ and chemical engineering unit operations ⁽¹⁰⁾. Their adoption and application in the production of chemicals led to manufacturing process simplification and improvements in life style and life longevity. Products that improved life style became additives and the products that extended life were called pharmaceuticals. Interestingly their synthesis processes and equipment did not change except pharmaceuticals needed higher quality scrutiny as human lives depended on them. 

Fitting processes in the existing equipment that started about 70+ years ago has led to excessive use of solvents for most of the API manufacturing processes and is a standard practice for API manufacture. “Art of fitting processes” has minimized capital investment for APIs and has become the pharmaceutical industry norm. This fits pharma’s business strategies for low yearly volume products that are needed for most of the APIs (one kilogram of API can produce ONE MILLION of one milligram tablets (10000 kilo converts to 100 million tablets). Practice of fitting processes has led to low ~about 35% equipment utilization ⁽¹¹⁾. These practices have also led to highest organic emissions (solid, vapor and effluent) waste per kilo of product ⁽¹²⁾. Since the same equipment can be used to produce different APIs, government regulators came along and cGMP practices became mandatory. Cleaning in between each batch and different products is necessary to prevent cross contamination of products. Excessive amounts of solvents are needed to fit the process in the equipment for the highest conversion they can achieve has brought us to the current situation where global warming is knocking on our doors. As explained later creating an environmentally friendly process is the NEW challenge for the pharmaceuticals. We have the wherewithal that is needed but have to master it. I have been fortunate as I practiced environmental conservation for the last 55+ years and have been mindful. 

PATHWAYS TO EMISSION REDUCTION IN FINE/SPECIALTY/ADDITIVES/COLORANTS (LIFE STYLE) AND PHARMACEUTICALS: API (DISEASE CURING CHEMICALS) AND THEIR FORMULATIONS:

Chemical industry and that includes life extending (API) and life style improving (additives) products do not need to name existing methods as new manufacturing technologies ⁽¹³⁾ but apply the fundamentals of science and engineering that are taught to us differently. Laboratory practices teach us the reaction chemistry ⁽⁹⁾. How we translate them to produce a product ⁽¹⁰⁾ is up to each chemist and chemical engineer. As suggested earlier environmental conservation has been part of chemical engineer and chemist’s teaching legacy but their degrees of application has varied. Yearly production volume of each chemical dictates the manufacturing process for each chemical i.e. would they be a batch ⁽¹⁴⁾ or a continuous ⁽¹⁵⁾ process. Their definitions have been established and are over 100 years old. Calling a batch process a continuous process has become in vogue lately. Continuous processes are product specific.   

OUR LEARNINGS AND TEACHINGS: FITTING THE PROCESS IN THE EXISTING EQUIPMENT:

Since the inception of the fine/specialty/coatings/additives and pharmaceuticals industry (active pharmaceutical ingredients (API) and their formulations) chemists and chemical engineers as stated earlier have mastered the science and engineering of fitting their processes in the existing equipment. This tradition started in earnest about 70+ years ago when chemical companies dyes, colorants and other chemicals found that some of their molecules could cure diseases ^(6,7,8). This is just a reminder to us all. 

PATH TO GET TO NET ZERO:

In the fine/specialty chemicals and their younger cousin API and their formulations show us pathways ^(9,10) that we are taught but have not exploited totally. We start with the synthesis in round bottom flask. In my own way I call commercial reactors larger round bottom flasks that have built in heating and cooling systems. This is due to the process developers taking a short cut of fitting chemistries in the existing equipment where various unit operations can executed. Reason for this path has been our laboratory teachings and availability of existing plant equipment. Unless we are proactive ⁽¹⁶⁾ to get to Net Zero, it is very likely that the chemical industry and which includes API and fine/specialty chemicals, will not make much progress. Out of the box thinking is needed. It has to be a collaborative effort and village’s ^(6,7) help is necessary. 

Each chemical optimally reacts with the selected chemical to produce the desired product. Physical chemistry ⁽¹⁷⁾, unit processes ⁽⁹⁾, reaction kinetics ⁽¹⁸⁾ and unit operations ⁽¹⁰⁾ show/teach us how mutual behavior of chemicals can be capitalized on to create excellent and simple processes ^{(6,7,8, 19, 20, 21, 22, 23, 24, 25, 26, 27)}. If the pharmaceuticals (API) need to get to Net Zero they will have to collectively capitalize on physical properties ⁽¹⁶⁾ of chemicals used and produced, unit processes ⁽⁹⁾ and unit operations ⁽¹⁰⁾ differently. Such processes compared to their current processes would be generally get lot closer to NET ZERO. If the pharmaceutical industry cannot get to NET ZERO outliers like Steve Jobs ^{(28, 29)} would be needed at every company. In addition giving new names to existing methods is not going to change the landscape ⁽³⁰⁾. Industry will have to be proactive. 

I am emphasizing it again that understanding and exploitation of physical and chemical properties along with reaction kinetics ⁽¹⁸⁾, thermodynamics ⁽³¹⁾, unit processes ⁽⁹⁾ and unit operations ⁽¹⁰⁾ give us opportunities to scale up and commercialize many chemical processes using smaller sized equipment. That immediately leads to solvent reduction per kilogram of the product. Net Zero happens naturally. These are exhilarating experiences. 

CAPITALIZING ON MUTUAL BEHAVIOR OF CHEMICALS:

Why we have not capitalized on mutual behavior is an intriguing question and the answer may be simple. We are taught fundamentals of chemistry and chemical engineering but may not be exposed “how to manipulate and capitalize on them to create excellent processes”. That comes only with hands on experience or when we see examples of how one capitalizes on mutual behavior to create simple and excellent process. They generally are eureka moments. In many cases this results in solvent reduction and/or reaction simplification through reduced time and process simplification.   

Knowledge (physical properties of reactants, their mutual behavior, unit processes, unit operations and understanding of various available processing equipment) would be applied to according to production volumes for the existing and new products. Creativity and imagination can simplify many processes at minimum cost and/or investment. I have emphasized many times over to drive a point that we have opportunities to get to “Net Zero”. 

Learning curve to capitalize on mutual behavior of chemicals used and produced in every reaction is generally  short as every chemist and chemical engineer knows the fundamentals of chemistry and chemical engineering of each product they produce. They have to be creative and imaginative to apply them. However, many would likely say “it can’t be done”. Saying “NO” is the simplest answer to anything different from what we are used to . This is human nature. Examples of how mutual behavior can be capitalized and are shared ^{(6, 7, 8, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,48, 49)}. 

Yes, again a totally different thinking and execution of manufacturing processes will be necessary. Basically to minimize solvent use per kilo of each product requires capitalizing on the mutual behavior of solution or slurry of each raw material, intermediate and finished product. Process is very simple. As soon as the chemistry of each product is defined it is necessary that the village ^{(6, 7, 8)} gets involved to develop, design and commercialize the product. This is a deviation from current practices. Knowledge of physical and chemical properties and their mutual behavior specially solubilities have to be well known. If they are not known they will have to be developed. The whole process development has to be internalized. This is extremely helpful during the life of the product for process design, changes and any troubleshooting of the manufacturing process and changes. Underlying question we have to ask ourselves is “what can be done to have an all liquid process”. This will minimize using inert liquids as solvents, a major step towards “Net Zero”. 

A simple example would be a low melting solid starting material could be dissolved in a solvent, solution made and fed to a reactor at e.g. 40% concentration vs. fed as liquid at 100% concentration in an inline circulating loop to finish the reaction. There are many examples of such reaction systems in the references ^(6,7,8). Not only the solvent can be was minimized but possibly a batch process could be converted to a batch campaign process or a totally continuous process. Experienced chemical engineers can further simplify processes by using modular and/or equipment ^(6,7,8) that may exist on their sites. Pilot plant and its equipment can be a gold mine. If done right some of the products could be that some of the APIs that have consolidated global volume of about 100,000 kilos per year or more could consolidate and be produced using continuous process rather than batch processes at multiple sites. 

ISSUES THAT WOULD HAVE TO BE DEALT WITH: 

One underlying question for the pharmaceutical industry is that it is very aware of having the highest emissions per kilo ⁽¹²⁾ of product in the chemicals related industries but it has not been proactive to improve its manufacturing technologies to lower them. Is it the costs involved in lowering emission through commercializing better processes and not getting the desired return or the regulatory hurdles that are expensive that prevent companies to make an attempt? I don’t want to speculate the answer and let the pundits cogitate over the issue. Whatever the answer, pharmaceutical industry has to deal with the issue that has been overlooked. It cannot procrastinate any longer.  

There are challenges. We can call them “ROADBLOCKS” to get to Net Zero. They are different for brand and generic products. Even with some commonalities most likely each will have different pathways. All of the necessary work to get to NET ZERO has to be done at internally at each company as the chemists and chemical engineers are most familiar with their products and processes. They are the product and process experts ^{(6, 7, 8)}. Outsiders may be able to guide them but the detailed work has to be internalized. Outsourcing work, it is my guess, will extend time as the learning time will further delay the process. I don’t think companies want to share their family jewels. It is best to discuss the brand and the generic products separately. 

NEW BRAND AND NEW GENERIC PRODUCTS:

I am not going to go in the details but everyone who is involved in Net Zero should understand that the process starts when the chemistry is written on paper i.e. the process starts with inception of the product. Village ^(6,7,8) has to get involved right away as if the product is going to be a success and commercialized. Even if it is not, it is an excellent opportunity to known the chemicals used and produced. It will be a learning opportunity for how the process equipment can be manipulated to simplify processes. Engineers can think, scout and tinker with the different processing equipment and cross fertilize from different industries. Every effort has a common goal and that is minimize solvent use and produce the highest quality product. This is a significant deviation from current practices. As indicated earlier even if the product is not commercialized, it will be a team effort and useful for future projects. This will be total landscape change with significant resistance.

EXITING BRAND AND GENERIC PRODUCTS:

“Net Zero” pathways for the existing brand and generic products will be different in many ways but will also be similar. Who is going to invest and what would be the return and its value will be a major concern and question. If there is no product cost reduction, which means no payout, no one will pay for the investment. If company’s costs go up even after solvent reduction and they get passed on to the patients i.e. distributors keep their profits, overall drug prices will go up and there will be mass uproar against  “Net Zero”. Every such program could come to screeching halt. Way out of this dilemma could be direct sales to patients and eliminating the current distributors and let the competition dictate the sale price. Competition will define the new landscape. Current pharmacy benefit managers (PBM) will not like that and will interfere for “Net Zero” becoming a reality. In US Congress would have to get involved. Likelihood of that happening is minimal to none. 

Regulators could demand bioequivalence of products from alternate processes. Proving that could be expensive and time consuming. Brand companies would not do anything for the products currently under patent unless they assure product performance with new processes. Regulators will have the final say.    

It is very likely that in its effort to achieve API manufacturing landscape could change. This could happen due to the needed investment, regulatory expenditures, pressures, pharmacy benefit managers (PBMs) and realignment of the manufacturing and  changing landscape. There may be additional questions. If 50% to 60% reduction can be achieved in the next 15 years, it will be a major accomplishment. I have made an attempt that I believe would lead to “Net Zero”. It is a start and will need fine tuning. Doing something is better than doing nothing. Please share your knowledge. It is an opportunity to preserve our planet “EARTH”. Thank you. 

Girish Malhotra, PE

EPCOT International

References:

 

1.     Green Chemistry: https://www.acs.org/greenchemistry/what-is-green-chemistry.html Accessed September 15, 2024

2.     Net Zero: https://eciu.net/analysis/infographics/net-zero-history

3.     Decarbonizing: https://www.unepfi.org/grt/2016/programme/decarbonizing-finance/ Accessed September 10, 2024

4.     What is Net Zero: McKinsey & Co. Accessed November 2022

5.     Witte C. et. al. Decarbonizing API manufacturing: Unpacking the cost and regulatory requirements, July 26, 2024 McKinsey & Co. July 31, 2024

6.     Malhotra, Girish:  Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter April 2022

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

8.     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

9.     Shreve, R. N. Unit Processes in Chemical Engineering, Industrial and Engineering Chemistry,1954, 46, 4, pg., 672, Accessed June 22, 2020. 

10.  McCabe W. L & Smith J. M. Unit Operations of Chemical Engineering McGraw-Hill Book Company Second Edition 1967 

11.  Schrader, Ulf: McKinsey & Co. Operations can launch blockbuster in pharma, February 16, 2021

12.  Sheldon R.A. The E factor 25 years on: the rise of green chemistry and sustainability, Green Chemistry  https://pubs.rsc.org/en/content/articlelanding/2017/gc/c6gc02157c/unauth#!divAbstract , 2017, 19, 18-43 Accessed February 17, 2021 

13.  Malhotra, Girish: Manufacturing Technology Innovations in Pharmaceutical Manufacturing, Profitability through Simplicity, February 23, 2024 

14.  Batch Process, https://en.wikipedia.org/wiki/Batch_production Accessed June 1, 2019

15.  Continuous Process https://en.wikipedia.org/wiki/Continuous_production, Accessed June 1, 2019

16.  Malhotra, Girish: Why Fitting a Square Plug in a Round hole is Profitable for Pharma and Most Likely Will Stay? Profitability through Simplicity August 1, 2014

17.  Levine, Ira: Physical Properties Sixth Edition 2009 McGraw Hill

18.  Levenspiel, O. Chemical Reaction Engineering, John Wiley & Sons Inc, 1972, Second Edition, Accessed December 20, 2020

19.  Sociochemicology Sociochemicology 2013 

20.  Malhotra, Girish: Secret Life of APIs , Profitability through Simplicity, Feb. 13, 2013

21.  Malhotra, Girish: Rx for Pharma, Chemical Engineering Progress, 105 (3) March, 34-38 (2009), 

22.  Malhotra, Girish: Focus on Physical Properties To Improve Processes: Chemical Engineering, 119 (4), April, 63-66 (2012).

23.  Malhotra, Girish: Conflicts and opportunities in the Life of APIs, Chimica Oggi-Chemistry Today Vol. 31 (4) July/August 2013 pgs. 10-13

24.  Malhotra, Girish: Focus on Physical Properties To Improve Processes: Chemical Engineering, Vol. 119 No. 4 April 2012, pgs. 63-66, 

25.  Malhotra, Girish: Process Simplification and The Art of Exploiting Physical Properties

Profitability through Simplicity March 10, 2017

26.  Malhotra, Girish: Capitalizing on Mutual Behavior and Chemical Reactivity of Chemicals, Profitability through SimplicityMay 29, 2023

27.  Malhotra, Girish: Chemicals tell us how to exploit their behavior for better processes. Clues are ignored. Should we? Profitability through Simplicity, June 20, 2023

28.  Malhotra, Girish: Can the Combination of Creative Destruction and “Steve Jobs’ Traits” Lead to Pharma QbD Spring? Profitability through Simplicity, April 15, 2012 

29.  Malhotra, Girish: Does the Pharmaceutical Industry Need A Steve Jobs? Profitability through Simplicity, November 8, 2011  

30.  Malhotra, Girish: Is the New Terminology Going to Make the Pharmaceutical Processes Environmentally Friendly and Economic? Profitability through Simplicity, June 5, 2012

31.  Dodge, B. F. Chemical Engineering Thermodynamics, McGraw-Hill Book Company, 1944 

32.  Malhotra, Girish: Quick Review of Chemicals Related Process Development, Design and Scale up Considerations, Profitability through Simplicity, November 7, 2018

33.  Malhotra, Girish: Considerations to Simplify Organic Molecule (API) Manufacturing Processes: My perspective, Profitability through Simplicity, April 20, 2019

34.  Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing (API) and Formulation Drive to NET ZERO (Carbon Neutral)? Profitability through Simplicity, April 29, 2021 

35.  Malhotra, Girish: Climate Change and Greening of Pharmaceutical Manufacturing, Profitability through Simplicity, January 24, 2022 

36.  Malhotra, Girish: Pharma’s Active Pharmaceutical Ingredient Manufacturing: Their Environmental Impact and Opportunities, Profitability through Simplicity,  March 3, 2022 

37.  Malhotra, Girish: Art and Science of Chemical Process Development & Manufacturing Simplification https://www.aiche.org/ili/academy/webinars/art-and-science-chemical-process-development-manufacturing-simplification May 17, 2023

38.  Malhotra, Girish: Chemicals tell us how to exploit their behavior for better processes. Clues are ignored. Should we? Profitability through Simplicity, June 20, 2023

39.  Malhotra, Girish: Considerations to have an excellent environmentally friendly and economic chemical process? Profitability through Simplicity, August 28, 2023

40.  Malhotra, Girish: Marriage of Science and Technology in Active Pharmaceutical Ingredient (API) Manufacturing and their Formulations: Is it for real? Profitability through Simplicity, September 21, 2023

41.  Malhotra, Girish: Process Simplification and Net Zero: Capitalizing on Physical and Chemical Properties of Reactants and Intermediate, Profitability through Simplicity, August 20, 2024

42.  Malhotra, Girish: The Good, The Bad, and The Ugly (1) Complexities of the Pharmaceutical Manufacturing, Profitability through Simplicity, April 9, 2018, Contract Pharma June 2018 Vol. 20 No.5

43.  Review of Continuous Process for Modafinil, Continuous Processing in the Chemical and Pharmaceutical Industry II, 2009 AIChE Annual Meeting, November 10, 2009,Nashville, TN. 

44.  Malhotra, Girish: Analysis of API (Omeprazole): My perspective, Poster Session: Pharmaceutical Engineering, 2009 AIChE Annual Meeting, November 11, 2009, Nashville, TN. 

45.  Malhotra, Girish: Alphabet Shuffle: Moving From QbA to QbD - An Example of Continuous Processing, Pharmaceutical Processing, February 2009 pg. 12-13

46.  Malhotra, Girish: EXPLOITATION OF QBD ELEMENTS FOR A BATCH/CONTINUOUS PROCESS https://www.slideserve.com/elia/exploitation-of-qbd-elements-for-a-batch-continuous-process International Pharmaceutical Academy October 19-20, 2009

47.  Malhotra, Girish: Chemicals tell us how to exploit their behavior for better processes. Clues are ignored. Should we? Profitability through Simplicity, June 20, 2023 

48.  Malhotra, Girish: Use of Tradition, Creativity, Imagination and Technology Innovation in Propofol Manufacturing, Profitability through Simplicity, March 21, 2024

49.  Malhotra, Girish: USP 11,267,798 B2: Manufacture of Piperine (1) An Excellent Teaching Tool, Profitability through Simplicity, June, 17, 2024