Profitability through Simplicity

Role of Village and Triumvirate in Process Development of Isoniazid :- a Tuberculosis Drug

2026-09-29T19:03:19.104-04:00

In the past I have discussed how the Village and Triumvirate[unit processes, Sociochemicology and unit operations] ^1,2,3,4,5can assist in developing, expediting and commercializing excellent processes that maximize profits and have minimal environmental impact. Purpose of this post is to share how commercially available equipment not used in the chemical and or pharmaceutical manufacturing along with sociochemicology can be exploited to create significantly simple manufacturing processes.

In this post I have reviewed synthesis of Isoniazid [isonicotinic acid hydrazide]. Two alternate processes are reviewed. Readers should not be bound by my perspective and can use their own knowledge and experiences to commercialize an excellent process.

Chemistries mentioned in routes ^{(6, 7, 8, 9)}are similar. 4-cyanopyridine is reacted with caustic to produce isonicotinamide which is reacted with hydrazine hydrate to produce isonicotinic acid hydrazide (Isoniazid) Figure 1.

Figure 1

	4-Cyano pyridine	50% NaOH	Isonicotinamide	Hydrazine hydrate	Isoniazid
Chemical Formula	C₆H₄N₂	NaOH	C₆H₆N₂O	N₂H₄	C₆H₇N₃O
MW	104	40	122	50	137
MP °C	76-79		155-157	2	171-173
BP °C	196	140-145	334	114	252
CAS	100-48-1	1310-73-2	1453-155-157	301-01-2	54-85-3

Table 1: Physical Properties of Figure 1 reaction components

In another process ⁽¹⁰⁾ isonicotinic acid is reacted with thionyl chloride and ethyl alcohol to produce an ester which is reacted with hydrazine hydrate to produce isoniazid.

Figure 2 ⁽¹⁰⁾

	Isonicotinic acid	Thionyl chloride	Ethyl alcohol	Ethyl isoniconitate hydrochloride
Chemical Formula	C₆H₅NO₂	SOCl₂	C₂H₆O	C₈H₁₀ClNO₂
MW	123	119	46	187
MP °C	310	-104.5		167
BP °C	Sublimes	75	78.5
CAS	55-22-1	7719-09-7	64-17-5	58827-14-8

Table 2: Physical Properties of some of the components in Figure 2

Based on Village and Triumvirate ^(1,2,3,4,5) analysis pathway since solvent use will be necessary, isonicotinic acid process (10) was not considered for further evaluation.

It surprising to note that European Patents ^(8,9)are based on the chemistry that had been in the public domain ^(6,7) before their patent filingsand are not acknowledged. This can potentially make their validity questionable. Details of cited batch processes are not known.

European Patent ⁽⁸⁾claims to be a laboratory based continuous process and suggests use of microreactors. Continuous process has an established definition ⁽¹¹⁾ and laboratory processes are never a continuous process. Microreactors are well known miniaturized version of plate and frame heat exchangers that have been used in chemical synthesis for over 70 years and are not a novelty. Flow chemistry is “new name” in the reaction chemistry domain for flow of fluids flow which happens to be the fundamental processing method of every chemical reaction since the advent of chemical processing. In my opinion filing ⁽⁸⁾isnot a new manufacturing process or method or chemistry and should not be acknowledged such.

What can the Village ^(1,2,3,4,5) do to simplify the 4-cyanopyridine based process?

Based on traditions of at least the last eighty plus years first instinct to commercialize the isoniazid process would be to start with a commercial agitated jacketed reactor. There are other methods however they are not considered. Since I do not have access to a laboratory to test the proposed process, it is suggested my perspective be reviewed, tested and modified, if necessary.

Based on my experiences of applying learnings from Village, Triumvirate ^(1,2,3,4,5)and chemistry of Figure 1 I have proposed the following flow diagram, Figure 3, as a potential pathway.

Figure 3: 4-Cyanopyridine based Process Flow Diagram for Isoniazid

After the initial feasibility is proven, instead of using and/or suggesting use of conventional reactors and heat exchangers, I am suggesting processing equipment that incorporates, exploits and uses every element of the Triumvirate ^(1,2,3,4,5). Since I have used similar equipment, I am comfortable discussing the suggested equipment. Anyone wanting to use similar equipment needs to exploit attributes of Triumvirate ^(1,2,3,4,5) for the best process. Benefits are small overall footprint, higher profits and flexibility to meet market demands.

The process instead of using a conventional reactor for the production of isoniazid can use commercially available inline tubular electric process heater ⁽¹²⁾ as reactor/s. Since this is an electric tubular heater, compared to conventional reactors, the heat input can be precisely controlled/modulated. Like conventional thermal fluid heaters or steam or hot oil systems are not required. Investment would be significantly lower and will have a very small foot print. Due to their performance flexibility, production rate can be modulated to meet variable production demand.

Every chemical engineer well versed in chemical process design will understand the following proposal. There are two potential ways to introduce 4-cyanopyridine in the process and produce isonicotinamide. It could be educted as a solid using circulating caustic reactant mix or introduced as a melt ^{(13, 14)}. Caustic solution would be metered and may be preferred as its water will provide the needed fluid for the process. Conventional reactors and processing equipment can also be used.

Produced isonicotinamide would react with hydrazine hydrate to produce isoniazid in a similar tubular heater ⁽¹²⁾ which would be crystallized using known methods with methanol as a solvent. Stoichiometry would be controlled by commercial process controllers. Economics of both routes should be compared.

Methanol could also be used from the start as it is needed for crystallization of isoniazid. However, this might lower the productivity due to solvent use. Water of caustic or additional amount could be added to the reaction mass. Suggested process would need to reviewed. Major advantage of this route is minimum solvent and energy use compared to conventional reactors based processes. Figure 3 suggested process has an additional advantage as the production rates can be modulated to meet every variable global demand.

Due to FDA’s lack of experience in process development and commercialization, it is very likely that inclusion of better and simpler manufacturing methods will not be included for the foreseeable future. FDA has basically hamstrung pharmaceutical industry in continuous shortage and antique manufacturing mode. Question we all need to ask FDA “does it have vested interest in technologies they float and/or promote”? I hope not. However, it seems that way.

My wishful thinking is someday rationality will sink at FDA and US Legislators and pharma manufacturing will move from “STONE AGE” to “Actual Intelligence” Age by following what the TRIUMVIRATE⁽⁵⁾ has been telling us about process manufacturing simplification. A change to better technologies has to happen and it will lead to lower prices, shortages and significantly reduce emissions.

Girish Malhotra, PE

EPCOT International

References:

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

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

3. Malhotra, Girish: Blog Profitability through Simplicity

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

5. Malhotra, Girish: The Process Development Triumvirate: Profitability Through Simplicity, Profitability through Simplicity,March 24, 2026

6. Gasson E. J. USP 2,830,994 Process for manufacture of isonicotinic acid hydrazide from pyridine nitrile

7. Sycheva, T.P., Pavlova, T.N. & Shchukina, M.N. Synthesis of isoniazid from 4-cyanopyridine. Pharm Chem J 6, 696–698 (1972). https://doi.org/10.1007/BF00771896

8. Watts Paul, EP 4041712 B1 WO 2021/069975/PCT

9. USP 6,734,309

10. CN 111138355 A

11. Continuous Process

12. Process Technology

13. Malhotra, Girish: Imagination, Creativity and Sociochemicology (1) in Chemical Process Development. Profitability through Simplicity, January 10, 2026

14. Malhotra, Girish: SOCIOCHEMICOLOGY: Designing Chemical Processes by Exploiting the Social Behavior of Molecules,Profitability through Simplicity, Feb. 26, 2026

Sociochemicology: Its Birth and Value

2026-06-29T17:37:05.752-04:00

Sociochemicology ⁽¹⁾ is THINK DIFFERENT ⁽²⁾ phrase in the chemical world. Since most are not be familiar with the term and its evolution, it has its own journey. It is my journey also. It is practical inclusion of characteristics and behavior of chemicals in process design. It is not peer reviewed as there is no set charter, course or class room curriculum. Nothing new has been discovered. It is just based on how the chemicals behave with each other under the process conditions. We learn and use them to create excellent manufacturing processes.

My Journey:

Unknown to me my SOCIOCHEMICOLOGY ^(1,3) journey started in eighth grade chemistry class. The fact that different color gases evolve when acids react with metals intrigued and fascinated me/us. I needed to see this. I coaxed fellow students to join in my project. Since we did not have glassware, we used concrete steps of the house as the test tube. We collected different acids and metal pieces and poured acids on different metals/coins to see the colors of gases produced and smelled their pungency. Experiments were a great success but were reprimanded for pitting the concrete. This w as my first experience with chemicals showing their behavior.

I entered our college organic chemistry laboratory Fall of 1959 and for the first time saw lab benches with stands, round bottom flasks, magnetic and propeller agitators, condensers and beakers etc. Euphoria sank in that we are going to be experimenting with chemicals that we have been studying in the chemistry classes. Our professor gave us a tour of what is what. The fume hood and the Bunsen burners: how to lite them ON and turn them OFF etc.. It was exhilarating. Safety tips, handling of chemicals and the glassware suggested that we are going to be scientists and engineers.

Our teacher’s first instruction was NEVER add water to the acid but do it the other way i.e. slowly add acid to water. Explanation was that when strong acid is added to water with inadequate mixing it generates heat and contents can boil over causing injury. Acid should be added slowly to water to absorb the heat of solution. Heat will dissipate in the water and will not boil over and cause a chemical accident by erupting water. It made sense. This was our first lesson about how the physical and chemical properties of chemicals influence and interact with each other chemical but did not fully understand this value till an incident happened in our lab.

One of the fellow student must have not heard our professor or paid attention. He did exactly the opposite of what the professor had told us not to do and added water to concentrated sulfuric acid. The mix boiled out of the test tube and flew like a rocket to the ceiling and splashed over many students. Commotion set in and the lab emptied out in a hurry. No one was hurt but few days later our clothes had holes. Lesson learnt was respect chemicals, use them wisely and they can be our friend.

During my sophomore chemical engineering year, our organic chemistry lab our professor gave me the responsibility to manage the laboratory, chemicals, reagents and the lab supplies. In return, I was given permission to experiment and test different synthesis routes for dyes and chemicals from our organic chemistry book. This allowed me to test reactions listed in the book and beyond as long as they were safe. This freedom allowed me to learn more than what was part of the curriculum. Unknown to me seeds of “Think Different ⁽²⁾” were planted/reinforced/strengthened/bolstered. These experiments helped me later in my career.

For the last 60+ years, I have been involved in various roles in petrochemicals, fine/specialty chemicals, coatings, flavors and fragrances and other chemical industries. Roles have included reviewing chemistries, process development and design, commercialization, manufacturing, patent reviews and consulting clients at many different companies to simplify their manufacturing practices etc. This has been a continuous process. All along my career I had realized that each chemical has its unique and different behavior for each other and how we use them in our processes.

With time I learnt that we can manage and manipulate physical properties to simplify processing conditions by manipulating their physical state, how and where we add these reactants to the process. This facilitated and simplified our processes. This was/is similar to social manipulation of behavior of chemicals like human behavior to create friendships and relationships, Sociology ⁽⁴⁾. So in 2013 I appropriately coined mutual behavior of chemical relationships as “SOCIOCHEMICOLOGY ⁽¹⁾. Its use has grown from benchtop experiences, experiments and application of components of triumvirate ^(3,5)to critical elements of actual commercial processes. Due to lab equipment limitations, behavior and benefits of many chemicals cannot be easily tested and/or measured easily in laboratory. However, using chemical engineering design principles, behavior of chemicals can be used in process designs and processes simplified. Without their incorporation most commercialized processes are larger version of the round bottom flask experience.

We used elements of sociochemicology profusely for every batch ⁽⁶⁾ and continuous processes ⁽⁷⁾. Their inclusion allowed us to simplify processes. Some of the unit processes ⁽⁸⁾ were e.g. continuous/batch diazotization, sulfation, sulfonation, amidation, chlorination, nitration and alkylation. In addition, our processes included batch and continuous unit operations ⁽⁹⁾ e.g. decantation, filtration, crystallization and spray drying to name a few.

Sociochemicology ⁽¹⁾ delivers simplicity: an ultimate sophistication and a creator‑centric philosophy.

Sociochemicology’s Path and Considerations:

We have to recognize that the process chemistry shows us the feasibility of the reaction path and process. What generally works in the lab has to be modified and fitted in the existing equipment or new equipment has to designed for the process. Final commercialized process has to be safe and economical.

We are taught, know and have all the tools to create excellent processes but still are stuck in 80+ years old “round bottom flask” mode especially in pharmaceuticals. Why? Simple answer. We are willing to pay for inefficient processes and in the process do not care how we leave the Earth when we leave i.e. highest emissions. This is especially true for pharmaceuticals ⁽¹⁰⁾. It is up to us to challenge ourselves. If we do not, we will be stuck in the tradition of bull going around in circles⁽¹¹⁾. Food and Drug Administration (FDA)⁽¹²⁾also has to change its ways if it/we want manufacturing technology innovation in pharmaceuticals. If a DARK HORSE using methods shared ⁽^{13, 14,15,16, 17)}can show how to change the landscape, there can be a domino effect.

The following needs to be considered for commercial processes and the village has to be an integral part ^{(13,14,15,16, 17)}. There are other ways. There is not enough space to enumerate every option. Product volume plays a significant role in process selection, equipment sizing and use. Traditions of using what equipment is available in-house and from the vendors has to be evaluated, not an easy choice. Equipment vendors will challenge options. In addition, we have to always scout equipment that is used in other industries/applications and can be used in the chemical manufacturing. There will be considerable resistance from within the companies as well as users. These can be overcome through higher profits and better product quality.

We have to be always mindful in our process development/design of the fundamental fact is that every reaction happens in liquid phase. Thus, our intention has to be how to create all liquid phase. Village ^{(13,14,15,16, 17)}offers its input and expertise. Some of the considerations are enumerated. Creativity and imagination is necessary.

1. Solid raw materials as a melt offer opportunities to control process stoichiometry and can reduce solvent need. Fluid flow and process temperatures can be controlled. Excess solvents facilitate the process but can become unnecessary as they occupy reactor equipment space, a prime real estate. Heat of the molten liquids speed the reaction rate.

2. Can the solid raw material instead of dissolving in solvent can be educted in the process thereby minimizing additional solvent? This cannot be tested in the lab.

3. Gas can be used as liquid not only it can reduce solvent use but also can facilitate reaction rate. Gas, if added as liquid, can be used to control the reaction temperature and heat of exotherm as the liquid converts to gas. We exploited physical and chemical properties to our advantage.

4. Exotherms of the reactions cannot be exploited in the laboratory to facilitate and speed the reactions. Labs generally do not have the equipment or the set up to test. Ingenuity like raising the laboratory process reaction temperature comes in handy. In actual production set up using proper unit process ⁽⁸⁾ and unit operation ⁽⁹⁾, exotherms can be exploited in many ways leading to reduced solvent use, equipment size and investment.

5. Mutual solubilities or their lack of cannot be exploited in the lab development set up. They can be tested. However, they can be used in a commercial process to facilitate the process. There are creative ways to exploit.

Unknown to our equipment vendors we used plate and frame heat exchangers (now called micro or flow reactors) and crystallizers differently. Other equipment was also used differently than the suggested use. Each company has to decide how it can capitalize on mutual behavior of chemicals i.e. sociochemicology of the reactants to have an optimum process. Overall economics has to be evaluated.

We all know that without flow of liquids, centuries old practice, no reaction takes place. Since flow of fluids in lab equipment is not directly translatable to commercial equipment, what does “Flow Chemistry” really mean and what is its value. Similarly “Micro-reactors” are a fancy name for plate and frame heat exchangers that have been around and used since mid-fifties. Their use in lab development processes is not directly translatable to commercial processes. Each application and inclusion in a commercial process has to be justified. Thus suggesting “flow chemistry and micro-reactors” are new process advances in chemical and pharmaceutical manufacturing is like dressing an old house with a new coat of paint and calling it a new house, a misconception.

Rational for giving new names to the traditional methods and equipment is not clear. In addition, especially micro reactors are expensive and may not fit every process. Each need has to be justified. Some of the existing commercial equipment can be used to accomplish the same objective and simplify the processes. Scale up of round bottom glassware (laboratory) to a commercial vessel (manufacturing) is not directly translational.

Incorporation of the above is very possible in fine/specialty chemicals that enhance life style but not in API as the equipment/process. This is due to regulatory stranglehold and/or our inaptitude. We can practice creative designs but since the process has to be re-validated by FDA ⁽¹²⁾ after initial approval, a time consuming and expensive process each company has to share its intellectual property. No company wants to invest in better methods. Current regulatory approval methods have to change to allow incorporation of innovative processes ⁽¹³⁾. Simpler method would be that companies be allowed to proceed as long as they make sure that the product quality and performance is not compromised from the established specs. This would bring much needed manufacturing technology innovation to pharmaceuticals.

Process improvements and enhancements that come from inclusion of sociochemicology practices is difficult to test in the laboratory equipment. They are designed in commercial processes and are based on application of mutual social behavior of chemicals and used equipment. In addition any sociochemicology based designs being proprietary would not be published.

Since FDA and other regulators are not familiar with many of the nuances of sociochemicology and if they insist on scrutinizing new and innovative methods before a drug manufacturing can be approved, no one will include and/or simplify their manufacturing processes as is the case now. From experience we included sociochemicology based designs.

Due to limitations of the laboratory equipment, it is not easy to test mutual social behavior of the chemicals. Test of behaviors of chemicals can be a challenge but are doable if the experiments are properly designed. Creativity, imagination and knowledge of mutual behavior of the chemicals has to be included in design of such experiments. Stoichiometry i.e. the product cost and quality will be optimum. Process designed using the generated information will meet and/or exceed FDA stipulated product specifications. This would be a stark change from the current practices and the most difficult to accept and implement at the companies and FDA ⁽¹²⁾. If we want innovation in chemical/pharmaceutical manufacturing we have to be an outlier and THINK DIFFERENT ⁽²⁾. FDA’s methods have to change ⁽¹⁸⁾, a hard thing to implement and accept.

Again to re-emphasize commercial process is judicious inclusion of the Triumvirate⁽³⁾:unit processes ⁽⁸⁾, sociochemicology and unit operations⁽⁹⁾. The THREE DOTS ⁽¹⁹⁾ have to be connected. So let us STAY HUNGRY and STAY FOOLISH ⁽¹⁹⁾ and “THINK DIFFERENT ⁽²⁾” thereby creating excellent manufacturing processes that are green and economical. It is best if all of the above comes internally from each company as they define and select its own pathway.

Incorporation of TRIUMVIRATE ⁽⁵⁾ in pharmaceutical manufacturing will result in manufacturing technology innovation, significantly reduce emissions per kilo of product and that will be a game changer.

Girish Malhotra, PE

EPCOT International

References:

1. Malhotra, Girish: Sociochemicology

2. Apple Think Different

3. Malhotra, Girish: Sociochemicology: Redefining Chemical Process Design for Efficiency and Sustainability, Profitability through Simplicity

4. Sociology

5. Malhotra, Girish: The Process Development Triumvirate: Profitability Through Simplicity, Profitability through Simplicity

6. Batch Process

7. Continuous Process

8. Shreve, R. Norris: Unit Process in Chemical Engineering, Ind. Eng. Chem. 1954, 46,4,672

9. Unit Operation

10. Sheldon R.A. The E factor 25 years on: the rise of green chemistry and sustainability, Green Chemistry

11. Bull going around in circles

12. FDA

13. Malhotra, Girish: Profitability through Simplicity

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

15. 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

16. Malhotra, Girish: Report: Strategies for Improving Batch or Creating Continuous Active Pharmaceutical Ingredient (API) Manufacturing Processes, March 2017

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

18. Malhotra, Girish: For Domestic Pharma Manufacturing: Reorganize CDER, Profitability through Simplicity

19. Steve Jobs Stanford Commencement Address 2005

Exploitation and Capitalization of Mutual Behavior of Chemicals (Sociochemicology) and Process Equipment for the Manufacture of Propofol

2026-05-05T11:22:00.002-04:00

Sociochemicology ^(1,2,3,4)is an important member of the triumvirate ⁽⁵⁾necessary for the development of every life style (additives) and life span (pharmaceuticals) improvement chemical. Physical state of chemicals used and produced in the process along with the equipment used play a significant part in process selection and their design. Each has its say and influence in process development. From my perspective these phenomenon are very much recognized but may and/or not fully capitalized on.

Purpose of this note is not to be critical of the lab development and commercialization process/es but allow us to understand and capitalize on how the influence of state of materials used and produced in chemical processes provide us the process simplification opportunities and clues. Unit processes and operations can be and need to be exploited to simplify the process. Chemistry and process of propofol is used as an example.

Commercialization: Batch vs. Continuous Process:

We have to accept and acknowledge chemical processes have a definition to be a batch process or a continuous process ^(1,2,3,4). Chemistry processed in any processing equipment that is not specifically designed for the process is generally a batch process. In such processes intermediate products are held over time for further processing. Equipment specifically designed to produce a product and processed without being held for time for the next reaction process step operates 24x7x350 hours per year, is a continuous process. Claiming a lab or plant process where intermediate reaction product is held to be processed for some time is a batch process and calling it a continuous process is mis-representation of reality.

Each product’s raw materials and intermediates along with physical and chemical properties and nuances of process equipment need to be exploited. Any experienced process design chemist and/or chemical engineer, i.e. part the village ^(1,2,3,4,5) once exposed to the chemistry in the lab can create simple processes if they are well versed in exploiting social behavior of chemicals and process equipment. It is emphasized again that laboratory just shows the pathway. Economic processes are build. Imagination, creativity and experience of chemists and chemical engineers are of vital importance ^(1,2,3,4,5). Impact on environmental conservation can be effortless and efficient.

Propofol Manufacture:

Table 1 outlines four alternate propofol synthesis routes. These chemistries are similar and involvement of Village ^(1,2,3,4) and triumvirate ⁽⁵⁾ is necessary from the onset. Information can be used to select the most economical process. Ease of availability of the raw materials, their prices and business strategy drive the selected process. One will have to test the selected pathway using knowledge and experience. Based on global volume of propofol active ingredient the synthesis and its formulation can be a continuous process.

Friedel-Crafts reaction generally use aluminum chloride. It is a challenge to handle in the lab and the plant. Significant investment is needed to have a safe process. Production of Propofol ^{(6, 7, 8, 9)} uses Propofol uses concentrated sulfuric acid instead of aluminum chloridein their Freidel Craft reaction. This is much safer route. Each of the referenced process uses solvents.

For each case discussed in Table 1 creative and imaginative chemical engineer and chemist with the help of village ^(1,2,3,4,5) can easily select and design a manufacturing process that can be modulated to meet variable global production demand and even be used to produce other products if equipment modifications are needed.

Each cited chemistry in Table 1 is very similar except for some of the reactants. Paths ^(6,9) use hydroxy benzoic acid and 2-ethoxyethanol or ethyl alcohol for the decarboxylation step to produce propofol. Paths ^(7,8) use methylparaben as the starting raw material and use ethylene glycol for the decarboxylation step ⁽⁸⁾. Physical properties can be exploited to simplify the process and create an all liquid process that can be totally controlled using commercially available control technologies. Several other published routes are not discussed.

Pramanik Process ⁽⁶⁾
H₂SO₄ + IPA	NaOH +2-ethoxyethanol
4-hydroxy benzoic acid ----------------> 3,5-diisopropyl-4-hydroxybenzoic acid -------------------------> Propofol
Vinet Process ⁽⁷⁾:
H₂SO₄ + IPA	NaOH +2-ethoxyethanol
Methyl paraben -----------> 3,5-di-isopropyl-4-hydroxybenzoic acid ---------------------------------> Propofol
Chodankar (USP 11,767,281 B2) ⁽⁸⁾
H₂SO₄ + IPA	NaOH +2-ethoxyethanol
Methyl paraben -----------> 3,5-di-isopropyl-4-hydroxybenzoic acid ---------------------------------> Propofol
Coeuillas A. et.al ⁽⁹⁾
H₂SO₄ + IPA	NaOH +ethyl alcohol
4-hydroxy benzoic acid ----------------> 3,5-diisopropyl-4-hydroxybenzoic acid -------------------------> Propofol

Table 1: Process chemistries of Propofol

Table 2 is compilation of properties of the chemicals used in various propofol processes. Economics and ease of manufacturing process indicates that process based on methyl paraben route due to its lower raw material price and reaction temperatures could be the preferred route. Methyl paraben can be used as a melt and reacted with sulfuric acid and isopropyl alcohol to produce 3,5-Diisopropyl-4-hydroxybenzoic acid. By products produced would be water soluble and they can be separated using a differential gravity decanter to produce excellent feed for the distillation step.

Village’s ^(1,2,3,4,5)creativity, process engineering and reaction kinetics would be needed to have an all liquid process. My conjecture is that the higher reaction temperatures will keep the reaction mass as a melt, speed the reaction and minimize solvent use. Each route would have to be tested in the laboratory and piloted to commercialize the most economic process.

	FORMULA	MOL. WT.	MP °C	BP, °C	CAS NUMBER
4-Hydroxy benzoic acid	C₇H₆O₃	138	214.5		99-96-7
H₂SO₄	H₂SO₄	98	10.2	337	7664-93-9
Iso propyl alcohol	C₃H₈O	60	-89	82.6	67-63-0
3,5-Diisopropyl-4-hydroxybenzoic acid	C₁₃H₁₈O₃	222	146	343.5	13423-73-9
Methyl Paraben	C₈H₈O₃	152	131	265	99-76-3
NaOH 50%	NaOH	40	12	140	1310-73-2
2-Ethoxyethanol	C₄H₁₀	90	-70	135	110-80-5
2-Ethylene glycol	C₂H₆O₂	62	-12.9	197.3	107-21-1
Ethyl alcohol	C₂H₆O	46	-114	78.2	64-17-5
Propofol (2,6-Diisopropylphenol)	C₁₂H₁₈O	178	18	256	2078-54-8

Table 2: Physical properties of chemicals used in synthesis of Propofol Process

Based on the global demand ⁽¹⁾ unformulated propofol can be produced using modular plants. Validity of process patent ⁽⁸⁾ due to similar chemistries being on the public domain might need a review.

Commercialization:

Each product’s raw materials and intermediates along with physical and chemical properties and nuances of process equipment need to be exploited. Any experienced process design chemist and/or chemical engineer, i.e. part the village ^(1,2,3,4,5) once exposed to the chemistry in the lab can create simple processes if they are well versed in exploiting social behavior of chemicals and process equipment. It is emphasized again that laboratory just shows the pathway. Imagination, creativity and experience of chemists and chemical engineers are of vital importance ^(1,2,3,4,5). Impact on environmental conservation can be effortless and efficient.

In each of the cases discussed above every creative and imaginative chemical engineer and chemist with the help of village ^(1,2,3,4,5) can easily select and design a manufacturing process which can be modulated to meet variable production demand and even used to produce other products if equipment modifications are needed.

We have to accept and acknowledge chemical processes have a definition to be a batch process or a continuous process. Chemistry that can be processed in any processing equipment that is not specifically designed for the process is a batch process. Generally in such processes intermediate products are held over time for further processing. Equipment specifically designed to produce a product and is processed without being held for time for the next reaction process step operate 24x7x350 hours per year is a continuous process. Claiming a lab or plant process where intermediate reaction product is held to be processed for some time is a batch process and calling it a continuous process is mis-representation of reality.

It is emphasized that we with the inclusion of village ^(1,2,3,4,5)have to review each process chemistry and by exploiting their chemical and physical properties can commercialize excellent environmentally friendly economic processes.

Girish Malhotra, PE

EPCOT International

References:

1. Malhotra, Girish Profitability through Simplicity

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

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

4. 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

5. Malhotra, Girish: The Process Development Triumvirate: Profitability Through Simplicity, March 24, 2026

6. Pramanik C. et.al. Commercial Manufacturing of Propofol: Simplifying the Isolation Process and Control on Related Substances Org. Process Res. Dev. 2014, 18, 152−156

7. Vinet, Laurent et.al. Process Intensive Synthesis of Propofol Enabled by Continuous Flow Chemistry Org. Process Res. Dev. 2022, 26, 2330-2336

8. Chodankar N.K. USP 11,767,281 B2 Manufacturing and Purification Technology for High Purity Propofol September 23, 2023

9. Coeuillas A. et.al. Process Intensified Continuous Flow Synthesis of Propofol December 24, 2025

The Process Development Triumvirate: Profitability Through Simplicity

2026-03-24T09:04:00.004-04:00

Why Chemistry, Properties, and Equipment Must Work Together from the Onset

Every chemical—whether a lifestyle-enhancing and/or life-extending product—has a theoretical and practical legacy and pathway through which it is developed, scaled up, and commercialized.

Exploitation of the following triumvirate impacts the overall process, product quality, economics, and environmental outcome.

• Process chemistry (unit processes)

• Sociochemicology (physical and chemical properties)

• Process equipment (unit operations)

Paper chemistries (unit processes) show us the theoretical pathway. Laboratory experiments validate them. How the “VILLAGE” (chemist, chemical engineer, manufacturing, purchasing, and accounting) exploits these using the triumvirate to create an excellent process depends on collective imagination, creativity, and the ability to harness the mutual behavior of the physical and chemical properties (Sociochemicology) of raw materials, intermediates, and final products, along with the capabilities of process equipment (unit operations).

Once the village realizes the benefits and success of such collaborative efforts, they become committed advocates.

In my 60+ year career, I have been fortunate to work with and learn from members of such a “VILLAGE.” Thoughtful inclusion and application of the elements of the triumvirate have consistently resulted in economic processes. In many cases, capital investment was also reduced compared to processes where chemistries were forced into existing equipment—what I describe as “fitting a square plug into a round hole.”

Exploitation of Sociochemicology is of tremendous value. Learnings from reaction kinetics and thermodynamic properties must be fully utilized (as discussed in my books and blogs) ^1,2,3,4. Differences in solubility and density can reduce reaction volumes, leading to smaller equipment and lower capital investment. Solvent usage can often be reduced or eliminated, and overall productivity is generally improved.

Triumvirate-based designs are simpler and more productive compared to designs where chemistry is forced to fit existing equipment. They also generally result in higher profitability.

Laboratories are excellent for proving chemical feasibility. However, translating this into a simpler and more economical process requires imagination, creativity, and full exploitation of Sociochemicological behavior along with appropriate use of process equipment. All elements of the triumvirate must be considered and integrated.

Paper chemistry is a good starting point. The laboratory can demonstrate feasibility, but it cannot replicate what imagination and the collective contribution of the village (chemists, chemical engineers, manufacturing, accounting, purchasing, and maintenance) can achieve. For every successful process, imagination and creativity are essential.

Process development typically begins in round-bottom flasks, and process schemes are demonstrated at the laboratory bench. Due to tradition, the elements of the triumvirate are often not fully exploited. This is due to equipment limitations, established practices, and initial resistance when new ideas are proposed. However, with success, skeptics often become strong supporters.

The following case illustrates this point (additional examples are discussed in my publications ^1,2,3,4.

A company, whose identity is not disclosed, successfully commercialized products using triumvirate-based thinking. Encouraged by this success, it developed and commercialized a continuous process that had not previously been conceived.

Every organic chemistry textbook discusses diazonium reactions and suggests that, due to their exothermic nature, they are generally carried out at around 0°C. The following reaction is well known:

R–NH₂ + 2HCl + NaNO₂ → RN₂Cl + NaCl (1)

Due to the instability of the diazo intermediate, it is typically reacted immediately with subsequent reagents. However, breaking the reaction into steps suggests the following:

R–NH₂ + HCl → R–NH₂.HCl (2)
R–NH₂·HCl + HCl + NaNO₂ → RN₂Cl + 2H₂O + NaCl (3)

This stepwise nuance of chemistry was commercialized over 55 years ago by an assembled “village” as a continuous process. It operated at approximately 40°C for about 7,200 hours per year. Each intermediate was immediately converted to the next intermediate to the final product through subsequent reactions (sulfation, chlorination, amidation, etc.), followed by isolation and purification. Some patents discuss similar chemistries. If they were commercialized is not known.

A batch methylation was converted to continuous process resulting is significant reduction of solvent use. Other chemistries can also be similarly exploited to create simpler processes. In many cases, solvent usage can be significantly reduced or eliminated. Several such examples are discussed ^1,2,3,4. We must challenge traditional ways in which chemistries have been and continue to be practiced.

Learnings from these and other successes show that triumvirate-based approaches can be extended to a wide range of chemical processes. Yes, naysayers can be convinced—it often takes just one success. In my 60+ years in process development, commercialization, and manufacturing, I have seen many change their perspective.

The question we must ask ourselves is: “Is there an alternate way?”

To summarize, triumvirate-based designs are simpler and more productive than those that force processes into existing equipment. They generally deliver higher profitability. Such processes are inherently simpler, supporting the principle that: “Profitability is Simplicity.”

Girish Malhotra, PE

EPCOT International

References:

Malhotra, Girish: Blog Profitability through Simplicity
Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011
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
Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter April 2022

SOCIOCHEMICOLOGY: Designing Chemical Processes by Exploiting the Social Behavior of Molecules

2026-02-22T11:33:00.006-05:00

A Personal Note from Girish Malhotra

For more than sixty years, I have practiced Sociochemicology — the deliberate exploitation of the mutual behavior of chemicals to simplify manufacturing.

This is not theoretical chemistry. It is the product of decades of careful observation, experimentation, and disciplined thinking. I have seen countless processes burdened by unnecessary steps, wasted energy, and avoidable complexity. I have also seen the profound benefits when simplicity, creativity, and understanding of molecular behavior are applied intentionally.

I share this work not for recognition, nor to claim discovery, but to pass on what I have learned before I leave this planet. My hope is that others — chemists, chemical engineers, and curious minds — will engage with these ideas, challenge them, improve them, and carry them forward.

Science progresses not just through reaction mechanisms or calculations, but through insight, imagination, and disciplined observation. Sociochemicology is my attempt to capture that essence and make it practical.

If even a few minds are inspired to think differently, question inherited norms, and design processes more intelligently, then this work will have served its purpose.

For more than sixty years, I have practiced a method of process design that I later named Sociochemicology — the deliberate exploitation of the mutual behavior of chemicals to simplify manufacturing.

It is not a new branch of chemistry.
It is not theoretical abstraction.
It is applied physical chemistry used intentionally to eliminate unnecessary process burdens.

Most process development begins with a reaction scheme and builds outward. The emphasis is on conversion, yield, and purity. Existing equipment is a facilitator rather than a strategic design variable. Product quality deviations are managed.

Sociochemicology begins differently. It asks:

How do these molecules behave together under realistic manufacturing conditions — and how can that behavior be used to eliminate steps rather than create them?

The Central Premise

Chemicals do not behave in isolation. They interact socially — through solubility differences, phase behavior, crystallization tendencies, density differences, acid-base relationships, thermal characteristics, kinetic preferences, and other physical property differences.

In many industrial processes, we ignore this “social behavior” during early design. As a result:

We dissolve what we later must separate.
We overreact and then purify.
We neutralize only to re-acidify.
We introduce solvents that complicate recovery.

Then we add equipment, controls, and validation layers to manage the complexity we created.

Sociochemicology reverses this logic. Instead of forcing chemistry and managing consequences, we allow molecular behavior to guide sequencing and staging from inception.

Profitability Through Simplicity

For decades, I have advocated what I call Profitability through Simplicity ⁽¹⁾. Not minimalism for its own sake, but disciplined elimination of non-value-adding operations.

Simplicity in manufacturing yields:

Thoughtful capital investment
Reduced energy consumption
Fewer separations
Less waste
Minimal solvent use
Shorter cycle times
Improved robustness
Lowest cost

Yet simplicity is often resisted. Complexity creates institutional comfort. Departments form around managing problems. Validation structures grow around inherited designs.

Elimination can feel disruptive. But industrial progress rarely comes from adding steps. It comes from questioning

why they exist.

Sociochemicology in Practice

Sociochemicology does not require exotic technology. It requires disciplined observation and creative application of physical chemistry principles.

It means designing processes around:

Differential solubility rather than brute-force purification
Controlled precipitation rather than evaporative concentration
Selective crystallization rather than chromatographic rescue
Mutual phase behavior exploited intentionally
Equipment used as a behavioral amplifier rather than a containment vessel

In site-based chemistries such as Omeprazole, Phthalimide, Metformin, Modafinil, Gabapentin and other active ingredients, simplification did not come from discovering new reactions. It came from reordering steps, staging additions differently, and allowing inherent molecular tendencies to perform separations naturally ^(2,3,4).

The chemistry was known. The behavior was underutilized. The innovation lay not in reaction discovery, but in interaction management. Alternative routes to established processes needed to be exploited — and we did.

Why It Is Rarely Taught

Academic training emphasizes reaction mechanisms, kinetics, thermodynamics, unit processes and unit operations. These are essential foundations.

However, curricula often do not emphasize free thinking in process staging — the art of asking:

• What happens if we change the order?

• What if we avoid dissolving this component?

• Can we precipitate selectively before impurity formation?

• Can the equipment environment be used to influence behavior?

Industrial design frequently follows precedent. Once a route is validated, it becomes institutionalized.

Sociochemicology challenges inherited structure. It suggests that many “necessary” unit operations and unit processes are artifacts of early decisions rather than chemical inevitabilities.

Not Magic — Discipline

Sociochemicology ⁽¹⁾ is sometimes misunderstood as intuitive or anecdotal. It is neither.

It is rooted in:

• Solubility parameters

• Thermodynamic equilibria

• Acid-base interactions

• Mutual solubilities and insolubilities

• Mass transfer behavior

The difference is not scientific rigor — but emphasis. Traditional development asks: “How do we make this reaction work?”

Sociochemicology asks: “How do we make the entire sequence self-organizing?”

A Practical Test

Consider any multi-step API manufacturing process.

For each step, ask:

1. Does this operation exist because of intrinsic chemistry?

2. Or does it compensate for an earlier design decision?

If it is compensatory, simplification may be possible. Often the greatest improvements come not from new molecules or new platforms, but from eliminating what should never have been introduced.

The Future Opportunity

Artificial intelligence and modeling tools may facilitate and optimize defined process structures. However, optimization assumes that the structure itself is appropriate. Simplification requires something different - deliberate understanding of mutual physical behavior and the willingness to question inherited laboratory sequences.

No algorithm replaces thoughtful interrogation of molecular behavior. Imagination and disciplined understanding of physical properties remain essential.

The opportunity ahead is not merely automation of existing complexity — but redesign grounded in behavioral exploitation. Sociochemicology provides a framework for that redesign.

Sociochemicology provides a framework for that redesign. It is not revolutionary chemistry. It is disciplined attention.

Invitation

I have practiced the principles of Sociochemicology since early 1960s, long before the term was coined. Many real-world applications are described in my published work and articles.

But the concept gains power only through discussion. If you believe a process step cannot be simplified, I welcome the example.

Progress begins with conversation.

Editorial refinement support provided by AI tools.

Girish Malhotra PE

EPCOT International

References:

1. Malhotra, Girish Blog Profitability through Simplicity

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

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

Imagination, Creativity and Sociochemicology (1) in Chemical Process Development

2026-01-10T13:52:00.008-05:00

Artificial intelligence (AI) is taking on the world to be the answer to everything. With its considerable noise, I thought it would be interesting to understand its knowledge about chemistry, equipment, process centricities, process development and design methodologies. This note is not pouring water on every chemist and/or chemical engineer’s efforts past, present and future or an effort that is being made but sharing what our band of chemists and chemical engineers did and still practice. “Hats off to all of my mentors and colleagues as we had the opportunity to explore and exploit our imagination and creativity”. Only by review we can understand and/or improve what is being attempted. Perspective presented is not influenced by “for or non-profit” organizations.

Since “Artificial Intelligence (AI)” is being talked about as the “go to” for all the answers, I thought it would be just wonderful to get its perspective and opinion about the three (chemistry, equipment and process) centricities and also it would be interesting to understand its views on chemistry, equipment and process centricities about process development and design methodologies. I am comparing AI’s perspective to my learnings and experiences.

Initial responses from two sites (not referenced) were long (more than three pages). I was not looking for a treatise or a dissertation but simple answers. By re-asking the question I received the following truncated responses. Longer responses might be acceptable to many but most trained chemists and chemical engineers would find them long and daunting. At least I did. I re-asked each site to simplify their responses and they are follows.

Centricities to me describe different aspects of process design and manufacture of a chemical product. Each prioritizes a different phase of the overall process. Site “A” compared to Site “B” had some details.

Site “A”:

· Chemical Centricity: The primary focus is on the molecule or formulation itself and its desired function or performance, often driven by a chemist in the lab. The goal is to identify a specific chemical or mixture that satisfies complex customer requirements, with less initial emphasis on the manufacturing process or equipment.

· Equipment Centricity: The approach is driven by the existing or available equipment/hardware. The product and process must be designed to work within the constraints and capabilities of the current machinery and facilities, which can be common in contract manufacturing or leveraging existing infrastructure.

· Process Centricity: The emphasis is on developing the most efficient, safe, and cost-effective manufacturing process to produce high volumes of a given chemical. This is typical for large-scale commodity chemicals where process optimization (yield, cost, safety, sustainability) is the key to profitability, and the product itself is already well-defined.

Site “B”:

· Chemistry-centric: Focus on reactions & molecules.

· Equipment-centric: Focus on machines & tools.

· Process-centric: Focus on the whole flow & control.

Each site itemizes university teachings and suggests consideration of chemistry recipe, equipment hardware and process steps individually and sequentially to create an economic, safe process that complies with environmental regulations. There is nothing wrong about the methods taught in our universities. They are science based. Each site has excellent capability to scout the landscape and what has been done but does not have the capability to differentiate between a complex or simple economic process. It just refers them.

Published literature and patents referenced by the two sites are references the published lab work/curiosity and most likely will never be commercialized. This observation is based on synthesis routes published for the products that are/were commercial before the articles were published. Logical question is why was the work not done before the products were commercialized. Seems significant dollars were wasted on the work of no value.

I was banking on AI sites to reveal something very different and enlightening about the chemistries and processes I was exploring but THAT did not happen. I guess I was expecting too much. May be AI sites are not ready to advise on process development options/routes etc. at least for now. I don’t think AI platform will be ready for the near future. May be tomorrow but as we knowTomorrow never comes. It might come tomorrow.

Methods Used and Some Examples:

We have to recognize that in fine/specialty chemical hemisphere there are two class of chemicals. One that “improves lifestyle” and one “extends life”. The later class are called pharmaceuticals. Their molecules, their chemistries and their manufacturing practices and methods are same as “improve lifestyle chemicals”. The ONLY difference is product quality and use. They are produced under strict guidelines. They are covered under FDA’s cGMP guidelines ⁽²⁾. Pharmaceutical quality cannot be compromised and has to be repeatable for time immemorable. One subtle fact we overlook is that the manufacturing processes of products that improve lifestyle can be continuously improved whereas the processes for pharma products generally require FDA reapproval ⁽³⁾, an expensive process. Following examples illustrate how and what we did and would do to create excellent, economic and environmentally friendly processes from the onset. They can be used by anyone.

My Experiences and Perspectives:

We did not call classify our product and process development methods in centricities as we had ONE TASK and it was to create and commercialize the best economic process. Yes we did start with round bottom flask with its agitator, piloted the process but simultaneously worked on what it will take for a commercial process design.

For an excellent, economic and environmentally friendly chemical process and blending operations there are some basic guidelines and rules that every chemical engineers and chemists follows. They have been established since principles of chemistry and chemical engineering were recognized almost a century ago. These was instilled in me in my sophomore year of our chemical engineering curriculum. Initially I did not understand them but went along as everyone else had. Later, when I started practicing them I realized their value.

Our teachers taught us fundamentals of chemistry and chemical reactions, reaction kinetics, thermodynamics, unit operations ⁽⁴⁾(mixing, heat exchange, filtration, distillation, pumping, crystallization etc.], unit processes ⁽⁵⁾ [amination, nitration, hydrogenation, reduction, sulfation, chlorination etc.. McGraw Hills and other publishers have published series of books ^{(6, 7)}on the subject and they were and still are a godsend.

They also taught us all about physical and chemical properties ⁽⁸⁾. It is expected that we understand and figure out their mutual interaction, how to manipulate and marry them to create excellent and economic processes. We were/are exposed to all these but have no hands on experience. Thus, we carry our teachings as a myth. These parables become a reality when we get involved in process development, commercialization and manufacture of, petrochemicals, fine specialty chemicals, flavors and fragrances, additives, coatings and pharmaceuticals. It has been an exhilarating experience.

Laboratory process development starts with lab supply houses. There is a difference between lab processes and commercial processes. As soon as chemistry seemed feasible we switched to commercially available materials. This allowed us to build supply chain relationships and familiarity with their material. This influences commercial processes. Imagination and creativity in creating excellent processes is impeded if we do not work from the onset with commercially available materials. In our efforts we did not realize that we were unknowingly following some principles mentioned in “The Art of War”⁽⁹⁾in our effort to commercialize unique processes.

Our methods were/are a “GEMISH” of all centricities suggested by AI sites applied simultaneously. They worked well. In our product, process development and manufacturing Village (chemists, chemical engineers, accounting, manufacturing, quality control and purchasing) would be involved as soon as the synthesis chemistry of the chemical was written ^{(10, 11, 12)}. That meant lab experiments, raw material sourcing, pilot plant testing and commercial process. Our mission always was how along with unit processes, unit operations, reaction kinetics, thermodynamics etc. we can apply physical properties, synthesis steps and process equipment (i.e. Sociochemicology) ^{(10,11,12, 13,14, 15)}to commercialize a product.

All of the above [chemistry, equipment and process] have been and are the three centricities that simplify and make manufacturing processes very economical and environmentally friendly and are THE fundamentals of chemical process design. How they are applied is company’s choice.

Examples:

Through the following examples I am sharing my experiences and perspectives about the synthesis of certain fine/specialty chemicals and active pharmaceutical ingredients (API). Some of the processes have been commercial for over sixty years. They still can be improved. Discussion can also be applied to products being developed and/or are commercial. For the existing products FDA approval ⁽³⁾might be needed. Imagination, Creativity and Fundamentals of Chemical Engineering and Chemistry have to be exploited and applied.

Each written reaction stoichiometry tells us its reaction mechanism. It is up to us to understand it, test it and execute it commercially as intended. We prove the reaction feasibility in a round bottom flask and/or alike equipment. However, we do not or are not able commercially execute it. This is due to forms of raw materials available, tradition and the equipment used. In most of the cases the lab chemistry cannot be scaled up to have an economic commercial process. Effort is needed.

Lab processes using available raw materials are modified to fit in the existing and/or new equipment. This is an age old practice. Other options like modular plants are a possibility to have a hand and glove process. However, companies are have not considered and/or decided this route due to many reasons e.g. trained and experienced personnel and capital investment. Most commercial processes are not designed for the chemistry. Chemistries are designed and fitted in the equipment. Unless a judicious attempt is made, we might not able to capitalize on the unit processes and sociochemicology ^{(5, 6, 7, 9, 10,11, 12, 13,14, 15)}of the reactants in a commercial process. Process can be simplified if companies include something similar to the Village ^{(10,11, 12)}mentioned earlier. A concerted effort has to be made to incorporate them in the commercial process. Imagination and creativity is needed. Following are few examples.

Diazotization:

Aromatic amines used to produce respective diazo compound generally use hydrochloric acid and sodium nitrite. It is a very straight forward reaction as illustrated. “R” is the desired hydrocarbon amine.

RNH₂ + 2 HCl + NaNO₂----> RN₂Cl + 2 H₂O + NaCl (1)

It is well known that diazo formation is a two-step reaction. As illustrated hydrochloride produced from amine reaction with hydrochloric acid reacts with sodium nitrite to produce the diazonium salt that is used for further reaction. (2,3)

RNH₂ + 2 HCl ----> RNH₂Cl (2)

RNH₂HCl + HCl + NaNO₂---> RN₂Cl + 2 H₂O +NaCl (3)

Due to exothermic diazo reactions it is recommended they be generally conducted at/or below zero degree centigrade temperatures. Solubility of amine hydrochlorides chlorides in water is well known. This can be used to advantage. Since the reactions are exothermic, value of heat of reaction can also be capitalized on to speed up the reaction. Proper precautions have to be taken. By capitalizing on solubility of amine hydrochlorides and further reaction with sodium nitrite produces the respective diazonium salt in water that is water soluble. This allows the reactions to be easily done at room or higher temperatures.

It is not done as it cannot be easily demonstrated in the laboratory. Concept of hydrochloride formation followed by diazonium salt can be easily done in a properly designed process. Higher temperature speeds the reaction rate and this can be used to advantage. Imagination and creativity along with proper process equipment design makes this feasible. Since diazonium salts are water soluble this can eliminate use of solvents that is suggested in most of the published information. A water based continuous commercial process has been operating since 1970 ⁽¹⁵⁾.

Diazo chemistry has been commercial for over ONE hundred years and the solubility of its intermediates in water is well known. In many of the published papers, use of very expensive flow reactors and as if flow chemistries, (is it a new science as no reaction takes place without flow?) along with solvent use is suggested as a way for continuous diazo process. They are not at all necessary as commercially available equipment costing about 10-25% of the flow reactors is commercially available. Chemical engineers have not recognized value of the existing equipment. Since they cannot be tested in the lab process, value of such equipment has been ignored.

We have to acknowledge that laboratories prove reaction feasibility but imagination and creativity of chemical engineers and chemists i.e. the experience and knowledge of the Village ^{(10,11, 12)}needs to be harnessed. That comes from familiarity with processing equipment and process chemistry and is extremely helpful. Experience of having a continuous diazo process i.e. practice of where and how reactants were added has been successfully tested in production of acrylic latex polymerization.

Phthalimide:

Synthesis of Phthalimide was documented since 1919 ⁽¹⁶⁾. Imagination and creativity led to different manufacturing processes.

Phthalic Anhydride + Ammonia -----> Phthalimide + H₂O (4)

The described process ⁽¹⁶⁾suggests adding ammonia gas from cylinders in molten phthalic anhydride (PA) in cast iron pans heated to about 240 °C. It is presumed that the pans had no lids. Product was cooled, crushed and ground. Other references suggest different ways to produce phthalimide e.g. reacting phthalic anhydride or phthalic acid with urea ⁽¹⁷⁾, using a bubble cap tray column with top feed of liquid phthalic anhydride and bottom feed of ammonia ⁽¹⁸⁾, feeding liquid ammonia in molten phthalic anhydride⁽¹⁹⁾ in an agitated tank to produce phthalimide in batch operation.

Imagination, creativity and sociochemicology ^(1,13) was applied to continuously produce phthalimide by simultaneously feeding molten phthalic anhydride and liquid ammonia (around 1965) in stochiometric control to a properly designed small reactor in a reactor. In this process as liquid ammonia vaporizes in molten phthalic anhydride it agitates the melt to produce phthalimide that overflows in the larger reactor. Heat of reaction and liquid ammonia, as it vaporizes, assures complete mixing, a very ingenious design. No solvent is used. Produced water vapor is easily quenched.

Learning can be translated to other design applications. In this process designers exploited and capitalized physical properties and state of the raw materials to commercialize a continuous process. Simplicity of the process allowed it to meet variable product demands. It is interesting that it took about 50 years to have a simple solventless commercial process.

Metformin Hydrochloride:

Metformin hydrochloride, used for diabetics, is a very high volume product. Its global demand is expected to reach about 156 thousand metric tons by 2035 ⁽²⁰⁾. Its chemistry and chemical structure suggests dicyandiamide, dimethyl amine and hydrochloric acid are reacted to produce 1,1-dimethylbiguanide hydrochloride i.e. metformin ⁽¹²⁾.

Dimethyl amine + Dicyandiamide + Hydrochloric acid ----> Metformin Hydrochloride (5)

Different commercial processes ⁽¹²⁾ use solvent. In one of the routes use of wiped film evaporator is used to produce the API. In the other alternate routes Oslo type crystallizer ⁽²¹⁾or other crystallizer use is suggested to produce the API Fig. 1.

Figure 1: Metformin Hydrochloride Manufacture

A solventless chemistry (Figure 2) similar to phthalimide process discussed above is very possible for metformin hydrochloride production where molten dicyanamide and liquid dimethyl amine in stoichiometric ratio are fed to a reactor to produce liquid metformin. Liquid metformin would then be converted to metformin hydrochloride by quenching in commercial hydrochloric acid (37%). Quench would be further processed either using an Oslo type crystallizer (21) or a wiped film evaporator. Direct acid quench route similar to phthalimide process discussed earlier can be easily designed and commercialized. It has not been tested.

Dicyandiamide + Dimethyl amine -----> Metformin + Hydrochloric acid -----> Metformin hydrochloride
Dicyandiamide	Dimethyl amine	Metformin	Hydrochloric acid	Metformin hydrochloride
MW 84	MW 45	MW 129	MW 36.5	165.6
MP °C 208 - 211	BP°C 7-9	MP°C 205.07	BP°C 48	MP°C MW 165.5
CAS 461-58-5	CAS 124-40-3	CAS 657-24-9	CAS 7647-01-0	CAS 1115-70-4

Figure 2: Solventless Metformin process

Compared to the existing processes this process has major advantage. Commercial grade raw materials are used. There is no solvent use or any recycling of materials is involved. Process designers will apply existing chemical engineering fundamentals and process control technology for the process. Based on the commercial success of phthalimide process metformin process would be a commercial success. FDA should not have to approval issues if the process is diligently designed. This product might need bioequivalence testing.

Dicyandiamide + Dimethyl amine ------> Metformin + Hydrochloric acid ------> Metformin Hydrochloride

Figure 3: Metformin hydrochloride Process schematic

Commercial chemistries use solvents. Chemistry outlined in Figure 2 & 3 is a solventless process. It is an extremely simple process and the product quality will depend on the process designer’s imagination and creativity to have an excellent process.

Described processes suggest that if we understand the chemistry of any reaction, understand the physical and chemical properties of the chemicals used and produced, can harness the equipment available used in any industry and apply our imagination and creativity, excellent processes can be commercialized. We can reduce the amount of solvents used and improve productivity of the processes thereby lowering costs. Since the annual volume of most of the APIs is not high cross fertilization and use of modular plants can be very helpful and needs to be considered. For that each company might have to review its staffing.

If process developers are constrained by of the available processing equipment, it is very likely their imagination and creativity is/will also be stifled. We have all the skills and knowledge to accomplish what is necessary. Onus is on us to exploit our learnings and have to figure out how to get there and it is not an easy task. Unless we are challenged, process developers/designers basically are comfortable with following established traditions and by fitting the processes in commercially available equipment following what we consider is easily doable.

AI in future might be able to make some humanoid suggestions but the responsibility still will be on us humans to understand the recommendations, test and implement them to simplify manufacturing. Human imagination and creativity still will be paramount.

Girish Malhotra, PE

EPCOT International

References:

1. Malhotra, Girish: Sociochemicology: Redefining Chemical Process Design for Efficiency and Sustainability, Profitability through Simplicity, February 26, 2025

2. FDA cGMP

3. FDA: Development & Approval Process

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

5. Shreve, R. N. Unit Processes in Chemical Engineering, Industrial and Engineering Chemistry, 1956

6. McGraw Hill Chemical engineering Series

7. Perry's Chemical Engineers' Handbook, 9th Edition

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

9. Sun Tzu: The Art of War, Simon and Schuster

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

11. 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,

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

13. Malhotra, Girish: Sociochemicology, May 30, 2013

14. Malhotra, Girish: Profitability through Simplicity

15. Malhotra, Girish: Capitalizing on Mutual Behavior and Chemical Reactivity of Chemicals, Profitability through Simplicity,May 29, 2023

16. Cain, John C. The manufacture of dyes, 1922

17. Boehme W. R. et. al. Production of Phthalimide USP 3,819,648 Dawe’s Laboratories.

18. Hetzel E. et. al. Continuous Manufacture of Phthalimide USP 4,001,273 BASF Aktiengesellschaft

19. Schlaudecker G. F. Process for the Production of Phthalimide USP 2,668,326 Maumee Development Company

20. Metformin HCL Market - Global Industry Size, Share, Trends, Opportunity, and Forecast, 2020-2035

21. Oslo Crystallizers

Revised UPDATE: US Domestic Generic Pharma Manufacturing needs Shorter Approval Time and Lower ANDA Fee

2025-12-18T10:31:00.000-05:00

This is an abbreviated post of my previous blog post ⁽¹⁾.

REVISIONS INCLUDE 45 DAYS APPROVAL TIME OF THE GENERIC DRUGS FROM EARLIER 90 DAYS AND LOWER FILING FEES.

For more than two decades US Government has been aware of potential political and strategic supply chain issues related to the continued sourcing of the generic drugs. In spite of many congressional hearings and Executive Orders to mitigate the issues, dependence still exists. Basically no viable solution has been proposed.

Looking at the landscape, US Food and Drug Administration (FDA) and Pharmacy Benefit Managers (PBMs) have stood in the way of bringing generic drug manufacturing home. There may be disagreement on this but in my opinion US FDA’s time approval consuming system, fraught with “its analysis paralysis” results in approval delays. It is litigious and any benefits are not known to the consumers. Hatch-Waxman Act intended to facilitate generic drug supplies has become a way to delay their availability.

Fascinating that FDA has had the capability to change and simplify the approval landscape but squarely has done nothing. My conjecture: FDA’s major focus is on approval of new drugs. Generic approvals are just an obligation to assure “out of patent” and imported drugs being sold meet US safety and performance standards. Their prolonged approval times have stand in the way of them being manufactured in USA. No investor will invest in a US based generic plant with an unknown ROI (return on investment) timetable. My conclusion is that no one at FDA understands this. This has to change. No effort has been made to simplify their approval times. Discussed process is simple and doable. It makes an excellent case of “Nondestructive Creation”. However, it will be passionately resisted by everyone involved with approval of pharmaceuticals.

CDER (Center for Drug Evaluation and Research) at FDA has to be split in BRAND (NDA) and GENERIC (ANDA) Approval Groups. It can be done in three months or less. Each will operate as an independent business unit. FDA’s internal knowledge of methods will help and be of great value. Their performance will be measured by the number of filled and approved drugs in each fiscal year with no carry overs as is done today.

Every brand company whose patent expires in five years will make available in the public domain except for their manufacturing process product details (solubilities, bioequivalence, toxicity, all of the relevant information etc.) that are considered necessary for FDA approval. Due to vested interests FDA, Patent Attorneys, Legislators and Brand companies will resist. Unless US government intervenes no change will happen. Each filing company can develop and commercialize their own manufacturing process to meet specifications detailed in the mock application.

Each group will be responsible for approval of their respective drug categories. ANDA approval time will be 45 days from the day of filing. If no action is taken for 45+ days, it will result in automatic approval of the generic drug. If any marketed approved drug does not meet established expiring brand quality standards, addressed later, company will be banned for selling drugs in USA. Seeing what ANDA group can accomplish, my conjecture is that NDA approval time table will become shorter than the current times, a benefit for the brand companies.

ANDA group at CDER fill a mock application documenting every detail for each “going off patented” drug. Each company interested in producing the drug in USA will replicate the information if they want their generic drug approved. These applications will also be a test of FDA’s own capabilities, credibility and effectiveness to understand manufacturing processes, its own review processes and what to expect from the companies.

Company wanting to produce the generic drug can commercialize their own process. They will have to make sure that they can produce (replicate) the brand, now generic, product in every detail. It is expected that FDA’s ANDA group will understand the submitted manufacturing process. They can do an unannounced site inspections. 45 days does not give FDA sufficient time to inspect the manufacturing site.

With respect to company’s manufacturing process, equipment and test methods FDA will have to rely on random sampling of the product and have it tested by an approved independent laboratory to ensure product meets quality. Any deviation from the agreed standard would be subject to company stopping production and stop sales in USA for six months till the issue is remediated. Any repeat noncompliance would result in complete shutdown of the company. It is expected that the reduced approval time will result in lower ANDA review fees an added incentive for the companies to establish manufacturing in USA.

All of the above might look ominous and challenging. It is not as every experienced chemical engineer and chemist will have all of the information available. It is up to FDA and the interested company to capitalize on the opportunity.

USA government for its part will have to assure that Medicare, Medicaid and Veterans Administration buy their generic drugs from US manufacturers. PBMs would not be allowed to distribute domestically manufactured generic drugs. Task at hand is challenging and USA has never shrugged from any challenges.

Girish Malhotra, PE

President

EPCOT International

Reference:

1. Malhotra, Girish: For Domestic Pharma Manufacturing: Reorganize CDER November 6, 2025

For Domestic Pharma Manufacturing: Reorganize CDER

2025-11-06T12:56:00.016-05:00

For more than two decades US Government has been aware of potential political and strategic supply chain issues related to availability of the generic drugs. Many congressional hearings have been held on the subject (too many references to cite) that have not led to domestic supply of the generic drugs. Multiple Executive orders ^{(2, 3)}have been issued by various US Presidents that have not resulted in any progress in addressing the issue related to drug shortages and bringing pharma manufacturing home. Department of Health and Human Services (HHS) ⁽⁴⁾along with US Food and Drug Administration’s ⁽¹⁾ management hierarchy have been and are very aware of dire possibility of US being held a drug supply hostage but have ignored and not proposed any path or plan to make sure that the generic drugs can be sourced domestically. It is well known that US’s greater than 80% of the generic drugs are sourced from India and China.

With no progress on the issue, US can be held hostage for its healthcare needs. Yes HHS ⁽⁴⁾ has doled out monies to many entities to come up with plans to reduce shortages or bring manufacturing home. Most prominent being PHLOW Corp.⁽⁵⁾and many others to figure out methods and plans to alleviate potential drug shortages. However, the projects have been meaningless and have yet to deliver any positive results. Had they been successful, HHS ⁽³⁾ would have bellowed its horn/s.

Since CDER, Center for Drug Evaluation & Research ⁽⁶⁾ at FDA ⁽¹⁾ is responsible for approving the brand and generic drugs, responsibility of making sure shortages do not happen and the supplies are not curtailed, it has to make sure there is a plan. If there is or was a plan it has not been presented to the US Congress and/or Legislators or is in public domain.

Since HHS ⁽⁴⁾ and US FDA’s ⁽¹⁾ management hierarchies have ignored and not proposed any viable path or plan to obviate this potential national security threat, a plan to assure continuous supply of US produced generic drugs is presented. Route and views presented are my own and not influenced by any profit making and non-profit organization. It is based on my sixty plus years of experience in business and manufacturing management, process development, product commercialization, strategic and intellectual property management where the mission has been “Profitability through Simplicity” ⁽⁷⁾. Presented plan has been discussed with former regulators and they have been enthusiastic about my proposal.

FDA’s ⁽¹⁾ ANDA ⁽⁸⁾ Filing and Approval Process:

FDA ⁽¹⁾ publishes a yearly activity report ⁽⁹⁾for the generic drugs. It is complex and only well-versed can understand it. It does not tell exactly how many applications were filed in any fiscal year and how many of those filed in the fiscal year were approved.

Going forward the generic drug ⁽⁸⁾approval pathway, that will bring their manufacturing home has to be simple. To achieve returns that are acceptable to any investor, CDER ⁽⁶⁾ has to create the landscape that would attract investment. At this point I do not believe there is any. In its effort FDA ⁽¹⁾ recently announced NEW Priority Pilot ⁽¹⁰⁾ has to be carefully reviewed. Irony is that this is rehash of a plan proposed in 2006 ⁽¹¹⁾ which obviously did not and has not improved filing processes and/or brought any generic manufacturing home. I wonder if its value or purpose has been understood. It seems more to be a legal document rather than a road map that can be readily used.

Proposed Plan:

Under the proposed plan CDER ⁽⁶⁾ where brand NDA ⁽¹³⁾ and generic ANDA ⁽⁸⁾ drugs applications are reviewed has to be split in two distinct groups. Discussion here is focused on generic drugs and its experience and time lines can be adopted by the brand ⁽¹³⁾ team also. Each group would perform as a business unit with their performance being measured on the basis of filled and approved generic and brand applications. Under the proposed plan if the approval time for the generic drugs ANDA ⁽⁸⁾ exceed three months ⁽¹²⁾, their review and approval processes need to be changed and simplified to meet the three months approval requirement.

For the generic drugs ⁽¹⁰⁾ every investor would want to start getting a return in a reasonably short time e.g. three months ⁽¹²⁾ after they file their ANDA ⁽¹⁰⁾ approval application and have an approved plant producing salable products. They do not have unlimited time to invest and expect “maybe return” from an idle plant that will be approved 12 to 48 months after filing the approval paper work, the current scenario. CDER’s ⁽⁶⁾ current processes and methods do not and would not meet their expected time table. They have to be changed.

Since US Government has not been successful in bringing generic manufacturing home, it might be prudent to consider the proposed plan along with a tender process ⁽¹⁴⁾and/or a Puerto Rico model ⁽¹⁵⁾ to attract investors in setting up ANDA ⁽⁸⁾manufacturing operations in USA.

Under the proposed plan simplification of the NDA ⁽¹³⁾ and ANDA ⁽⁸⁾ approval processes, as suggested earlier FDA ⁽¹⁾ would have to reorganize CDER ⁽⁶⁾ as two different operating entities, Generic ⁽⁸⁾ and Brand ⁽¹³⁾. Each drug category will have their own review teams. Discussion here is focused on generic drugs and its experience and time lines could be adopted by the brand ⁽¹³⁾team also.

Why the reorganization of CDER ⁽⁶⁾is being recommended? Rational is by having separate brand and generic drug approval entities/organizations, each would be held accountable for its approval performance. They will have to be run as “for profit” entities or as manufacturing organizations where their performance is measured by the results of each fiscal year. This suggestion due to accountability criterion would face highest resistance from FDA ⁽¹⁾ and HHS ⁽⁴⁾.

Each group (brand and generic) with in CDER ⁽⁶⁾ will operate similar to a manufacturing organization they will approve applications (call them products) meeting “quality by design” criterion rather than FDA’s and pharma’s current “quality by analysis” ways. FDA ⁽¹⁾ is very familiar with these two terms as it adopted and promoted them early 2000. Each group, ANDA ⁽⁸⁾ & NDA ⁽¹³⁾, has to present to the US population and the US Congress unlike the current method ⁽⁹⁾ how many applications were filed and are approved in each fiscal year (October 1 of the current year to September 30 of the next year). This way any issues related to their performance can be quickly addressed.

Expectations of ANDA ⁽⁸⁾ approval time, THREE months ⁽¹²⁾, are necessary and critical to every investor as they want to start getting a return on their investment in a reasonable time. No one will invest in US otherwise. Another option each investor has to be given is the opportunity of directly distribute ⁽¹⁶⁾ drugs if they chose to do so. PBMs (pharmacy benefit managers) ⁽¹²⁾ will not like this option. Product quality and consistency has to be paramount ⁽¹²⁾. Investors will have to be tighten their manufacturing processes to assure quality is not compromised ⁽¹²⁾.

For any company to invest in US manufacturing they have to select and decide the product they want to produce. It is suggested that FIVE years ⁽¹⁷⁾before a patent is to expire, the brand company and US FDA ⁽¹⁾ will make public every detail of the approved drug, dosages, drug performance, purity, solubility, dissolution and stability profile or anything that FDA’s ⁽¹⁾ ANDA ⁽⁸⁾ group considers critical for approval and domestic production ⁽¹⁰⁾. There will be bruhaha about this requirement from within FDA ⁽¹⁾ as the core competencies of its personnel will be tested. Companies holding patents most likely will block the suggested five year requirement.

Sharing brand drug details would prevent the practice of smuggling brand drug samples ⁽¹⁸⁾ to determine their performance and emulate them for the corresponding generic drugs. We have to recognize and demand from FDA ⁽¹⁾ that their sole objective for existence is to assure brand and generic drugs meet the quality and performance. If by providing the details about the drug’s facilitates the commercialization process, takes the guess work out and reduces commercialization time of generics, it is good for the country and humanity. Each drug producing company has the obligation that their product meets the expected standard and performance. Any excursion should be treated as criminal violation and treated such ⁽¹²⁾. US Congress has to decide the penalties.

For all the above to happen FDA’s ⁽¹⁾ ANDA ⁽⁸⁾ Group will have to provide potential investors MOCK filled applications ^{(7,19,20,21,22,23,24,25)} for every “to be” generic drug which if followed accurately will minimize the filing and approval time. These applications would act as a roadmap that can be followed by anyone who wants to produce any generic drug. These will include everything from raw materials, manufacturing processes, testing methods, bioequivalence, product performance, solubility and any other information FDA ⁽¹⁾ considers is necessary for approval. ANDA ⁽⁸⁾ group should provide the necessary information as if they themselves were filing the paperwork for an approval. Again, the allocated FIVE ⁽¹⁷⁾ years for sharing information about the to expire brand drug will give each investor ample time to develop and commercialize the best and economic manufacturing process and be producing quality drugs from the onset. It is my conjecture that this time will lead to incorporation of better manufacturing technologies ⁽²⁵⁾.

I am sure that the suggested need for ANDA’s ⁽⁸⁾ mock application filing ^{(7,19,20,21,22,23,24,25)} would raise considerable uproar within FDA ⁽¹⁾, the brand pharma companies and the supporting communities. We have to recognize that without such information the current long approval processes will continue and no one would invest in USA manufacturing facility for the generic drugs. ANDA ⁽⁸⁾ group personnel at CDER ⁽⁶⁾ with their years of experience in reviewing and examining various generic applications should not have any problem preparing mock documents. Their knowledge and experience will be put to test.

Since the mock filled applications will be based on experience of CDER ⁽⁶⁾ personnel any and every question from applicant would have been addressed or can be quickly resolved. It is expected these applications are based on real information needed by FDA every bit of “analysis paralysis” that can happen, will be completely eliminated resulting in faster approvals. Any flaws in the mock applications that lead to filing and approval delays will suggest that the personnel at FDA are not qualified to review such filings. Mock filled applications will help filing of brand drugs also.

Provisions of Hatch-Waxman Act ⁽²⁵⁾ or any other similar act will have to be reviewed, revised and/or updated so that the necessary filing information is available to every potential investor and there are no bottlenecks.

Reorganization of FDA ⁽¹⁾ should not take more than three months. All the above suggested information should be available to potential investors in a short time after reorganization of CDER ⁽⁶⁾. There will be significant resistance to the proposed change. It is possible that the reorganization of CDER ⁽⁶⁾ might require Presidential action with accountable timelines to bring generic pharmaceutical manufacturing home. Reorganization has to be on war footing and the reorganization has to be treated as a remedy to national generic drug supply threat.

If the proposed reorganization or similar effort does not become a reality, nothing will change and no one will invest any money in generic drug production is USA. It is reiterated that FDA ⁽¹⁾, HHS ⁽⁴⁾, and other groups including US Legislators might interfere in the suggested plan.

FDA ⁽¹⁾ or the brand company suggesting the data that is necessary for generic drug filing is proprietary. However it is essential for approval is blocking commercialization of the generic drugs. President or the US Congress may have to re-write the current laws if the brand companies and FDA ⁽¹⁾ interfere or delay the commercialization of generic drugs.

Generic drug producer company has to have the option to sell the drug directly to patients by routes and methods of its choosing. If for some reason any approved generic drug that is on the market fails FDA’s ⁽¹⁾ independent testing and drug efficacy distribution company (pharmacy benefit managers) has to be held accountable ^{(3, 12)}. Overseas companies have drugs on DMF⁽²⁷⁾ list. They might be using this listing to promote their products in other countries. If these companies are not producing for sale in USA they should be delisted if they do not have sustained sales in USA e.g. two years.

What has been proposed above for domestic drug manufacturing pathway needs to be reviewed, thought through and modified to create a landscape that will bring generic drug manufacturing home. If USA does not make an effort nothing will change.

October 3, 2025 FDA proposal ⁽¹⁰⁾ suggests that companies will get a priority review if they did their bioequivalence studies in the United States. Irony is that the testing will be on imported generics. It is ironic that FDA is still not thinking of bringing generic drug manufacturing home.

Again, presented here is an alternate to bring generic manufacturing home that has not been proposed or discussed. May be it is time. I have not dotted every “i” and crossed evert “t”. I ask you the readers to add them as comments to make the process easier and better.

Girish Malhotra, PE

EPCOT International

References:

1. Food and Drug Administration

2. Federal Register https://www.federalregister.gov

3. Malhotra, Girish: Implementing Executive Orders on Domestic Production of Critical Medicines and Achieve Most Favored Nation Pricing, Profitability through Simplicity, June 11, 2025

4. Department of Health and Human Services (HHS) https://www.hhs.gov

5. Phlow Corporation: Trump-era federal Covid Contract recipient has yet to meet major deadlines, July 9, 2022

6. Center for Drug Evaluation & Research

7. Profitability through Simplicity

8. Abbreviated New Drug Application

9. Generic Drugs Program Activities Report - FY 2024 Monthly Performance Accessed October 30, 2025

10. ANDA Prioritization Pilot to Support U.S. Generic Drug Manufacturing and Testing, Accessed October 3, 2025

11. Prioritization of the Review of Original ANDAs, Amendments, and Supplements Accessed October 31, 2025

12. Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability, Profitability through Simplicity, December 6, 2019

13. New Drug Applications (NDA)

14. Malhotra, Girish: An Outlier Plan to Bring Pharmaceutical Manufacturing to USA in One Year, Profitability through Simplicity, April 28, 2025

15. Malhotra, Girish: US’s Self Sufficiency for Generic Drugs: A Supply Dilemma and Potential Solutions, Profitability through Simplicity, March 31, 2022

16. Malhotra, Girish: Identifying the Root Causes of Drug Shortages and Finding An Enduring Solution, Profitability through Simplicity, December 7, 2018

17. Malhotra, Girish: Implementing Executive Orders on Domestic Production of Critical Medicines and Achieve Most Favored Nation Pricing, Profitability through Simplicity, June 11, 2025

18. Eban, Katherine, Bottle of Lies Harper Collins 2019

19. Malhotra, Girish: ANDA (Abbreviated New Drug Application) / NDA (New Drug Applications) Filing Simplification: Road Maps are a Must, Profitability through Simplicity, May 11, 2017

20. Malhotra, Girish: What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days? Profitability through Simplicity, October 24, 2025

21. Malhotra, Girish: Simplified Roadmap for ANDA/NDA Submission and Approval will change Pharma Landscape, Profitability through Simplicity, November 25, 2018

22. Malhotra, Girish: Implementing Executive Orders on Domestic Production of Critical Medicines and Achieve Most Favored Nation Pricing Profitability through Simplicity June 11, 2025

23. Malhotra, Girish: Strategies to Increase Generic Drug Competition and Bring Manufacturing to The United States of America, Profitability through Simplicity March 16, 2020

24. Malhotra, Girish: Executive Order 14293 & FDA Processes Profitability through Simplicity, August 8, 2025

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

26. Hatch-Waxman Act

27. Drug Master Files (DMF) Accessed November 2, 2025

FDA’s ANDA Prioritization Pilot and Possibilities of its Success

2025-10-07T07:41:00.007-04:00

On October 3, 2025 CDER FDA ⁽¹⁾ announced “New ANDA (abbreviated new drug application) Prioritization Pilot to Support U.S. Generic Drug Manufacturing and Testing” ⁽²⁾ process it would like to experiment with in its efforts to bring generic manufacturing home to USA.

FDA has ignored the need for US manufacturing and not done anything even after numerous testimonies in front of US Congress by various responsible FDA personnel and US Presidential Executive orders ⁽³⁾. The recent proposal/experiment ⁽¹⁾ to bring generic drug manufacturing home is due to considerable pressure from the current US Administration.

Following is part of FDA’s acknowledgement ⁽¹⁾ and proposal to bring generic drugs manufacturing home.

Overreliance on foreign drug manufacturing and testing creates risks both to national security and patient access, and undermines investments in U.S. research, manufacturing and production,” said Dr. George Tidmarsh, M.D., Ph.D., Director of FDA’s Center for Drug Evaluation and Research. “It also slows down reviews and costs taxpayers more money, as these foreign research and testing sites must be inspected by FDA, and foreign inspections take more time to prepare for and are more expensive to conduct than domestic inspections ⁽²⁾.

The proposed process is flawed, in my estimation, as it has not been thought through and has significant limitations. Perspective presented is my own and not influenced for any outside influencers.

Several proposals to bring generic drug manufacturing home have been proposed ^(3,4,5,6,7) and all have been shared with CDER ⁽¹⁾. Without a 90 day roadmap (4) FDA’s current effort will go no where.

In the current proposal ⁽²⁾ it seems that that every ‘t” has been not crossed and every “i” has not been dotted. It relies on an old FDA proposal ⁽⁸⁾. Was this ever tested? If it was successful why it was not implemented.

Under the current proposal ⁽¹⁾ for the companies to apply for FDA’s consideration they have to meet the following requirements.

1. ANDA applicants have to conduct the required bioequivalence testing in the United States.

Does FDA have a list of companies that are in the public domain and is their testing acceptable to US FDA? Is the list in public domain? Would FDA accept bioequivalence test results from the US based companies and have they been approved? What is their track record?

2. One of the requirements for the priority review ⁽²⁾ is that “company’s products are made in the U.S. using exclusively domestic sources for APIs.” This would mean raw materials and equipment.

Have the authors and proposers of the guidelines ⁽²⁾ checked the availability of raw materials in USA? Does FDA know and understand that majority of the raw materials are not available in USA? Has FDA thought through the raw material availability limitation? This will result in very few, if any, companies to qualify for “priority review submission”. There are and/or gaping deficiencies in the proposed path ⁽²⁾. Even ONE success should not be considered a total success. US has long ways to go before it can call bringing generic drug manufacturing home.

With that being the case how many companies will qualify and would be able to fulfill the basic requirements of the new proposal ⁽²⁾. Based on nonavailability of US raw materials FDA’s ANDA Prioritization Pilot ⁽²⁾ is destined to failure and possibilities of its success are close to zero on a scale of one to ten. Is this proposal just a window dressing to show the current administration, US Congress and public at large that it is doing something to bring generic drug manufacturing home.

3. The new Pilot ANDA ⁽¹⁾ is based on a program that was proposed by FDA ⁽⁸⁾in 2006. Was that program ever tested ⁽⁸⁾and/or adopted by FDA and or any pharmaceutical company? What are the results? I do not know its success or it has been sitting on the shelves and gathering dust. HAs it been brushed and/or tested/ updated for its validity and applicability to meet 2025 economic and political needs. Are there any case successes?

It seems the current proposal is being suggested under duress and the new proposal ⁽²⁾ is just a trial balloon destined for failure?

US FDA needs to address the doubts cast above and will be cast by many. Another question FDA needs to address is “does it have sufficiently experienced personnel who have prepared the latest proposal and have walked such a talk”. Answers to the above questions will be very interesting. I am sure there are additional questions from others.

Girish Malhotra, PE

EPCOT International

References:

1. CDER

2. New ANDA Prioritization Pilot to Support U.S. Generic Drug Manufacturing and Testing FDA.gov October 3, 2025

3. Malhotra, Girish: Profitability through Simplicity

4. Malhotra, Girish: ANDA (Abbreviated New Drug Application) / NDA (New Drug Applications) Filing Simplification: Road Maps are a Must. Profitability through Simplicity, May 11, 2017

5. Malhotra, Girish: Simplified Roadmap for ANDA/NDA Submission and Approval will change Pharma Landscape, Profitability through Simplicity, November 25, 2018

6. Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability, Profitability through Simplicity, December 6, 2019

7. Malhotra, Girish: What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days? Profitability through Simplicity October 24, 2025

8. Prioritization MAPP CENTER FOR DRUG EVALUATION AND RESEARCH MAPP 5240.3 Rev. 6

Let us "THINK DIFFERENTLY'. It is time especially for pharmaceuticals

2025-09-23T11:38:00.001-04:00

This ⁽¹⁾ is an interesting report of spending tax payer (over billion dollars) and company money with no return. Perspective presented is mine and not influenced by any "for or none profit entity".

Goals are noble but the pathway is very prickly and difficult as it has been spun many times in the last 10 plus years with no results.

Companies who need to innovate their processes and technologies do it themselves as we all have been taught the fundamentals of chemistry, chemical engineering and their applications. If we cannot then we have an issue with our teaching and practice methods.

FDA's suggestion of advanced manufacturing technologies suggested ELEVEN YEARS ago has gone nowhere. New names have been given to the same dance.

REAL continuous manufacturing has been taught (nonstop) i.e. raw materials in and product out and practiced for over 80 or more years and pharma has avoided considering it. It needs to revisit as creativity and imagination is needed. It has been done successfully in fine/specialty chemicals, older cousin of pharmaceuticals (active ingredients and their formulations. Pharmaceuticals are still stuck at "B" (batch) and to move to the adjoining letter "C" (continuous) totally different landscape and methods are needed. We need to "THINK DIFFERENTLY".

Like other projects "Equip-A-Pharma" will also be a failure. Why? Companies have to have a need for the technologies for their products. No need no project and monies get squandered. Products need different tunes to dance. It cannot be the same tune and different dances. It will go nowhere, my conjecture.

HHS comment "Traditional pharmaceutical manufacturing is often too rigid and slow to adapt to changing demands". There is reason as its affiliate FDA has never been on the same page. Again companies have to write their own music and lyrics.

Battelle Memorial Institute and Aprecia; BrightPath Laboratories; Rutgers University; and the Mark Cuban Cost Plus Drug Company have chased and are chasing a dream on someone else's dollar. It is easy to go that route.

Lastly artificial intelligence (AI) is the supposedly the answer but its actual ignorance (AI) of reality is an issue and comes in the way.

We have the knowledge and desire to excel but if we are going to sing 60 year old music today, not many will listen. Observations are welcome.

Girish Malhotra, PE

EPCOT International

Reference:

Advanced Mfg. in Pharma: Where Does It Play? September 18, 2025

Physical Properties of Chemicals, their Mutual Behavior i.e. SOCIOCHEMICOLOGY and Process Simplification

2025-09-08T08:38:00.002-04:00

Linked is an OLD article (April 1, 2012) might be of interest. It is not April Fool's day pun.

“Focus on Physical Properties To Improve Processes https://lnkd.in/ea7nECDN”

Social behavior of chemicals coined as "Sociochemicology" https://lnkd.in/eFCFE-Rk capitalized can simplify and innovate chemical manufacturing processes.

1. Process Simplification and The Art of Exploiting Physical Properties, Profitability through Simplicity (https://lnkd.in/eViU6nW) March 10, 2017

2. Sociochemicology: Redefining Chemical Process Design for Efficiency and Sustainability, Profitability through Simplicity https://lnkd.in/e-PeH5AV, February 26, 2025

These might be of interest.

Girish Malhotra, PE

EPCOT International

Executive Order 14293 & FDA Processes

2025-08-08T16:03:00.000-04:00

US FDA posted a press release “FDA Announces New FDA PreCheck Program to Boost U.S. Drug Manufacturing” ⁽¹⁾ outlining its NEW PROGRAM to strengthen its processes. It proposes a PreCheck in response to EO14293 ⁽²⁾.

FDA ⁽¹⁾ has suggested TWO steps and they are:

1. First, the Facility Readiness Phase provides manufacturers with more frequent FDA communication at critical development stages, including facility design, construction, and pre-production. This phase also encourages companies to provide a comprehensive facility-specific information through a Type V Drug Master File (DMF), such as site operations layout and description, Pharmaceutical Quality System elements, and Quality Management Maturity practices. This facility-specific DMF can be incorporated by reference into a drug application as appropriate.

2. Second, the Application Submission Phase centers on streamlining development of the Chemistry, Manufacturing, and Controls section of the application through pre-application meetings and early feedback.

I am presenting my understanding of FDA’s PreCheck Program processes. I have no financial relationship with any for profit and/or nonprofit organization.

FDA personnel, my conjecture, will never have complete understanding and/or command of each product and process as that is the jurisdiction of the company producing the products. Companies know their manufacturing processes better than anyone else. If they do not then every chemical and pharmaceutical company has a major problem. FDA through this ⁽¹⁾ is suggesting they know more about company’s processes, products and manufacturing. As a regulatory body FDA or for that matter EPA also has to rely on what the company is presenting and saying will do to produce quality product/s. Is FDA suggesting that companies do not understand their product, process and manufacturing processes? With that being the case how FDA personnel, that has minimal and/or no experience in process development, manufacturing and commercialization will be able to advise a company of “facility phase readiness”. FDA just put a CART BEFORE THE HORSE and exposed itself for telling the world that best of the chemical/pharmaceutical companies don’t know much about what they commercialize.

It is my understanding that currently FDA and companies meet to address any questions through in-person meetings. In PreCheck what will be different from the current situation. I would be tempted to call this a case of “sanctioned delays”.

Meeting product’s established quality specification, performance and following cGMP guidelines is company’s responsibility and should be demanded by FDA from every company to produce their products. FDA and or any other regulatory body should have the authority to stop production ⁽³⁾ if they do not deliver expected product quality. FDA should very clearly define the information that each company needs to submit for approval. What FDA has issued is complex and needs simplification. My best postulation is even FDA personnel cannot fill an application. USA needs to adopt and consider processes where NDA(new drug application)/ANDA (abbreviated new drug application) ^(3,4,5) can be approved in 90 days. They have been discussed since 2017 and for EO 14293 to be a success their adoption and implementation is critical ^(3,4,5).

I posted my first reaction about FDA’s PreCheck on LinkedIn ⁽⁶⁾ when I saw the news release ⁽¹⁾. I consider this as an official sanction for the delays. EO 14293 ⁽²⁾ will never come true as there is no timetable to be met. Without any timetable for domestic production for critical drugs, FDA’s processes ⁽¹⁾ are of no value to US population.

We have to recognize that it is company’s responsibility to produce quality drugs and FDA’s responsibility to expedite the approval process. Fact that the Presidents of The United States have issued Executive Orders ^(2,7,8,9) for the expeditious manufacture of critical drugs and it seems no one has taken responsibility for their implementation. It seems they ^(7,8,9) have been ignored and gone by the wayside. How FDA’s PreCheck, a new name for existing practice will promote domestic production?

FDA’s processes need revamp. If not done the issue of critical drugs and shortages will keep rearing its UGLY head every so often. There are many vested interests that will interfere ⁽¹⁰⁾ in the process and need to stay out the way.

Girish Malhotra, PE

EPCOT International

References:

1. FDA Announces New FDA PreCheck Program to Boost U.S. Drug Manufacturing August 7, 2025

2. EO14293 Regulatory Relief To Promote Domestic Production of Critical Medicines, May 5, 2025

3. Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability Profitability through Simplicity, December 6, 2019

4. Malhotra, Girish: What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days? Profitability through Simplicity, October 24, 2018

5. Malhotra, Girish: Simplified Roadmap for ANDA/NDA Submission and Approval will change Pharma Landscape, Profitability through Simplicity, November 25, 2018

6. LinkedIn August 7, 2025

7. Executive Order 13588 Reducing Prescription Drug Shortages, October 31, 2011

8. Executive Order 13944 Ensuring critical medicines are made in US August 14, 2020

9. Executive Order 14017 America’s Supply Chains Feb. 24, 2021

10. Malhotra, Girish: Most Favored Nation Pricing & Bringing Pharmaceutical Manufacturing Home, Profitability through Simplicity, July 13, 2025

Most Favored Nation Pricing & Bringing Pharmaceutical Manufacturing Home:

2025-07-13T11:05:00.002-04:00

Discussion of high drug prices, shortages and brining pharma manufacturing home has been an ongoing subject and it is discussed in every Congress. Executive orders (too many to cite) have been issued and nothing has changed. Interference besides pharmaceutical companies comes from TORS. Who are TORS? They are Distributors, Regulators, Legislators and Litigators. Each has financial interest and do what they can do to derail any and every progress.

Current administration has issued Executive Orders ^(1,2,3) and we will have to see if anything happens as there are many vested interests in their way to prevent their implementation. Perspective presented is unbiased and not influenced by an for profit and non-profit organization.

To get to Most-Favored-Nation pricing and bring pharma manufacturing home, the current business model along with how pharmaceuticals are distributed in the United States will have to change. All of these are going to be a challenge. Companies with about 2.5 TRILLION dollar revenue (pharmaceutical benefit managers (distribuTORS), pharmaceutical companies, health insurance etc.) will exert every bit use of political influence on (legislaTORS), litigaTORs and RegulaTORS. Reason is very simple. Too much distribution disruption and relearning pharma’s development and manufacturing capabilities can be avoided by money if status quo can bought. However, if the current US administration forces the issue, things will have to change staring from pharma’s methods (product development, manufacturing) and regulatory approval methods. Distribution will be disrupted. Alternate approval methods will have to considered and implemented ⁽⁴⁾.

For the last twenty years I have discussed manufacturing technology issues and published solutions in articles, my blog and books. Manufacturing processes of the Active Pharmaceutical Ingredient (API) and their formulations are bench top processes. I call them round bottom flask and mortar and pestle processes. They could be easily fitted in the equipment of the age and have been the main stay of pharma manufacturing.

Most of the chemical synthesis manufacturing processes and methodologies are batch processes fitted in the existing equipment. Reasons and rational are simple. Minimize investment. There are other ways improve manufacturing process that also minimize investment, discussed in the books. cGMP practices have to followed irrespective of the equipment used. Involvement of the VILLAGE from inception of the product can simplify the manufacturing processes i.e. lower cost. I am not going into the reasons and rationale but internal complacency, tradition and regulatory needs have been an impediment in use of better processing methods ^(5,6,7). Process of continuous improvement does not exist in pharma manufacturing as each modification has to be approved by the regulators, a very expensive process. Result is companies are afraid to make even minor tweaks to the processes.

To bring pharma manufacturing home and companies to profit their practices have to become current. Very creative and imaginative chemical engineers and chemists at the pharmaceutical companies with the cooperation of FDA can BRING PHARMA MANUFACTURING HOME. No such attempt has been made. Billions are being invested in antiquated methods and manufacturing technologies (too many to cite). These will not deliver what is expected by the current US administration.

If any headway has been made at least it is not obvious. I am not sure about recent announcements for new plants that will come on stream in few years should be a consideration of bringing manufacturing home. This is a harsh observation but is a reality. Question is what do they do for US’s short term needs. It seems more of a public relation ploy in front of legislators and press.

In order to bring manufacturing home, pharmaceutical companies have to proactive and be directed by a Pharma Czar ⁽⁸⁾ who directly reports to the President of the United States. Drug distribution methods and policies will need to be modified. Again undue influence of TORS will have to be warded off.

Fitting processes not only has not only been less productive but also results in high emissions per kilo of the drug. Yes it minimizes investment but there are alternates. They can lower manufacturing costs and they need to be considered ^(4,5,6,9). Involvement of village would be necessary as after the fact ways that have been practiced have to go by the wayside.

I have presented my perspective in the following and good, experienced chemists, chemical engineers and business folks need to review. They can practice and/or modify to bring manufacturing home and lower drug prices. Following have been presented to bringing pharma manufacturing home and ways to improve profits.

1. Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability December 6, 2019

2. Malhotra, Girish: Health and National Security Issues for the USA and Is The United States of America Prepared May 8 , 2020

3. Malhotra, Girish: A road map for driving pharmaceutical manufacturing back to the USA by 2025 October 8, 2020

4. Malhotra, Girish: US’s Self Sufficiency for Generic Drugs: A Supply Dilemma and Potential Solutions March 31, 2022

5. Malhotra, Girish: Roadmap to Reduce Drug Shortages and Bring Pharma Manufacturing Home (US) October 30, 2023

6. Malhotra, Girish: Remedy of US’s Drug Supply Chain Shortages and Domestic Production of Generic and Brand Drugs April 15, 2025

7. Malhotra, Girish: An Outlier Plan to Bring Pharmaceutical Manufacturing to USA in One Year April 28, 2025

8. Malhotra, Girish: Implementing Executive Orders on Domestic Production of Critical Medicines and Achieve Most Favored Nation Pricing June 11, 2025

9. Malhotra, Girish: An Unconventional Analysis: Can the Wrath of Most Favored Nation Pricing ⁽¹⁾ be Avoided by Bringing Pharmaceutical Product & Process Development and Manufacturing Practices to 21^st Century? July 8, 2025

To accomplish the objectives of MFN pricing ⁽²⁾ the MOST IMPORTANT AND CRITICAL item is that every manufacturing change and practice has to come INTERNALLY FROM THE PHARMACEUTICAL COMPANIES as they have command of their culture, process chemistries, understand their manufacturing landscape and every other detail. There are very many vested interests (regulators, consultants, contract manufacturing organizations) that will vie to meddle in but no one knows the business better than folks at the companies. Over the years many have stepped in with no results. Focus has to be razor sharp. Task is not going to be easy unless it is tried and tested internally nothing will change. Companies have the knowledge and what it will take to bring manufacturing home. With the resident talent and application of chemical engineering fundamentals, creativity and imagination the factory costs can be reduced, profits improved and profits improved ^{(5, 6, 7, 8).} We need to exploit them. Change has to come and is overdue. May the FORCE be with you.

Girish Malhotra, PE

EPCOT International

1. EO 14293 Regulatory Relief To Promote Domestic Production of Critical Medicines Accessed May 5, 2025

2. EO 14297 Delivering Most-Favored-Nation Prescription Drug Pricing to American Patients Accessed May 15, 2025

3. Executive Order 14273 Lowering Drug Prices by Once Again Putting Americans First Accessed June 2, 2025

4. Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability Profitability through Simplicity December 6, 2019

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

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

7. 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

8. Malhotra, Girish: Profitability through Simplicity

An Unconventional Analysis:

2025-07-08T16:41:00.000-04:00

Can the Wrath of Most Favored Nation Pricing ⁽¹⁾ be Avoided by Bringing Pharmaceutical Product & Process Development and Manufacturing Practices to 21^st Century?

I have shared my learnings and experiences in process development, technology innovation, manufacturing and business practices ^{(2, 3, 4, 5, 6)}. With the looming threat of lowering the selling prices of the brand drugs through EO 14297, in this post I am sharing what are some of the things companies need to considered to avoid its wrath. Forcing brand drug sale prices by 50% or so to match e.g. European prices will have a significant impact on the P&L of every brand pharma company. However, I perceive this an opportunity for the pharmaceutical companies to lower drug prices, enhance their profits through increased affordability. Effort will simultaneously improve manufacturing technologies and reduce their environmental impact.

I am not suggesting to follow and/or do what I am sharing but let your imagination and creativity take you/us to create products and processes that are our best effort. Discussion is applicable to every chemical business (fine/specialty, coatings, their younger cousin Active pharmaceutical ingredients and their formulations). Perspective presented is mine and is not influenced by any for profit and non-profit entity.

My review is based on cost analysis. Our understanding of costs can assist us to improve processes and methods to enhance profits. I am not challenging any methods but suggesting that as part of continuous improvement, review of the current methods and practices for every profit and cost center can lead us to improve profits. Every little improvement is worth the effort. Readers are welcome to share their thoughts.

To avoid the wrath of Executive Order EO 14297 ⁽¹⁾ pharmaceutical companies will have to review their research and development, commercialization, manufacturing and business practices. I am sure that most companies, first blush, would say it cannot be done. However, unless an ongoing concerted effort is made, the current and upcoming US Government administrations can force change of the current practices and they may not be to our liking. Litigations will ensue.

US Drug Prices vs. Rest of the World:

For that last number of years there has been a conversation about the high brand drug prices in the United States compared to other developed and underdeveloped countries. The explanation given by the pharma companies is that price for each brand drug are the highest in their effort to recover the product development costs ($1-2 billion). Everyone has bought this explanation and believe it to be true. However, no independent body/person, has been given a verifiable explanation/justification for these costs. Prices in other developed counties are lower as their healthcare systems have been able to negotiate the sale prices. Prices in developing countries are low just for sheer volume of drugs needed. They pay for the fixed costs and keep the factories operating. Law of economics tell us that no company runs a charity and no one is going to sell their products at a loss unless we all missed the explanation/s.

Proposed EO 14297, if enforced, would influence the balance sheet of every brand pharma company. In Table 1 company “X’’’s real drug, not identified, is analyzed. At this writing the world population is about 8.2 Billion ⁽⁷⁾. US population (347 million ⁽⁸⁾), is slightly less than 5% of the global population. It is interesting, just for numbers sake, to compare the sales of this hypothetical drug in USA vs. rest of the World. Numbers are estimates but are close to the numbers for a real drug. Anyone can do a similar analysis for any drug.

Numbers in Table 1 tell us a story. It is logical to conclude that if the Company “X” is selling the drug at an average sale price of $0.75 per tablet in other countries and is not losing any money. This prices is less than ten percent of the US selling price. Prices ⁽⁹⁾ in other countries range from $3.00 to $0.55 per day for the 5 mg tablet. If the company has a 50% margin (this includes local pharmacist’s profits), the lowest factory cost could be ~ $0.18 per 5 mg. (based on my manufacturing and costing experience) tablet which includes the API and inert excipients. With this being the case, US selling price in a mutually subsidized healthcare system is alarmingly high.

	United States	Global	Total
Population	347,000,000	8,200,000,000	8,547,000,000
Percent using (assumption)	0.42	0.42
Tablets per yr.	531,951,000	12,570,600,000	13,102,551,000
Average Price /tablet, $	9.83	0.75
Revenue, $/yr.	5,229,078,330	9,427,9500,000	14,657,028,330
Tablet, mg	5	5
API needed Kilo/year, kg	2,700	62,853	65,553

Table 1: Sales of a Real (unidentified) Drug ⁽⁹⁾

Table 1 shows the amount of API is needed to satisfy US needs vs. rest of the world. USA population’s API needs are less than 10% of the global population’s needs. Even if it was 10%, still the API volume is small. Drug for US needs can be produced at a single site. API for US demand could be imported and formulated. However, the API for rest of the world is being produced outside US and its formulation taking place at one or more sites outside USA. Without the global market, US selling price of the drugs will be higher than the current prices.

Pharma companies need rest of the world market to absorb the fixed costs and maximize their profits. Claim that US brand pharma bear the cost of new drug may be right but in reality rest of the world bears significant portion of the ongoing costs and that is not well understood and/or recognized. We have to acknowledge that the US sales volume is not large enough and the sales to other countries contribute to each line item of the balance sheet and maximize every company’s profits. In other words they contribute to keep Pharma companies in business. US alone cannot be in business of inventing new drugs. Simply it is a “mutual appreciation society”.

Pharma companies suggest that to develop a new drug it can take up to TWO billion dollars. These numbers to me are a hearsay as I have not been able to verify these by an “independent” entity. If EO 14297 ⁽¹⁾ is implemented i.e. reduce the selling price for this drug by 50% in USA, it can wipe out significant funding for the discovery of a “NEW DRUG”. To recoup the loss would mean that pharma will have to look at each line item of its balance sheet i.e. how to conserve. This means business model change.

Pharma: What to look for?

Pharma companies, if EO 14297 ⁽¹⁾ is implemented most likely will have to reconfigure their business model. Every “t” and every “i” will have to be meticulously crossed and dotted for marketing, sales, product and process development, and manufacturing. It is time to shed 50+ years old business model. It needs to change as the WORLD has changed.

Marketing and sales expense along with every line item will have to be reviewed. My speculation is that if a new drug for a disease is more effective than any existing drug, it will sell by word of mouth. Advertising might have to be minimized and that will be a line item savings. Let the best drugs sell based on the efficacy and performance rather than force feeding what majority of the customers do not understand.

Most likely Research and Development would have to be treated as a profit center instead of a cost center. This would require each company to review their product discovery, processes development and manufacturing methods to lower their costs. “Village”^{(2, 3, 4, 5, 6)}, unlike the current tradition, would have to be involved from inception of every product development as there will be no opportunities to re-invent and optimize the drug’s manufacturing processes after the product enters clinical trials and is commercial. Effort to re-invent the manufacturing process for a brand drug i.e. under patent would be expensive as the regulators most likely would ask to reconfirm its efficacy and characteristics.

If the above is implemented pharma landscape will change from inception. My expectation is that complete command of the product and process will reduce the regulatory approval time and lead to longer NDA “in-patent” time meaning instead of patent expiring in approximate 10-12 years might get additional 4-5 years of patent life. This could compensate lost revenue due to EO 14297’s inclusion.

I don’t know how many chemists and chemical engineers associated with any pharmaceutical product, process development and manufacturing are familiar with the cost analysis but it would be enlightening and of great value if the VILLAGE ^{(2, 3, 4, 5, 6)} gets involved in the product development from the start of product discovery. It is expected that some of the village members would be able to share the value of “what if” of the product development, process stoichiometry and manufacturing before a sample is submitted for clinical trials. An optimized process before it is scaled up for rigorous testing does not take time. This information can and should be used to optimize the process and minimize its environmental ill-effects. (references).

My conjecture is that inclusion of EO 14297 ⁽¹⁾ on pharmaceutical landscape will be beneficial to the overall pharma landscape and could reduce drug shortages and lower prices. It is best if the pharma companies took the reins and saddled the horse. Government intervention should be the last resort. Direct marketing is another option. Besides pharma companies the biggest obstacle will be the US private sector, Pharmacy Benefit Managers (PBMs) who along with their influencers will make sure EO 14297 ⁽¹⁾ it is not implemented ⁽¹²⁾.

Girish Malhotra, PE

EPCOT International

1. EO 149297: Delivering Most-Favored-Nation Prescription Drug Pricing to American Patients

Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability, John Wiley & Sons, February 2011
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
Malhotra, Girish: Research Report: Strategies for Improving Batch or Creating Continuous Active Pharmaceutical Ingredient (API) Manufacturing Processes, March 2017
Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter April 2022

6. Malhotra, Girish: Profitability through Simplicity

7. Current World Population https://www.worldometers.info/world-population/

8. United States Population (live https://www.worldometers.info/world-population/us-population

9. Pharmacy Checker.com https://www.pharmacychecker.com/

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

11. Malhotra, Girish: NET ZERO for Active Pharmaceutical Ingredient & Fine/Specialty Chemicals: Nondestructive Creation, Profitability through Simplicity, November 7, 2024

12. Malhotra, Girish: Implementing Executive Orders on Domestic Production of Critical Medicines and Achieve Most Favored Nation Pricing, Profitability through Simplicity, June 11, 2025

Implementing Executive Orders on Domestic Production of Critical Medicines and Achieve Most Favored Nation Pricing

2025-06-11T17:59:00.004-04:00

Pharmaceutical and the Drug Distribution companies have “Profitability through Sick Care” as their mission. One invents new drugs/treatments and the other distributes them. Bottom line: PROFITS are the goal and pharmaceuticals just happen to be the media. “Simplicity” in product and process development and manufacturing should always be on the forefront as they make sure that the companies are profitable. We are short on “Simplicity” aspects.

Recently three EOs ^{(1, 2, 3)} were promulgated. Each has ambitious goals. However, based on the performance of the past EO’s ^{(4, 5, 6)} even after disbursing money ⁽⁷⁾ their success in delivering what is expected (domestic manufacturing and lower pricing) is highly unlikely unless methods of their execution are changed. In order to meet the objectives of the EO’s ^(1,2) fundamental changes are needed. Suggested implementation methods are reviewed. Perspective presented here is mine and is not influenced by any “for profit and non-profit” organization/s. Processes suggested in the three EO’s ^{(1,2, 3)} most likely will not lead to expected results as they do not have a total timetable. This is obvious as they suggest a time of 180 days for initial review and analysis.

Without any deadlines and time line goals spelled in the EOs ^{(1, 2, 3)} a PROJECT CZAR with “accountability responsibility” has to be appointed. S/he has to be directly accountable to the President of The United States. Without such person most of the TORS ”DistribuTORS i.e. PBMs, LegislaTORS, RegulaTORS, LitigaTORS and even the produCERS and/or other unknows/knowns due to their influences and vested interests, it is very possible that these EOs ^(1,2,3)will meet the fate of earlier EOs ^{(4, 5, 6)} and will end up in a “do nothing” pile. Very bold and aggressive actions are needed for their success ^{(8, 9, 10, 11)}. As Yoda says “Do or do not. There is no try”.

EO 14293 ⁽¹⁾:

“Domestic production of critical drugs” is a noble objective. Success of this EO is dependent on fixing the current broken regulatory filing system. No one would admit that. Broken are FDA’s needed filings requirements for regulatory approvals methods and pharma’s manufacturing technologies. EO 14293 ⁽¹⁾ does not acknowledge these but this is a reality everyone knows. If everything was good there should not be any or very little back and forth between regulators and companies about the information exchange and approvals.

Improvements to the existing filing and review system/methods have to be created, tested and implemented. They would be based on the information available and used in the current methods. Fallacies of the current system can be used as an example and need to be corrected. To meet the objectives EO ^{(1, 2, 3)} improvements in both, regulatory approval (FDA) and manufacture of a drug, are a must. It is my conjecture that if an attempt is made, we could bring critical and generic manufacturing home within ONE YEAR ^{(8, 9, 10, 11)}. This will require focus and effort.

Alternate to building a new plant/s, it is possible to repurpose existing fine/specialty chemical plants. Creative use of the available existing equipment along with process robust design not only can minimize investment, commercialization time ^{(12, 13, 14)}and but also lower total manufacturing costs. Chemical engineers are very well trained in this task. To experienced chemist and/or chemical engineer this is not difficult. On the pharma manufacturing platform chemical engineers and chemists are still fitting their processes in the existing equipment ^{(15, 16)}, an 60+ years old practice. Alternate process equipment and manufacturing process options need to be investigated ^{(12, 13,14)}. They have to be done by the process engineers and process chemists at the company sites.

Improvements at FDA:

Results of regulatory process approval reduction time will lead to reduction in New Drug Application (NDA) and Abbreviated New Drug Application (ANDA) approval times ^(10,11). Pharmaceutical industry and US population will benefit immensely. It will lead to higher return on US Tax Payer investment through faster availability of brand and generic drugs. Every manufacturing company will benefit. Done correctly it could lead to bringing generic drug manufacturing home. FDA’s NDA and ANDA approval processes have to be equated to a “manufacturing process” where continuous improvements are needed. Without these improvements the topic of NDA and ANDA filings and their timetable will be discussed perpetually. As suggested earlier a CZAR is needed for the EO’s ^(1,2,3) to become a reality and till that happens these EO’s or like other EO of past ^(4,5,6) will not achieve their goals.

In Sec. 3 EO 14293 ⁽¹⁾ acknowledges that FDA needs review of the current regulation processes. Filing instructions (equivalent to manufacturing process instructions ⁽¹²⁾ for NDA and ANDA have to be precise and simple that any educated person can fill them and the completed application will lead to approvals in short time like 90 days from the initial filing.

A quick method is suggested. If within 15 days of NDA and ANDA submission there are deficiencies, applicant should be informed. The filing company would have another 15 days to complete and re-submit the necessary information. If all of the submitted information is acceptable, the applicant should be informed and this would give USFDA another 60 days to grant and/or deny the filing ^(8,9,10,11). It is my perspective that changes at FDA’s review and approval process will also fulfill requirements of Section 9 of the EO 14293 ⁽¹⁾.

In the pharmaceutical industry process development for the brand and generic drug products paths have commonalities ^(12,13,14). For commercial manufacture companies have to shed their current version of laboratory bench top or similar processes that have been practiced for the last 60+ years and practice what is science and engineering based ^{(12, 13, 14)}. Pharmaceuticals have to move from equipment centricity ^{(15, 16)} to process centricity ⁽²⁰⁾. Nothing new has to be invented. Only fundamentals of chemistry and chemical engineering need to be applied intelligently from product and process inception by the village ^{(12, 13, 14)} for the production of brand and generic products.

Section 3 of EO 14293 ⁽¹⁾ mentions “emerging technologies” that enable the manufacturing of pharmaceutical products active pharmaceutical ingredients, key starting materials, and associated raw materials in the United States”. I do not know what are these “emerging technologies” as they have never been explained by US FDA citing verifiable commercial examples. Manufacturing technology development and their practices are product specific, it best to be done by the practitioners of the technology rather than being suggested by the regulators who do not have much hands on experience in their development and commercialization.

It is ironic that the manufacturing processes and practices at most pharma companies are about 60+ years old bench top methods. FDA staff should be focusing on simplifying the NDA and ANDA approval methods and times rather than talking about “emerging technologies”. My conjecture is that FDA’s shortened approval time and direct marketing to patients, as explained later i.e. quicker and higher profits, will be the best incentive to develop and commercialize better technologies. Higher and quicker profits will be the result.

Lately unnecessary jargon (old methods/technologies in new names; too many to name) are being introduced. Still they have to be commercialized by the companies. FDA cannot and should not coax companies to consider what companies cannot justify on commercial scale. They have the process developers, designers and manufacturing personnel who acting as the VILLAGE ^(12,13,14) can design and commercialize economic product specific processes. It is suggested that the EO 14293 ⁽¹⁾ CZAR consider options discussed ^{(8, 9, 10, 11, 12, 13, 14)} and use process designers/developers at the companies with manufacturing experience do their task.

Hatch-Waxman Act ⁽¹⁷⁾, it impacts the pharma landscape immensely is not mentioned in any of EOs ^(1,2,3) . It has to be revised and updated. Since the discussion here is about domestic manufacturing it is suggested that FIVE years before a patent is to expire brand company US FDA should make public every detail of approved drugs dosages, its drug performance and profile. By having the drug details companies that want to produce the generic drug will develop the best manufacturing processes, technologies that are economic. FDA approvals will also be fast. Direct sales to patients present an opportunity to manufacture the drug with the best process, highest quality at the highest profit. Every “TOR” mentioned earlier will make sure there are no changes made in the current practices and such disclosures do not happen. In reality TORs will make every attempt to swing the pendulum to tighten and extend current provisions of the Hatch-Waxman Act ⁽¹⁷⁾ in their favor. Artificial Intelligence sites ^(18,19)when asked “Does Hatch-Waxman Act ⁽¹⁷⁾ needs a change?” It suggested it is 40 years old and categorically needs revisions and simplification.

Improvements at Pharmaceutical Companies:

Section 1 of the EO ⁽¹⁾ discusses the time it takes to build a new manufacturing facility in United States and is equally difficult to repurpose existing idle facilities to produce active pharmaceutical ingredients and formulate them. I disagree with the time suggested to repurpose a facility to produce Active pharmaceutical ingredients (API) and formulate them ^{(8, 9,10, 11)}. It is my belief that with FDA fixing its filing, permitting and approval processes (NDA and ANDA) and pharmaceutical companies following good design and engineering practices ^{(12,13, 14)} will move companies practice of fitting processes in existing equipment ^{(15, 16)} to process centricity ^(20).This may sound a daunting task but with the equipment, sometimes available at the pilot plants and idle plants, can be repurposed to accommodate most unit processes ⁽²¹⁾ and unit operations ⁽²²⁾. Out of the box thinkers and outliers are needed. They exist at every pharmaceutical company especially at their older cousin fine/specialty chemical company.

It is my assumption that improvements in regulatory approval i.e. shortening the approval times for the brand companies will extend their patent’s life i.e. higher profits. Brand and generic companies will also benefit as they will have better asset utilization ^{(8, 9, 23)}. It is my expectation that real application of chemical engineering and chemistry will result in “Profitability through Simplicity”. Discussion about Good Manufacturing Practices (cGMP) ⁽²⁴⁾ are not included in the discussion as they are the corner stone of pharmaceutical manufacturing and expected to be followed.

EO 14297 ⁽²⁾ and EO 14273 ⁽³⁾:

Ways to implement EO 14293 ⁽¹⁾ has been discussed earlier. Its inclusion would be needed for implementaion of EO 14297 ⁽²⁾and EO 14273 ⁽³⁾. This going to be extremely challenging and difficult as the healthcare distributors (PBMs), their allies and every brand pharmaceutical company would come out with every INFLUENCER (TOR), explained earlier, against all three EOs. Reasons are very simple. They will have to change their business practices of the last forty plus years significant percentage of their profitability could be a stake. They may have to re-learn many things. Change is difficult. Hatch-Waxman ⁽¹⁷⁾ as discussed earlier has to be updated.

Just to refresh TORS are LegislaTORS, RegulaTORS, LitigaTORS and the DistribuTORS. However if EO 14293 ⁽¹⁾ is properly implemented brand pharmaceutical companies and their TORS could and would benefit. If the distribuTORS do not change their methods to accommodate and include EO 14293 ⁽¹⁾ in there business practices, US Government has another way to force the change by letting the generics be sold directly by their producers by passing the distributors or set the sale prices so that the profits at the companies are not severely compromised. Either way PBM profits would be impacted. Change will be challenged. Federal Trade Commission (FTC) will have to establish very strict ground rules to prevent direct sale price collusion. Since profits are involved business creativity and imagination of US entrepreneurs will play a strong roll in pharma’s distribution landscape. This will be a challenging regulatory road.

US Government has to eliminate drug TIERS ⁽²⁵⁾, an artificial way instilled by the distribuTORS to sell same disease curing drugs at different prices. Since US FDA approves different drugs for the same disease there should not be any TIERS ⁽²⁵⁾. It would be best if these are eliminated. Let the drug price, patient and their doctor decide what is best for the patient. This along with direct sales to patients, due to their vested interests, will be resisted by the three TORS i.e. Pharmacy Benefit Managers and their allies distribuTORS, LegislaTORS and LitigaTORS. Direct sales to patients is the best option to lower drug prices. As I have indicated earlier through better technologies and manufacturing practices drug producing companies will have higher profits. This will also bring innovation in drug development, manufacturing and distribution methods.

Brand drug sales in USA and other countries are sold at variable prices. US prices are the highest. Explanation of high US prices is justified as recouping the product development, commercialization costs and limited patent life. This does not make sense as many drugs under patent are sold at significantly lower prices outside USA which happens to be about be less than 5% of the global population. My conjecture is that by selling brand drugs at affordable prices in most countries brand companies are recovering their fixed manufacturing costs. US Due to world’s current highest prices government has a justification for using the Most-Favored-Nation prescription drug pricing. US government will have to negotiate with the brand companies US selling prices. Brand companies and PBMs will have to negotiate sale prices and that would treading on a new turf.

Selling price comparison is illustrated in Table 1.

Drug	Company	US Price	Overseas Price
Sovaldi	Gilead	$84,000 for 84 doses ⁽²⁶⁾	$900.00 for 84 dose India
Eliquis (2.5 mg) ⁽²⁷⁾	Pfizer/Bristol Myers	$ 9.67 per tablet	$ 0.68/ tablet (International price)

Table 1: Drug Price Comparison

Table 2 is a rough calculation of the factory cost and selling price of Eliquis. Numbers are best estimates. Cost analysis of other drugs are reviewed ^{(12, 13, 28)}.

Eliquis production cost
API cost, $/kilo	4,779.00 ⁽²⁹⁾
Conversion cost to tablet
Inert ingredient cost, $/kilo estimate	5,000.00
Labor cost, $ kilo	4,000.00
Factory cost, $/kilo	13,279.00
ONE KILOGRAM produces 1,000,000 tablets of ONE milligram.
Each Eliquis tablet is 2.5 milligram. ONE kilo will produce 400,000 Eliquis tablets
Factory cost of each 2.5 mg tablet, $ = 13,279/400000 = 0.034
Profit margin 200%
Factory Selling price, $ per tablet = 0.068

Table 2: Manufacturing Factory Cost (estimate)

Some of the cost numbers (ingredient and labor) used are high estimates. Even with these numbers the factory selling price is just 10% of the international price and less than ONE percent of the US price. Similar cost examples can be developed.

If US Government sets the selling price to be e.g. $5.00 per 2.5 mg tablet, Pfizer/Bristol Myers Squibb are not going to like the numbers. However, to recover some of the lost dollars this gives them an opportunity to review their costs associated with R&D, Process Development, Manufacturing and others to see how they can become more efficient and recoup some of money. There will other latent advantages from developing efficient processes (high conversion yield). Similar analysis for the generic drugs illustrates the price differentials between US price and prices in India ^{(12,13, 28)}.

It is striking that the same drug is sold at vastly different prices ⁽²⁷⁾ outside USA. Is it a case of the pharma company’s using overseas sales to cover their fixed costs or is it a case of price negotiation or whatever they can get away with? Gilead was selling AIDs drugs at exorbitant prices in Africa till Cipla, India ⁽³⁰⁾ challenged its prices and sold the drug at $350.00 per year, an affordable price. Someone stood up to big pharma and the world benefited.

Summary:

Recent EO’s ^(1,2,3) are suggesting that FDA, pharmaceutical companies and their distributors re-look at the landscape of the last forty years and change or the change will be made for you. The following needs to happen:

1. Review, facilitate and shorten FDA’s review and processes

2. Hatch-Waxman Act ⁽¹⁷⁾: Overhaul needed to minimize patent abuse leading cause of high US drug prices

3. Repurposing using process centricity ^(20,21) is easy and has to be carefully thought through

Benefits of improvements would be higher profits for the pharma companies through faster approvals, longer patent life, use of better process centric ⁽²⁰⁾ manufacturing technologies and lower pollution ⁽³¹⁾, lower drug prices, real possibility of brining manufacturing home. However, EO’s ^(1,2,3) suggesting 180 day review essentially means nothing will happen i.e. dead on arrival. A very aggressive time table is needed for their incorporation.

As discussed earlier Hatch Waxman Act ⁽¹⁷⁾ needs to be updated to the current times and is overdue. It is interesting to note that AI platforms (CHATGPT and Perplexity) ^(18,19) suggest that the loopholes to stifle generic entries have been exploited. As suggested earlier all of the performance, purity, solubility and whatever data is necessary for its generic version should be declared by the patent holding company and USFDA about FIVE years before the patent expires. Congress will have to facilitate that but many of the TORS ( mentioned earlier) have and will resist any change. Only a Presidential action can change that. However, every business specially pharmaceuticals and their allies will say “SHAME”. FDA, a tax payer funded entity, often has taken side of the pharmaceutical companies. It should refrain from doing that. Neutrality is healthy in the long run.

Discussion with Dr. Albinus M D’Sa ⁽³²⁾ has been extremely helpful in the preparation of this perspective.

Based on my experiences it is my conclusion that USA can achieve the objectives of the THREE EXECUTIVE ORDERS ^(1,2,3)provided it uses the RIGHT experienced personnel. The CZAR for this project has to report to the President Of The United States. Without that kind of accountability these EO’s are not going work. Implementation and incorporation is going to be a challenge. We have the knowledge and experience of pieces and parts but need to reconfigure so that US is not paying the highest prices for the brand and generic drugs. Effort would be needed. Let us give it a go.

Girish Malhotra, PE

EPCOT International

1. EO 14293 Regulatory Relief To Promote Domestic Production of Critical Medicines Accessed May 5, 2025

2. EO 14297 “Delivering Most-Favored-Nation Prescription Drug Pricing to American Patients” Accessed May 15, 2025

3. Executive Order 14273 Lowering Drug Prices by Once Again Putting Americans First Accessed June 2, 2025

4. Executive Order 13588 Reducing Prescription Drug Shortages, October 31, 2011

5. Executive Order 13944 Ensuring critical medicines are made in US August 14, 2020

6. Executive Order 14017 America’s Supply Chains Feb. 24, 2021

7. Trump-era federal Covid contract recipient has yet to meet major deadlines Accessed May 17, 2025

8. Malhotra, Girish: An Outlier Plan to Bring Pharmaceutical Manufacturing to USA in One Year

Profitability through Simplicity April 28, 2025

9. Malhotra, Girish: Remedy of US’s Drug Supply Chain Shortages and Domestic Production of Generic and Brand Drugs Profitability through Simplicity, April 15, 2025

10. Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability, Profitability through Simplicity, December 6, 2019

11. Malhotra, Girish: US’s Self Sufficiency for Generic Drugs: A Supply Dilemma and Potential Solutions, Profitability through Simplicity, March 31, 2022

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

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

14. 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

15. 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

16. Equipment centricity

17. Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act)

18. ChatGPT.com

19. Perplexity.ai

20. Malhotra, Girish: Process Centricity is the Key to Quality by Design, Profitability through Simplicity April 6, 2010

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

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

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

24. cGMP Practices

25. Understanding Drug Tiers

26. Washington Post December 1, 2015

27. Pharmacychecker.com Accessed June 1, 2025

28. Profitability through Simplicity

29. Eliquis API price https://www.pharmacompass.com/active-pharmaceutical-ingredients/eliquis June 1, 2025

30. Indian Company Offers to Supply AIDS Drugs at Low Cost in Africa February 7, 2001

31. Malhotra, Girish: NET ZERO for Active Pharmaceutical Ingredient & Fine/Specialty Chemicals: Nondestructive Creation, Profitability through Simplicity, November 7, 2024

32. Dr. Albinus M. D’Sa

An Outlier Plan to Bring Pharmaceutical Manufacturing to USA in One Year

2025-04-28T21:14:00.005-04:00

The following comment on my recent post “Remedy of US’s Drug Supply Chain Shortages and Domestic Production of Generic and Brand Drugs⁽¹⁾has led to the development of this post.

"Excellent Article! I agree with every thought within it, and would add that once a firm is approved, Medicare, Medicaid and Veterans Administration should be obligated to buy from a domestic, US manufacturer. This would provide a ready market to tap into.

Your references too cover the other necessary incentives: 1) Tax free enterprise zones located throughout the US, 2) a preferential priority approval process for domestic Manufacturers of 90 days, and 3) a direct manufacturer to patient sale process without middle men and a transparent price and commission with and without insurance. ------ Dr. Albinus Marian D’Sa

For the last ten plus years most of the conversation has been about the brand drugs. There has been discussion about the nonavailability or high prices of the generic drugs due to tariffs and other political causes but no one has talked about or proposed any pathway to remediate the situation. I have outlined a US Government sponsored “Tender Program” that would make the basis to bring generic pharmaceutical manufacturing home. It is my belief is that its success will address drug cost and shortage issues and it could be expanded to other healthcare needs.

Most will without reviewing the plan will say that the title in itself is outlandish to say the least and non-achievable. However, the reality discussed can very different. Unless we review and discuss the objective along with the pathway of what we have to accomplish nothing will happen. We in USA have what it takes to get things done and lower generic drug prices by directly serving the needs of Medicaid, Medicare and Veterans Administration patients. Suggesting “it cannot be done” is not an option. It even could force patients to ration their necessary medicines over food ⁽²⁾. Anyone who thinks it cannot be done should not be reading any further. Perspective presented here is not influenced by any “for profit and/or nonprofit” organization.

I would call the task “ask not what your country can do for you - ask what you can do for your country-JFK” moment. A gemish of “can do” chemists, chemical engineers, logistics wizards along with participation of “can do” legislators, bureaucrats and technocrats would be needed. What is presented here has not been “thunked, thoughted out and discussed” in detail with masses but is based on our teachings, experiences, outlier thinking and accomplishments.

We have had number of Presidential Executive Orders, conversations and testimonies (too many to reference) to reduce/eliminate shortages but there has been no progress. Due to lack of any progress to produce most drugs in USA ^(3,4,5), a different “outlier” pathway is proposed. Many could say this proposal is ridiculous, not doable and fraught with pitfalls. May be it is, but in absence of any viable suggestion/attempt, this or something similar needs to be reviewed or considered. It will need every bit of help from the folks who are experts in walking through the regulatory, legislative and vested interest maze. “Can’t be done folks” are not needed. If the task was easy it would have been done long time ago. It might sound that I am repeating myself and I am, but the point is that in our NATIONAL INTEREST we need to do something that most outliers do. We have been challenged and succeeded to every contest if we want to.

Plan:

USA government will ask any global company or companies for tender bids (proposal) with experience in the manufacture of active pharmaceutical ingredients (API) and their formulations to start producing the top ten generic drugs, Table 1 ⁽⁶⁾ in ONE year using their manufacturing facility or facilities based in USA. Once approved they have to operate the viable facility/is for the next five years. If for any reason a company decides to stop/withdraw during the term, they would be barred from the US market for the next five years. There will be no drug tiers for any the generic drugs ^(7).

These tender will have to meet requirements of the US Government processes. As I don’t know many of the US government tender process details, people familiar will have to participate and make sure things are organized for smooth execution.

Companies need to bid to supply the listed drugs (Table 1) to the Medicare, Medicaid and Veteran’s Administration of the United States of America. US Government will guarantee this patient base. Government will also facilitate establishment of the facilities.

At least two companies will have to bid for each product. This will prevent price gouging. Qualification basis would be their product quality of the last two years. Company can bid for multiple drugs. Companies will have to follow US Federal Trade Commission guidelines.

US Government will work with State governments and US Legislators for the establishment of such facilities ^{(3, 4, 5)}.

FDA has to make sure that it is asking every company necessary information so that their submission is complete and there is no missing information to assure approval. FDA will review and grant abbreviated new drug applications ANDAs in 90 days ^{(8, 9, 10)}. In addition the produced products will be approved under FDA’s SLEP program ⁽¹¹⁾.

Table 1: Tender offering by US Government

1) Tender winning company/s will set up manufacturing facility in US to produce the active pharmaceutical ingredient (API) and its formulations. Companies and FDA will have to work hand and glove for all of the approvals. It is critical that companies start selling their approved products as soon as they have all of the necessary approvals and can produce the drug. Finished tablet sales produced in US have to be happen in the first year. For the success of tender based manufacturing it is critical that company start earning their desired return on their investment from the first year. They should be able to achieve higher margins than they are currently being achieved by all of the middle men involved in the distribution of generic drugs ^{(12, 13, 14)}. US government has to assure that all of the necessary timelines to produce the drugs are met. FDA approvals on timely basis are critical ^{(3, 4, 5)}.

2) Each tender company will have to become a US based entity governed by US Corporate Laws.

3) US Government will guarantee each company the necessary land, utilities, environmental permits. Each company working with US FDA will have to invest in US facility and demonstrate that all what is necessary to produce the designated/approved quality product is operational. Product quality will be randomly checked. Any non-compliance or deviation from the agreed/established standard would be a disqualification and could lead to closure of the manufacturing facility. All incurring losses will be companies responsibility.

4) Each tender will be valid for five years and depending on company’s product quality performance could be renewed for the next five years. If during the term of tender product quality does not meet the established standard, company would be barred to produce and sell any product in USA.

1) Key raw materials needed for the API and their formulations will be sourced from the US based manufacturing companies. US government will have to support the involved infrastructure companies.

Pharmaceutical manufacturing companies will have to develop, design and commercialize processes that would not live “square plug in a round hole” ⁽¹⁾, a 60+ years old practice. There are manufacturing methods ^{(12, 13, 14)}they could consider. Chemists and chemical engineers are taught the fundamentals, may need to brush up and think differently.

Table 2: Company Responsibilities

I am sure there are many other “i’s” that need to be dotted and many “t’s” that need to be crossed if such a route is endorsed by US Congress, population at large and different pharmaceutical vested interests. US Government will have to convince companies to venture out this “delicate” path and it is not going to be easy.

This route suggested here is and will be a major perturbation for US healthcare industry. Many with vested interests will make every effort through their legislators and influencers to make sure this pathway is obliterated before it sees light of the day. If any alternate path was easy it would have been adopted years ago. Let’s see who are the “brave hearts”.

Direct sales to Medicare, Medicaid and VA patients (estimated to be about 55 million) will be of great value to the tender wining company/s. My conjecture is that the manufacturing companies will have higher profits compared to their current selling prices to PBMs and their allies. This will be a big win for free competition.

Using the top 10 drugs ⁽⁶⁾ and their common dose one can calculate their annual API (active pharmaceutical ingredient) and the needed formulations. This is a good place to start.

Rank	Drug Name	Prescriptions (2022)	Total Patients (2022)	Prescriptions/ Patient/year	Milligram /Dose	Kilos /year (approx.)
1	Atorvastatin	114,509,814	26,640,141	4.29	10	97,000
2	Levothyroxine	98,970640	20,225,373	4.89	0.1	738
3	Metformin	92,591,486	20,122,987	4.6	500	3,672,445
4	Lisinopril	88,597,361	19,816,361	4.47	10	72,300
5	Amlodipine	69,786,684	16,699,810	4.17	5	30,500
6	Metoprolol	66,413,692	15,007,908	4.42	25	137,000
7	Albuterol	61,948,347	17,902,020	3.46	-	-
8	Omeprazole	56,300,064	13,879,629	4.05	20	101,000
9	Losartan	54,815,411	12,690,563	4.31	50	231,600
10	Gabapentin	49,961,066	10,571,700	4.7	10	38,600

Table 3: Prescriptions and patients per year ⁽⁶⁾

Manufacturing Technologies:

Numbers in Table 1 may not be of interest to many chemists and chemical engineers to determine the total active pharmaceutical ingredient (API) for each drug and number of finished tablets per drug. Village ^(12,13,14) has to decide on type of manufacturing process (batch or continuous) and the formulation facility needed for each product to satisfy US annual needs. It is expected that the “Village” has the expertise. Creativity and imagination can lead to very innovative manufacturing processes ^{(12, 13, 14)}.

Based on the chemistry, a quick review of the kilos needed for each of the drug in Table 1, astute members of the village can decide on needed type of manufacturing facility. Based on my experience, some of the APIs can be produced using a continuous process ^{(12, 13, 14, 15,16)}. It is my belief that the manufacturing processes for metoprolol and losartan can be simplified also. Albuterol is a liquid and not included. Levothyroxine dosage is in micro grams and can be campaigned in a properly designed equipment. Knowledge, experience, creativity and imagination of every village ^{(12,13, 14)}member will be put to test. All of the necessary manufacturing equipment is available in USA. Formulations would definitely need continuous processes. Technology and equipment exist but due to tradition has been used for batch processes. Value of continuous processes has been described and enumerated many time over in every chemical engineering books ^{(12,13, 14)}. Chemists and chemical engineers have to lead the process development, design and commercialization effort. They can work with equipment vendors to select the process equipment, technology and methodology.

US Government (Legislators) along with Food and Drug Administration, Federal Trade Commission and local governments play an active role in my suggestion/proposal ⁽³⁾. Another piece of the puzzle that has to fit in hand and glove will be the manufacturing API methods and their formulations. We have to divide them in two paths. Each is easy if looked at separately. Sequential API manufacture and their formulation at single site once thought through works well.

Of the ten formulated drugs I have reviewed chemistry of four of the actives. Each can be commercially produced using continuous processes ^{(12, 13, 14, 15,16)}. Their investment and environmental footprints will be smaller than the current methods. I have not reviewed their raw materials but should be readily available in USA. Other drugs can also be similarly produced continuously and their chemistries might need a review and some process development. Tender based manufacturing with improved FDA approval practices present a unique opportunity to produce the needed drugs at a breakneck speed if USA wants to produce the drugs and supply to the patients in the three groups mentioned above.

What has been suggested/proposed above is a herculean task and is not easy. Significant effort would be required from legislators, regulators, litigators and benefactors (pharmaceutical companies) and a unified effort would be needed. This would be a case of “do or do not and there is no try -- Yoda”. To protect health of USA population against political blackmail resulting in high drug costs, such an effort is necessary.

I believe that to produce and sell generic drugs under the US Government tender offer program is an excellent opportunity to revolutionize pharmaceutical manufacturing processes and technologies for ages to come.

Challenges:

We should not forget that the adoption of this and/or any proposed plan would be a challenge to many participants of the current system i.e. how they conduct their business. We all know that we are set in our ways and do not want to change. However, in US’s national interest the proposed change is necessary. There are “TORS” who stand out. They are LegislatORS, RegulatORS. LitigaTORS and “K StreetORS” who have led to the creation of the current system. Instead they would have to put national interest ahead of their personal interest.

Hurdles will also come pharmacy benefit managers and the supply chainers, I call them distribuTORS. US Congress will have prevent them so that they do not kill this effort. We have to remember their profits will be impacted. Every effort will be made to obliterate any thought of success of this effort.

US legislators most likely would have to change the current regulations that are in the books for the approval of abbreviated new drug applications (ANDA). Regulators will have to change the information that has to be submitted by the companies for the approval of the ANDA applications. Companies submitting ANDA applications would have to learn and submit the necessary information so that ANDA can be approved as quickly as possible in less that 90 days ⁽¹⁾.

In summary for the winning tender system to work the and company to produce drugs in USA and success each of the following has to happen.

1. Every time line has to be met by the bid winning companies.

2. FDA has the systems in place to approve ANDAs in 90 days.

3. All of the necessary environmental , construction approvals, for the manufacturing site/s are met on a timely basis.

4. Legislators work in the interest of USA based patients rather than the current middle men (TORS).

5. Federal and state laws be in place to enable Medicare, Medicaid and Veterans Administration to purchase drugs for domestic supply in preference to foreign manufacturers.

6. Laws have to be in place to prevent middle men (like Pharmaceutical Business Managers), insurance companies and other “TORS” from gaming the current system and minimizing profits of the manufacturers.

Above is an attempt and I would request/suggest readers to chime in and take this or similar plan to their legislators for further consideration and approval. Unless we the people demand meaningful changes in the current ways, nothing is going to change.

Girish Malhotra, PE

EPCOT International

References:

1. Malhotra, Girish: Remedy of US’s Drug Supply Chain Shortages and Domestic Production of Generic and Brand Drugs, Profitability through Simplicity, April 15, 2025

2. Malhotra, Girish: Drug Prices: Food vs. Medicine - A Difficult Choice for Some, Profitability through Simplicity, June 16, 2011

3. Malhotra, Girish: US’s Self Sufficiency for Generic Drugs: A Supply Dilemma and Potential Solutions, Profitability through Simplicity, March 31, 2022

4. Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability, Profitability through Simplicity December 6, 2019

5. Malhotra, Girish: Roadmap to Reduce Drug Shortages and Bring Pharma Manufacturing Home (US), Profitability through Simplicity, October 30, 2023

6. The Top 50 Drugs Prescribed in the United States

7. Understanding Drug Tiers October 22, 2023

8. Malhotra, Girish: What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days? Profitability through Simplicity, October 24, 2018

9. Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability, Profitability through Simplicity, December 6, 2019

10. Malhotra, Girish: Simplified Roadmap for ANDA/NDA Submission and Approval will change Pharma Landscape, Profitability through Simplicity, November 25, 2018

11. Expiration Dating Extension

12. Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter May 2022

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

Malhotra, Girish: Considerations to Simplify Organic Molecule (API) Manufacturing Processes: My perspective, Profitability through Simplicity, April 20, 2019
Malhotra, Girish: Alphabet Shuffle: Moving From QbA to QbD - An Example of Continuous Processing, Pharmaceutical Processing, February 2009 pg. 12-13

Remedy of US’s Drug Supply Chain Shortages and Domestic Production of Generic and Brand Drugs

2025-04-15T21:03:00.001-04:00

USA is the largest consumer of Brand and Generic drugs. Discussion here is centered around generics as they are the largest volume (84%) ⁽¹⁾ to serve the needs of US population but is very applicable to brand drugs also. Most of the US drugs are imported. Threat of US not having sufficient supply of these drugs has been there and is real. It has been talked about and discussed for quite some time. Conversations and congressional hearings⁽²⁾have been held. Projects ^{(3, 4, 5)}have been initiated by HHS (BARDA) and others to alleviate problem/s have no meaningful results and the problems still prevail. From my perspective all these attempts have been a charade. There is nothing meaningful on the horizon. With potential of tariffs on drugs, US needs to wake up and remedy the situation before it is too late.

National Academy of Sciences ⁽⁶⁾in its most meaningless report even suggested that US should build foreign alliances to curb shortages ⁽⁷⁾. For national security reasons these recommendations ⁽⁶⁾should have been questioned. Different US presidents have issued executive orders as far back as 2011 ^{(8, 9)}and nothing meaningful has resulted to reduce shortages or attain self-sufficiency. To bring pharma manufacturing home revamp of pharma’s business model, discussed later, along with US’s creativity and imagination is needed. This is critical. Since the industry is profitable need to change has never been a consideration.

Why US has not made any progress in brining pharma manufacturing home when it can send man to the moon and bring him back. Pharma, my conjecture, has not addressed issue and/or may be does not understand the real root cause of the problem even after repeated discussions and attempts. Perspective presented is my own and is not influenced by any for profit and/or not for profit organization.

Pharma companies are stuck in the current business mode (Figures 1 & 2) since middle of the last century. This is due to what I label as “equipment centricity ⁽¹⁰⁾” (Figure 1) rather than “process centricity ⁽¹¹⁾”. Since pharma has been profitable it considers itself invincible and no need to change its operating and business model has been on their radar. Figure 2 is the result of Figure1.

Pharma’s “equipment centricity ⁽¹⁰⁾” i.e. fitting different chemistries in the same equipment has forced companies to follow stringent drug safety regulations and prescribed cGMP regimen. Downside has been low asset utilization ⁽¹²⁾. All the related costs become part of the product cost. It also has the highest hydrocarbon emissions per kilo of product ⁽¹³⁾. All of the related costs are passed on to the patients. Since the customer pays for the added costs, need for “process centricity ^{(11 )}” has not been a consideration.

With the prospect of tariffs on pharmaceuticals unless immediate steps are taken US population could suffer immensely. If US is really serious about bringing generic and brand drug manufacturing home, it has to emulate an effort like going to moon and/or create a consortium that has no outside political and regulatory meddling. Alternate business and operating model, not a rocket science, has to be adopted. Pharma manufacturing has to move from “equipment centricity ⁽¹⁰⁾” to “process centricity ⁽¹¹⁾”. If it does not this discussion will continue.

Why Equipment Centricity:

Why has the pharmaceutical industry dwelled on and is content with “equipment centricity”? The answer is simple. Since inception ^{(14, 15, 16)} manufacture of active pharmaceutical ingredients (API) and their formulations can be accomplished by modifying the processes to fit in the available existing equipment. This minimized new capital investment. With this pathway it accepts rigorous drug safety regulations and less than optimum use of processing equipment ⁽¹²⁾. “Equipment centricity ⁽¹⁰⁾” related costs are born by the patients.

Process Centricity ⁽¹¹⁾:

This is not a new concept for the chemists and chemical engineers. It is pure and simple application of fundamentals of chemistry, chemical reaction engineering, processing and economics taught in our business, science and engineering curriculums ^{(14, 15, 16)} to create an excellent process. It is widely used in the fine/specialty chemical industry, older cousin of pharma. It is ironic that every reaction chemistry tells us how the “process centricity ^{(11 )}” works and how it can be exploited. Even then pharma lives in its old tradition of fitting a square plug in a round hole “equipment centricity ⁽¹⁰⁾” (Figure 1).

By overlooking “process centricity ⁽¹¹⁾” especially in active pharmaceutical ingredient (API), pharma is not involving the “village” ^{(14, 15, 16)}from product inception. As a result it misses out on applying nuances of mutual and social behavior of chemicals, Sociochemicology ^{(14, 15, 16, 17)}, to create excellent processes. Some might consider this combination to be difficult. It is not. We are taught everything we need to know but have not fully capitalized on their value. We have the knowledge, creativity and imagination to accomplish the impossible.

Path Forward:

If US wants to bring pharma manufacturing home, companies will have to internalize move from “equipment centricity” ⁽¹⁰⁾ to “process centricity” ⁽¹¹⁾. My estimate at least 180 days working 24/7 hours might be needed for each product provided it has the needed processing equipment, infrastructure, available raw materials, approved site and process. It is very possible that US might not have properly trained manpower for such task.

In order for US to bring pharma manufacturing every “t” will have to be crossed and every “i’ will have be dotted. Brand and/or generics cannot be manufactured tomorrow in any available equipment . It will take time as the process and the facilities have to be approved. Processes to manufacture products just cannot be fitted in any available equipment. On top of it US does not have much of any raw materials needed for the drugs. Processing methods, equipment centric or process centric, have to be tested. Drug efficacy has to be tested. All of the above issues have to be dealt with and addressed.

Companies interested in reducing/alleviating drug shortages and bringing pharma manufacturing to USA should be carrying the baton from product identification, process development, their commercialization and distribution. They have to transition from “equipment centricity” ⁽¹⁰⁾to “process centricity” ⁽¹¹⁾based model for the API and their formulations. Village ^{(14, 15, 16)}would have to be involved. This can happen by as stated earlier by capitalizing on mutual social behavior of chemicals ^{(14, 15, 16, 17)}, proper unit operations ⁽¹⁸⁾ and incorporating “process centricity” ⁽¹¹⁾. It will be able to accommodate variable volumes to meet patient needs in a properly designed plant.

Simply said pharma’s marriage and addiction to “equipment centricity” ⁽¹⁰⁾ has been insurmountable and inseparable as significantly less effort is needed to commercialize a product. Had the chemical/pharmaceutical industry been “process centric” ⁽¹¹⁾ things would have been different. It would have had the agility to produce many different products with minimal investment. It is possible that the industry would not have gone “offshore” as USA would have led the manufacturing technology knowledge curve.

CDMOs (contract development and manufacturing organization) and equipment suppliers will resist the suggested shift to “process centricity” ⁽¹¹⁾ based manufacturing. For their success they will have to support “process centricity ⁽¹¹⁾. Since CDMOs rely on “equipment centricity” ⁽¹⁰⁾ there should not be any surprise if US based CDMOs move overseas. It is time for pharma to consider alternate business model if it wants to bring pharma manufacturing to the largest market, USA.

FDA will have to reconfigure itself and its approval processes for NDA (new drug application) and ANDA (abbreviated new drug application) by reducing their approval times to 90 days ⁽¹⁹⁾. Environmental and other regulatory approval times will have to be reworked. Every “K Street” ⁽²⁰⁾ residents would be an influencer. Legislators will have to participate in bringing manufacturing home by creating a FOUR STATE model and rejuvenating “Puerto Rico” ^(21,22)type model. It will be an added opportunity to bring jobs home.

Companies (pharma and Pharmacy Benefit Managers (PBMs) will have to guarantee product quality and would have to accept sever penalties for any and every deviation ⁽¹⁹⁾. Companies will have to have total complete knowledge and command of the production and distribution process. Since every NDA and ANDA drug is FDA approved drug tiers ⁽²³⁾ have to go. They artificially raise prices. Direct sales to patients have to be allowed. Price, quality and drug efficacy based competition is the best way to reduce shortages.

Unlike the past efforts that have resulted in nothing a collective thought through effort needs to be made. There will be resistance from every vested interest.

Recent announcements by Eli Lilly ⁽²⁴⁾ $27 Billion, Johnson & Johnson ⁽²⁵⁾ $55 billion, Novo Novartis ⁽²⁶⁾ $23 billion are “equipment centric” ⁽¹⁰⁾ projects for their brand products. These are not going to be commercial at least for the next 4-5 years and will not produce products to fill tariff related immediate needs. Once patents for their drugs expire these investments could become the “white elephants” of no value looking for home.

Simply said pharma’s marriage and addiction to “equipment centricity” ⁽¹⁰⁾ that has been inseparable and insurmountable needs to change. My conjecture is that “process centricity” ⁽¹¹⁾effort will be a “win-win” situation for the companies and a BIG win for the patients. Task is going to be challenging. US has never shrugged from any challenge. Let us be brave and get going.

Girish Malhotra, PE

EPCOT International

References:

1. U.S. Pharmaceutical Statistics

2. Woodcock, Dr. Janet: SECURING THE U.S. DRUG SUPPLY CHAIN: OVERSIGHT OF FDA’S FOREIGN INSPECTION PROGRAM December 10, 2019

3. Phlow Corporation Pharmaceutical Technology July 16, 2020

4. DOD Awards $69.3 Million Contract to CONTINUUS Pharmaceuticals to Develop US-based Continuous Manufacturing Capability for Critical Medicines January 15, 2021

5. API Innovation Center

6. BUILDING RESILIENCE into the Nation’s MEDICAL PRODUCT SUPPLY CHAINS National Academies of Sciences, Engineering, and Medicine, 2022

7. Malhotra, Girish: Has US lost its Business Acumen, Creativity and Imagination for its Healthcare Needs? Profitability through Simplicity, June 6, 2022

8. EO 13588 Reducing Prescription Drug Shortages October 31, 2011

9. EO 13944 Combating Public Health Emergencies and Strengthening National Security by Ensuring Essential Medicines August 6, 2020

10. Equipment centric https://images.app.goo.gl/Qi2UZKqu4qHdLWvu6

11. Malhotra, Girish: Process Centricity is the Key to Quality by Design, Profitability through Simplicity April 6, 2010

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

13. Sheldon R.A. The E factor 25 years on: the rise of green chemistry and sustainability, Green Chemistry

14. Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter May 2022

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

16. 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

17. Malhotra, Girish: Sociochemicology, May 30, 2013

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

19. Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability, Profitability through Simplicity, December 6, 2019

20. K Street

21. Malhotra, Girish: US’s Self Sufficiency for Generic Drugs: A Supply Dilemma and Potential Solutions, Profitability through Simplicity, March 31, 2022

22. MacEwan, Arthur: The Effect of 936 May 2016

23. Understanding Drug Tiers Accessed October 22, 2023

24. Eli Lilly April 14, 2025

25. Johnson and Johnson April 14, 2025

26. Novartis April 14, 2025

Sociochemicology: Redefining Chemical Process Design for Efficiency and Sustainability

2025-02-26T12:18:00.005-05:00

In the ever-evolving landscape of fine/specialty chemical and pharmaceutical manufacturing, efficiency, sustainability, and cost-effectiveness are paramount. Traditional process design often relies on incremental optimizations, overlooking the inherent behaviors of chemicals in reaction environments. However, there exists an underutilized approach—Sociochemicology—that capitalizes on the mutual interactions of chemicals and processing equipment to drive process simplification, manufacturing innovation, and ultimately, 'Net Zero' emissions.

What is Sociochemicology?

Sociochemicology strategically harnesses the physical properties of chemicals (both used and produced), their interactions with solvents, and the processing environment to achieve efficient and sustainable manufacturing. Instead of merely scaling up lab-scale reactions into existing process equipment, this approach exploits reactant properties and equipment capabilities to enable highly efficient, near 'Net Zero' chemical synthesis.

Core Principles of Sociochemicology:

· Maximizing Process Yields: Leveraging inherent chemical behavior and unit operations for efficiency.

· Eliminating Unnecessary Steps: Understanding how reaction components influence one another to streamline processes.

· Optimizing Equipment Utilization: Tailoring process conditions to align with the natural behavior of the chemicals.

· Integrating Cross-Industry Equipment: Adapting machinery from other industries to enhance synthesis for APIs and fine/specialty chemicals.

Why is Sociochemicology Important?

Current chemical and pharmaceutical manufacturing methods often involve excessive complexity, leading to inefficiencies, waste, high solvent use, and elevated costs. By applying Sociochemicology, manufacturers can:

· Reduce solvent usage and energy demands.

· Enhance reaction conversion yields even in existing processes.

· Improve sustainability by designing processes that naturally mitigate unwanted byproducts.

· Reduce capital expenditures by developing inherently efficient processes that require fewer resources.

Real-World Applications:

While Sociochemicology is not widely recognized as a formal concept, its principles have been unknowingly employed in many successful industrial processes. By deliberately applying these principles, companies can improve existing processes and design inherently efficient, environmentally sustainable ones from the outset.

For example, in API manufacturing and fine/specialty chemicals, understanding reactant interactions can significantly reduce solvent usage and improve overall process efficiency.

The Path Forward:

Despite its potential, Sociochemicology remains largely absent from mainstream chemical engineering discourse. This needs to change. As sustainability and cost pressures mount, the industry must embrace innovative frameworks that work with the natural tendencies of chemicals rather than against them.

For in-depth case studies and examples, detailed discussions are available in various references (see below).

Join the Conversation:

This is not just a theoretical framework—it is a practical approach that can reshape manufacturing. Let’s discuss how it can apply to your processes. Reach out and join the conversation via email: girish@epcotint.com or LinkedIn.

Let’s challenge conventional thinking and rethink chemical manufacturing!

Girish Malhotra, PE
EPCOT International

Girish Malhotra has been advocating process simplification and efficiency in chemical and pharmaceutical manufacturing for over five decades. With hands-on experience, he developed the concept of Sociochemicology to offer a practical, efficiency-driven alternative to conventional process design.

References:

1. Malhotra, Girish: Sociochemicology, May 30, 2013

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

3. 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

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

5. Profitability through Simplicity

An Update: Artificial intelligence in Pharmaceutical/Chemical Process Development, Manufacturing & Net Zero [Post of March, 31, 2023]

2025-02-14T13:36:00.002-05:00

In recent years talk of AI (artificial intelligence)^(1,2) has picked up speed and progressively been touted as the methodology/technology to go to for new products, manufacturing process technology development, quality, supply chain, and inventory management etc. for the active pharmaceutical ingredients (API) and fine/specialty chemicals. When fully developed and incorporated, it is suggested and expected to be the salvation of almost every current shortcoming. I have not heard much about the use of AI based applications in the pharmaceutical products and fine specialty chemicals, if it is happening.

This post is an update on my last post on the subject ⁽³⁾. There is no financial relationship with any “for profit” and non-profit” organization. We all know that API and fine/specialty chemicals are organic chemicals that have similar skeletal structures and manufacturing processes. The only difference is that one set enhance life style and the other extends/prolongs life. Many are suggesting value of AI in the new pharmaceuticals discovery and/or their manufacturing. I wonder how much of own monies has been invested or spent in R&D and manufacturing by who are suggesting the perceived/resulting benefits. Are there verifiable examples? If any of the pharmaceutical companies are exploring AI applications, they are not being discussed in open forums.

Application/inclusion of AI in pharmaceuticals is possible and it can happen by taking one step at a time. Since the pharmaceutical manufacturing is regulated, my conjecture is that what all is being practiced today and is in the pipeline will not change for the brand as well as the generic drugs. Related expense is too high and no business is going to absorb it and/or pass it on to the patients. Potential application of AI to process quality and manufacturing process control is suggestive that our universities have done an inadequate job of training process designers. Every AI proposed manufacturing specific application will have to be ROI justified and tested especially if it impacts manufacturing. Regulatory approval could be a deterrent.

New Product/Drug Identification:

AI based new drug product scouting for a disease is a possibility. Someone has to pay for the effort. No one knows the time or the investment AI route will take. Time and expense for AI based effort has to be lower that the current effort. Someone will have to take a leap of faith. If it takes same as the current time and money, AI based effort will fizzle out.

Product Manufacturing Process:

Once a potential product is suggested/selected by AI or a current method, the real task of taking the identified product to commercialization begins. If the companies stay with their current practices and methods ⁽⁴⁾ nothing will change and companies will not achieve Net ZERO ⁽⁵⁾. AI recommended methods will have to be better and economic.

I thought it would be a great idea to ask ChatGPT ⁽¹⁾ what does it know about sociochemicology ^(5,6,7). It could not give any answer. On sharing a video link ⁽⁶⁾ that briefly explains sociochemicology, it was very quick to understand and share its value in development of efficient chemical processes and achieving “Net Zero ⁽⁵⁾ ” in pharmaceutical and specialty chemicals. Its search capabilities are impressive.

I decided to check out what AI can suggest for process chemistry and manufacturing routes for few chemicals I am very familiar with. I tested ChatGPT⁽¹⁾ and Perplexity⁽²⁾ by asking my credentials. “Results were interesting. They accurately identified few things but could not give details. I was told by others that AI it is constantly learning and it becomes better by answering questions. I asked additional questions and it cited some of my work.

I queried ChatGPT ⁽¹⁾ about the following chemicals.

Saccharin:

I asked ChatGPT ⁽¹⁾ about the manufacture of saccharin. It gave me a process practiced by Monsanto which was abandoned in late sixties. When reminded that there is an alternate process starting with phthalic anhydride, it gave me its process details. It was significantly different and complex chemistry compared to what we practiced which was phthalic anhydride based also. It surprised me as I was involved with scale-up and manufacture of our chemistry, a continuous process that operated year round with scheduled shut downs for maintenance etc..

Omeprazole:

I asked about Omeprazole chemistry. ChatGPT ⁽¹⁾ does not suggest how to execute the its chemistry. Chemistry outlined in USP 7,227,024 ^(8,9)is an alternate process. Compared to ChatGPT ⁽¹⁾ suggested process ‘024 based process’s execution is very simple and can be produced using a continuous process. It includes some of the sociochemicology ^(6,7)based teachings.

Metformin Hydrochloride:

ChatGPT ⁽¹⁾ suggests a process chemistry. It does not suggest its manufacturing process. A quick review of this chemistry suggests it can be a challenge to commercialize. An alternate chemistry and method ^{(10, 12)} suggest a safer continuous manufacturing processing.

AI suggested chemistries for the above three products are not economic as better and economic processes were/are commercial. Use of sociochemicology ^(6,7) is profusely incorporated in each of the above actual and suggested processes ^(8,9,10,12) .

Future Path:

Considering pharma’s current commercialization and manufacturing practices, about 60+ years old ^{(10, 11, 12)}, each of the following that could be AI based will have to be considered and evaluated for their economic and commercial merit.

· If the drug discovery is going to take same/similar time like the current time and path, my speculation is that all the euphoria and the related investment in AI could be lost. It can provide chemistries for the identified product but I am not sure it can generate and economic processes. This observation is based on the three chemistries I inquired about. Would AI be able to suggest the most optimum chemistry and manufacturing processes for the new molecules is not known? Even if it does, each would need a thorough review and it will have to be tested.

· For inclusion of AI each company will have to decide its commercial details e.g. business model, economics, investment, operating strategies etc.. One would expect that village’s (chemists, chemical engineers, purchasing, maintenance, accounting) journeyto “net Zero” ^{(6, 12,13)} would begin when a chemical molecule is identified and/or speculated as a potential drug candidate. If a pharma company decides to fit the process in its available equipment ⁽⁴⁾, its manufacturing methods will stay 60+ years old ^{(10, 11, 12, 13)} and it will not achieve “net zero ⁽⁵⁾”.

· If companies want economic “net zero”⁽⁵⁾ processes they will have to exploit mutual behavior of chemicals, sociochemicology ^{(6, 7)} and Real Information/Intelligence (RI) ^{(5, 6, 7, 10, 11, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23)} and exploit capabilities of the processing equipment that are available and being used in other manufacturing industries ⁽⁵⁾. It is interesting to note that each process chemistry tells us about the chemicals used and produced. Their sociochemicological behavior can be capitalize on to create excellent manufacturing processes ^{(10, 11, 12, 23)}. It seems somehow pharma industry has not been capitalizing on this information. Their inclusion and consideration along with use of modular processes ^{(10, 11, 12, 23)} can deliver excellent Net Zero ⁽⁵⁾ processes.

· Many are suggesting application of AI for e.g. inventory control, quality control, manufacturing efficiencies, process control and supply chain etc. in pharma. It is difficult to postulate the impact of new applications. I don’t know whether if any of the AI based application suggesters have invested their own money to test their applications in pharma’s current manufacturing operations and received regulatory approval. Considering regulatory challenges this could be hard.

If pharma companies decide to bring their manufacturing from antiquity to today and move forward, AI might be of value. However, each company will have to decide their incorporation based on cost, value and regulatory interference. Let us see where does AI lead pharma in the next two years. It would be worth re-visiting the topic.

Girish Malhotra, PE

EPCOT International

1. ChatGPT https://chatgpt.com

2. Perplexity https://www.perplexity.ai

3. Malhotra, Girish: Artificial intelligence in Chemical Process Development, Manufacturing & Net Zero, Profitability through Simplicity, March 31, 2023

4. Malhotra, Girish: Square Plug In A Round Hole: Does This Scenario Exist in Pharmaceuticals? Profitability through Simplicity, August 17, 2010

5. Malhotra, Girish: NET ZERO for Active Pharmaceutical Ingredient & Fine/Specialty Chemicals: Nondestructive Creation, Profitability through Simplicity, November 7, 2024

6. Malhotra, Girish: Sociochemicology , May 30, 2013

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

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

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

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

11. 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

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

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

14. Malhotra, Girish: Profitability through Simplicity

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

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

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

18. McGraw Hill Chemical engineering Series https://www.book-info.com/series/McGraw-Hill+chemical+engineering+series.mobi.htm

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

20. Gasteiger J.: Chemistry in Times of Artificial Intelligence ChemPhysChem 2020, 21, 2233– 2242 Accessed March 21, 2023

21. Perry, J. H. et.al. Chemical Engineer’s Handbook Fourth Edition: McGraw-Hill Chemical Engineering Series, 1963

22. Levenspiel, O: Chemical Reaction Engineering, John Wiley & Sons 1999

23. Malhotra, Girish: Process Simplification: Is the Best Answer: New Terminologies or the Application of Fundamentals? Profitability through Simplicity, December 14, 2024

Process Simplification: Is the Best Answer: New Terminologies or the Application of Fundamentals?

2024-12-14T13:50:00.001-05:00

Lately new terminologies e.g. flow chemistry, continuous manufacturing, plug flow reactors, process intensification to name a few have become the new way or the buzz words to develop, solve and/or commercialize active pharmaceutical ingredients (API) and some fine/specialty chemical processes. I am not sure everyone understands them and whether these will create economic and environmentally friendly processes. Based on my experience, names do not create excellent processes but fundamental understanding and their application heat and mass balance, physical and chemical properties, reaction kinetics, thermodynamics and mutual behavior of chemicals used and produced have and going forward will continue to assist. To develop and commercialize any chemical process the chemist and the chemical engineer has to have complete command of the physical properties and their mutual behavior and interaction of chemicals with the processing equipment i.e. the “sociochemicology” ^{(1, 2, 3, 4, 5, 6, 7, 8)}.

Questions raised in the following analysis could and/or should be asked from the onset for each product and process that is commercialized. My observation is that each process development chemist and chemical engineer has to act as a “Village” ^{(3, 7)}, spend time and understand the chemistry and chemical engineering of each reaction that is commercialized. Such an effort has and will continue to create optimum processes that are very profitable at active pharmaceutical ingredient stage (API), fine/specialty chemical and are also environmentally friendly. These practices/learnings are also applicable to formulations. I have no vested interest and/or relationship with any nonprofit and or nonprofit organization.

Following is my analysis and observations related “A Continuous Process for Manufacturing Apremilast. Part I: Process Development and Intensification by Utilizing Flow Chemistry Principles ⁽⁹⁾. There are 23 authors and some of them have left Amgen before the article was published.

Figure 1: Schematic of production of Otzela

The following abstract gives authors perspective. However it raises multiple questions at least for me.

Abstract:

Herein, we report the development of an integrated continuous manufacturing (CM) process for the penultimate step in the synthesis of apremilast, the drug substance (DS) of the commercial product Otezla. This development effort was motivated by the desire to create an alternative manufacturing configuration with a significantly smaller footprint and to impart intensification resulting in a more sustainable process. Three primary aspects of the existing batch process had to be addressed to achieve this goal:

(1) long reaction time

(2) low solubility of the starting materials and intermediates in the primary reaction solvent (THF)

3) extensive postreaction unit operations contributing to significant solvent waste

Key features of the intensified CM process include the following:

· use of a plug-flow reactor (PFR) to access increased reaction temperatures (130 °C), resulting in a shorter reaction time to reach the target conversion (>18 h in batch to 30 min in flow);

· replacement of THF with DMSO to solve solubility issues related to starting materials and reaction intermediates, and

· development of a multistage continuous MSMPR (mixed-suspension, mixed-product removal) crystallization upon addition of water as antisolvent to the end-of-reaction stream containing apremilast.

This intensified CM process reduced the number of primary unit operations from nine to three (67% reduction). Moreover, it can be executed at commercial scale using a compact manufacturing skid. Part I of this manuscript series highlights the effort to develop the novel process and the corresponding kg-scale demonstration of the optimized process. Part II describes the process characterization and development of a control strategy in detail to ensure process efficiency and robustness of the small-footprint continuous skid.

Table 1: Abstract

Questions:

1) Global sales of Otezla were ~2.2 billion dollars in 2023 and are decreasing. U.S. Patent 7,427,638 expires September 2025 and has been extended ⁽¹⁰⁾. This would make the product generic and its global sales, dollars, would be an unknown. Most likely they will decrease. Companies other than Amgen would produce the product. Why there was no effort made to improve the chemistry and manufacturing process before the product was commercialized. Since the patent ‘638 does not expire till 2028 my question is “Is any of the information published confidential?” I am not sure about the intent of this paper ⁽⁹⁾.

2) Based on dosage (2 tablets of 30 mg per day) and the current selling price $6,000 per month, annual API needed to serve the global market would be about 750 kilograms per year. What would be the generic sales is an unknown?

3) This article claims the process to be a “continuous process” and this raises many questions when there is an established definition of “Continuous Manufacturing ⁽¹¹⁾”. It clearly states continuous usually means operating 24 hours per day, seven days per week with infrequent maintenance shutdowns, such as semi-annual or annual. In hours this would be close to 7,400 hours per year taking about 1000 hours for maintenance.

Based on published sales and selling price of Otzela ⁽¹²⁾ total production of Otzela API would be about 750 kilograms per year. If it were to be produced using a continuous process ⁽¹¹⁾ its production rate would about 0.1 kilo per hour. This would be uneconomical. Every company will produce their product using batch a process. My best estimate is that production of Otezla has to be a batch process and the product would be campaigned. Claiming that Otzela production is a “Continuous Process” is an outrageous claim when it is produced using a batch process. World would like to have a clear explanation from Amgen for its claim. If a batch process is called a continuous process then it suggests that there is total disregard and mockery of established definitions which have been accepted by American Chemical Society, publisher of this article and American Institute of Chemical Engineers.

Even if the Apremilast (Otezla) yearly production doubles up when the product becomes generic, with the current landscape of API manufacture there will be two options. Fit the process in existing equipment that is most suitable or design a dedicated plant for its production. In the latter case, the equipment will sit idle when not used to produce Otzela. Company will have to decide. Having a dedicated equipment for this product would be an unproductive investment.

In my career I have developed, commercialized, managed fine/specialty chemicals, older cousins of API operating at production rates of about 100 Kilos/per hour to 1,800 kilos per hour operating about 7,200 hours per year. Batch products had annual production that ranged from 100,000 to 400,000 kilos per year. Many of these batch produced products were campaigned in designated equipment. I am not sure about the euphoria or advantage behind calling a batch production a continuous production. I am sure everyone would like to know.

3) Based on number of authors (TWENTY THREE) ⁽⁹⁾ and their time, my conjecture is Amgen has spent in excess of FIVE million dollars. I wonder what is the return on this investment. Based on the article I am not sure if the process in its current state is ready for commercialization. Additional manpower i.e. investment would be needed for the process that still needs to be developed, tested using alternate equipment and commercialized. If an alternate process is commercialized, there could be significant changes from the original process. That could mean the final production process would need necessary regulatory approval.

I don’t believe Amgen is ready to invest that money when it knows that by late 2028 this product will be a generic. With Amgen’s patent expiring in February 2028 ⁽¹⁰⁾ Amgen’s strategic advantage would be anyone’s guess. All this work raises questions about the rationality of this paper (9) and related work. Fundamental question is why Celgene did not do the necessary work before the product was commercialized. What is the rationale and incentive for the current work and its “return on investment”?

4) Why did Celgene/Amgen wait this length of time (four or five years before the patent expiration) and did not do the necessary work to reduce solvent use from the onset of its commercialization? It seems there was no effort to get to “Net Zero” ⁽¹³⁾.

5) This paper ⁽⁹⁾ suggests use of alternate equipment. Does Amgen know what that alternate equipment is and has it been tested. My conjecture is that significant work would be needed to prove the viability of the suggested equipment. Would/are the alternate equipment that have been available and traditionally used in fine/specialty chemical industry be considered ^{(1, 3)}? It is possible that chemists and engineers at Amgen may not be familiar with such equipment.

6) Some of the raw materials are from the supply houses i.e. Sigma Aldrich, rather than from commercial suppliers. This suggests that Amgen is still depending on high purity raw materials that are high priced vs. commercially available raw materials.

7) I wonder if Amgen personnel had the time to define the solubility and other physical properties and the mutual interaction of the chemicals used, intermediates and produced. This information is critical and should have been developed and used in the development of an optimum process. They could have developed the necessary data like we had/have done for the chemicals we commercialized ^{(1, 2, 3)}. Yes it is a challenge but the rewards are there as the information can be used to trouble shoot the process. Before the Internet came around suppliers readily provided chemical property data ⁽¹⁴⁾.

8) It is very interesting to note that Amgen suggests that the reaction time was reduced to about 30 minutes from 18 hours. Question needs to be addressed how and why this was not addressed before NDA (new drug application) was filed. Same question holds for reducing number of unit operations, long reaction time and low solubility of the starting materials and intermediates in the primary reaction solvent (tetra hydro furan, THF) and extensive postreaction unit operations contributing to significant solvent waste. If Amgen is still using their inefficient process, then what and where is its environmental responsibility. Did developers ever think and/or consider environmental conservation ⁽¹³⁾?

9) There is mention of PFR (plug flow reactor) use. Has Amgen used such devices in the manufacture of any of its APIs? Has Amgen considered other equipment that is commercial and is used in the manufacture of fine/specialty chemicals ^{(1, 2, 3, 7)}? Are the chemists and chemical engineers at Amgen familiar with use of back mix flow reactors? They have been and are used in the manufacture of fine/specialty chemicals, older cousins of APIs.

10) Lots of “fancy verbiage” has been introduced by the pharmaceutical industry to state that is cut above its older sibling fine/specialty chemical industry (e.g. substoichiometric, process mass intensity etc.). No matter what the pharmaceutical industry claims 2+2 will always be 4, Sun is always going to rise in the East and male of the species is will not be pregnant. Introducing new verbiage is not going to change established facts. Have we forgotten simple verbiage like mass balance, heat of reaction, value of mutual behavior of chemicals and chemical reaction kinetics etc. to develop and simplify the chemical processes. Another term is “flow chemistry”.

11) Searching “flow chemistry” does not give any clear definition of what it means. When chemists and chemical engineers are asked about the “flow chemistry” or “continuous process” ⁽¹¹⁾ they are not able to give differentiating definition of either. What they recite is not any different from the established definitions of “batch process” ⁽¹⁵⁾ or “continuous process”⁽¹¹⁾. If “flow chemistry” is the new way for all of the chemical reactions then the question is what were the chemists and chemical engineers doing/teaching who built the foundation of the chemical and pharmaceutical industry. They created and commercialized very many useful processes and products which included disease curing molecules called API ⁽³⁾. May be my generation and authors of McGaw Hills Chemical Engineering Series ⁽¹⁶⁾are all wondering what does it mean. New verbiage does not mean anything if one does not understand the fundamentals.

12) One very basic question is “if what has been suggested in some of the articles is an improved and efficient process” then why are inefficient processes was commercialized and monies are being invested in equally cumbersome process where specialized equipment might be needed and it might not be used to produce any other product.

Based on reviewing the paper I have serious doubts that any further work would be done to improve and commercialize this chemistry especially if the process needs regulatory approval. If Amgen just publishes the data it created it could be of value for future generations.

COMPARISON OF SIMILAR CHEMISTRIES:

When developing a process it is critical and necessary that the “Village” ^{(1,2,3, 5)} be involved from the onset. Literature gives us lots of knowledge for free. Following is a comparison of two chemistries. Reason for the examples is “did Celgene do sufficient literature search to explore prior art?” Stoichiometry USP 7,109,203 ⁽¹⁷⁾ and a similar chemistry that has been commercial since 1970 tell us that for Product “X” no effort was made from the onset to have an excellent process. Product “X” operated about 7,200 hours per year for many years. Product from patent ’203 would require significant work prior to its commercialization.

Figure 2: USP 7,109,203 NOVARTIS

Mole Ratio	Patent ‘203	Product “X”
Aromatic Amine	1.0	1.0
HCl	14.0	2.4
NaNO₂	0.97	1.1
SO₂	25.9	4.5
Solvent	Acetic acid	None
CuCl₂	0.50	0.068

Table 2: Comparison of two steps of a reaction schemes

A review of the patent ‘203 illustrates that 2-chloro-4-bromobenzensuflfonyl chloride is produced in a single pot and processed further. One can see that the process for Product “X”, similar chemistry, is synthesized in two steps in a very eco-friendly back mix flow reaction process. It is difficult to understand use of acetic acid in ‘203 as a solvent as it will have to be neutralized and takes up productive reactor space. Purpose of the illustration is that proper process can be developed and commercialized if an effort is made.

Again the emphasis is that lab synthesis shows the pathway and it can be complex. Breaking down the reaction for 2-chloro-4-bromobenzensuflfonyl chloride in two steps simplifies the process and directs us to create an ecofriendly process. However, one has to recognize that breaking the reaction in two steps is not feasible for every reaction in the lab. It can only be envisioned and tested by a chemist and/or chemical engineer who is familiar and experienced in creating such processes.

In addition chemists and chemical engineers have be familiar with other process schemes like “back mix flow reactors” ^{(12, 13 )} and what other methods across the industrial fields are available and can be used in the manufacture of products under discussion.

Product “X”’s reaction scheme and similar reactionshave been commercially practiced in the fine/specialty chemical industry older cousin of API for more than fifty years ^{(1,2,3,4,5,7,13).} Some have been briefly reviewed ^{(5, 7)}. We have to recognize and acknowledge that we are taught principles of chemistry and chemical engineering but are not trained to create processes that have minimum ecological impact. This comes from “hands on experience” when chemists and chemical engineers who are involved in scale up and process design have the knowledge and the command of every nuance of sociochemicology ^(6,16)reaction kinetics, solubilities etc. of the chemicals involved and produced.

By calling the same widget by different name is not going to make it a new widget or technology i.e. flow chemistry. It just tells us that we have not paid attention to the history and fundamentals of chemistry, chemical engineering and the resulting technologies that have been practiced at least for the last 80 years.

Naming fundamentals as stated above whose ancestors have been well practiced since mid-nineteen sixties does not make them new. Using an inline static mixer or adding a fluid at the inlet of the pump improves mixing and ensuing reactions is capitalizing on creativity and imagination ^(1,2,3). One has to admit and recognize that without “flow” of fluids no reaction, batch or continuous, will ever takes place. Thus “Flow Technology” is nothing new, at least in my book.

It is necessary that the “Village” ^(1,3) be involved from inception and development of the process. Without such an effort we will continue to “after thought” process improvements that may never be commercialized especially for the manufacture of brand APIs.

Purpose of the post is not to find faults of Amgen or any other company but we all should collectively apply the fundamentals of science and engineering technology, do the right things to have economic and environmentally friendly processes. We have it all what it takes. Let us unleash our creativity and imagination. It is time.

Girish Malhotra, PE

EPCOT International

References:

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

2. 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

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

4. Malhotra, Girish: Capitalizing on Mutual Behavior and Chemical Reactivity of Chemicals, Profitability through Simplicity, May 29, 2013

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

6. Malhotra, Girish: Sociochemicology May 30, 2013 Accessed January 13, 2023

7. Malhotra, Girish: Profitability through Simplicity

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

9. Hsieh, Hsiao-Wu et al: A Continuous Process for Manufacturing Apremilast. Part I: Process Development and Intensification by Utilizing Flow Chemistry Principles https://doi.org/10.1021/acs.oprd.3c00400 Org. Process Res. Dev. 2024, 28, 1369−1384

10. Amgen wins patent appeal on Otzela (Apremilast) https://www.amgen.com/newsroom/press-releases/2023/04/amgen-wins-patent-appeal-on-otezla-apremilast Accessed November 20, 2024

11. Continuous Production/Manufacturing

12. AMGEN REPORTS FOURTH QUARTER AND FULL YEAR 2023 FINANCIAL RESULTS https://www.prnewswire.com/news-releases/amgen-reports-fourth-quarter-and-full-year-2023-financial-results-302055131.html Accessed November 27, 2024

13. Malhotra, Girish: NET ZERO for Active Pharmaceutical Ingredient & Fine/Specialty Chemicals: Nondestructive Creation, Profitability through Simplicity, November 7, 2024

14. Malhotra, Girish: Information Challenges for Product, Process Development and Process Design: A Reality Check, Profitability through Simplicity, April 10, 2011

15. Batch Production http://bit.ly/31dzpo3

16. McGraw Hill https://www.scribd.com/document/318719966/Docs

17. USP 7,109,203 Sulfonamide Derivatives Novartis AG

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

2024-11-07T11:05:00.002-05:00

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

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
Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter April 2022
Malhotra, Girish: Profitability through Simplicity
Levenspiel, O. Chemical Reaction Engineering, John Wiley & Sons Inc, 1972, Second Edition, Accessed December 20, 2020
Malhotra, Girish: Sociochemicology May 30, 2013 Accessed January 13, 2023
Shreve, R. Norris: Unit Process In Chemical Processing, Ind. Eng. Chem., 1954, 46 (4), pp. 672–672
Unit Operation, https://en.wikipedia.org/wiki/Unit_operation, Accessed July 11, 2017
Malhotra, Girish: Quick Review of Chemicals Related Process Development, Design and Scale up Considerations, Profitability through Simplicity, November 7, 2018
Process Technology
Wattco
Malhotra, Girish: Capitalizing on Mutual Behavior and Chemical Reactivity of Chemicals, Profitability through Simplicity, May 29, 2023
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
Malhotra, Girish: Analysis of API (Omeprazole): My perspective, Poster Session: Pharmaceutical Engineering, 2009 AIChE Annual Meeting, November 11, 2009, Nashville, TN
Malhotra, Girish: Art and Science of Chemical Process Development & Manufacturing Simplification, AIChE May 17, 2023
Malhotra, Girish: Considerations to Simplify Organic Molecule (API) Manufacturing Processes: My perspective, Profitability through Simplicity, April 20, 2019.
Malhotra, Girish: Square Plug In A Round Hole: Does This Scenario Exist Pharmaceuticals?, Profitability through Simplicity, August 17, 2010
Malhotra, Girish: Information Challenges for Product, Process Development and Process Design: A Reality Check, Profitability through Simplicity, April 10, 2011
Schrader, Ulf: Operations can launch the next blockbuster in pharma, McKinsey & Co., February 21, 2021
What is Net Zero? McKinsey & Company , October 25, 2024
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:

2024-10-02T17:00:00.008-04:00

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

Process Simplification and Net Zero: Capitalizing on Physical and Chemical Properties of Reactants and Intermediate

2024-08-20T10:02:00.003-04:00

Fine/specialty chemicals that extend life are labeled as active pharmaceutical ingredients (API) whereas the same class of chemicals that enhance life style are just called an additive. An excellent example is Dimethyl Fumarate. Initially used as a biocide found its use as a cure for multiple sclerosis. Manufacturing processes for both are exactly the same but the selling price as a drug is more than 1,000 times the selling price as a biocide. Exact same fundamentals of chemistry ⁽¹⁾ and chemical engineering ⁽²⁾ are applied to the manufacture of each category of products. Major difference between the two is quality stringency and social perception of how each influences human life. They are priced accordingly.

Perspective presented on process chemistries and manufacturing processes is a joint effort with Dr. Charles Kausch ⁽³⁾ and is not influenced by any “for profit and/or nonprofit” organization.

Current Laboratory Developments:

From inception of organic chemistry to produce chemical synthesis chemists and chemical engineers test their hypothesis in the laboratory using round bottom flask or similar laboratory vessel that is fitted with an agitator and adequate provision for heating/cooling of the reaction mass. If any of the reaction ingredients are a solid at room temperature, a suitable solvent/s is/are selected and the chemistry tested at a temperature and conditions to demonstrate reaction feasibility. They quantify reaction conditions to obtain the highest yield. Their laboratory practices are scaled up for the commercial production of the products. These practices started over 80+ years ago and continue. Not much has changed.

Since most of the active pharmaceutical ingredients (APIs) and many of the fine/specialty chemicals do not have high yearly production volume to be produced year, they are produced using the existing equipment by modifying the process which is fitted in the existing equipment: reactors, pumps, heat exchangers etc. of varying size where necessary unit operations ⁽²⁾ can be executed to produce the desired product/s. Batch process (4) is the way. Continuous processes ⁽⁵⁾ are seldom used even if they could be used.

Current methodologies depend on using large amounts of inert solvent/s. As much as 50-70% of the reaction mass are solvent/s that are recovered and reused. This practice to develop processes and manufacture products has worked well for the last 80+ years and most processes are batch processes.

Any change to consider alternate processes e.g. continuous process ⁽⁵⁾ would be a significant shift. Involvement of village ^{(6,7,8 9,10)} would be necessary. To accomplish the needed change, it is possible that many companies might have to reconfigure their business model and manpower. This could be difficult to accept and adopt.

Why the current methods are used is a great question to ask? Answer is simple. Traditionally at universities we are taught how the reactions work. In the laboratory we are taught how to prove the manufacturing chemistry. At profit making organizations traditions taught at the universities continue. Once the process feasibility is proven, no or minimal effort is exercised is to improve them or look for alternates. Due to commercialization pressure, as the chemistry and synthesis method/s tested in the lab work, most seldom have the time to experiment with other synthesis/manufacturing strategies. As the saying go “if it isn’t broken don’t fix it” prevails.

However, current practices have a consequence. They have an environmental impact and lower equipment utilization^{(6, 7, 8)}. Equipment has to be cleaned for the production of the next or the same product to be produced in the same equipment. Even with solvent recovery and reuse processes have high environmental impact.

Pharmaceutical industry even after recognizing its environmental impact, in our estimation, has been a laggard in improving/lowering its environmental impact ^{(11, 12,13,14)}. If it wants to change totally, out of the box thinking and methods are needed.

Chemists and chemical engineers have to look and evaluate alternates to the current practices if they want to minimize environmental impact, improve asset utilization, improve profits and pass on savings to the users. Traditions are going to come in the way. If companies are able to sell directly to patients i.e. bypass the current distribution channels product quality assurance will be the highest priority. This would also lead to manufacturing technology innovation. However, likelihood of direct sales to patients and ensuing innovation will be resisted and impeded by the current distribution channels, regulators and may be by the manufacturing companies.

For change to happen practices of the last 80+ years need to be modified. Thinking that if it is not broken it does not need to be fixed has to go. We have to apply the teachings and commercialize them differently. Creativity and imagination would be needed ^(6,7,8,9,10).

What all has been discussed above is being used in additive sector of the fine/specialty chemicals. It needs to be applied to the API and their formulations also. Few of the processes that have been and are commercial have been discussed ^(6,7,8,9,10). Expanding and incorporating these methodologies in the API sector have the following benefits.

1. Reduce environmental impact

2. Improve profitability

3. Reduce commercialization time

4. Improve asset utilization

Continuous effort is needed. We do not need to procrastinate. Another significant benefit of the suggested practices are they can reduce drug shortages and improve affordability. All these could lead to higher sales.

Figure 1: Reaction chemistry for the preparation of Diclofenac

Methodology:

Alternate method/s to develop a process involves capitalizing on physical and chemical properties of each chemical produced and used in a reaction, reaction mechanism, heat of reaction and reaction kinetics ^{(15, 16)}. In the cases discussed ^(6,7,8,9,10) their influence has been exploited to minimize the reaction time and achieve high process yield. Use of alternate equipment ^{(9, 17,18)} that is commercial and is being used in chemical and other manufacturing industries is important. Due to tradition of not exploring alternate application of technologies from other industries and the value derived from these exploitations is mostly overlooked.

Diclofenac synthesis ^{(19, 20)}:

Through discussion of Diclofenac synthesis some of the alternates possibilities that we believe will simplify manufacturing are reviewed. These as usual will have to tested and even modified for better results.

Figure 2: Physical Properties of reactants in the production of Diclofenac

Having compiled the physical properties of the starting and intermediate products one can evaluate and consider if the solubilities and melting point of the chemicals can be capitalized on.

For the first reaction step, formation of 2-Chloro-N-phenylacetamide (a liquid), chloroacetic acid is a solid at room temperature and is low melting point compound. This presents opportunities. It could be metered in as a liquid above its melting point. A suitable organic that could be used as a liquid/solvent could also be used. This organic solvent would be the solvent of choice.

Sequential reaction loops like illustrated in Figure 3 can be used to produce diclofenac. Instead of using reactors chemists and chemical engineers need to consider alternate equipment ^{(17, 18)}that can be used as an inline reactor. Generally the equipment mentioned are not traditionally used as reactors but have been used since early 1970s in place of reactors. Cost of the suggested equipment are significantly lower, as much a 50%, than the traditional equipment used in the chemical industry e.g. microreactors that are being touted for similar use. There has to be economic justification for the equipment to be used. Evaluation and justification is very dependent on knowledge and creativity of the chemists and chemical engineers involved in process development and design.

Sequence of addition of reactants is dictated by the reaction kinetics. Methods discussed can be applied to every reaction step. Due to batch nature of the laboratory process most are generally not able to practice that. Such methodologies have been practiced time after time by astute and creative chemists and chemical engineers but seldom mentioned as most of the discussion is on batch processes that are laboratory based. In-line heat exchanger/Reactor, preferably an electric sourced would be preferred. Addition of each reactant addition Solvent selected has to be such that it will facilitate each reaction step. Preferred temperature of addition of each reactant should be above their melting point. This allows the precise stoichiometric control of the process. Solvent may not be separated from the reaction mass till completion of all of the reaction steps leading to isolation and purification of diclofenac.

Aluminum chloride can be added two ways. It can be slurried in a solvent and added as a paste or a suspension can be made using a suitable thickener and could be metered in. This would be similar to use of thickeners in the water/solvent based coatings ⁽⁶⁾.

All of the suggestions above are an effort to simplify the manufacturing processes. Compared to the traditional ways to execute the chemistry above methods present a different way of execution of chemistry. Cross fertilization of methods that work in other manufacturing processes need to be explored. Simplest thing we all can say is “IT CAN’T BE DONE or NO” has to go. Skepticism will have to be overcome by testing each step and its execution. Based on successes of other products ^(6,7,8,9,10) every chemist and chemical engineer can extend the concepts to every chemistry the develop and commercialize. Creativity, imagination and outlier thinking would be needed.

Figure 3: Schematic of each in-line reaction steps.

Again, process and manufacturing technology innovation in API manufacturing and their formulations needs to move away from 80+ year old traditions/methods. Two obstacles will have to be overcome. They are “self-doubts” of chemists, chemical engineers and management at each company and “doubts” of drug regulators worldwide. Process innovation has to start and have support of each company’s village ^(6,7,8,9,10). Product quality has to be a must. Value of such collaboration has been proven time after time in almost every chemical related manufacturing except for API and their formulations . It is time for pharmaceutical manufacturing to come to 21^st century.

Girish Malhotra, PE

EPCOT International

Dr. Charles Kausch, Adjunct Professor

Lorain County Community College, Akron OH

References:

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

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

3. Dr. Charles Kausch

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

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

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

8. Malhotra, Girish: Research Report: Strategies for Improving Batch or Creating Continuous Active Pharmaceutical Ingredient (API) Manufacturing Processes, March 2017; AVAILABLE FREE

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

10. Malhotra, Girish: Profitability through Simplicity Accessed June 26, 2024

11. Net Zero Burke, J. What does net zero mean? https://www.greenbiz.com/article/what-does-net-zero-mean, May 2, 2019 Accessed April 27, 2021

13. Schrader, Ulf: Operations can launch the next blockbuster in pharma McKinsey & Company, February 2021

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

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

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

17. Process Technology

18. Plate & Frame Heat exchangers

19. Wang, L et. al. Six-Step Continuous Flow Synthesis of Diclofenac Sodium via Cascade Etherification/Smiles Rearrangement Strategy: Tackling the Issues of Batch Processing, Chemistry – A European Journal Accessed June 24, 2024

20. Chen F et. al. Method of Synthesizing Diclofenac Sodium US 2023/0234911 A1

USP 11,267,798 B2: Manufacture of Piperine (1) An Excellent Teaching Tool

2024-06-17T14:27:00.005-04:00

US patents that relate to fine/specialty chemicals are an excellent platform where their synthesis details are shared. Their manufacturing methods and details are left to the imagination of chemists and chemical engineers who take the synthesis route using unit processes ⁽²⁾ and appropriate unit operations ^(3,4) from the lab to the manufacturing floor. This tradition has been ingrained for the manufacture of fine/specialty chemicals that are used to enhance lifestyle as well as the chemicals that extend life. These are called active pharmaceutical ingredients (API) which are formulated to appropriate dispensable dose. However, there is a significant difference about the quality rigor each product has to follow.

Fine/specialty chemicals that enhance life style have to meet their quality standards. API manufacturing methods have to meet stringent quality standards that are approved by regulatory bodies. This is necessary as they are used to cure diseases. Altering their manufacturing process can require companies to prove product efficacy and that can be an expensive time and money process. As a result API manufacturing process improvements are stalled and or even might not happen. How the API manufacturing processes are scaled up depends on individual company. Most of the API manufacturing patents detail the synthesis route and share clues and if capitalized on can lead to a very economic and environmentally friendly process that has low emissions ^{(5, 6)}.

Reviewing in-process patent filings and granted patents teach ways to review/learn chemical process synthesis and their manufacturing practices ⁽⁷⁾.

The exercise here is not questioning the knowledge and skills of the people and/or the reaction scheme/process but how the information can be used to create simpler processes. Questioning and exploring what we do in the laboratory is and has been an excellent learning and gratifying process simplification tool, at least for me. I am sure others have similar experiences and come up with better and easier ways to simplify chemical synthesis and manufacturing.

Generally majority of the chemical synthesis processes are fitted in the existing equipment. This is due to speed to market especially after API regulatory approval. Chemistries outlined in the patents give us the reaction mechanism for every reactive process. We can capitalize on that knowledge to commercialize using most appropriate unit operations ^(3,4) an economic and environmentally friendly process ^{(5, 6)} and move away from the traditions of the last SIXTY PLUS years. Modular plants or equipment of the size used in pilot plants might be the answer as only select number of APIs have the volume to have dedicated plants. This requires re-evaluation of fine/specialty chemical and API business model. Due to profitability and constantly changing API landscape and regulatory hurdles only an outlier company would be willing to step up to the challenge. Perspective presented is my own and not influenced by any for profit and/or nonprofit organization.

Every reaction chemistry and synthesis process tells us how the product can be produced. Laboratory is its proving ground. Synthesis is demonstrated in the laboratory and commercialized by generally fitting it in the available existing equipment. This entails using excessive amounts of reactants and solvents. This is necessary for adequate mixing and heat transfer. Solvents, when feasible, are recovered and reused. As discussed later, creativity and imagination of the village ^{(8, 9, 10, 11)}for process simplification, reduced solvent use and the ensuing benefits need to be incorporated from the onset.

Chemistries outlined in the patents give us the reaction mechanism for every/most reactive process. We can capitalize on that knowledge to commercialize using most appropriate unit operations ^(3,4) an achieve our environmental obligations ^{(5, 6)}.

USP 11,267,798 B2 ⁽¹⁾, luck of the draw, perfectly outlines the reaction chemistry and steps for the production of Piperine. Writing the reaction steps (Figure 1) is necessary as it familiarizes everyone with the reaction chemistry and the process. Reaction intermediates and byproducts are identified. Based on their chemical nature, methods for safe handling and disposal can be selected. Stoichiometry shared in the patent is just an example of what has been used to create a product and generally are not optimum.

With creative application and combination of unit processes ⁽²⁾, unit operations ^{(3, 4)} and reaction kinetics ⁽¹²⁾ manufacturing process of piperine can be simplified. It is possible that the practitioner might have to move away from the tradition of moving away of fitting new reaction chemistries in the existing equipment. Such a move might necessitate deviating from tradition.

Preparation of (2E)-1(1-piperridinyl)-2-buten-1-one (Example 1):

To a well stirred mixture of crotonic acid (100 gms, 1.16 moles) DMF (1.0 ml) in dichloromethane 500 ml was added thionyl chloride (100 ml, 1.34 moles) dropwise under N₂atmosphere at 25-30° C. and stirred for 14 hours at 30-35° C. After completion, reaction mass was concentrated and diluted with MDC (1000 ml) and cooled to 0° C. Piperidine (310.0 ml, 3.15 moles) was added drop wise over a period of 3 hours below 10° C. The reaction mixture was then agitated at 25-30° C. for 7 hrs. After completion, the reaction mixture was filtered and filtrate was sequentially washed with water (2×500 ml), 5% dil. HCl 500 ml, 5% sodium bicarbonate (500 ml) and finally with brine solution (500 ml). Organic layer was evaporated to obtain title compound as dark brown colored oil.

Yield: 110.0 grams     HPLC Purity: 95%  Yield of Example 1 step: 61.9%

Figure 1: Scheme 2: Synthesis of Piperine from Crotonic Acid USP 11,267,798 B2 ⁽¹⁾

Preparation of (2E)-1(1-piperridinyl)-2-buten-1-one (Example 2):

To a well stirred mixture of crotonic acid (50 gms, 0.580 moles) DMF (1.0 ml) in toluene (500 ml) was added thionyl chloride (50 ml, 0.670 moles) dropwise under N₂atmosphere at 25-30° C. and stirred for 10 hours at 35-40° C. After completion of the reaction additional 250 ml toluene is added to reaction mass. Piperidine (150.0 ml, 0.500 moles) was added drop wise over a period of 3 hours below 10° C. The reaction mixture was then agitated at 25-30° C. for 7 hrs. The progress of the reaction was monitored by HPLC. After completion, the reaction mixture was filtered and filtrate was sequentially washed with water (2×250 ml), 5% dil. HCl (250 ml), 5% Sodium bicarbonate (250 ml) and finally with brine solution (250 ml). Organic layer was evaporated to obtain title compound as dark brown colored oil.

Yield: 65.0 gms HPLC Purity: 95%. Yield of Example 1 step: 73.2%

Preparation of Piperine (Example 3):

To a well stirred mixture of (E)-1-(Piperidin-1-yl) but-2-en-1-one (100.0 gm, 0.653 moles), benzyl triethyl ammonium chloride (27.0 gm, 0.118 moles) in DMSO (1000 ml) was added piperonyl aldehyde (88.0 gm, 0.586 moles) at 25-30° C. Aq. NaOH (4.7 gm 0.118 moles in 100 ml water) was added drop wise over a period of 45 min. The reaction mixture was then stirred at 25-30° C. for 12-15 hours. After completion of reaction it was quenched in water (5000 ml) and further stirred at 25° C. for 2.0 hrs. The precipitated solid was isolated by filtration, washed with water and dried under vacuum at 55-60° C. to yield title compound piperine as yellow solid.

The crude piperine was purified by crystallization from 500 ml toluene to obtain crystalline solid.

Yield: 89.0 gm. HPLC Purity: 99.95% Yield of this step: 47.8%

Preparation of Piperine Example 8:

To a well stirred mixture of (E)-1-(Piperidin-1-yl) but-2-en-1-one (225.0 gm, 1.468 moles), benzyl triethyl ammonium chloride (67.0 gm, 0.294 moles) in DMSO (2250 ml) was added piperonyl aldehyde (198.5 gm, 1.322 moles) at 25-30° C. The reaction mixture was stirred for 15-20 mins and aq. NaOH (24.0 gm 0.6 moles in 225 ml water) was added drop wise over a period of 45 min. The reaction mixture was then stirred at 25-30° C. for 5 hours. After completion of reaction it was quenched in water (6750 ml) and further stirred at 25° C. for 1.0 hr. The precipitated solid was isolated by filtration, washed with water and dried under vacuum at 55-60° C. to obtain title compound piperine as yellow solid.

Yield: 301.0 gm Yield of this step: 71.87%

Depending on the route selected Piperine yield based on the above examples could be between 29.6 to 52.6%

Table 1: Physical Properties of chemicals used in the preparation of Piperine

Analysis of Process Stoichiometry:

Information about the process similar to what is illustrated in Figure 1, Table 1 and Table 2 should be compiled for every process step and reaction chemistry. Figure 1 illustrates the reaction chemistry and is of utmost value. Using the information similar to figure 1 the developers can collect every physical and chemical property ^{(8, 9, 10, 13, 14, 15)} of the chemicals used and produced in each reaction step e.g. molecular weight, density, mutual solubilities, boiling/melting point, azeotropic behavior and viscosity etc. Compiled information facilitates every chemist and chemical engineer in creating an optimum process. They can also be considered and used to modify the process.

Information is of utmost importance in the process design, handling, safety, storage and use. They teach us how the chemicals can and need to be handled at every process step. More we know about the chemicals used, intermediates and the final product produced, the task of scale up, design and commercialization becomes easier and is facilitated. Compilation of such information might be considered redundant but is of value and a treasure as long as the product is being produced by the company. Every chemist and chemical engineer can use the information. Using their creativity and imagination can optimize and economize the process.

This information is also necessary for process simplification, design and improvement. It is very possible that some or many of the physical and chemical properties of the chemicals ^{(8, 9, 10, 13, 14, 15)}used and produced might not be readily available from the databases and/or vendors. They might have to be generated internally. A word of caution. Physical and chemical properties ^{(8, 9, 10, 13, 14, 15)}provided by the vendors need to be verified for accuracy.

Table 2 is compilation of theoretical and actual amounts of key chemicals used to produce (2E)-1(1-piperridinyl)-2-buten-1-one and piperine. It lists mole ratios and yields relative to the crotonic acid, selected as the KEY component, in Example 1 and Example 2. Solvents are excluded. Example 2 has less than theoretical amount of piperidine per mole of crotonic acid but has higher yield. Yield variation between the two routes is significant and it suggests a review of the reported information and its validity. Molar ratios for the preparation of Piperine as also illustrated.

Active reactants concentration in the total reaction mass is about 20% in each reaction. What can be done to conduct the reaction at higher concentration and what would be the result? Generally active concentration of key raw materials is low and that is based on tradition. Based on the chemistry and chemical engineering fundamentals and creativity alternates to do the reaction at higher concentrations ^{(8, 9, 10)}need to be explored and tested.

Another word of caution when acquiring chemicals from different vendors. They generally want to know how and where their product will be used. General answer should be “chemical synthesis” rather than pharmaceutical. Some vendors even go to the extent of signing confidentiality agreements before Moment they know use of chemical is for a pharmaceutical synthesis, prices go up. Their rationale is pure chemical will produce higher purity product. This is not true as the product developer/producer will produce and process the product to meet their own specification. Supplier has to meet buyer needs to produce a product that meets their quality standards. Commercially available raw materials are competitively priced and generally suppliers make every effort to make a deal.

USP 11,267,798 B2 ⁽¹⁾ suggests Piperine can be purified using toluene or isopropyl alcohol with yields ranging from 79.2-80.5%. This suggests that an optimum process can be developed. Every astute chemical engineer and chemist for the subject patent using unit operations ^{(3, 4)} can figure out how to handle evolved SO₂and hydrochloric acid gas. Use of eductors and inline scrubbing is a possibility. Creativity and imagination is needed ⁽¹⁰⁾.

Based on my experiences I would expect a reasonable excess of piperidine used per mole of crotonic acid for both examples. Molar ratios of piperidine to crotonic acid in examples 1 and 2 in Table 2 need scrutiny. Using different process schemes piperine overall yield varies between 29.6% to 52.6%. Village team members ^{(8, 9, 10, 11}⁾ should review so much variation. My conjecture is that if they were involved from the onset the overall process yield higher than ~75% could be achieved. Even if the process is not going to be commercialized each chemical process development becomes a fertile training ground for excellence.

Table 2: Relative ratio of key reactants

With the start of development process product cost analysis ^{(8, 9, 10}⁾ of the wet chemistry is a very important exercise that needs to be done. Such exercise allows selection of the most profitable process. Again expertise of the village ^{(8, 9, 10,}¹¹⁾can be of great benefit for the process development chemists and chemical engineers as they select the most profitable process. Prices of each ingredient used in the illustrated examples are readily available. My crudest factory manufacturing cost ^{(8, 9, 10}⁾, without putting lot of effort, piperine factory should be less than $40 per kilo. If the conversion cost of any product is equal to or exceeds the raw material cost, it suggests that the commercialized process needs a rigorous review and redesign. Overall yield of less than 75% also suggests that the chemistry needs to be reviewed.

Information similar to what is compiled in Table 2 can be used to understand what the patentee is citing in their granted or in-process patent. Compared to theoretical yield of a process chemistry, shortfalls of the process are highlighted right away. I am not a patent expert but based on the variations validity of the patent could be questioned.

Generally when a process is experimented in the laboratory many overlook the fact that someday the process, if the product has high economic value, will be commercialized and the lab developed processes could pose commercialization challenges. Fundamentals of chemistry and chemical engineering have to be applied from the onset of process development to reduce/minimize process development time. To me laboratory is an important cog in the whole scheme.

Expect for benzyl triethyl ammonium chloride (phase transfer catalyst) all of the organic chemicals used and produced are liquid at 40 ºC or above. Since the reactants and the reaction products are liquid at above 40 ºC, They present an opportunity to minimize solvent use in the reaction and present an opportunity to review the reaction stoichiometry to optimize the yield of each reaction step.

Example 1 & 2 for the preparation of (2E)-1(1-piperridinyl)-2-buten-1-one give us clues. Boiling points of dichloromethane (~ 40 °C) and toluene (110 °C) can be used to advantage by raising the reaction temperature (taking advantage of doubling the reaction rate with every 10 °C rise in temperature ⁽¹²⁾. Every chemist and chemical engineer knows and practices associated value. Generally these considerations come in play only when village ^{(8, 9, 10, 11)}is involved from beginning of product and process development. Reduced reaction time impacts type of equipment used and its investment.

Dichloromethane and toluene reactions are being conducted at room temperatures or near room temperatures for 10-15 hours suggest that value of reaction rate ⁽¹²⁾ is not part of the laboratory experiments. They present an opportunity. Are the low yields due to side reaction products being produced when the reactions are being carried out for prolonged time period? Potential of sequential reactions i.e. crotonic acid  crotonyl chloride (2E)-1(1-piperridinyl)-2-buten-1-one  piperine does exist and needs to be considered. At certain annual production volume a continuous manufacturing ⁽¹⁶⁾ is very possible.

Some could easily say that when developing a laboratory synthesis process all of the information discussed above is not necessary. Some could say lab experiments just illustrate feasibility. Unless an outlier attempt is made from the onset, especially in the synthesis of active pharmaceutical ingredients no process simplification effort is made when a molecule enters regulatory filings. Village’s ^{(8, 9, 10, 11)} involvement is necessary and of great value. Low yield suggests many opportunities. Chemicals that enhance lifestyle have different quality needs and their processes can be continually improved.

My conjecture is that if the laboratory syntheses can be simplified and commercialized the time and investment needed to improve the commercial processes can be significantly reduced.

It is again emphasized that every nuance of the reaction and that includes how and where the chemicals are added, their physical properties ^{(8, 9, 10, 13, 14, 15)}i.e. melting point, boiling point, reaction temperature/s mutual solubilities and/or insolubilities can be exploited and capitalized on to create an excellent process. In the reviewed patent higher temperature reactions are eluded. From these claims it becomes obvious that the process chemistry was tested but the results are not known. Testing reaction at higher temperatures has to become a habit from the start of process development. Village ^{(8, 9, 10, 11)} helps in such exploitations.

It is possible to use crotonic acid as a melt or a solution at appropriate temperature and thionyl chloride can be metered in stoichiometrically controlled amount. Availability of appropriate equipment has to be explored for every chemical manufacturing applications. We are generally not taught or are familiar with many of the equipment that is available from other industries and can be used in the manufacture of fine/specialty chemicals.

In the first reaction step hydrochloric acid and sulfur-di-oxide are the reaction byproducts and have to be removed in a way that they do not impede reaction progress. How they would be removed are different for a batch or continuous process.

It would be ideal if piperidine which is liquid at room temperature can be added sequentially to the reaction mass to produce (2E)-1(1-piperridinyl)-2-buten-1-one. Reaction temperature will have to be maintained at an appropriate temperature to assure all of the liquid mass is liquid. Benzyl triethyl ammonium chloride can be introduced as a solution. Based on the discussion one can conjecture that reaction mass is all liquid and is easy to process and flow control. Piperine being a solid at room temperature can be crystallized using most suitable crystallization process, separated and dried.

Equipment size and processing methodology ^{(4, 8, 9, 11)} will dictate the selected method. Again, companies have to evaluate alternate processes and methods and that includes process equipment design and size to suit their technologies. Strategies that are different from the current methods that have not been considered need to be evaluated. Once we see the benefits of what all has been discussed process development and simplification methodologies become second nature.

Information discussed and reviewed is necessary for process design, equipment design and troubleshooting needs that arise during the life of product being produced by the company. All of the compiled/documented information which includes rationale for its process design and operating methods becomes part of the process design manual, the “Holy Book” for that product. Information complied is also helpful for every regulatory filing, compliance, training and trouble shooting.

Again, purpose of the analysis of USP 11,267,798 B2 is not to find errors in methods used by others but present my perspective and consider opportunities to optimize, have an excellent environmentally friendly and economic process. Creativity and ingenious application along with combination of chemical and physical properties ^{(8, 9, 10, 13, 14, 15)}and unit operations ^{(3, 4)} lead to excellent manufacturing processes ^{(8, 9, 10)}. This has been proven many times over and can repeated for every active pharmaceutical ingredient synthesis.

Girish Malhotra, PE

EPCOT International

Phull M. S. et. al. USP 11,267,798 B2 “Process for the Preparation of Piperine”, CIPLA Limited
Shreve, R. Norris: Unit Process In Chemical Processing, Ind. Eng. Chem. 1954, 46, 4, 672
Unit Operations https://bit.ly/2Rp3Xlu
Chemical Engineer’s Handbook, Fourth Edition, McGraw-Hill Chemical Engineering Series
Burke, J. What does net zero mean? https://www.greenbiz.com/article/what-does-net-zero-mean, May 2, 2019 Accessed April 27, 2021
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
Malhotra, Girish: Patents: Should We Change Our Intellectual Property Model/Strategies? Profitability through SimplicityOctober 5, 2012
Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability John Wiley & Sons, February 2011
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
Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter April 2022
Kalam, APJ Abdul, Wings of Fire: An Autobiography of APJ Abdul Kalam, Sangam Books Ltd, 1999 Accessed January 31, 2024
Levenspiel, O: Chemical Reaction Engineering, John Wiley & Sons 1999
Malhotra, Girish: Sociochemicology May 30, 2013
Malhotra, Girish: Focus on Physical Properties To Improve Processes: Chemical Engineering, Vol. 119 No. 4 April 2012, pgs. 63-66
Malhotra, Girish: Process Simplification and The Art of Exploiting Physical Properties, Profitability through Simplicity, March 10, 2017
Continuous Production https://bit.ly/2Rp3Xlu

Pharma’s Advanced Manufacturing Technologies: REALITY OR FIGMENT OF IMAGINATION

2024-04-04T16:20:00.000-04:00

USFDA at least since 2013 ⁽¹⁾ has been promoting use of advanced manufacturing technologies (AMT) and that includes “continuous manufacturing (CM) ⁽²⁾ for the manufacture and reduce shortages of drugs ^(3,4,5). It has held various conversations and even involved National Institute of Sciences (NAS). This report “Building Resilience into the Nation's Medical Product Supply Chains ⁽⁶⁾ is a disturbing as it suggests increasing reliance through foreign relationships.

FDA ⁽⁷⁾ has continued to convince the pharmaceutical industry to use advanced manufacturing technologies (AMT) but seems like no one is buying what it has been selling.

What are these technologies is not clear. Do AMT include manufacture of API along with their formulations or anything else? A clarification from FDA was asked from its CDER/OPPQ/Office of Policy for Pharmaceutical Quality. A very terse response was received “they will respond in several weeks”. This is especially enlightening and interesting when FDA has been touting to the world to adopt such technologies. If FDA is trying to promote adoption of better manufacturing technologies, it would be beneficial if they were more forthcoming in addressing asked questions.

Even after all the conversations and congressional hearings and claims that these will reduce shortages FDA’s effort that has not resulted in any progress in commercializing AMTs at the pharmaceutical companies. This basically suggests that this effort is not going anywhere. If after effort of more than five years and millions of tax payer dollars that have been doled out to universities and other institutions nothing meaningful has happened. It basically suggests that companies are not buying what USFDA is selling.

It is ironic that FDA wants companies to incorporate “continuous manufacturing (CM)⁽²⁾” but has not shared what is its understanding and definition. In the manufacturing world there is an established definition ⁽²⁾. It would be interesting how FDA’s definition compares with the established definition. It also needs to very clearly explain what does it call “drug manufacturing”. Is it just formulation of active pharmaceutical ingredients (API) or combination of manufacture of APIs and their formulations? We have to remember that without API there is not drug. It is just a placebo.

FDA has called formulation of certain cancer cure drugs (limited global population which means limited demand) as continuous processes (CM) ⁽⁸⁾. Involved companies formulate batch produced API to finished products. Since these products are formulated on stop and go basis i.e. batch production ⁽⁹⁾, the underlying question is why FDA distorting facts and calling these processes CM. Is it trying to convince the pharma industry that it needs to change its manufacturing practices? Justification and rationale are needed. Even press has been talking about CM ⁽²⁾ when they have no idea what it means.

Based on formulation and compaction technologies that have been commercial and are used to produce many products, question that needs to be addressed is “why the pharmaceutical industry has not adopted established (more than fifty years) technology “en masse”. Is it lack of experience, business model or regulatory interference or being comfortable and profitable with quality by “analysis paralysis” processes?

It is a well-known fact that industry invents drug products. New and/or existing technologies and methods are used produce quality products. However, FDA’s telling the industry that new technologies need to be approved ⁽¹⁰⁾ before they can be implemented is a deterrent for brand and generic drug industry. No one knows what these technologies are. businesses. With FDA’s staff having minimal to no or minimal experience in product and process development, design and commercializing any drug molecule and their manufacturing processes, it would amount to further delays from the current times in brand and generic products. This is an un-necessary interference and oversight of a company. Question is how FDA will help.

Industry should be meeting the necessary drug performance criterion using the methods and processes it has developed, tested inhouse and would want to commercialize ASAP. Every product goes through three steps a) lab, b) pilot plant and c) commercial scale. This will be true for every product if it will be produced using a continuous process ⁽²⁾. Due to FDA staff’s limited experience suggested pre-approval review etc.⁽⁷⁾ will result is further commercialization delays as they have no hands on experience of process development. This will result in further commercialization delays. If the industry does not see value in this effort they will not change their existing practices and/or consider any new technologies.

USFDA has to be very clear of the pathway it wants industry to follow to implement new technologies. FDA has to layout parameters/questions regarding the technology it wants to the industry to address along with a timetable. Goal has to be commercialization of drug in minimal time after its efficacy has been recognized by the pharma company and proven. Pathway for brand and generic drug will be different. There is big gap between FDA and industry as no headway has been made to improve manufacturing technologies. Industry has to recognize financial value and they do not see it as they are profitable.

May be it is time for FDA to consider alternate ways so that the pharma industry’s manufacturing can come to 21^st Century. It has tried to corral and impress US congress using its resources, as discussed earlier, but no one has budged. It is my conjecture that nothing will change unless the pharmaceutical industry (development and manufacturing) gets involved. They would not till they see a return. Alternate presented is my own and not influenced by any “for profit and nonprofit” organization.

Pharmaceutical industry would be enthusiastic and welcoming if products produced using better manufacturing technologies could be commercialized much sooner than the current times for NDA (new drug applications) and ANDA (abbreviated new drug applications). For that to happen the triumvirate (FDA, Pharma companies, and Pharmacy Benefit Managers (PBM)) have to change the current methods. My thoughts are a stretch and will face resistance from each. Most will come from FDA and PBMs. Pharma companies most likely would like them as they will lead to shorter time needed for commercialization i.e. higher revenues and profits.

FDA:

FDA when it comes to NDA and ANDA approval needs to eliminate every pre-approval meetings and that includes any new manufacturing technology introduction and use templates to get information it would consider necessary for their review and approval ^(11,12). These meetings are suggestive that the applicant companies do not know and/or understand what all is necessary for approval and they have to teach FDA what is the rationale and value of their innovations. Once FDA has the knowledge, it is possible that approval times could be reduced from current times ^{(13, 14, 15)}.

Is FDA personnel due to lack of their experience in process development, scaleup and commercialization especially in “continuous” API and formulations using these meetings to further delay approvals. Basically this could be considered that FDA is learning on the fly what all is necessary for approval. FDA needs to create its expectation guidelines for every new (NDA) and existing (ANDA) drug each applicant company has to follow. These guidelines would be routinely updated so going forward companies. Assimilation of this suggestion will be difficult for FDA.

Pharma companies:

Pharma companies have to have every “t” crossed and “i” dotted when it is submitting information required by FDA for their NDA and ANDA as if they will consume first tablet that comes of the production line and their life depended on it. For continuous API manufacturing and their formulations it is very likely that pharma’s current manufacturing landscape would have to be changed ^{(16, 17, 18)}. Companies would be challenged by FDA as they might have to familiarize FDA personnel with nuances of continuous manufacturing. Not having any process development, scale up and commercialization experience this can be a challenge. Chemists and chemical engineers will need company support, a challenge.

PBMs:

For Pharma companies to get excited about consideration and incorporation of newer and better manufacturing technologies, in addition to faster approval than current times, they should be allowed to direct market their FDA approved products by bypassing the formulary lists. Patient and physician should be deciding which approved drug they want to use. PBMs should not be interfering in patient’s life. Having a choice of drug would bring highest quality product at the best price competition to market. Competition is healthy and good for encouraged. PBMs are not required to meet quality standards. They should be held accountable ⁽¹⁴⁾.

Yes in the final analysis suggestions made here could be considered radical and not to the linking of parties involved. FDA has been going around with all sorts of permutations and combinations but nothing meaningful has materialized. It has not created an environment to innovate. Pharma industry has ignored FDA’s suggestions. PBMs have no interest in reducing shortages. Unless the accountability is shared by each party involved, US drug system (manufacturing, approval and distribution) have and will limp along and patient will continue to suffer.

Path forward:

With FDA’s effort of more than eight years, no progress has been made to incorporate proven better manufacturing technologies used elsewhere in API manufacture and their formulations. Pharma manufacturers are comfortable with the current methods that have been in use from 1940-‘50s as they are profitable ⁽¹⁸⁾. PBMs have no interest in what manufacturing methods/technologies are used as they just sell/distribute drugs to patients at their partial monopoly prices. Shortages have become way of life. An outlier approach is needed if we want to reduce shortages and include better manufacturing technologies.

FDA could promote the modified filing process with a stipulation that companies will have faster approvals than the current times i.e. higher profits. As part of the buy in for shorter approval time, FDA could use its legislative clout and bypass the current marketing channels i.e. formulary constraints. Manufacturers would offer the drugs to patients through alternate channels. PBMs will resist these suggestions as their stranglehold on generic markets would be influenced.

Suggested pathway should encourage generic manufacturers to invest in better manufacturing technologies i.e. continuous API manufacturing and their formulations. If FDA’s test with generics is a success, it could be extended to brand drugs. Yes brand drug product and process information requirements for approval will be different but the current logjam of slow action will be broken.

FDA would need to start the approval simplification process by creating templets that detail information needed for approval. Creation of information asking templets ⁽¹⁴⁾ could be test of FDA’s internal knowledge and competence. There could be significant internal resistance as the review and approval methods would change. FDA’s pre-meetings etc. would have to be curtailed. This would place the onus of convincing FDA to grant the approval. Companies have more to lose if they do not receive timely approval. Such a change is needed if we collectively want to simplify the age old process. To implement the suggested change FDA may have to avail congressional help, if necessary.

Companies may include additional information, some of it could be redundant. Excess of submitted information may help the approval process. In the proposed process FDA personnel will still have an opportunity to ask for additional information ⁽¹⁴⁾to complete the review resulting in grant and/or denial. Review and grant process will have defined time window. Once ANDA is approved certain restrictions could be placed on the filing company i.e. it cannot transfer the approved ANDA to any other profit making company in the next twelve months and it has to produce the product for sale in USA within 1-4 months of the approval. Success with generics could be applied for brand drugs.

Since companies will have FDA decision in a finite time rather than unknown time, they should be enthusiastic about the suggested process. They would be able to commercialize their manufacturing process innovations and get a better return on their investment. Yes in the final analysis suggestions made here are radical and may not to the liking of some involved.

FDA and US Congress have been talking and making noise but no solution has been proposed. As suggested earlier chemical engineers are not practicing unit processes ⁽¹⁹⁾ and unit operations ⁽²⁰⁾ they have been taught to the fullest extent. The process outlined ^{(16, 17,18)} will allow them to incorporate them and create excellent processes to produce quality products. It is time pharma manufacturing comes of age.

Product and manufacturing process technology innovation comes from pharma companies. They do their first part but as said earlier dur to profitability they have lagged on the second part. Unless responsibility to reduce shortages is shared by each party involved, US drug system (manufacturing, approval and distribution) will continue to limp along and patient will suffer. It is time to consider better alternate processes to reduce shortages that include better manufacturing technologies and alternate drug distribution model. We have the minds and chutzpah to excel. Time is now.

Girish Malhotra, PE

EPCOT International

References:

1. Strategic Plan for Preventing and Mitigating Drug Shortages Accessed March 31, 2024

2. Continuous Production

3. TESTIMONY OF JANET WOODCOCK, MD December 10, 2019

4. Agency Drug Shortages Task Force October 30, 2019 https://www.fda.gov/drugs/drug-shortages/agency-drug-shortages-task-force

5. Malhotra, Girish: Identifying the Root Causes of Drug Shortages and Finding An Enduring Solution, Profitability through Simplicity, December 7, 2018

6. Building resilience into the Nation’s Medical Product’s Supply, National Academy of Sciences https://nap.nationalacademies.org/read/26420 Accessed April 22, 2022

7. Advanced Manufacturing Technologies Designation Program, Guidance for Industry, December 2023 https://www.fda.gov/media/174651/download

8. Malhotra, Girish: Batch, Continuous or "Fake/False" Continuous Processes in Pharmaceutical Manufacturing,Profitability through Simplicity, July 20, 2017

9. Batch Production https://en.wikipedia.org/wiki/Batch_production

10. Lifecycle of an Emerging Technology Program (ETP) https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/lifecycle-emerging-technology-program-etp

11. Malhotra, Girish: Can the Review and Approval Process for ANDA at USFDA be Reduced from Ten Months to Three Months? Profitability through Simplicity, March 25, 2017

12. Malhotra, Girish: What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days? Profitability through Simplicity October 24, 2018

13. Malhotra, Girish: Strategies to Increase Generic Drug Competition and Bring Manufacturing to The United States of America, Profitability through Simplicity, March 16, 2020

14. Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability, Profitability through Simplicity December 6, 2019

15. Malhotra, Girish: Roadmap to Reduce Drug Shortages Profitability through Simplicity October 30, 2023

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

17. 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

18. Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation DeGruyter April 2022

19. Shreve, R. Norris: Unit Process In Chemical Processing, Ind. Eng. Chem., 1954, 46 (4), pp. 672–672

20. Unit Operation, https://en.wikipedia.org/wiki/Unit_operation , Accessed July 11, 2017

Profitability through Simplicity

Role of Village and Triumvirate in Process Development of Isoniazid :- a Tuberculosis Drug

Sociochemicology: Its Birth and Value

Incorporation of TRIUMVIRATE (5) in pharmaceutical manufacturing will result in manufacturing technology innovation, significantly reduce emissions per kilo of product and that will be a game changer.

Exploitation and Capitalization of Mutual Behavior of Chemicals (Sociochemicology) and Process Equipment for the Manufacture of Propofol

The Process Development Triumvirate: Profitability Through Simplicity

SOCIOCHEMICOLOGY: Designing Chemical Processes by Exploiting the Social Behavior of Molecules

Imagination, Creativity and Sociochemicology (1) in Chemical Process Development

Revised UPDATE: US Domestic Generic Pharma Manufacturing needs Shorter Approval Time and Lower ANDA Fee

1. Malhotra, Girish: For Domestic Pharma Manufacturing: Reorganize CDER November 6, 2025

For Domestic Pharma Manufacturing: Reorganize CDER

FDA’s ANDA Prioritization Pilot and Possibilities of its Success

On October 3, 2025 CDER FDA (1) announced “New ANDA (abbreviated new drug application) Prioritization Pilot to Support U.S. Generic Drug Manufacturing and Testing” (2) process it would like to experiment with in its efforts to bring generic manufacturing home to USA.

Let us "THINK DIFFERENTLY'. It is time especially for pharmaceuticals

Physical Properties of Chemicals, their Mutual Behavior i.e. SOCIOCHEMICOLOGY and Process Simplification

Executive Order 14293 & FDA Processes

US FDA posted a press release “FDA Announces New FDA PreCheck Program to Boost U.S. Drug Manufacturing” (1) outlining its NEW PROGRAM to strengthen its processes. It proposes a PreCheck in response to EO14293 (2).

FDA (1) has suggested TWO steps and they are:

2. Second, the Application Submission Phase centers on streamlining development of the Chemistry, Manufacturing, and Controls section of the application through pre-application meetings and early feedback.

Most Favored Nation Pricing & Bringing Pharmaceutical Manufacturing Home:

An Unconventional Analysis:

Implementing Executive Orders on Domestic Production of Critical Medicines and Achieve Most Favored Nation Pricing

An Outlier Plan to Bring Pharmaceutical Manufacturing to USA in One Year

Remedy of US’s Drug Supply Chain Shortages and Domestic Production of Generic and Brand Drugs

Sociochemicology: Redefining Chemical Process Design for Efficiency and Sustainability

An Update: Artificial intelligence in Pharmaceutical/Chemical Process Development, Manufacturing & Net Zero [Post of March, 31, 2023]

Process Simplification: Is the Best Answer: New Terminologies or the Application of Fundamentals?

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

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

Process Simplification and Net Zero: Capitalizing on Physical and Chemical Properties of Reactants and Intermediate

USP 11,267,798 B2: Manufacture of Piperine (1) An Excellent Teaching Tool

Pharma’s Advanced Manufacturing Technologies: REALITY OR FIGMENT OF IMAGINATION

Incorporation of TRIUMVIRATE ⁽⁵⁾ in pharmaceutical manufacturing will result in manufacturing technology innovation, significantly reduce emissions per kilo of product and that will be a game changer.

On October 3, 2025 CDER FDA ⁽¹⁾ announced “New ANDA (abbreviated new drug application) Prioritization Pilot to Support U.S. Generic Drug Manufacturing and Testing” ⁽²⁾ process it would like to experiment with in its efforts to bring generic manufacturing home to USA.

US FDA posted a press release “FDA Announces New FDA PreCheck Program to Boost U.S. Drug Manufacturing” ⁽¹⁾ outlining its NEW PROGRAM to strengthen its processes. It proposes a PreCheck in response to EO14293 ⁽²⁾.

FDA ⁽¹⁾ has suggested TWO steps and they are: