The Process Development Triumvirate: Profitability Through Simplicity

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:

1. Malhotra, Girish: Blog Profitability through Simplicity  
2. Malhotra, Girish: Chemical Process Simplification: Improving Productivity and Sustainability   John Wiley & Sons, February 2011
3. 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

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

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

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

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

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. Copyright © 2024 American Chemical Society

 

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 reactions have 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