All opinions are my own.

Friday, February 23, 2024

Manufacturing Technology Innovations in Pharmaceutical Manufacturing:

If we look at the history of disease curing products aka drugs, we will see that they started to appear about 80-90 years ago. Rapid discovery of disease curing value of existing and new disease curing chemicals and ease of their manufacture in the existing equipment being used to manufacture dyes and colorants led to an accelerated growth of the pharmaceutical industry (1). Discussion presented here is my own with the hope that any and all ambiguities I have will be clarified. Discussion is not influenced by any for profit, non-profit or regulatory body. 

 Pharmaceutical manufacturing technologies and methods: 


About 80-90 years ago chemical processing equipment was available and being designed for the dye and colorant industry. Many fundamentals of chemical engineering and unit operations (2,3,4,5) were explained and applied for the manufacture of various organic chemicals also called fine/specialty chemicals. They simplified manufacturing processes. Chemical engineering principles, manufacturing technologies and chemistry teachings of yester years are still the fundamental building block in every chemical manufacturing process. Active pharmaceutical ingredients (API) and their formulations are part of the same domain.  Some may disagree with this statement but one cannot change fundamentals as the methods are the same. Bio drugs are not part of the discussion. 


Competition and profitability has played a significant role in the development of the pharmaceutical industry. APIs, life span extenders, synthesized use same or similar equipment that was used in 1940-1960s. Except for normal enhancements/innovations with time, basic unit processes and operations have not changed. Fundamental processes and synthesis methods have not changed also. Execution methods might have changed. 


Fine specialty chemical companies, from (1940’s-’70s) who discovered disease curing molecules re-branded themselves as drug/pharmaceutical companies. They patented their molecules and formulations. This is very simple explanation of the landscape change. Except stricter regulatory requirements there in not much differences between fine/specialty and disease curing chemicals. Some may not agree but that is a historic reality.  


Due to extended time expended in discovery of disease curing molecule and regulatory approval companies have a limited patent life. To maximize profits, speed to the market is the utmost necessity. Ability and creativity of chemists and chemical engineers for use of existing equipment has been the operating mantra. Process inefficiency (low conversion) and equipment downtime (6) which can amount to as much as 50% of the available yearly equipment use time are accepted. All of these costs are passed on to the patient. 


Discussion here is focused on API manufacture. For formulation operating tactics, needs and philosophies are different and not part of the conversation. In the production of every product whether it is an organic additive chemical or a drug molecule annual volume of the product is important. They are based on economics and dictate manufacturing technology and methodology. No one is going to invest in any equipment and technology that is specifically designed for a product and is going to be used for a short time e.g. few weeks per year unless it is a monopoly case, patented product. Company find an alternate method/way to produce the product if any alternate equipment is/was available or modify the process to produce the product. This has been the operating philosophy in the pharma’s active ingredient (API) manufacture. As soon as the patent expires many may jump in with better manufacturing technologies. 

Still with opportunity to use better manufacturing technologies for API and their formulations innovation has stalled due to speed to market, profits and regulations. For innovation, there has to be grass root effort. Unfortunately brand companies do not have the time as their focus is speed to market and immediate profits. Generic companies have the opportunities but they have followed methods and practices of the brand companies and have not spent time to investigate/practice technologies that are better than practiced by the brand companies. My conjecture is that drug purchasing model used especially for USA drug distribution has prevented manufacturing technology innovation (7). If the generic companies could sell directly to US patient base, innovation in manufacturing technologies and methods (8) will change the landscape and shortages could be minimized and/or disappear (9)

On the API manufacturing and technology landscape few new terms have been recently introduced. I am told that they are the new technologies and simplify chemistry, process development and reduce commercialization time. These are:  

1.     Flow Chemistry

2.     Continuous manufacturing

3.     Process intensification

I do not find them anything close to new innovation but new names for well-known and practiced methods/technologies that have existed and practiced for the manufacture of chemicals for the last eighty years. I call these “fancy dance foot work” but the dance or the music has not changed. 

Flow Chemistry: I have asked for definition and clarification but have not been given a plausible answer. Folks who mention this on their curriculum vitae have not been able to explain and give definition of the term and/or an example and compare with traditional methods. Internet search suggests “Flow chemistry involves the use of channels or tubing to conduct a reaction in a continuous stream rather than a flask” (10, 11)

It is suggested that “Flow Chemistry simplifies chemistry and process development. I am not sure of this claim. I just wonder how solids would flow unless they are in liquid or solution state. Solids will have to be solubilized and that is no different from the current methods. In addition, based on the illustrated schematics it seems significant pre-engineering and investment would be need for the equipment needed. I wonder how versatile will be the applicability of the assembled equipment for different chemistries. Could they be used for other process developments? Would modifications be needed? I am not sure. 

Reviewing suggested process development methods based on use of flow chemistry (10, 11) they look to be expensive and cumbersome. This is based on the fact that information needed and used in traditional process development methods, knowledge of the physical properties of chemicals and their mutual behavior (1) would still be needed before “flow chemistry” based process contraptions described in (10, 11) can be assembled and used. A side by side economic analysis of the “flow chemistry” and traditional methods is necessary. My speculation is that the proposed methods will turn out to be financially expensive and time consuming. I hope use of term “Flow Chemistry” is not being used to impress others. 


Based on literature search and what I understand, incorporation of the proposed methods if possible, will be complex, expensive and time consuming. Results will be no better than what can be accomplished by current and proven methods. 


Based on my more than half a century of experiences in the chemical industry as a chemical engineer, generally there is methodology followed for development of chemical synthesis processes. Most of us are familiar with the methods. Reactants in appropriate solvent are added to a round bottom flask or similar equipment with its agitator and condenser and other necessary equipment. Reaction feasibility and safe operating conditions are defined. Chemist/chemical engineer generally  try different process conditions for process optimization. Next step is scale up and commercialization. 


Information i.e. physical, chemical properties, mutual behavior of chemicals used and produced, reaction kinetics i.e. fundamentals of chemical engineering (3, 4, 5) have to be collected by the village (1,13) and used for process development. My conjecture is that if all this is done, time needed for economic process technology development would be significantly reduced. Companies developing manufacturing technologies have to make process technology development a group activity (1,13).


My conjecture is that exploring what is called “flow chemistry” is an unnecessary stop i.e. prolonging process development and commercialization time. API developers/manufacturers need to think very hard on the value of proposed methods. There is an easy way to address and answer the question and it is “would the developer chemist/ chemical engineer invest their own money to develop the information that can be produced by simpler and quicker methods? 


We have to remember that majority of the APIs are produced using batch processes as they are fitted in the existing equipment. Information generated by “flow chemistry” methods might satisfy lab curiosity but may have minimal commercial value. Existing methods/practices can generate the same information faster. 


Continuous Manufacturing: In recent years “continuous processing” (14) is being touted as the way to produce APIs. No one has been able to give a satisfactory definition of “continuous processing”. When asked the definitions are confusing and they end up calling a batch process a continuous process. 

Following is my understanding of any continuous process. In every continuous chemical related process raw materials are introduced in appropriate equipment and using different unit processes and unit operations they are converted to the desired product. Each step has to be time independent. If there is fluid movement interruption, the process ceases to be a continuous process. We cannot modify established principles to suit our fancy. This also applies to drug formulations.   

Every continuous process is product specific and if another product process does not use the same unit operations, it cannot be produced year round in the same equipment. No one is going to invest in product specific equipment that is not operating year round. It is not going to have the desired financial return. 

Certain existing API products that are produced by batch process can be produced using continuous processes but for them business and operating model would have to change (1). It is my perspective that under pharma’s current sales and distribution model APIs do not have the volume to be produced continuously. An outlier producer and a different sales and distribution model (8) will be needed for continuous API production. Yes, formulations can be operated continuously but can be a challenge.  

Process intensification: This terminology is a new one for methods that have existed since the advent of chemical manufacturing and been used at least since 1960s for the manufacture of fine/specialty chemicals. If use of venturi flow, plate and frame heat exchangers, static mixers, eductors and restricted spaces to improve and enhance mixing of liquids to improve reaction chemistry is considered process intensification then this is not a new technology. It is an old art. Creativity and imagination help. Equipment economic analysis is a must.  


I hope we have not forgotten fundamentals of chemical engineering. Renaming existing methods that have been and are commercially used as new technologies is not ethical. Microreactors are capital intensive and have limited use. Similar results can be achieved by using existing alternate equipment.  


Since I am still learning, any verifiable examples are welcome. Intent here is not to challenge anyone’s knowledge or creativity but learn and augment knowledge. I have been able to use the wisdom taught by wizards of chemical engineering (3,4,5). I believe flow chemistry and process intensification are application of principles of chemical engineering that have existed and used but are worded differently to attract attention to be new. 


All said and done we have to remember what works in the lab does not necessarily work in the plant. Everything has to be proven before it becomes commercial. I welcome any and every meaningful discussion. API manufacturing platforms, that exist and have been continually improved, need to be judiciously considered and applied (2, 3, 4, 5). New names for the existing methods are not going to win any laurels. 


Judicious involvement of village (1) is needed from product inception state. This concept of technology development unlike science, is a group activity (13). Some of the processes that are the result of such village/group activity are reviewed (1). Unless there is change in how the process and technology is developed and used to commercialize better API manufacturing technologies, not much will change. Calling established processes and/or methods by new names is not new technology and is not going to reduce process development and commercialization time.



Girish Malhotra, PE


EPCOT International


1.     Malhotra, Girish: Active Pharmaceutical Manufacturing: Nondestructive Creation De Gruyter April 2022 Accessed February 17, 2024

2.     Unit Operations Accessed February 17, 2024 

3.     Unit operations of Chemical Engineering, McCabe, W.L. Smith et. al McGraw Hills Inc. 1993, Accessed February 17, 2024

4.     Walker William H. et al Principles of Chemical Engineering, McGraw Hill Book Co. Inc. 1933

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

6.     OEE Benefits for Pharmaceutical, BioTech and Medical Device Manufacturers in Life Sciences, Pharmaceutical Technology August 27, 2015

7.     Malhotra, Girish: USA’s Annual Ritual of Drug Sourcing/pricing and Shortages, Profitability through Simplicity, November 25, 2023 Accessed February 15, 2024 

8.     Malhotra, Girish: Simplified Process Development and Manufacturing of Fine/Specialty Chemicals & Active Pharmaceutical Ingredients, Profitability through Simplicity, Feb 14, 2023 

9.     Malhotra, Girish: Roadmap to Reduce Drug Shortages and Bring Pharma Manufacturing Home (US) Profitability through Simplicity, October 30, 2023 Accessed February 17, 2024

10.  Plutschack M. B. et al: The Hitchhiker’s Guide to Flow Chemistry Chemical Reviews, 2017, 11718, 11796-11893 Accessed February 17, 2024

11.  Guidi, M.  et al How to approach flow chemistry Chem. Soc. Rev.2020,498910-8932, Accessed February 17, 2024

12.  Malhotra, Girish: Chemicals tell us how to exploit their behavior for better processes. Clues are ignored. Should we? Profitability through Simplicity, June 20, 2023 Accessed February 17, 2024

13.  Kalam, APJ Abdul, Wings of Fire: An Autobiography of APJ Abdul Kalam, Sangam Books Ltd, 1999 Accessed January 31, 2024

14.  Continuous Processing   Accessed February 12, 2024

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