All opinions are my own.

Thursday, September 21, 2023

Marriage of Science and Technology in Active Pharmaceutical Ingredient (API) Manufacturing and their Formulations: Is it for real?

I have been a practicing chemical engineer more than 55 years. When I was part of the corporate world, I had the opportunity and privilege of working with the most creative and daring chemists and chemical engineers who practiced and taught me and others how science and technology discussed and reviewed in our text books can be married to create excellent manufacturing processes that produced quality product all the time. If there were bumps, we considered them as learning experiences. We learnt, improved and commercialized better processes than originally conceived.   

For the last 25+ years I have been reviewing and discussing application of science and technology to simplify and improve their application/adoption in the manufacture of fine/specialty chemicals that include API, coatings, resins and polymers. APIs are no different from specialty chemicals. One extends life and the others improve life style. APIs are formulated with inerts to facilitate dispensing. 

Many might disagree with this statement but the unit processes (1) used in synthesis of both (APIs and other chemicals) are exactly the same or similar. Same unit operations (2) are used. Basic point is API manufacturing and their formulations are no different from any other specialty chemical manufacturing with the difference being the first has to meet a distinct and strict quality regimen. 

Kranzberg’s Laws:

A while ago I came across two papers “The Unity of Science - Technology” (3) and “Technology and History: Kranzberg’s Laws" (4) written by Dr. Melvin Kranzberg and I thought it is best to share. Even though written about 50 years ago, they are worth a read by every “C” suite occupant especially by gatekeeper of every investment for products and their manufacturing that include pharmaceuticals and fine/specialty organic chemicals. Every company can benefit.   

In 2017, these laws written over 50+ years ago, at the dawning of smart phones and social media, reappeared in The Wall Street Journal (5). Most may not have heard of these laws. I equate them to technology’s technology’s Hippocratic Oath (6). These have been applied in the development of products and will continuously be applied for better products, processes and every technological innovation.  They are: 


1.     Technology is neither good nor bad; nor is it neutral.

2.     Invention is the mother of necessity.

3.     Technology comes in packages, big and small.

4.     Although technology might be a prime element in many public issues, nontechnical factors take precedence in technology-policy decisions.

5.     All history is relevant, but the history of technology is the most relevant.

6.     Technology is a very human activity.

Pharmaceutical Industry: 

Review of these laws (4) indicates that their teachings can be easily applied to the pharmaceutical industry and used to improve the prevailing landscape. As I expressed earlier, it is possible that pieces parts of these laws are being applied unknowingly. Perspective presented is mine and is not influenced by any for profit and nonprofit entity. My discussion emphasis is on chemical synthesis part the drug manufacturing. These are very applicable to the formulations also.  

Dr. Kranzberg’s “The Unity of Science - Technology” (3) article is an exceptional summary of mutual relationship of science and technology. It tells us that their confluence can and does result in excellent products that are produced using excellent processes. I found the following excerpt from “The Unity of Science – Technology” (3) very interesting and apropos as it applies well to pharmaceutical products, their manufacturing technologies for API production and formulations. 

“History suggests that science and technology, though wedded today, went through a long, indifferent courtship. They grew independently, almost oblivious of each other’s existence. Each made a point of ignoring the other’s presence, or took scornful note of it. Upon reaching the age of puberty-the Scientific Revolution in the case of science and the Industrial Revolution in the case of technology - mild flirtation ensued. There were in tentative, even furtive, meetings of the hands, shy glances, and a few reluctant embraces. 


The marriage, when it came at last, was a marriage of convenience and necessity, certainly not love match. Insofar as military needs helped bring about many a daring and secretive meeting, the ceremonies, when finally reached, can be called a shotgun wedding; and the couple, predictively, have not lived happily ever after. 


Each partner has retained a good deal of independence, though lately both have been having identity problems. There are constant bickerings about who is contributing most to the marriage. Frequently, they are not on speaking terms. They quarrel over mutual responsibilities, the education of their offspring, and, as might be expected, the household budget. 


It is a very modern marriage, without any nonsense about merger in the old common law entity of the dominant male who owns all the property and is liable for all of his wife’s slanders and crimes. Science and technology live independently, yet coordinately, as if they had but one joint bank account and one car. Divorce is frequently discussed. It is invariably rejected, however, because of scandal which will surely deface public image of the parties and because, I suspect, of the indisputable pleasures of the hurly-burly on the chaise lounge, not to mention the learned faculties of the bed.”


Articles (3, 4) are worth a read for everyone in “C” suite, technocrat and especially gatekeepers of every investment. They go back as much a 50+ years but the content of these is very applicable even today especially in the manufacture of APIs and their formulations. 


Pharma’s Birth:


My assessment is based on the fact that the pharmaceutical industry has very diligently applied “Kranzberg’s Laws (4)” to the drug discovery part with the recognition that some chemical molecule/s have disease curing value. This started at dyes and chemical companies (in late nineteenth century and first half of the twentieth century) (7) . Due to excellent profitability to serve human needs, many 

companies switched from fine/specialty and dye making to become a pharmaceutical company (7). In this transition companies have overlooked manufacturing excellence. 


Companies realized that the synthesis and formulation of disease curing molecules to dispensable dose could be done by fitting the manufacturing processes in the existing equipment. Processes were/are generally not optimized. As long as the equipment was clean and quality product can be produced, need for product specific equipment or optimized perfect process was/is not necessary. Quality repeatability is paramount. Due to high profitability, discovery of disease curing molecules and speed to market were/are the mantra of the pharma companies.  


To reiterate, the need to invest in product specific manufacturing technologies (7,8,9,10) exist but have been overlooked. Companies and regulators have achieved quality by repeated analysis/testing and cleaning the equipment between batches of same/different products (11). All of the associated costs are passed on to the patient who needs her/is medicines to extend life. Equipment makers have also benefited from this scenario as the equipment is being used in batch production (12) even if the same equipment was/is or could be used in the fine/specialty chemical sector for continuous production (13) of chemicals. Regulatory requirements (11) and the current level of profits from the current model could be an encumbrance and be in the way of pharma’s manufacturing technology innovation. 


To summarize pharma’s current scenario, one could say the marriage between science and technology, when it applies to manufacturing, exists but is not perfect. Has the US’s current drug distribution system the cause of the lack of manufacturing technology innovation. This is my perspective. If pharmaceuticals had been like other industries, i.e. direct competition to customer allowed everyone will see significant advances in manufacturing technologies. Has the drug distribution system stymied manufacturing innovation?    


Pharma’s Marriage:


In the pharmaceutical industry, drug discovery/development and their manufacturing, we can say, are two marriage partners.  


1.     Drug discovery 

2.     Drug manufacturing


They live together but as stated by Kranzberg (3) do not have an excellent marriage. It is best to explain this relationship. Again, perspective presented in mine.


In PhRMA’s marriage a significant part of the relationship is missing. I call “drug discovery” the science and “drug manufacturing” the technology of the pharmaceutical world. Their current relationship can be called as “marriage of convenience”. Many would disagree but this is my perspective. The most meaningful missing part of this relationship is the mutually combined creativity and imagination of each partner to produce perfect quality product using an excellent manufacturing process.  


“Drug discovery” happens due to creativity and imagination. Same traits are needed to create excellent “drug manufacturing” processes but the speed to market, past practices (of about 70+ years), intervene. This could also be due to deficit or shortcomings of people experience, lack of creativity and imagination excellence as the developed product is scaled up and commercialized. Most of the time the commercial processes look like a larger laboratory process. 


We are taught the fundamentals needed to scale up. However, speed to manufacture negates or minimizes application of knowledge learnt, creativity and imagination to create and commercialize excellent processes. 


Quality drug products are produced through repeated in-process testing, analysis and correction rather than through “outstanding processes” that will produce “on quality” products from the onset. Current practices have existed for the past 60+ years. In a competitive world, pharma’s practices would be considered expensive, unaffordable and companies would fail. However, in the pharmaceutical world these costs are absorbed by the patient as they want to extend life. Actually companies have thrived. 


Process developers create a laboratory process. Most of the time they do not understand the pain chemical engineers have commercializing the developed process. Only way the minimize the pain is to get the village (7)involved from product inception. Village consists of chemists, process development chemical engineer, manufacturing, maintenance, accounting and purchasing (7). This lets the most creative process commercialized in the shortest time and enhance profits. Patent life could increase. 

Generics also need to use the village (7) from the onset. As stated earlier traditions of the last 60+ years rule the landscape where the village (7) is generally not involved. Like brand drug companies, generics have to have excellent processes and need to optimize as they have to compete with other producers of the same product. They can react to shortages quickly. 


In recent years to get around the “internal talent deficit”, drug discovery companies have and are conveniently relying on using/having surrogate relationships with CDMOs (contract development and manufacturing organizations) and CMOs (contract manufacturing organizations) (14). Developed chemistry/manufacturing process does not have to be manufacturing ready optimized as it is going to be outsourced to a CMO/CDMO (14). These are marriages of convenience. In these relationships, speed to market still intervenes and even might take precedence. Many might not recognize or want to accept pharma’s this posturing. However, it is a reality. 


Outsourced organizations are taking processes that are developed in-house, tweak them to fit in their equipment to make them better. They may not be optimum as speed to market is still the key. We have to remember that anytime a product and its process is presented to the regulators, it cannot be changed. It is carved in stone. Any re-approval/modification can be expensive. This prevents and/or minimizes process of continuous improvement that is expected and is normal for every manufacturing process. 


One could question the current regulations, especially when it comes to process improvements. Most likely regulator’s current posture is due to companies not taking their responsibility to produce quality drugs seriously. This raises a question. Are the in-process testing requirements too stiff or have the regulations gone too far to create high drug prices and ongoing shortages? Current drug distribution system (15) prevents direct patient competition and is also part of the problem (10). Competition creates excellence in manufacturing technologies. It is the missing element in pharma.  


There are ills with the current manufacturing practices. They come from low process yields due to unoptimized processes and fitting processes in the available equipment. Processes fitted in the existing equipment can only work with high solvent use, even when recovered and recycled (7, 8, 9,10). This results in pharma having the highest emissions per kilo of the products (16). Some in the pharmaceutical industry do not accept such numbers. 


Can Marriage of Science (Drug Development) and Technology (Drug Manufacturing) be Saved? 


In brand pharma’s marriage “drug discovery” development of new drugs for various ailments was and is the basis of each company’s mission. From inception of the drug industry, as discussed earlier, new drug discovery has been an internal task or comes through acquisitions. Commercialization was an internal thing. However, it is being increasingly outsourced to CMO or CDMOs (14). Due to speed to market, process optimization and environmentally sound process (technologies) have gone by the wayside. Patent life of the brand drug also influences commercialization speed. Generally companies own the product and the process. Outsourcing is minimizing this ownership. As indicated earlier getting the village (7) involved might extend patent life. 


Generic API drug and their formulators generally will do their best to have an optimum process. They have time before they commercialize. Most of them may improve the API chemistry. However, it will still be executed using a batch process (12) in the existing equipment. This is true for API formulations also. Their current business model prevents them to do that even when better processes can be developed and commercialized (10, 17, 18, 19). Since these companies know the molecules they want to produce, they should include the village (7, 8, 9) to create, develop and commercialize a very environmentally friendly continuous process (13) vs. a batch process (12). Effort is needed. 


Technologies and methodologies exist and continue to evolve (7, 8, 9). Companies have had these opportunities to take advantage of economies of scale but have followed age old practice of the fitting processes in existing equipment. Best way to describe the landscape is existing processes are essentially an extension of the laboratory process and use of existing equipment. Not many have explored use of modular technologies (7). My conjecture is that past tradition are an obstacle. 


Inclusion and use of modular processes and operations will need experienced resources which they might not have. Internalization of process development will fill the gap and can only happen if the current business model is changed. Likelihood of that happening is very dismal. Only an “outlier pharmaceutical company” using a different product and process development and manufacturing philosophy will attempt it. Every such investment will have to be internally justified. 


On the pharmaceutical landscape not enough effort has been devoted to evaluate alternate business options. Many could say they do not have the time. They do have time. All along they have been looking at the glass half empty vs. being half full. They have not evaluated long term impact of their current practices. As suggested earlier manufacturing process development effort has to be put in from inception of drug molecule (7, 8, 9, 10) to create excellent processes. 


Review of the various synthesis chemistries suggests that the laboratory chemistry has been scaled up to produce molecules in the plant and real chemical engineering may not have been applied to create excellent processes. Process developers need to exploit physical properties, mutual behavior of reactants and unit operations to create excellent processes (7). This observation is based on their process descriptions. My conjecture is that the total time spent could be less than the current time to scale-up and commercialize if village (7) is involved from molecule inception.  


Outsourcing of process development, manufacturing and regulatory compliance could give the companies short-term profitability boost but for the long term it can be a disaster for sustained better quality, drug affordability and environment as CDMO companies will not be putting any effort in continuous improvement to lower costs. Their interest is to produce products for their profitability and not for sustained availability. They could dump the existing lower profitability businesses. In addition, companies will not have the marriage they started with but would switch to new products that improve their own profits. 


It is well documented and known best marriages are a continuous effort. Temporary relationships with CDMOs/CMOs are fragmented marriages and long term not the best operating option on the pharma landscape. Continued outsourcing practices could progressively lead to increased shortages. It will be bad for the pharma companies as they will lose their public image, product and process technology superiority leading to some of the companies disappearing in the sand storm they have been creating in the recent years. To save marriage of Science (Drug Development) and Technology (Drug Manufacturing) “outliers” are needed. Any volunteers? 


Girish Malhotra, PE




EPCOT International 

1.     Unit Processes in Organic Synthesis. P. H. Grogginess, Fist Edition, McGraw-Hill Book Company Inc. New York and London 1935

2.     Unit Operations https://en.wikipedia.org/wiki/Unit_operation

3.     Kranzberg, Melvin: THE UNITY OF SCIENCE—TECHNOLOGY, American Scientist Vol. 55, No. 1 (March 1967), pp. 48-66 Published By: Sigma Xi, The Scientific Research Honor Society

4.     Kranzberg, Melvin: Technology and History: "Kranzberg's Laws" Technology and Culture Vol. 27, No. 3 (Jul., 1986), pp. 544-560 (17 pages) Published By: The Johns Hopkins University Press

5.     Mims, Christopher: The Six Laws of Technology Everyone Should Know, The Wall Street Journal, November 26, 2017

6.     Hippocratic Oath

7.     Malhotra, Girish: Active Pharmaceutical Ingredient ManufacturingDe Gruyter April 2022

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

9.   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

10.  Malhotra, Girish: Profitability through Simplicity

11.  Facts About the Current Good Manufacturing Practices (CGMP) May 31, 2023

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

13.  Continuous Production https://bit.ly/2Rp3Xlu

14. CMO/CDMO https://en.wikipedia.org/wiki/Contract_manufacturing_organization

15.  Malhotra, Girish: Opportunities to Lower Drug Prices and Improve Affordability: From Creation (Manufacturing) to Consumption (Patient), Profitability through Simplicity, March 9, 2018

16.  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 

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

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

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

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