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

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 N₂ atmosphere 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 N₂ atmosphere 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 SO₂ and 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

1. Phull M. S. et. al. USP 11,267,798 B2 “Process for the Preparation of Piperine”, CIPLA Limited
2. Shreve, R. Norris: Unit Process In Chemical Processing, Ind. Eng. Chem. 1954, 46, 4, 672
3. Unit Operations https://bit.ly/2Rp3Xlu
4. Chemical Engineer’s Handbook, Fourth Edition, McGraw-Hill Chemical Engineering Series
5. Burke, J. What does net zero mean? https://www.greenbiz.com/article/what-does-net-zero-mean, May 2, 2019 Accessed April 27, 2021 
6. 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
7. Malhotra, Girish: Patents: Should We Change Our Intellectual Property Model/Strategies? Profitability through SimplicityOctober 5, 2012  
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: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation De Gruyter April 2022
11. Kalam, APJ Abdul, Wings of Fire: An Autobiography of APJ Abdul Kalam, Sangam Books Ltd, 1999 Accessed January 31, 2024
12. Levenspiel, O: Chemical Reaction Engineering, John Wiley & Sons 1999
13. Malhotra, Girish: Sociochemicology May 30, 2013   
14. Malhotra, Girish: Focus on Physical Properties To Improve Processes: Chemical Engineering, Vol. 119 No. 4 April 2012, pgs. 63-66
15. Malhotra, Girish: Process Simplification and The Art of Exploiting Physical Properties, Profitability through Simplicity, March 10, 2017
16. Continuous Production https://bit.ly/2Rp3Xlu

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

 

President

 

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 Manufacturing, De 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