ENVIRONMENTAL CONSERVATION (GREEN CHEMISTRY, NET ZERO, DECARBONIZING) IN ACTIVE PHARMACEUTICAL INGREDIENTS (APIS) & FINE/SPECIALTY CHEMICAL MANUFACTURING:

I am sure most of us have heard and/or read about “Green Chemistry (1998) ” ⁽¹⁾, “Net Zero (2009)” ⁽²⁾ and then Decarbonizing” ⁽³⁾. Before we can tackle them we need to understand what do these mean and how they came about in chemical manufacturing processes needs to be understood. Before these words became in vogue environmental conservation has been the basic necessity of each process design and manufacture of every chemical but did not have high emphasis. Protecting our environment has been chemist and chemical engineer’s  legacy but the degree has varied. 

It is speculated that an investment of ~$9 trillion dollars ⁽⁴⁾ per year would be needed has to achieve 90% Net Zero or Decarbonization by 2050. What is the basis of this money, how it is going to be spent and how much of these monies are allocated to pharmaceuticals is an unknown. What methods and/or technologies will lead to decarbonization of API have not been proposed or even conjectured ⁽⁵⁾. The proposed yearly (~$9 trillion per year) amount is so large that It is beyond anyone’s imagination. I hope someone from McKinsey & Co. can shed some light on the numbers their breakdown and the technologies that will lead to decarbonizing of pharma APIs.

I am presenting my perspective and is not influenced by any “for profit or nonprofit” organization. It is also worth refreshing how did the industry arrive at the current situation. I have been involved in various capacities with environmental conservation in organic chemical (includes fine/specialty chemicals, additives, coatings and pharmaceutical and petrochemical industries since 1968. I believe there are simple ways to get to Net Zero in API manufacturing and their formulations but effort is needed. A concerted effort would need diligent application of principles of chemistry and chemical engineering. I am sure companies can achieve the target/s with lower spending. I am sharing methods that I have practiced and work. I have respectfully repeated myself to drive the point home. We have an excellent opportunity to reduce pharma’s carbon footprint. 

HOW DID PHARMA GET TO THE CURRENT SITUATION? 

Most of the chemical synthesis innovation started with the manufacture of dyes and colorants in Europe ⁽⁶⁾. Wood vats were used as they were available. These reaction vessels were open top or had wood lids. With time metallurgy developed. Processing equipment developed and mechanical agitators became the norm. As the mechanical engineering and metallurgy developed agitated vessels/reactors reaction vessels had lids and jackets that were necessary to heat and or cool the reactions other processing equipment ^{(6, 7, 8)} came about. With time process controls methodologies developed and have greatly assisted manufacturing processes. 

Dye and colorant manufacturing companies ⁽⁶⁾ in Europe discovered many of the chemicals had disease curing value, they became the titans of pharma landscape ⁽⁶⁾. Companies also discovered that same organic chemistries applied to dye chemicals and disease curing chemicals. By changing the solvent amount used in the recipe their manufacturing processes could be fitted in the existing equipment. Cleaning of the equipment in between processes and products minimized cross contamination. This led to minimum new investment for the API (disease curing) synthesis chemicals. These practices have since continued.  

While the chemicals were being developed, knowledge of chemistry and how manufacturing practices of the chemicals was being standardized. There were simultaneous developments in chemistry unit processes ⁽⁹⁾ and chemical engineering unit operations ⁽¹⁰⁾. Their adoption and application in the production of chemicals led to manufacturing process simplification and improvements in life style and life longevity. Products that improved life style became additives and the products that extended life were called pharmaceuticals. Interestingly their synthesis processes and equipment did not change except pharmaceuticals needed higher quality scrutiny as human lives depended on them. 

Fitting processes in the existing equipment that started about 70+ years ago has led to excessive use of solvents for most of the API manufacturing processes and is a standard practice for API manufacture. “Art of fitting processes” has minimized capital investment for APIs and has become the pharmaceutical industry norm. This fits pharma’s business strategies for low yearly volume products that are needed for most of the APIs (one kilogram of API can produce ONE MILLION of one milligram tablets (10000 kilo converts to 100 million tablets). Practice of fitting processes has led to low ~about 35% equipment utilization ⁽¹¹⁾. These practices have also led to highest organic emissions (solid, vapor and effluent) waste per kilo of product ⁽¹²⁾. Since the same equipment can be used to produce different APIs, government regulators came along and cGMP practices became mandatory. Cleaning in between each batch and different products is necessary to prevent cross contamination of products. Excessive amounts of solvents are needed to fit the process in the equipment for the highest conversion they can achieve has brought us to the current situation where global warming is knocking on our doors. As explained later creating an environmentally friendly process is the NEW challenge for the pharmaceuticals. We have the wherewithal that is needed but have to master it. I have been fortunate as I practiced environmental conservation for the last 55+ years and have been mindful. 

PATHWAYS TO EMISSION REDUCTION IN FINE/SPECIALTY/ADDITIVES/COLORANTS (LIFE STYLE) AND PHARMACEUTICALS: API (DISEASE CURING CHEMICALS) AND THEIR FORMULATIONS:

Chemical industry and that includes life extending (API) and life style improving (additives) products do not need to name existing methods as new manufacturing technologies ⁽¹³⁾ but apply the fundamentals of science and engineering that are taught to us differently. Laboratory practices teach us the reaction chemistry ⁽⁹⁾. How we translate them to produce a product ⁽¹⁰⁾ is up to each chemist and chemical engineer. As suggested earlier environmental conservation has been part of chemical engineer and chemist’s teaching legacy but their degrees of application has varied. Yearly production volume of each chemical dictates the manufacturing process for each chemical i.e. would they be a batch ⁽¹⁴⁾ or a continuous ⁽¹⁵⁾ process. Their definitions have been established and are over 100 years old. Calling a batch process a continuous process has become in vogue lately. Continuous processes are product specific.   

OUR LEARNINGS AND TEACHINGS: FITTING THE PROCESS IN THE EXISTING EQUIPMENT:

Since the inception of the fine/specialty/coatings/additives and pharmaceuticals industry (active pharmaceutical ingredients (API) and their formulations) chemists and chemical engineers as stated earlier have mastered the science and engineering of fitting their processes in the existing equipment. This tradition started in earnest about 70+ years ago when chemical companies dyes, colorants and other chemicals found that some of their molecules could cure diseases ^(6,7,8). This is just a reminder to us all. 

PATH TO GET TO NET ZERO:

In the fine/specialty chemicals and their younger cousin API and their formulations show us pathways ^(9,10) that we are taught but have not exploited totally. We start with the synthesis in round bottom flask. In my own way I call commercial reactors larger round bottom flasks that have built in heating and cooling systems. This is due to the process developers taking a short cut of fitting chemistries in the existing equipment where various unit operations can executed. Reason for this path has been our laboratory teachings and availability of existing plant equipment. Unless we are proactive ⁽¹⁶⁾ to get to Net Zero, it is very likely that the chemical industry and which includes API and fine/specialty chemicals, will not make much progress. Out of the box thinking is needed. It has to be a collaborative effort and village’s ^(6,7) help is necessary. 

Each chemical optimally reacts with the selected chemical to produce the desired product. Physical chemistry ⁽¹⁷⁾, unit processes ⁽⁹⁾, reaction kinetics ⁽¹⁸⁾ and unit operations ⁽¹⁰⁾ show/teach us how mutual behavior of chemicals can be capitalized on to create excellent and simple processes ^{(6,7,8, 19, 20, 21, 22, 23, 24, 25, 26, 27)}. If the pharmaceuticals (API) need to get to Net Zero they will have to collectively capitalize on physical properties ⁽¹⁶⁾ of chemicals used and produced, unit processes ⁽⁹⁾ and unit operations ⁽¹⁰⁾ differently. Such processes compared to their current processes would be generally get lot closer to NET ZERO. If the pharmaceutical industry cannot get to NET ZERO outliers like Steve Jobs ^{(28, 29)} would be needed at every company. In addition giving new names to existing methods is not going to change the landscape ⁽³⁰⁾. Industry will have to be proactive. 

I am emphasizing it again that understanding and exploitation of physical and chemical properties along with reaction kinetics ⁽¹⁸⁾, thermodynamics ⁽³¹⁾, unit processes ⁽⁹⁾ and unit operations ⁽¹⁰⁾ give us opportunities to scale up and commercialize many chemical processes using smaller sized equipment. That immediately leads to solvent reduction per kilogram of the product. Net Zero happens naturally. These are exhilarating experiences. 

CAPITALIZING ON MUTUAL BEHAVIOR OF CHEMICALS:

Why we have not capitalized on mutual behavior is an intriguing question and the answer may be simple. We are taught fundamentals of chemistry and chemical engineering but may not be exposed “how to manipulate and capitalize on them to create excellent processes”. That comes only with hands on experience or when we see examples of how one capitalizes on mutual behavior to create simple and excellent process. They generally are eureka moments. In many cases this results in solvent reduction and/or reaction simplification through reduced time and process simplification.   

Knowledge (physical properties of reactants, their mutual behavior, unit processes, unit operations and understanding of various available processing equipment) would be applied to according to production volumes for the existing and new products. Creativity and imagination can simplify many processes at minimum cost and/or investment. I have emphasized many times over to drive a point that we have opportunities to get to “Net Zero”. 

Learning curve to capitalize on mutual behavior of chemicals used and produced in every reaction is generally  short as every chemist and chemical engineer knows the fundamentals of chemistry and chemical engineering of each product they produce. They have to be creative and imaginative to apply them. However, many would likely say “it can’t be done”. Saying “NO” is the simplest answer to anything different from what we are used to . This is human nature. Examples of how mutual behavior can be capitalized and are shared ^{(6, 7, 8, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,48, 49)}. 

Yes, again a totally different thinking and execution of manufacturing processes will be necessary. Basically to minimize solvent use per kilo of each product requires capitalizing on the mutual behavior of solution or slurry of each raw material, intermediate and finished product. Process is very simple. As soon as the chemistry of each product is defined it is necessary that the village ^{(6, 7, 8)} gets involved to develop, design and commercialize the product. This is a deviation from current practices. Knowledge of physical and chemical properties and their mutual behavior specially solubilities have to be well known. If they are not known they will have to be developed. The whole process development has to be internalized. This is extremely helpful during the life of the product for process design, changes and any troubleshooting of the manufacturing process and changes. Underlying question we have to ask ourselves is “what can be done to have an all liquid process”. This will minimize using inert liquids as solvents, a major step towards “Net Zero”. 

A simple example would be a low melting solid starting material could be dissolved in a solvent, solution made and fed to a reactor at e.g. 40% concentration vs. fed as liquid at 100% concentration in an inline circulating loop to finish the reaction. There are many examples of such reaction systems in the references ^(6,7,8). Not only the solvent can be was minimized but possibly a batch process could be converted to a batch campaign process or a totally continuous process. Experienced chemical engineers can further simplify processes by using modular and/or equipment ^(6,7,8) that may exist on their sites. Pilot plant and its equipment can be a gold mine. If done right some of the products could be that some of the APIs that have consolidated global volume of about 100,000 kilos per year or more could consolidate and be produced using continuous process rather than batch processes at multiple sites. 

ISSUES THAT WOULD HAVE TO BE DEALT WITH: 

One underlying question for the pharmaceutical industry is that it is very aware of having the highest emissions per kilo ⁽¹²⁾ of product in the chemicals related industries but it has not been proactive to improve its manufacturing technologies to lower them. Is it the costs involved in lowering emission through commercializing better processes and not getting the desired return or the regulatory hurdles that are expensive that prevent companies to make an attempt? I don’t want to speculate the answer and let the pundits cogitate over the issue. Whatever the answer, pharmaceutical industry has to deal with the issue that has been overlooked. It cannot procrastinate any longer.  

There are challenges. We can call them “ROADBLOCKS” to get to Net Zero. They are different for brand and generic products. Even with some commonalities most likely each will have different pathways. All of the necessary work to get to NET ZERO has to be done at internally at each company as the chemists and chemical engineers are most familiar with their products and processes. They are the product and process experts ^{(6, 7, 8)}. Outsiders may be able to guide them but the detailed work has to be internalized. Outsourcing work, it is my guess, will extend time as the learning time will further delay the process. I don’t think companies want to share their family jewels. It is best to discuss the brand and the generic products separately. 

NEW BRAND AND NEW GENERIC PRODUCTS:

I am not going to go in the details but everyone who is involved in Net Zero should understand that the process starts when the chemistry is written on paper i.e. the process starts with inception of the product. Village ^(6,7,8) has to get involved right away as if the product is going to be a success and commercialized. Even if it is not, it is an excellent opportunity to known the chemicals used and produced. It will be a learning opportunity for how the process equipment can be manipulated to simplify processes. Engineers can think, scout and tinker with the different processing equipment and cross fertilize from different industries. Every effort has a common goal and that is minimize solvent use and produce the highest quality product. This is a significant deviation from current practices. As indicated earlier even if the product is not commercialized, it will be a team effort and useful for future projects. This will be total landscape change with significant resistance.

EXITING BRAND AND GENERIC PRODUCTS:

“Net Zero” pathways for the existing brand and generic products will be different in many ways but will also be similar. Who is going to invest and what would be the return and its value will be a major concern and question. If there is no product cost reduction, which means no payout, no one will pay for the investment. If company’s costs go up even after solvent reduction and they get passed on to the patients i.e. distributors keep their profits, overall drug prices will go up and there will be mass uproar against  “Net Zero”. Every such program could come to screeching halt. Way out of this dilemma could be direct sales to patients and eliminating the current distributors and let the competition dictate the sale price. Competition will define the new landscape. Current pharmacy benefit managers (PBM) will not like that and will interfere for “Net Zero” becoming a reality. In US Congress would have to get involved. Likelihood of that happening is minimal to none. 

Regulators could demand bioequivalence of products from alternate processes. Proving that could be expensive and time consuming. Brand companies would not do anything for the products currently under patent unless they assure product performance with new processes. Regulators will have the final say.    

It is very likely that in its effort to achieve API manufacturing landscape could change. This could happen due to the needed investment, regulatory expenditures, pressures, pharmacy benefit managers (PBMs) and realignment of the manufacturing and  changing landscape. There may be additional questions. If 50% to 60% reduction can be achieved in the next 15 years, it will be a major accomplishment. I have made an attempt that I believe would lead to “Net Zero”. It is a start and will need fine tuning. Doing something is better than doing nothing. Please share your knowledge. It is an opportunity to preserve our planet “EARTH”. Thank you. 

Girish Malhotra, PE

EPCOT International

References:

 

1.     Green Chemistry: https://www.acs.org/greenchemistry/what-is-green-chemistry.html Accessed September 15, 2024

2.     Net Zero: https://eciu.net/analysis/infographics/net-zero-history

3.     Decarbonizing: https://www.unepfi.org/grt/2016/programme/decarbonizing-finance/ Accessed September 10, 2024

4.     What is Net Zero: McKinsey & Co. Accessed November 2022

5.     Witte C. et. al. Decarbonizing API manufacturing: Unpacking the cost and regulatory requirements, July 26, 2024 McKinsey & Co. July 31, 2024

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

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

8.     Malhotra, Girish: Chapter 4 “Simplified Process Development and Commercialization” in “ Quality by Design-Putting Theory into Practice” co-published by Parenteral Drug Association and DHI Publishing© February 2011

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

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

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

12.  Sheldon R.A. The E factor 25 years on: the rise of green chemistry and sustainability, Green Chemistry  https://pubs.rsc.org/en/content/articlelanding/2017/gc/c6gc02157c/unauth#!divAbstract , 2017, 19, 18-43 Accessed February 17, 2021 

13.  Malhotra, Girish: Manufacturing Technology Innovations in Pharmaceutical Manufacturing, Profitability through Simplicity, February 23, 2024 

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

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

16.  Malhotra, Girish: Why Fitting a Square Plug in a Round hole is Profitable for Pharma and Most Likely Will Stay? Profitability through Simplicity August 1, 2014

17.  Levine, Ira: Physical Properties Sixth Edition 2009 McGraw Hill

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

19.  Sociochemicology Sociochemicology 2013 

20.  Malhotra, Girish: Secret Life of APIs , Profitability through Simplicity, Feb. 13, 2013

21.  Malhotra, Girish: Rx for Pharma, Chemical Engineering Progress, 105 (3) March, 34-38 (2009), 

22.  Malhotra, Girish: Focus on Physical Properties To Improve Processes: Chemical Engineering, 119 (4), April, 63-66 (2012).

23.  Malhotra, Girish: Conflicts and opportunities in the Life of APIs, Chimica Oggi-Chemistry Today Vol. 31 (4) July/August 2013 pgs. 10-13

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

25.  Malhotra, Girish: Process Simplification and The Art of Exploiting Physical Properties

Profitability through Simplicity March 10, 2017

26.  Malhotra, Girish: Capitalizing on Mutual Behavior and Chemical Reactivity of Chemicals, Profitability through SimplicityMay 29, 2023

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

28.  Malhotra, Girish: Can the Combination of Creative Destruction and “Steve Jobs’ Traits” Lead to Pharma QbD Spring? Profitability through Simplicity, April 15, 2012 

29.  Malhotra, Girish: Does the Pharmaceutical Industry Need A Steve Jobs? Profitability through Simplicity, November 8, 2011  

30.  Malhotra, Girish: Is the New Terminology Going to Make the Pharmaceutical Processes Environmentally Friendly and Economic? Profitability through Simplicity, June 5, 2012

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

32.  Malhotra, Girish: Quick Review of Chemicals Related Process Development, Design and Scale up Considerations, Profitability through Simplicity, November 7, 2018

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

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

35.  Malhotra, Girish: Climate Change and Greening of Pharmaceutical Manufacturing, Profitability through Simplicity, January 24, 2022 

36.  Malhotra, Girish: Pharma’s Active Pharmaceutical Ingredient Manufacturing: Their Environmental Impact and Opportunities, Profitability through Simplicity,  March 3, 2022 

37.  Malhotra, Girish: Art and Science of Chemical Process Development & Manufacturing Simplification https://www.aiche.org/ili/academy/webinars/art-and-science-chemical-process-development-manufacturing-simplification May 17, 2023

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

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

40.  Malhotra, Girish: Marriage of Science and Technology in Active Pharmaceutical Ingredient (API) Manufacturing and their Formulations: Is it for real? Profitability through Simplicity, September 21, 2023

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

42.  Malhotra, Girish: The Good, The Bad, and The Ugly (1) Complexities of the Pharmaceutical Manufacturing, Profitability through Simplicity, April 9, 2018, Contract Pharma June 2018 Vol. 20 No.5

43.  Review of Continuous Process for Modafinil, Continuous Processing in the Chemical and Pharmaceutical Industry II, 2009 AIChE Annual Meeting, November 10, 2009,Nashville, TN. 

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

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

46.  Malhotra, Girish: EXPLOITATION OF QBD ELEMENTS FOR A BATCH/CONTINUOUS PROCESS https://www.slideserve.com/elia/exploitation-of-qbd-elements-for-a-batch-continuous-process International Pharmaceutical Academy October 19-20, 2009

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

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

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

US’s Self Sufficiency for Generic Drugs: A Supply Dilemma and Potential Solutions

The following are reviewed. 

 

1.     US Pharmaceutical supply vulnerability and an Antidote

2.     Thoughtless US government spending in the name of US’s self-sufficiency/ manufacturing technology

3.     US’s Pharma Supply Security

 

Landscape, perspective and potential solution presented are my own. They are a place to start. If US does not do anything, lack of supplies will come to haunt its population. There is no financial relationship with any entity. 

 

US Pharmaceutical (Generic Drug) Supply Vulnerability: 

 

Generic drugs make about 89% of the prescription drugs dispensed in USA ⁽¹⁾. Most of them are imported. US due to their continued supply may not consider them as its vulnerability. We need to recognize that US does not have the capability and capacity to produce many of the active pharmaceutical ingredients (API) and their formulations for the most generic  drugs. Lack of their continued supply can be used as a weapon to paralyze the country. Thus, a vulnerability exists.

 

The United States may be able to supply some drugs from its strategic stockpile ⁽²⁾ but as said earlier it does not be ability to sustain the long term needs. Unless US can produce its own generic/brand drugs, challenges will remain on an ongoing basis. This could be argued but we have recognize that the strategic stockpile ⁽²⁾ has limited supplies. This situation presents an opportunity to bring manufacturing home and lower the generic drug prices. 

 

Not much attention has been paid to this vulnerability. An old report about Homeland Risks ⁽³⁾ maybe still valid and very meaningful. An update is needed. Various plans, explanations and Executive orders have been proposed and nothing meaningful has resulted ^(4-10). Unless US takes bold steps to ward off the current situation, it will pay a heavy price for the healthcare of its population. 

 

We have to recognize that the current situation developed due to Hatch-Waxman law ⁽¹¹⁾ and lax environmental laws of other countries ⁽¹²⁾. US’s vulnerability can only be alleviated if it can manufacture its own drugs. Success in indigenous manufacturing as explained later could also lower generic drug prices. Effort will be necessary. However, the following will come in the way of bringing manufacturing home.

 

Industry has relied on manufacturing technologies that are more than 70+ years old. If the industry does not change its methodologies, generics produced in US will be the more expensive than the imports and US healthcare will suffer. For indigenous manufacturing, pharma will have to consider alternates business models/methods ⁽¹³⁾. 

 

US does not have many FDA approved API manufacturing plants that have the approved equipment to produce the needed/selected generic drugs. Unless planned, the processes will be fitted in the existing equipment. For formulations the existing plants will require product qualification and regulations will come in the way. Thoughtless fitting of the processes in the existing plants will result in high emissions per kilo of the product ⁽¹⁴⁾. Even if we had laboratory proven processes and the necessary commercial equipment, most likely the needed raw materials will have to be imported. This will be another challenge as US does not produce the needed fine/specialty chemicals that are the building blocks of the generic drugs. 

 

Since each process and product will have to have FDA approval, timely commercialization like “yesterday” due to any emergency will not happen. FDA’s track record in approval of generic drugs at best is dismal. They take about 36-48 ⁽¹⁵⁾ months for approval and would not admit this time per product. COVID-19 approval was an unsustainable exception. FDA will have to change its methods ^{(16, 17)}. Even if all of “t’s” are crossed and “i’s” are dotted by the companies and meet FDA’s requirements, its approval will be still needed. This means commercial availability of products will take time.

If through stroke of luck we had the approved product/process, equipment and raw materials and were able to produce the generic drug in the United States, their generic drug prices will go up by multiples of the current prices. This will be due to higher manufacturing costs and PBMs (pharmacy benefit managers) and supply chain participants insisting on keeping their profit margins. All this will make the drugs unaffordable. There are known ways to contain costs but will require different business model and operating strategies ⁽¹³⁾. They are discussed later. 

Antidote: 

Regulators ^(3-10) have been presenting plans for the last few years but the wheels have not resulted in anything meaningful.Legislators have had hearings but have no idea of how to solve the issue. They recognize the issue but have to depend on the industry (pharma companies, PBMs) and the regulators who due to profits and vested interests respectively have balked to address the issue/s. 

 

To assure continuous supply of the generic drugs and counter any strategic threat to US population, combination of methodologies outlined herein or something similar would have to be considered/adopted to assure US is not caught short-footed. Totally out-of-box thinking and execution would be needed ^{(13, 15)}. 

 

Four State Model (Puerto Rico Model):

 

A model similar to the one used in Puerto Rico ⁽¹⁸⁾ to attract pharma manufacturing could be used. US could create FOUR “pharma manufacturing zones” on the main land at the junction of four states each to produce generic drugs. This way SIXTEEN US states will benefit and support the pharmaceutical manufacturing ventures. 

 

For the “FOUR STATE MODEL” to succeed FDA’s rules and philosophies for generic approval and drug distribution will have to be modified ^{(19, 20)}. With generic factories being in sixteen states they could sell directly to patients at factory costs plus their reasonable margins. This would change the pricing landscape. Compliance with FDA regulations will not end. Spot checking of product quality will assure consistent quality. Any deviation would result in the factory not able to sell the products in the US market. An example of pricing is illustrated in Table 1 ⁽¹⁹⁾ . 

 

Drug	Metformin HCl	Ciprofloxacin	Levothyroxine	Atorvastatin
API cost $/kg (2)	4.00	25.00	4400.00	310.00
Inert excipients $/kg (@40%API cost)	1.60	10.00	1760.00	124.00
Conversion cost, $/kg(@40%API cost)	1.60	10.00	1760.00	124.00
Profit (@ 40% above)	2.88	18.00	3168.00	223.20
Total. $/kg	10.08	63.00	11088.00	781.20
Average Dose	500 mg	500 mg	0.112 microgram	20 mg
Formulator Sale price per tablet, $	0.005	0.032	0.001	0.008
Four State Model Factory Direct Sale price, $ per dose
Price, $ per tablet	0.03	0.10	0.10	0.10
Current Patient purchase price, $/tablet
Walmart	0.07	1.04	0.11	0.30
Rite-Aid With insurance	0.07	0.2	0.17	0.31
Rite-Aid Without insurance	0.7	4.77	0.82	3.97

 

Table 1: Factory sell prices vs. current sell prices ⁽¹⁹⁾

Many vested interests and that could include the legislators and the regulators will negate such plans on sight. PBMs and the supply chain will fight the above suggested plans “tooth and nail” as their profits would be drastically lowered. 

 

Focus on generic drugs would lead to manufacturing technology innovation which has been illusive to pharma as it has lived with its old “mortar and pestle” ways. We have all the knowledge and wherewithal to make the change ^{(13, 14, 15, 16, 17, 21, 22, 23)} if we incorporate principles of chemical engineering and chemistry from the onset of product/process development. Manufacturing technology innovation has been and is US HALLMARK but pharma has deliberately decided not incorporate it as their profits are assured. This is extremely ironic that pharmaceuticals, a subset of fine/specialty, has mostly ignored application of fundamentals of engineering and science ^{(13, 21, 22)}. As I have indicated naysayers will linger on and block any innovation. Unless bold steps are taken US could succumb to drug shortages and may not be able to take care of its masses. If we fail we will have no one but us to blame. With time learnings of generic success could be extended to brand drugs also.   

                                                            

Thoughtless US Government Spending:

 

As indicted earlier there is recognition of drug supply issues. US Government in its efforts to mitigate drug shortages and dependence has doled out monies that have no return. Funded enterprises have convinced US Government to spend close to billion dollars on pharma manufacturing technology innovation and bring manufacturing home. Some the technologies and methods to be developed in these programs are routinely taught at our universities and have been in existence for the last 70+ years. Since the companies are not using them commercially, there have to be rational reasons. Funding recipients and funders will disagree. Funding also begs a question “do the funders really understand what the funded organizations would do and deliver and their ROI?” For continued funding a periodic external audit of deliverables and their commercial viability is necessary. 

 

In 2020 BARDA, Biomedical Advanced Research and Development Authority of U.S. Department of Health and Human Services (HHS) granted PHLOW Corporation about $812 million in the pretense of bringing pharma manufacturing back to US when the company has no plant, no approved product or a process ⁽²⁴⁾. In the name of innovation and COVID-19, this company is outsourcing manufacturing at US based subsidiaries of foreign companies. This should not be considered as independence. Since the products or their processes that would be produced at this company’s facilities are not know or FDA approved, it is difficult to speculate their selling prices. If they are based on pharma’s current traditions, they will be higher priced than comparable imported drugs.  

 

Similarly Department of Defense (DOD) granted Continuus Pharmaceuticals $69.3 million to develop continuous manufacturing capabilities ⁽²⁵⁾ for critical drugs. Irony is that the company, with no commercial products, or DOD do not know which critical drugs they will test or are they FDA approved products/processes. Since this is research company, FDA does not know if the equipment is suitable to produce these drugs. Actually DOD or most of the companies including US FDA have created their own definition for a “continuous process” that is quite contrary to the established definition for continuous processes ⁽²⁶⁾ that have been practiced for the last 70+ years for the manufacture of fine/specialty chemicals but not API, a subset of fine/specialty chemicals. FDA would not detail on paper its definition.

 

To make a mockery of our engineering education and our universities’ intelligence US Congress through HR 4369 (National Centers of Excellence in Advanced and Continuous Pharmaceutical Manufacturing Act of 2021⁽²⁷⁾ and through S-2589 (Securing America’s Medicine Cabinet Act of 2021) ⁽²⁸⁾ are asking for funding for producing drugs using continuous processes which have been practiced for over 70+ years. HR 3851 Continuous Manufacturing Research Act Of 2021 ⁽²⁹⁾ fits the same frivolous spending category. 

Funding for Continuus Pharmaceuticals ⁽²⁵⁾,  HR 4369 ⁽²⁷⁾, S-2589 ⁽²⁸⁾ and HR 3851⁽²⁹⁾ are supported by FDA whose personnel have no hands-on experience in process development, scale up and commercialization of any  continuous processes per established definition ⁽²⁶⁾ practiced by chemical engineers for more than 70+ years. 

RAPID Institute (American Institute of Chemical Engineers, AIChE), New York, New York ⁽³⁰⁾ funding suggests that our universities have failed to teach chemical engineers and chemist how to practice chemical engineering and source raw materials. It is ironic that AIChE is the trade organization of chemical engineers where sourcing of raw materials is part of CHE101 classes.  

 

Universities teach the fundamentals that are creatively and imaginatively applied to commercialize excellent processes. However, pharma companies, as said earlier due to their “mortar and pestle” ways, have ignored the fundamentals when it comes to their manufacturing practices. Lack of application of the best practices of the fine/specialty chemical industry in pharma, a subset of this group, has been pharma’s way of life. This has resulted in it being the highest pollutant emitter per kilo ⁽¹⁴⁾ in the chemical segment. We have to remember that drugs are fine/specialty chemicals that have disease curing value. Thus, the best technologies that are being used elsewhere can be applied here also. 

 

US’s Pharma Supply Security:

 

US has been satisfied and content with its pharma supply chain as “half full” glass. However, the current global political turmoil, starting with oil and gas, very well could lead to global economic and business transformation. It could lead to “deglobalization”. Thus to assure the supply of essentials and that includes food and drugs, US needs to look at its “half full glass” differently as “half empty” and needs to assure it is full. Existing methods and technologies that have been applied successfully in the fine/specialty chemicals and overlooked in pharma could be applied differently to assure its continued supply. This will result in alternate business models. 

 

Pharma can be the easiest and quickest candidate for “deglobalization” as the relevant technologies needed for transformation are being practiced but inefficiently to furnish the current needs of US population ^{(14-17, 21, 22, 23)}. Outliers will be needed. They will result in a better landscape and alleviate the current drug dependence from other countries. Success will change healthcare practices of The United States. Even with the application of these newer methods development of new drug development will not be hampered. 

 

With respect to pharmaceuticals, we need to think rationally rather than act on the basis of useless euphoria. Till US does that we will go nowhere especially when it comes to addressing the “strategic needs”. We have the knowledge base ^{(14-17, 21, 22, 23)} and need to apply it. Piecemeal projects ^{(24, 25, 27-30)} are shear waste of monies, effort and time that United States of America cannot afford especially under the current global political environment. A project team ⁽¹⁵⁾ similar to Manhattan Project ⁽³¹⁾ has to be assembled for the task of bring pharmaceutical manufacturing home. 

 

FDA, PBMs, members of supply chain and even the legislators in the interest of wellbeing of the nation will have to shed their vested interests. Public welfare and needs have to come first. If US can send the human to the moon and bring him back safely, bringing pharmaceutical manufacturing home should be a cake walk. 

 

Girish Malhotra, PE

EPCOT International

 

1.     2017 Generic Drug Access & Savings in the U.S. https://accessiblemeds.org/sites/default/files/2017-07/2017-AAM-Access-Savings-Report-2017-web2.pdf  Accessed March 14, 2022 

2.     Sustaining the Stockpile:  https://www.phe.gov/about/sns/Pages/sustaining.aspx Accessed March 14, 2022

3.     Reliance on Foreign Sourcing in the Healthcare and Public Health (HPH) Sector: https://www.hida.org/App_Themes/Member/docs/GA/Industry-Issues/Emergency-Pandemic/Dept-Commerce-Study_Healthcare-Foreign-Sourcing.pdf  December 11, 2011 Accessed  March 20, 2022

4.     Executive Order 13944 of August 6, 2020, Accessed August 13, 2020 

5.     Executive Order 13588 -- Reducing Prescription Drug Shortages October 31, 2011, Accessed August 31, 2020

6.     Agency Drug Shortages Task Force, https://www.fda.gov/drugs/drug-shortages/agency-drug-shortages-task-force , Accessed September 1, 2020

7.     Woodcock, Dr. Janet: To Help Reduce Drug Shortages, We Need Manufacturers to Sell Quality — Not Just Medicine, October 24, 2019 Accessed November 6, 2019

8.     FDA Report | Drug Shortages: Root Causes and Potential Solutions October 29, 2019, Accessed November 6, 2019

9.     FDA is Advancing New Efforts to Address Drug Shortages, https://www.fda.gov/news-events/fda-voices/fda-advancing-new-efforts-address-drug-shortages  November 11, 2018 Accessed 

10.  Strategic Plan for Preventing and Mitigating Drug Shortages FDA October 2013 Accessed March 1, 2022

11.  Hatch-Waxman Law https://www.govinfo.gov/content/pkg/STATUTE-98/pdf/STATUTE-98-Pg1585.pdf September 24, 1984 Accessed March 10, 2022

12.  Malhotra, Girish: Why Have the Fine and Specialty Chemical Sectors Been Moving from the Developed Countries? Profitability through Simplicity February 9, 2009 Accessed March 10, 2022

13.  Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation Accessed February 28, 2022.

14.  Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing (API) and Formulation Drive to NET ZERO (Carbon Neutral)? Profitability through Simplicity April 29, 2021 Accessed February 28, 2022

15.  Malhotra, Girish: A road map for driving pharmaceutical manufacturing back to the USA by 2025 Profitability through Simplicity October 8, 2020 Accessed March 10, 2022

16.  Malhotra, Girish: Strategies to Increase Generic Drug Competition and Bring Manufacturing to The United States of America, Profitability through Simplicity March 16, 2020 Accessed March 11, 2022 

17.  Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability, Profitability through Simplicity December 6, 2019 Accessed March 20, 2022

18.  MacEwan, Arthur: The Effect of 936 May 2016 Accessed March 15, 2022

19.  Malhotra, Girish: Systematic Demystification of Drug Price Mystique and the Needed Creative Destruction, Profitability through Simplicity October 2, 2019 accessed March 8, 2022

20.  Malhotra, Girish: ANDA (Abbreviated New Drug Application) / NDA (New Drug Applications) Filing Simplification: Road Maps are a Must Profitability through Simplicity May 17, 2017 Accessed March 10, 2022

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

22.  Malhotra, Girish: Quick Review of Chemicals Related Process Development, Design and Scale up Considerations, Profitability through Simplicity November 7, 2018

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

24.  US government to grant up to $812M to newcomer Phlow Corporation for Covid-19 manufacturing: Bringing pharma home or ‘profiteering off pandemic’? Pharmaceutical Technology July 16, 2020 Accessed March 7, 2022

25.  DOD Awards $69.3 Million Contract to CONTINUUS Pharmaceuticals to Develop US-based Continuous Manufacturing Capability for Critical Medicines  https://www.defense.gov/News/Releases/Release/Article/2474092/dod-awards-693-million-contract-to-continuus-pharmaceuticals-to-develop-us-base/ January 15, 2021 Accessed March 8, 2022

26.  Continuous production https://bit.ly/2qAyc9f

27.  HR 4369 (National Centers of Excellence in Advanced and Continuous Pharmaceutical Manufacturing Act of 2021 https://www.congress.gov/bill/117th-congress/house-bill/4369/related-bills July 6, 2021 Accessed March 10, 2022

28.  S. 2589 - Securing America’s Medicine Cabinet Act of 2021 https://www.congress.gov/bill/117th-congress/senate-bill/2589?s=1&r=54 August 3, 2021 Accessed March 1, 2022

29.  H.R. 3851 Continuous Manufacturing Research Act Of 2021,  https://www.congress.gov/bill/117th-congress/house-bill/3851?r=6&s=1 June 11, 2021 Accessed February 27, 2022

30.  Commerce Department Awards $54 Million in American Rescue Act Grants to Increase Access to Advanced Manufacturing Opportunities https://www.nist.gov/news-events/news/2022/02/commerce-department-awards-54-million-american-rescue-act-grants-increase February 28, 2022 Accessed March 2, 2022 

31.  Manhattan Project  https://en.wikipedia.org/wiki/Manhattan_Project Accessed  March 15, 2022