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

 

Pharma’s Active Pharmaceutical Ingredient Manufacturing: Their Environmental Impact and Opportunities

Chemists and chemical engineers have their own perspectives when it comes to developing a process and commercializing it. It is interesting to note that same family fine/specialty chemicals and active pharmaceutical ingredients (API, a subset of fine/specialty family) have different techniques and strategies. Their development methodologies could be parallel but the pathways and results can be very different. Each could be quite simple and equally complex in their efforts to commercialize an economic process. 

Every company has to chart its own course, they feel comfortable with, for their profitability. However, with the recent limelight on “climate change” pharma companies will have to think and act differently from their practices when it comes to developing and commercializing a product. 

Purpose of this review is not to be critical or pick or choose what is the right product/process development strategy but to identify the opportunities that pharma could adopt and include to be proactive toward “climate change”. It well known that pharma has the highest emission factor among the chemical and related industries ^{(1, 2)}. 

 

Process Development:

 

Through analysis of a product’s chemistry existing landscape of an API is reviewed. Observations might not apply across the landscape but can be used as an example to improve the development of APIs. It is expected that this analysis will plant the seeds for the needed change that could lower pharma’s environmental impact ⁽²⁾. Change process and theri impact is not going to be instant. Considerable and ongoing effort will be needed. There is no financial relationship with any profit making and non-profit organization. 

I randomly selected molecule patented in US 10,669,279 B2 ⁽³⁾ and US 10,077,269 ⁽⁴⁾ for review. This molecule reduces the side effects (nausea, emesis, headaches and diarrhea) caused by COPD treatment using Roflumilat (Daliresp ®) and by Apremilast (Otzela ®) used for psoriatic arthritis (PA). Daily recommended dosage of this drug is 500 micrograms (COPD) and 60 milligrams (PA) respectively per day per year. COPD drug usage is in micrograms and that suggests that a separate tablet would have to be taken to counter the side effects. Same most likely would be true for Otezla. Since the invented drug will be new, based on pharma’s tradition of high pricing of any new drug, it is going to be multi folds expensive ⁽⁵⁾ compared to any existing drug that could be used to curb similar side effects. My expectation is that the company will do its best to expand market usage beyond these two diseases but the selling price can intervene wide spread usage.  

 

In the following example 1 of [USP ‘269 ⁽³⁾ and USP ‘279 ⁽⁴⁾ every chemist and chemical engineer will see that the process described is a laboratory synthesis and its translation to a commercial operation will be a challenge. Execution or scale up details are not discussed. Observations are made on solvent use and yield as they have environmental impact.

Fig. 1: Synthesis of Azetidin-1-yl[3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone (3) ^{(3, 4)}

 

Step 1. Synthesis of ethyl imidazo[1,2-b]pyridazine-2-carboxylate (C1) 

A mixture of pyridazin-3-amine (20 g, 210 mmol) and ethyl 3-bromo-2-oxopropanoate (82 g, 420 mmol) in ethanol (300 mL) was heated at reflux for 16 hours. After removal of solvent via distillation, the residue was taken up in 2 M hydrochloric acid (100 mL) and washed with ethyl acetate. The aqueous layer was basified to a pH of approximately 8 via addition of aqueous sodium bicarbonate solution and then extracted with chloroform; this organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Eluent: 20% ethyl acetate in petroleum ether) afforded the product as a brown solid. Yield: 8.0 g, 42 mmol, 20%. LCMS m/z 192.0 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl₃) .delta. 8.53 (s, 1H), 8.39 (dd, J=4.4, 1.6 Hz, 1H), 8.01-8.04 (m, 1H), 7.12 (dd, J=9.3, 4.4 Hz, 1H), 4.48 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H). 

Step 2. Synthesis of ethyl 3-iodoimidazo[1,2-b]pyridazine-2-carboxylate (C2) 

N-Iodosuccinimide (24.6 g, 109 mmol) was added to a solution of C1 (19 g, 99 mmol) in acetonitrile (250 mL), and the reaction mixture was stirred at room temperature for 24 hours. Additional N-iodosuccinimide (1 equivalent after every 24 hours) was introduced and stirring continued for a further 48 hours (72 hours overall), until complete consumption of starting material was indicated via thin layer chromatographic analysis. After removal of solvent in vacuo, the residue was taken up in dichloromethane and washed with 1 M hydrochloric acid and with water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure; silica gel chromatography (Eluent: 20% ethyl acetate in petroleum ether) provided the product as an off-white solid. Yield: 14.5 g, 45.7 mmol, 46%. LCMS m/z 318.0 [M+H].sup.+. .sup.1H NMR (300 MHz, DMSO-d₆) .delta. 8.74 (dd, J=4.3, 1.3 Hz, 1H), 8.18 (dd, J=9.2, 1.4 Hz, 1H), 7.41 (dd, J=9.3, 4.4 Hz, 1H), 4.35 (q, J=7.0 Hz, 2H), 1.36 (t, J=7.1 Hz, 3H). 

Step 3. Synthesis of ethyl 3-(4-chlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylate (C3) 

Aqueous sodium carbonate solution (3 M, 8.4 mL, 25 mmol) was added to a mixture of C2 (2.00 g, 6.31 mmol), (4-chlorophenyl)boronic acid (1.48 g, 9.46 mmol), and [1,1'-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II) (382 mg, 0.505 mmol) in 1,4-dioxane (32 mL). The reaction mixture was heated at 90º C. overnight, whereupon it was partitioned between ethyl acetate (150 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate (3.times.150 mL), and the combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) afforded the product. Yield: 1.25 g, 4.14 mmol, 66%. LCMS m/z 302.0, 304.0 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl₃) .delta. 8.39 (dd, J=4.3, 1.5 Hz, 1H), 8.09 (dd, J=9.3, 1.5 Hz, 1H), 7.65 (br d, J=8.5 Hz, 2H), 7.50 (br d, J=8.5 Hz, 2H), 7.17 (dd, J=9.3, 4.3 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.1 Hz, 3H). 

Step 4. Synthesis of 3-(4-chlorophenyl)imidazo[1,2-b]pyridazine-2-carboxylic Acid, Sodium Salt (C4) 

A solution of C3 (1.75 g, 5.80 mmol) in methanol (25 mL) and tetrahydrofuran (25 mL) was added to an aqueous solution of sodium hydroxide (2 M, 25 mL), and the reaction mixture was stirred at room temperature for 4 hours. The resulting solid was collected via filtration and washed with cold water (2.times.25 mL) to provide the product as a solid. Yield: 1.50 g, 5.07 mmol, 87%. LCMS m/z 274.0, 276.0 [M+H].sup.+. 

Step 5. Synthesis of azetidin-1-yl[3-(4-chlorophenyl)imidazo[1,2-b]pyridazin-2-yl]methanone (3) 

Compound C4 (1.40 g, 4.74 mmol) was combined with O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU, 2.92 g, 7.70 mmol) and N,N-diisopropylethylamine (3.56 mL, 20.4 mmol) in N,N-dimethylformamide (75 mL). After 2 minutes, azetidine hydrochloride (957 mg, 10.2 mmol) was added, and the reaction mixture was stirred at 50º C. overnight. After removal of solvent in vacuo, the residue was subjected to chromatography on silica gel (Gradient: 0% to 100% ethyl acetate in heptane) followed by trituration with ethyl acetate (30 mL) at 50º C.; this mixture was cooled to 0º C. and filtered. The collected solid was washed with diethyl ether (50 mL) and with cold ethyl acetate (15 mL). Subsequent recrystallization from ethyl acetate provided the product as an off-white solid. Yield: 980 mg, 3.13 mmol, 66%. LCMS m/z 313.2, 315.2 [M+H].sup.+. .sup.1H NMR (400 MHz, CDCl₃) .delta. 8.41 (dd, J=4.4, 1.6 Hz, 1H), 8.10 (br d, J=9.2 Hz, 1H), 7.75 (br d, J=8.6 Hz, 2H), 7.48 (br d, J=8.6 Hz, 2H), 7.19 (dd, J=9.2, 4.3 Hz, 1H), 4.46-4.57 (m, 2H), 4.17-4.28 (m, 2H), 2.28-2.39 (m, 2H). 

 

On review of the five process steps few things are very obvious. Excessive volumes and multiple solvents are being used at every step of each reaction along with low overall yield of Example 1 [about 3.48% = 0.2X0.46x0.66x0.87x0.66]. Such a low yield processes would be considered economically unviable process in fine/specialty chemical market. To every astute chemist and chemical engineer such yield numbers tell LOUD AND CLEAR that “the chemistry and the process needs help”. 

 

However, based on pharma’s practices of the last 70+ years, one can easily conjecture that the process chemistry developed in these patents has no consideration for their impact on climate change ^{(1, 2)}, yield  ⁽²⁾, cost or pricing ⁽⁵⁾. Since the invented drug will be new, based on pharma’s tradition of high pricing of any new drug, it is going to be multi folds expensive compared to any existing drug that could be used to curb similar side effects. Drug based on this API might have features above and beyond what is currently on the market but unless the drug is acquired through a mutually subsidized healthcare system, it will be prohibitively expensive ^{(5, 6)} and on the verge of being unaffordable to large population. Actually selling prices of API and their formulations are a small percentage of the drug selling prices. 

 

In addition, for a pharmaceutical product, cGMP practices will have to be followed and that means extensive cleaning will be required for each step/batch. Volume of solvent used in most processes can make the process simplification and their reduction a challenge. High solvent use also results in poor asset utilization ⁽⁷⁾. 

 

Patents USP ‘269 ⁽³⁾ and USP ‘279 ⁽⁴⁾ and every other API patent (brand or generic) present the following distinct opportunities. They can be considered and applied for every API synthesis. However, based on pharma’s tradition any such effort could be a challenge as process optimization is not an industry norm especially when the drug already has regulatory approval. 

 

1.     Yield improvement

2.     Solvent reduction

3.     Efficient asset utilization

 

If the average yield of each processing step in Example 1 of USP ‘269 ⁽³⁾ and USP ‘279 ⁽⁴⁾ is raised to 95% for each step, the overall process yield will be about 77.4% [0.95*0.95*0.95*0.95*0.95*= 0.774]. This will be about ~22 times higher than the overall yield from Example 1 of the reviewed patents. This would translate to significantly lower waste and reduction in number of solvents and their volume used in each step. All this will significantly improve the asset utilization and batch cycle times. Thus, there are opportunities for a green and economic process. Still, significant effort would be needed. 

 

For a low solvent use and higher overall yield process, every step of these patents will have to be redeveloped and optimized. These patents might be an extreme case but the thought can be extended to every brand and generic product API. Review of global patents could show many similar cases.  

 

Unless drastic changes are made to the USP ‘269 ⁽³⁾ and USP ‘279 ⁽⁴⁾ processes, my conjecture is that the process outlined if commercialized as is would exceed emission factor of 100 kg/kg ^{(1, 2)} for the product. Emission factor of 10 kg/kg of API could be set as a target across the board for API processes and formulations. Many camps could say that such a goal is impossible but unless we try it everything is impossible. Yoda has said it right “Do or do not, There is no try” ⁽⁸⁾. If pharma does not make an effort to do its part for climate change, its legacy for human health improvement would be irreparably tarnished. 

 

Effort has to be made from the onset of process development ^{(9, 10, 11)}  and has to be applied to every brand and generic API process development, their manufacture and formulations. If pharma does not include solvent reduction and yield improvement from inception of the process development, it is extremely difficult for the API manufacturer to do anything especially if the formulated API has been approved by regulatory bodies. No company wants to go through the expense and the time needed for re-approval. 

 

Analysis of patents of the most pharmaceutical companies suggest use of multiple solvents and recommend isolating intermediates for reuse. Isolation of solids adds to processing time and use of multiple solvents adds to what I call “separation complexity and anxiety”. Solvents have to be separated for re-use. Most process and product developers (chemists and chemical engineers) understand these scenarios but live with traditions. They have to challenge the current practices. They have to think that product being developed is their product and they have to manage the process in the plant. They would opt for simpler processes for manufacturing ease. Principles of chemistry and chemical engineering have to be applied for every process step. Unless the developers understand the operating challenges created by their processes not much progress will be made in the pharma product development. They have to adopt and rely on “nondestructive creation” practices ⁽⁹⁾. 

 

API processes related to brand drugs are the most complex. Generics do simplify them but still not enough to minimize the environmental footprint. Pharma has to minimize its footprint and Emission Factor ^{(1, 2)}. A total overhaul of its product development practices ^{(9, 10, 11)} is needed. Pharma will have to be mindfulness to its contribution to global warming which it has grossly neglected ^{(1, 2)}. With emphasis being placed on “global warming”, it is time for the pharmaceutical industry to do its part and take on the responsibility lower its impact on climate change. Pharma will have also have to be mindful of the ecotoxicity of its effluent ^{(12, 13)}. It has not paid much attention to it. It is time. There will be significant internal resistance. Regulators will be in a tizzy as they will lose the current stranglehold they have. 

 

Girish Malhotra, PE

 

EPCOT International 

 

1.   Malhotra, Girish: Active Pharmaceutical Ingredient Manufacturing (API) and Formulation Drive to NET ZERO (Carbon Neutral)? Profitability through Simplicity, April 29, 2021 Accessed January 24, 2022 

2.     Malhotra, Girish: Climate Change and Greening of Pharmaceutical Manufacturing, Profitability through Simplicity, January 24, 2022 accessed February 22, 2022

3.     Chapple et. al. US 10,669,279 B2 Pfizer Inc., Imidazopyridazine Compounds, Sept. 18, 2018 accessed Feb 22, 2022  

4.     Chapple et. al. US 10,077,269 B2 Pfizer Inc., Imidazopyridazine Compounds, June 2, 2020 accessed Feb 22, 2022

5.     Malhotra, Girish: Systematic Demystification of Drug Price Mystique and the Needed Creative Destruction, Profitability through Simplicity, October 2, 2019 Accessed February 25, 2022

6.     Malhotra, Girish: Opportunities to Lower Drug Prices and Improve Affordability: From Creation (Manufacturing) to Consumption (Patient), Profitability through Simplicity, March 9, 2018 Accessed February 28, 2022

7.     Benchmarking Shows Need to Improve Uptime, Capacity Utilization, Pharma Manufacturing, Sep 20, 2007 Accessed January 18, 2022

8.     Yoda:  https://www.starwars.com/video/do-or-do-not Accessed February 27, 2022

9.     Malhotra, Girish K.: Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation, https://www.degruyter.com/document/isbn/9783110702842/html April 2022

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

11. 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

12.   Larsson, D.G. Joakim et al. Effluent from drug manufactures contains extremely high levels of pharmaceuticals; Journal of Hazardous Materials, Volume 148, Issue 3, 30 September 2007,Pages 751-755 Accessed November 2007

13.  Malhotra, Girish: Pharmaceuticals, Their Manufacturing Methods, Ecotoxicology, and Human Life Relationship, Pharmaceutical Processing, November 2007, pgs. 24-26, Accessed August 10, 2009