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

Euphoria to Bring Pharma Manufacturing Home to United States its Reality and Challenges

With COVID-19 amongst us suddenly every “ator” (legislator, regulator, litigator, educator, political operator, news investigator, did I miss any other) has become a policy wonk and has proposals to bring pharmaceutical manufacturing home. It is interesting that many of these “ators” have never designed, developed or seen a manufacturing plant let alone a pharmaceutical plant ^{(1,2, 3)}. Some have noble thoughts but it is not like waving a wand or twitching a nose and plant making desired active pharmaceutical ingredients (API) and their formulations will appear. Some of the “ators” at regulatory bodies ⁽⁴⁾ and educational institutions (too many to name) are even talking about advanced manufacturing technologies which they know nothing about as they have never developed, designed, commercialized such technologies at profit making enterprises. We need to be skeptical and take all of the euphoria with grain of salt and tread through the maze carefully as the task at hand is not that easy as it sounds. I am presenting my perspective and have no financial relationship with any ators or any other nonprofit and/ profit making entity. 

Since WTO (World Trade Organization) agreement US has increasingly relied on outsourced medicines. If just thinking that a manufacturing plant will appear overnight and make USA self-sufficient in pharmaceuticals then we all are living in an unreal and a make belief world. Suddenly COVID-19 brought a rude awakening home that US cannot supply its populous many of the generic drugs and faces strategic and national security threat ^{(5, 6)} and suddenly every policy wonk (ator) as stated earlier has a proposal to remedy the situation overnight. 

Unfortunately, it is not easy to accomplish task at hand overnight and even in one year. In order to accomplish success many stars have to align and many established and stodgy policies will have to change. Many are the mainstay of FDA’s day to day working. Skeptics, procrastinators, Monday morning quarterbacks, would not be needed. Mover and shakers and can doers would be extremely useful. Lots of fiefdoms and kingdoms will have to accept change. 

In order to bring pharma manufacturing home FDA would have to re-write its ANDA review and approval policies. First and foremost being it has to create processes to get ANDA approval in 30 days if a company establishes a manufacturing plant to produce quality drugs in USA ^{(7,8, 9, 10, 11)}. FDA is going to resist change as it will loose its stranglehold on pharma companies. However, it can still hold pharma companies accountable for by shutting them down if they cannot produce quality at first inspection or random sampling of their product from the market place ⁽⁶⁾. 

In addition to FDA changing its approval procedures, many other things have to happen and done by the pharma manufacturing companies. They have to create processes that can be fitted in any existing plants in the United States. It will be challenging task. Fitting a square plug in a round hole is not a simple as it sounds ^{(12, 13, 14, 15)}. Significant effort would be needed to fit the processes in existing equipment. Even with availability of plants engineers will have to figure out and prove that their process modification and innovations would deliver quality products. We don’t have time for grass root plants. 

Since pharma product is a two-step process, API manufacture and their formulations, it is an excellent opportunity to develop realcontinuous formulation operations. Equipment technologies have existed for over 60 years but my conjecture is that most equipment vendors have stood in the way of such formulation processes. This is more due to fear of engineers at pharma companies not having experience, creativity and imagination to design, develop and commercialize excellent processes that will deliver quality product ⁽¹⁶⁾. Vendors need not hold hands of clients. This not any accusation but a reality. API except for few products do not have the product volume to be produced under established continuous process definition ⁽¹⁷⁾. 

Existence of FDA is a must. It should set policies and expectations. Let the companies deliver what it expects rather than telling how and what. FDA has to let the companies innovate rather than telling them what is good for them. If the companies don’t know that then they should not be in the manufacturing business. Engineers excel in what they develop, design and commercialize. Babysitting of companies has to stop. If companies don’t live up the expected minimum after one iteration, they should not be given 483 citation but shut down. 483 have become a medal of honor ⁽¹⁸⁾ for the companies. PBMs (pharmaceutical benefit managers) will have to restrained as their profits are going to be impacted. If not restrained, US population will see drug prices go up. 

If US can send the man to the moon and bring him back, bringing pharma manufacturing home is lot easier. If companies get started to bring manufacturing to the United States today, it will take time, effort, creativity and imagination to deliver. We have to acknowledge that US does not have sustained availability of raw materials to produce the necessary drugs. There is lot needed than just saying let’s bring pharma manufacturing home. It won’t happen in a blink. US needs lot of luck. 

Girish Malhotra, PE

EPCOT International 

1. Rosebush, Lee, Outsourcing U.S. Drug Manufacturing to China was a Mistake—A Lethal One | Opinion, Newsweek, May 5, 2020, Accessed May 22, 2020
2. Gibson, Rosemary, China Rx: Exposing the Risks of America’s Dependence on China for Medicine, U.S.-China Economic and Security Review Commission, July 31, 2019, Accessed May 22, 2020
3. A Blueprint  For Enhancing the Security U.S. Pharmaceutical Supply Chain, April 2020, Accessed May 22, 2020
4. US FDA, CDER, OPQ  
5. Malhotra, Girish: Health and National Security Issues for the USA and Is The United States of America Prepared, Profitability through Simplicity, May 8, 2020 
6. Malhotra, Girish: Strategies to Increase Generic Drug Competition and Bring Manufacturing to The United States of America, Profitability through Simplicity, March 16, 2020 
7. Malhotra, Girish: Long Term Drug Quality Supplies for US, FDA and A New Reality, Profitability through Simplicity, April 3, 2020
8. Malhotra, Girish: ONE PAGE Road Map to Reduce Drug Shortages, Assure Quality and Improve Affordability, Profitability through Simplicity, December 6, 2019
9. Malhotra, Girish: Impact of Regulations, Drug Manufacturing and Pharma Supply Chain (PBMs and allies) in Drug Shortages and Affordability Part 1, Profitability through Simplicity, March 8, 2019 
10. Malhotra, Girish, Impact of Regulations, Manufacturing and Pharmaceutical Supply Chain (PBMs) on Drug Shortages and Affordability Part 2, Profitability through Simplicity, April 3, 2019
11. Malhotra, Girish: What Is Needed for a Regulatory Approval of NDA/ANDA Filings in 90 Days?, Profitability through Simplicity, October 24, 2018
12. Malhotra, Girish: Square Plug In A Round Hole: Does This Scenario Exist in Pharmaceuticals?, Profitability through Simplicity, August 17, 2010
13. 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
14. Malhotra, Girish: A Radical Approach to Fine/Specialty API Manufacturing, Profitability through Simplicity, January 20, 2010
15. Malhotra, Girish: The Good, The Bad, The Ugly (1) Complexities of Pharmaceutical Manufacturing, Profitability through Simplicity, April 8, 2018
16. Vanhoorne, V, Vervaet, C: Recent progress in continuous manufacturing of oral solid dosage forms, International Journal of Pharmaceutics, April 15, 2020, Accessed May 20, 2020
17. Continuous Production,  Wikipedia
18. Malhotra, Girish: Are US FDA 483 Citations a "Medal of Honor" or “Rite of Passage” to Disgrace for the Pharma companies? Profitability through Simplicity, October 16, 2019

How Would US FDA Behave/React if They Were on the Receiving End?

Corona virus COVID-19 has given us all time to think and conjure up things that can upset the established apple cart or improve it. We need and that includes FDA to simplify FDA’s approval processes and method if we want the drug industry to come back to the United States and be able to supply needed essential medicines. We have an opportunity. There is no financial affiliation with any for profit and nonprofit entity. 

The current global epidemic is not the last one. We could have many. We need to be self-sufficient to access the needed drugs. Why I say this? In the current and any future epidemic countries will fend for their needs. Case in point is chloroquine. Many have speculated that chloroquine can help in treatment of COVID-19. It is in short supply in US. US FDA asked ⁽¹⁾ Ipca Lab, India, to supply the drug for the US market when in 2017 Ipca Labs⁽²⁾ was banned to exports to US. Interestingly Indian Government banned chloroquine exports ⁽³⁾. 

If we want pharma manufacturing to come back to US, the FDA current review and approval methods and processes ^{(4, 5)} need to streamlined and simplified. I am sure US has a list of essential drugs. Stockpiles might not help if we cannot manufacture the active ingredients and formulate them in US.  

Should the US population revolt to bring pharma manufacturing home? Besides lip talk our legislator and the regulators would not do anything. In addition to bringing pharma manufacturing home, they have to compete against the best manufacturing technologies outside to produce quality drugs at the lowest cost. Many stars will have to align. 

In my recent post ⁽⁵⁾ I have tried to describe the current approval and application process. I am not a master of the application process, but if the pieces and parts of what I understand are true, we have an opportunity to improve. This will give the industry an incentive to come to US. I call my perspective “nondestructive creation” or an outlier thinking. Some or many could consider all this a farfetched dream and can’t be done. Well most thought man could not go the moon and come back. Well, we did that and some.

US FDA, like any manufacturing organization, where continuous improvement is routine, has to improve and simplify its NDA/ANDA review and approval processes. FDA has to shed its lenient methods (483 citations which I call “medal of honor” and take a tougher stand ^(6,7). Best of the best in pharma have to compete for the largest market. It’s not just the new drugs. FDA has to hold their feet to the fire. In addition, we need to be able to manufacture lifesaving drugs in case we need them for the next pandemic. We are not ready today as we can’t get chloroquine as explained earlier.

Every manufacturer practices QbD from the get go for every product. Industry practices “continuous improvement” in everything they it does. If they did not their products would have a very short shelf life. FDA has been preaching “quality by design (QbD)⁽⁸⁾”. Has it been practicing them for its NDA/ANDA review and approval processes? In addition, what has FDA done with respect to incorporate “continuous improvement” in its review and approval processes. My conjecture is and many others would concur that FDA’s current NDA/ANDA processes are quality by analysis/aggravation processes and could use improvements. 

May be their understanding of QbD is different from what they have been preaching. If regulators believe their current ANDA/NDA application/review/approval process pathway is QbD based then we need to reexamine QbD definition. My conjecture is FDA would not be pleased to see their QbD rating if there was such a scale. As discussed earlier ⁽⁵⁾ no one really knows how much time it takes to get approvals. With that said, I wonder how many companies would want to establish manufacturing plants in the United States. 

We need to be proactive and not reactive in bringing manufacturing home. In that effort we can also improve regulatory practices. If we don’t do it, another epidemic might not be kind to the US population. 

Girish Malhotra, PE

President

EPCOT International

1.     FDA frees India’s Ipca Lab from import ban so it can ship unproven Chloroquine for COVID-19 treatments, FiercePharma, March 23, 2020

2.     FDA bans imports of Ipca Lab drugs, FiercePhama, June 19, 2017 

3.     India bans export of malaria drug Trump touted as coronavirus treatment, Fortune, March 25, 2020

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

5.     Malhotra, Girish: GDFUA II ANDA (Abbreviated New Drug Application) Review Target of 8-10 Months should be a Cause of Concern, Profitability through Simplicity, March 24, 2020 

6.     Malhotra, Girish: Are US FDA 483 Citations a "Medal of Honor" or “Rite of Passage” to Disgrace for the Pharma companies? Profitability through Simplicity, October 16, 2019

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

8.     Quality by Design for ANDAs, FDA.gov, Accessed March 26, 2020

Opportunities for Generic Pharma to Clear the Quality Stigma

Recently there has been significant press ⁽¹⁾in the United States about quality of generic drugs. India and China were singled out. Increased exposure (recalls and FDA citations) are par for the course. These are indications that issues of varying degree are there and they need to be addressed. Press in general looks for opportunities to get on the band wagon. It is ironic that many in press might not have any clue of what a drug is, how they are developed, costed or for that matter what the manufacturing processes entail but are riding the news horse. They have power of the pen. We must remember that negativity sells and influences. 

The current negativity unless harnessed is going to cause increasing damage and the publicity will not end soon. I consider this an opportunity for various companies to re-work/re-look the current business model/plans to see how and what can be done to improve the affordability of generic drugs to the largest global market while producing quality drugs. If nothing is done to excel in product quality eventually lack of action will come back and haunt generic pharma. 

होजायेगा(Ho Jaye ga) or 着什么急呀! (zháo shénme jí ya!) loosely translated what’s the hurryattitude must be shed. Quality must be delivered today as tomorrow never comes. If for any reason quality demanded by the customer is not respected and delivered, business in the long term will suffer. In this effort, it is possible that many egos may have to be shelved as lives are stake. Onus to correct perception of questionable quality, perceived or actual, is on the generic pharma companies.

Again, bottom line, the current negativity is an opportunity to harness and rein in the quality horse. Some costs may be there but done right they should be minimal or none and will be offset and will add to the bottom line. Long-term survival of generic pharma depends on quality and undeniably it must be their highest priority. First time quality should be the goal. It is well known that to re-work the product to achieve quality can cost as much as 40% ^{(2, 3)}that simply translates to lower profits. 

Presented is my perspective/perception which is based on the current landscape. There is no vested interest of any for-profit or non-profit entity. In addition, this is also not a solicitation or a recommendation but a suggestion that companies must overcome the prevailing negativity by using talent that can and does think out of the box and can resolve issues. Talent that can “walk the talk” rather than “talk the walk” is needed.

Acknowledgement and Capabilities:

Generics must acknowledge their quality issues internally and must take the bull by horns to fix the current negativity. Companies that are excelling need not worry but will have to stay the course and continuously improve. There will be internal denials and challenges that could be hard to swallow. That is to be expected. Change is needed. If anyone thinks that it is difficult and expensive to achieve quality, that notion needs to be challenged. They need to be asked “would they risk to take the medicines produced by their own company?”   

Chemists and chemical engineers are taught to produce quality the first time. It seems that somewhere between the university doors and plant floors, they faltered and have accepted and/or succumbed to the prevailing practices. I am not sure how they have lost their mojo. Doing right is cheap and fixing the wrong is costly and in pharma wrong can cost lives, an unacceptable occurrence. Again, lack of first-time quality is expensive ^{(2, 3)}. 

Frugality and creativity are the cornerstone of India’s ingenuity as exemplified by its extremely low-cost mission to Mars. Similar attributes are true for China. My question is why these traits are not being applied to pharma. 

What is needed for quality drugs? 

Most pharma plants operate are at about TWO Sigma level ^{(3, 4)}, a significant opportunity to improve. This might not hold true for every company but based on publicly available information, fragmented manufacturing could be the root cause of poor quality. 

Even though drug manufacturing is understood, it is good to re-visit the process. Every produced drug is a two-step process. An active pharmaceutical ingredient (API) is formulated with inert excipients to produce a dispensable dose. Method of API manufacture is dependent on the chemistry and volume needed. Since APIs are toxins that kill the disease-causing bacteria they are used in minute quantities. Thus, small quantities of API are needed to meet the needs as exemplified by the fact ONE kilo of API will produce ONE million tablets of one milligram @ 100% conversion. Table 1 is an illustration of API needed and tablets produced per year for 50 million patients. Needed API could be produced at a single plant but formulation most likely would be done at more than one plant.

Patients	milligrams	#/yr.	API, Kilo/year	Tablets/yr.
50,000,000	1	365	18,250	18,250,000,000
50,000,000	10	365	182,500	18,250,000,000

Table 1: Theoretical API and Formulation needs 

If I were to produce the needed API (Table 1 Illustration) for 50 million patients it will produced at a single plant. Multiple lines at the same site or multiple sites would be needed for formulation. In today’s landscape multiple plants will produce it. Multiple plants or lines would be need for formulations. it is imperative that the product quality meet established specifications and follow cGMP. 

Table 2 ^{(5 ,6, 7)} is an illustration for some named drugs. Potential of products being perfectly same is unlikely but it is necessary that they meet the accepted specifications. 

Drug	Number of API Sites	Number of FDF Sites
Ciprofloxacin	22	536
Atorvastatin Calcium	44	865
Omeprazole	87	768
Modafinil	29	70
Metformin HCl	77	752
Metoprolol	41	338

Table 2: Number of sites for APIs and Formulations

Since most APIs are manufactured and formulated at many plants (Table 2), based on my experiences and I am sure of others, ensuing processes have significant cost variations. Due to lack of economies of scale most of the processes are not optimum. Global API demand of ciprofloxacin, omeprazole, modafinil, metoprolol can be fulfilled from a single plant. FDF facilities for these products could be lot fewer than the current number. API and FDF plants for atorvastatin and metformin can be significantly lower the current numbers. 

If a company is producing many products in the same equipment, cGMP issues can result. Short production runs test operating personnel’s metal. This can happen across the board for generic drugs. Combination of above can result in two sigma quality. Due to nature of the processes and method of execution, quality in current manufacturing methods is most likely tested in rather than built in, an expensive process ^(3,4). These processes also can be a leading cause of quality infractions. Companies who rely on “after the fact quality” aka “quality by analysis/aggravation” rather than QbD, could apply fundamental of process design which every designer of a chemical process is expected practice. They could explore methods to have command of their processes ^{(8, 9)}. Internal resistance is very possible. Regulations also intervene to make such improvements.  

Another alternate to retain quality is through consolidation and taking advantage of economies of scale. Processes will be optimized. Quality will be consistent. Such processes will have significantly higher profitability than the current processes. Every chemist and chemical engineer knows and understands these fundamentals. It just behooves me why they don’t practice what they have learnt. Is it the corporate culture? As said earlier regulators do not facilitate process improvements either. 

Generic companies like any other profitable company have to continuously do self-evaluations of their operating and business practices and strategies. However, it seems not much has happened ^(10,11). Increasing 483s and recent issues e.g. valsartan are telling us that quality issues are persisting and things need to change.

USFDA due to repeated generic pharma quality issues could succumb to political and social pressure and could take significantly drastic stand of stopping import of these drugs. That would an unhealthy situation for the generic pharma and US populous. Health of Generic Pharma like any human patient is in their own hands. They can fool the doctor (FDA) some of the time but eventually when reality hits home, results can be pugnacious and difficult to handle. By ignoring quality generic pharma is playing with its own existence. Thus, it is in the interest of generics to stay on top of their quality game. 

Girish Malhotra, PE

EPCOT International 

1. Eban, Katherine: Bottle of Lies, Harper Collins Publishers, May 14, 2019 
2. Cost Of Quality: Not Only Failure Costs https://www.isixsigma.com/implementation/financial-analysis/cost-quality-not-only-failure-costs/
3. Hussain, A. S.: Pharmaceutical 6-Sigma Quality by Design, The 28^thAnnual Midwest Biopharmaceutical Statistical Workshop, Ball State University, Muncie, IN, May 23-25, 2005, Page 20, Accessed May 19, 2019
4. Shanley, Agnes: Will the Pharmaceutical Industry Ever Get to Six Sigma? Pharmaceutical Technology, July 2017
5. Malhotra, Girish: Impact of Regulations, Manufacturing and Pharmaceutical Supply Chain (PBMs) on Drug Shortages and Affordability Part 2, Profitability through Simplicity, April 3, 2019
6. Berndt, Ernest R., Conti, Rena M. and Murphy, Stephen J: The Generic User Fee Amendments: An Economic Perspective, NBER Working Paper 23642, August 2017
7. PharmaCompasshttps://www.pharmacompass.com 
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: US FDA citations to Ranbaxy are an excellent opportunity, Profitability through Simplicity, September 17, 2008
11. Malhotra, Girish: What do the Ranbaxy Citations Teach US? Profitability through Simplicity, February 4, 2014