API manufacturing and environmental sustainability

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Pharmaceutical industry’s evolution and history are fascinating (1, 2). Volumes can be written on how the industry and each company has shaped itself. Their evolution is a story. Discussion here is not about the companies but about the development of small molecule active pharmaceutical ingredients (API) (3), their manufacturing methods and environmental impact and how it can be minimized.

 

For ages and still, many vegetation plants and their extracts were and are used to cure many diseases. Genesis of the current pharmaceutical industry took place when the chemists of the early part of the last century working at dyes and colorant companies in Europe were able to synthesize the disease curing chemicals of the plants extracts. They also started to recognize the disease curing values of different fine/specialty chemicals.

 

Chemical synthesis processes for the small molecule APIs are no different from the synthesis of fine/specialty chemicals and dyes/colorants. Equipment used (reactors, pumps, agitated tanks that were available in dye/chemical plants) are easily adopted and used to produce the needed APIs. Unit processes and unit operations (4) used in the manufacture of either class of chemicals are the same. By tradition chemical processes get configured for the equipment (5, 6) that was/is generally available (Figure 1) rather than using the equipment that is best suited for the process. This has led to use of excessive amounts of solvents.

 

Since the production of different chemicals can be manipulated through varying amounts (generally large excess) of solvents and processing conditions, use of existing equipment, i.e. fitting the process (7) in the available equipment (Figure 1) became a normal practice (5, 6) and has continued for APIs.
With time, additional disease curing chemicals were discovered and that led to the evolution of the modern pharmaceutical industry.

 

To prevent cross contamination between different products in between equipment cleaning became a tradition and led to cGMP (8) practices. All these result in high emissions per kilo (9) of product even after solvent recovery and re-use. For pharma, this routine practice has not been a cause of environmental concern.

 

Companies using the existing equipment have progressively been able to synthesize and produce APIs (other fine/specialty chemicals) for curing different ailments. This practice has saved investors significant monies. Resulting manufacturing inefficiencies were/are not a cause of concern. Related costs were passed on to the patients, who pay them willingly to extend life. Methods of production, use of excessive amounts of solvent and resulting environmental impact, high emissions per kilo of product (9) are recognized but have not raised any concerns.

 

Cleaning equipment between batches results in equipment down time i.e. low asset utilization (10). Since the products are profitable, need to economize processing chemistries and methods during the life of patent were not and have not been a priority. Generic companies have followed the footsteps of the brand companies i.e. used fine/specialty chemical industry equipment. Generics have improved some chemistries but not enough to capitalize on economies of scale and/or better technologies. It has not been a priority.

 

For the last few years there has been considerable and at times passionate discussion about “Green Chemistry” in chemical related industries and that includes pharmaceuticals. “Climate Change” (11) and “Net Zero emissions” (12) have become “in-vouge”. Some brand pharma companies have proposed lofty goals (13). However, they are directed to fossil fuels or energy conservation. Most of the set goals do not apply to their API and formulation segments which happen to be the largest contributor of the emissions (14). If any of the company goals relate to API manufacturing or formulations, they are not clear. Generics have not declared their goals and/or time table for “Net Zero” emissions.

To achieve “Net Zero” status onus is on the pharmaceutical industry to innovate its API manufacturing and formulation practices to lower emissions and become green.

Change is necessary and is possible. Pharma’s traditions and profitability have prevented the industry to be proactive. Companies consider change to be a difficult process. It has been looking at the “glass being half empty, i.e. pessimistic”. Getting to consider this “glass to be half full, i.e. optimistic”, is not difficult.

For the brand and the generic products effort to minimize solvent use i.e. reduce emissions per kilo has to be the “mantra” from the onset of the product/process development. Companies may/will have to change their business model or operating methods. Since reducing the solvent emissions i.e. “Net Zero” has not been part of the most of business plans, change is not part of the consideration and can be difficult. Paradigm shifts are.

 

Methods to get to “Net Zero” have existed with our familiarity physical and chemical properties of organic and inorganic chemicals used and produced in the processes. This familiarity along with their mutual behavior i.e. solubility/insolubility etc. can be capitalized on to create excellent processes. They allow tweaking of unit operations. Industry has used them in some of the situations but has not put emphasis across every product. This has been due to traditions inherited from the fine/specialty chemicals practices and lack of need and recognition of ill-effects caused by emissions. Fine/specialty chemicals capitalize on them routinely to commercialize excellent processes. However, API manufacturing due to regulations gets “cold feet”.

 

Peter Drucker’s saying “Innovation can be systematically managed – if one knows where to look” (16) is very applicable for pharma manufacturing. Creative destruction (17) could be applied to pharmaceuticals but it will be too disruptive and should not be considered.

 

Pharma is an ideal case for application of “NONDESTRUCTIVE CREATION (18)”. To make necessary changes chemists, chemical engineers and entrepreneurs have to look at things differently i.e. “out of the box”. This involves alternate ways/methods of application of unit operations, unit processes and equipment to develop new and improve the current processes. Physical and chemical properties can and do assist. However, one has to understand how to capitalize on their values.

 

Change for simpler and economic processes has to happen from the inception of the chemistry as if the process will be commercialized. Many might think that this will take some additional time but has extremely high dividends as it save expense, improves profitability, product availability and affordability. Overall time spent will be less than the current times.

 

Having the right team which I call “the village (20)” is critical. It will challenge and review every step of the process and optimize it from the onset of the process development. We are taught physical properties but do not have absolute command on how to use and exploit their mutual behavior and interaction to create simple processes. We are also taught fundamentals of unit operations but their application has to be a “hands on” experience.

Combined manipulation of physical properties and unit operations can significantly simplify chemical synthesis and blending processes.

 

Familiarity/command with the physical properties of the starting materials, intermediates, process chemistry, unit operations and the process equipment give the developers, the village (20), a head start to develop and commercialize excellent processes. “Collaborative creativity” sets in and the village is able to do a “what if analysis” when they are developing the process in the laboratory and scaling up. By applying principles reaction kinetics and taking advantage of mutual physical properties excellent process with highest yield can be developed and commercialized. Challenging the process from laboratory allows the development of economic process and “net zero” becomes part of the development regime. Information generated can be quickly used to correct any deviation of the process, if any happens.

 

Village can review and cross-fertilize equipment and methods that are not necessarily being used in the fine/specialty chemical industries to create excellent processes. They can simplify many of the processes from the onset. Pilot plant and other equipment can be repurposed for modular designs and can simplify processes to have continuous processes or long product campaigns which has been an elusive dream in the manufacture of APIs (2). This will give chemists and chemical engineers an opportunity to fully capitalize on their creativity and imagination to create excellent processes which can lead to “net-zero” emissions.

 

Brand companies will significantly improve their API profitability if the methodologies discussed are applied from inception. Generic API manufacturers will benefit tremendously also. For the existing generic manufacturers hesitation could come from their current business practice of hopping between products to improve their profits. Their business model could change and consolidation could lead to higher profits through better technologies, improved asset utilization and economies of scale.

 

Alternate processes may challenge regulators as they may not totally understand new low solvent processes or continuous processes. Regulators do not know or understand continuous processes.

Since the regulators have very little experience in process development and manufacturing, it is very likely that they may raise many questions regarding alternate manufacturing processes. They still need to significantly improve their review processes for (NDA) and abbreviated new drug applications (ANDA). Industry cannot change the existing processes unless safety and efficacy of the product is proven. Regulators have to be informed and this can be an expensive process.

 

Various methods and options discussed (2) can lead to greening of the pharmaceutical manufacturing, APIs and their formulations and also make sure they are safe and meet their efficacy.

 

Figure 1. Square plug in a round hole (7).

 

Figure 2. Glass Full vs. Half Empty (15).

 

Figure 3. Thinking Out of the Box (19).

 

REFERENCES AND NOTES

1. A history of the pharmaceutical industry https://pharmaphorum.com/r-d/a_history_of_the_pharmaceutical_industry/ September 1, 2020 Accessed June 7, 2022
2. Malhotra, Girish K. Active Pharmaceutical Ingredient Manufacturing: Nondestructive Creation: https://www.degruyter.com/document/isbn/9783110702842/html De Gruyter April 2022
3. https://en.wikipedia.org/wiki/Small_molecule
4. Unit Operation and Unit Process https://chemicalengineeringworld.com/unit-operation-and-unit-process/ June 29, 2021Accessed September 20, 2021
5. Malhotra, Girish: Square Plug in A Round Hole: Does This Scenario Exist in Pharmaceuticals?, Profitability through Simplicity, August 17, 2010 Accessed May 3, 2022,
6. 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 Accessed May 3, 2022
7. Square Plug in a round hole, https://the-art-of-autism.com/the-shape-shift-square-pegs-dont-fit-into-round-holes/
8. Current Good Manufacturing Practice (CGMP) Regulations https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practice-cgmp-regulations September 20, 2021. Accessed September 25, 2021
9. 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#!div Abstract, 2017, 19, 18–43, Accessed February 17, 2021
10. Shanley, A. Flexible Pharma: Puzzling Out the Plant of the Future, Pharmaceutical Manufacturing, Nov/Dec 2009, pg. 14–21. Accessed January 10, 2021
11. Climate Change https://en.wikipedia.org/wiki/Climate_change Accessed September 8, 2021.
12. Burke, J. What does net zero mean? https://www.greenbiz.com/article/what-does-net-zeromean, May 2, 2019 Accessed April 27, 2021
13. Big Pharma and Sustainability: Tracking Companies’ Goals https://www.dcatvci.org/features/big-pharma-and-sustainability-tracking-companies-goals/ January 20, 2022 Accessed February 1, 2022
14. Daigneault, M: et.al. A red pill for green medicines https://www.chemistryworld.com/opinion/a-red-pill-for-green-medicines/4014770.article November 26, 2021 Accessed June 10, 2022
15. Glass Half Full https://medium.com/cuble/is-the-glass-half-empty-or-half-full-72829ad44035
16. Drucker, Peter F., The Discipline of Innovation, Harvard Business Review https://hbr.org/2002/08/the-discipline-of-innovation August 2002 Accessed August 25, 2021
17. Schumpeter, J. A. Creative Destruction” from Capitalism, Socialism and Democracy, New York, Harper, 1975, (orig. pub. 1942), pp. 82–85, accessed January 31, 2008
18. Hubbard, G. Nondestructive Creation https://www.strategy-business.com/article/07203?pg=0, May 29, 2007 (originally published by Booz & Company) Accessed December July 14, 2008
19. Thinking out of the Box https://www.123rf.com/photo_133820142_isometric-red-paper-plane-flying-from-white-open-case-thinking-outside-the-box-innovation-creativity.html?vti=n26n4dx3panq1tlu1l-1-97
20. Malhotra, G.: The Good, the Bad, the Ugly (1)complexities of Pharmaceutical Manufacturing, Profitability through Simplicity, https://pharmachemicalscoatings.blogspot.com/2018/04/the-good-bad-ugly-1-complexities-of.html , April 9, 2018 Accessed November 1, 2020.