All opinions are my own.

Thursday, April 29, 2021

Active Pharmaceutical Ingredient Manufacturing (API) and Formulation Drive to NET ZERO (Carbon Neutral)?

“Net Zero” (1) [emissions produced = emissions removed] is in vogue. It has significant value and will huge impact on the planet if we do nothing. Speculated target dates to achieve the goal are 2025, 2045, 2050 or thereafter. There will be a firm date soon. 


For the pharmaceutical industry “thereafter” might be the target to meet. This is based on magnitude of E Factor (environmental factor) from 2017 illustrated in Table 1 (2). It is difficult to say how much effort to date has been put in to reduce this factor. Based on the current status and the following analysis, it is most likely pharma has not done much. Thus, the task is going to be formidable. 


High “E-Factor” numbers (2) present an excellent opportunity to reduce emissions and waste quickly. Effort will be needed. This is my perspective. There is no financial or any other obligation with any educational/commercial or regulatory body. 



Tonnes per year

E Factor (Kg waste/kg product)

Total Annual Waste Tonnage

Oil Refining




Bulk Chemicals




Fine Chemicals









Table 1: “E Factor” in the Chemical Industry (2)


Reasons for Pharma’s High E-Factor:

To get to “Net Zero” in pharmaceuticals, which has the highest “E-Factor”, we need to understand the reasons. They will facilitate in implementing the right solution/s.


Pharmaceuticals have two distinct components API (active pharmaceutical ingredients) and their finished dose form (FDF) that are produced by blending API with inert excipients. Discussion here is focused on small molecule drugs that like fine/specialty chemicals, are similarly synthesized. Pharma’s highest “E-Factor” is due to its manufacturing practices. Improved manufacturing will lower the “E-Factor” and drive to “Net Zero”. 


One interesting fact for the pharmaceutical industry which has been least understood by the world at large is that a small quantity of API is needed to produce large number of tablets. Table 2 is an illustration of relationship between API needed and the produced tablets per year. 




# of Tablets/ person/yr.

API, Kilograms/year













Table 2: API and Tablets per year Relationship (3)


Using best estimates, annual global need of these randomly three selected drugs are illustrated in Table 3. Based on annual need, each API can be produced at a single plant. Multiple formulation plants would be needed to convert this plant’s output into solid dosage. However, at present these, API and finished dosages, are being produced at multiple API and formulation plants (4). Processes for each drug most likely are not the most efficient and have a high “E Factor”.









Global need, %




# people




mg needed/day




Tablets used # days/yr.




Total mg needed/day




API need Kg/Yr.  




Current Number of API Sites




Current Number of FDF Sites





Table 3: Annual API Need for the illustrated drugs


Why so many sites are producing the same API and their formulations? There has to be some rationale. The only explanation can be combination of high profitability of each producer, no external pressure to reduce their manufacturing related emissions and regulatory requirements and hinderances.


Large number of plants for API production and their formulations (4) tell us that each lacks value of economies of scale. Lower number of plants will use better technologies and should have significantly reduced waste. Fundamentals of chemical engineering teach that. Need to improve and lower pharma’s “E-Factor” has been well recognized (5,6,7,8, 9) but not much progress has been made to remedy the situation. Lack of progress suggests that the producer companies see ZERO or very low return in manufacturing technology innovation. 


What is Needed to Lower Pharma’s E-Factor:


In reality, API manufacturing and formulator companies don’t have to innovate much to lower their “E-Factor”. They are practicing all of the necessary manufacturing technologies. They have to repurpose and re-invent these technologies, unit processes and unit operations (10) and the knowledge that has existed and been practiced since the beginning of the twentieth century. Pharmaceutical manufacturing has to relinquish its “mortar pestle” mode and proactively apply the principles of science and engineering differently. In this effort pharma cannot forgo and has to practice FDA’s cGMP (11) requirements as their way of life.


Companies don’t have to rely on the regulators and the equipment vendors leading them as to how and what to do to innovate and produce quality products. Actually FDA have made innovation and continuous improvement more difficult by prolonged approval times (12,13) and meaninglessly suggesting what and how manufacturing should be done. Review and repurpose of the existing practices has to be the modus operandi. Nondestructive creativity is needed (14,15) if the companies want to repurpose and reinvent. Some of the methods (16, 17) have been reviewed. 


For the pharma to lower its “E-Factor” or achieve high “green chemistry” marks, they not only have to adopt “good chemistry” but also practice “good chemical engineering” as their way of life (8). Pharma manufacturers have the command and the knowledge of their patient’s needs and what is expected by the regulators. Pharma has to relinquish fitting different processes in the available equipment (18, 19). Many may not believe but fitting processes in the existing equipment requires use of excessive amount of solvent use, a major cause of high “E-Factor”. Though recovered and re-used, it still is a major contributor to pharma’s “E- Factor”. Formulation practices have to reconsidered as the existing technology applied properly can lower “E-Factor” significantly.


Each product illustrated in Table 3 can be produced using continuous synthesis (20) process. Thereby minimizing emissions from each synthesis plant. Solid dosage for these products can be similarly produced in minimum number of formulation plants. “E-Factor” from these continuous production plants would be magnitudes lower than over 1,350 plants currently being used. 


If the waste numbers from Table 1 are applied to the three drugs in Table 3 and “E-Factor” from Table 1 are applied numbers illustrated in Table 4 would be the waste for each of the API. Actual emissions for these drugs may be different but the industry average are used to illustrate their impact. Bold numbers are the emission numbers if they were reduced. 






Total Waste,


Kg. Waste per Kg. Product

Waste for each drug at different levels, Kilogram/yr. 
















E-Factor numbers if emissions are reduced. 







Table 4: Waste Generated for the APIs (Table 3) using Table 1 Waste numbers


Pharma has the tools and means (16, 17). Additional tools and means are reviewed in a manuscript under preparation (21).


Pharma while keeping its “market centricity” has to adopt “process centricity” (22) from the onset rather than believe that the manufacturing processes will be improved tomorrow. It would be like believing that tomorrow will come, if it ever will come. Any changes made in manufacturing processes after regulatory approval can influence the drug performance and are a major cause of lack of most process improvements.  


Global effort is needed to lower pharma’s “E-Factor”. Adopting uniform global effluent standards (23) would significantly reduce “E-Factor”. Regulators rather than becoming an encumbrance would have to actively change their “modus operandi” for reducing the approval time for brand and generic drugs (12, 13). Today the speculated ANDA (abbreviated new drug application) approval time is between 36-48 months as official approval times are not available. NDA (new drug application) approval time, unless emergency use authorization, are anyone’s guess. 


Overall task is not going to be easy. If it was, it would have been accomplished long time ago. In addition, there will be significant resistance from the involved businesses, regulators/governments and even patient communities. 


Minimizing/reducing the “E-Factor” is a multiple win. They lower manufacturing costs, protect public health and the environment and also lower the drug costs to the public.  


We need to ask ourselves “What would be our legacy for the generations to come?” Let us write it. 


Girish Malhotra, PE


EPCOT International


[1].           Burke, J. What does net zero mean? https://www.greenbiz.com/article/what-does-net-zero-mean, May 2, 2019 Accessed April 27, 2021

[2].           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

[3].           Malhotra, Girish: Pharmaceutical Quality: Concepts, Misconceptions, Realities and Remedies, Profitability through Simplicity, https://pharmachemicalscoatings.blogspot.com/2019/11/pharmaceutical-quality-concepts.html, November 4, 2019

[4].           https://www.pharmacompass.com

[5].           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

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

[7].           Malhotra, Girish: A Fine Chemical Version of Chernobyl? Patancheru, India: An opportunity for Quality by Design and Environmental Sustainability, Profitability through Simplicityhttps://pharmachemicalscoatings.blogspot.com/2009/02/patancheru-india-opportunity-for.html February 25, 2009 Accessed April 24, 2010

[8].           Scott. A.: Good Chemistry” Chemical Week March 15, 2010 Accessed April 2, 2010

[9].           Anastas P. et. al., Green Chemistry: Principles and Practice, Chem. Soc. Rev. https://doi.org/10.1039/1460-4744/1972 , 2010, 39, 301-312, Accessed April 21, 2021

[10].        Unit Processes and Unit Operations: https://encyclopedia2.thefreedictionary.com/Unit+processes Accessed November 5, 2020

[11].    Current Good Manufacturing Practice (cGMP) Regulations, US FDAAugust 21, 2020 Accessed March 10, 2021

[12].        Malhotra, Girish: Can the Review and Approval Process for ANDA at USFDA be Reduced from Ten Months to Three Months?, Profitability through Simplicity, https://pharmachemicalscoatings.blogspot.com/2017/03/can-review-and-approval-process-for.html March 25, 2017

[13].        Malhotra, Girish: Simplified Roadmap for ANDA/NDA Submission and Approval will change Pharma Landscape, Profitability through Simplicityhttps://pharmachemicalscoatings.blogspot.com/2018/11/simplified-roadmap-for-andanda.html November 25, 2018

[14].        Kim et al. Nondisruptive Creation: Rethinking Innovation and Growth, MIT Sloan Review, February 21, 2019  Accessed March 6, 2019,  

[15].        HUBBARD, G. Nondestructive Construction, TECH & INNOVATION https://www.strategy-business.com/article/07203?gko=dad6dMay 29, 2007 Accessed January 26, 2021

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

[17].     Malhotra, Girish: Strategies for Improving Batch or Creating Continuous Active Pharmaceutical Ingredient (API) Manufacturing Processes, Profitability through Simplicity https://pharmachemicalscoatings.blogspot.com/2017/03/strategies-for-enhancing-active.htmlMarch 20, 2017 Accessed April 25, 2021

[18].        Malhotra, Girish: Square Plug in A Round Hole: Does This Scenario Exist in Pharmaceuticals?, Profitability through Simplicityhttps://pharmachemicalscoatings.blogspot.com/2010/08/square-peg-in-round-hole-does-this.html August 17, 2010 Accessed March 31, 2021

[19].        Malhotra, Girish: Why Fitting a Square Plug in a Round hole is Profitable for Pharma and Most Likely Will Stay?, Profitability through Simplicityhttps://pharmachemicalscoatings.blogspot.com/2014/08/why-fitting-square-plug-in-round-hole.html August 1, 2014 Accessed March 31, 2021

[20].        Malhotra, Girish: Batch, Continuous or "Fake/False" Continuous Processes in Pharmaceutical Manufacturing, Profitability through Simplicity https://pharmachemicalscoatings.blogspot.com/2017/07/batch-continuous-or-fakefalse.html July 20, 2017 Accessed February 20, 2021

[21].        Malhotra, Girish: Book "Active Pharmaceutical Ingredient Manufacturing" Manuscript under preparation. Expected publication 2022

[22].     Malhotra, Girish: Process Centricity is the Key to Quality by Design, Profitability through Simplicity,  https://pharmachemicalscoatings.blogspot.com/2010/04/process-centricity-is-key-to-quality-by.html April 6, 2010 Accessed March 20, 2021

[23].        Malhotra, Girish: Can Uniform Safety, Health and Effluent and Manufacturing Standards Create Process Technology Innovation and Competition in Pharmaceuticals? Profitability through Simplicity, https://pharmachemicalscoatings.blogspot.com/2017/01/can-uniform-safety-health-and-effluent.html January 10, 2017 Accessed April 10, 2021