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The Green Chemistry

Approach to Pharma
By Michael Kopach at Eli Lilly &
As sustainability rises to the top of many organisations agenda, we see
Co, David Leahy at Bristol-Myers that being green is more than just reducing waste. Using green metrics,
Squibb and Julie Manley at the
ACS Green Chemistry Institute tools and technologies is better for the environment, safer for employees
and can have a positive impact on the companys bottom line.
Corporate sustainability is an article outlines an integrated and generate minimal waste.
emerging trend within the green chemistry approach to Green technologies such as
global economy and has been pharmaceutical manufacturing catalysis, biocatalysis, continuous
characterised as a key driver for through the use of green processing and recycling can all
innovation (1). The pharmaceutical technologies, performance metrics help achieve these goals. Catalytic
industry has embraced this and tools for green chemistry. transformations greatly extend
movement, and most companies the synthetic toolbox of process
in the sector have made significant Greener Technologies chemists, allowing for the direct
progress and set far-reaching and efficient formation of chemical
sustainability goals for the future. Fundamental to any green bonds not achievable using
One area of immense focus is chemistry approach to active traditional synthetic methods.
the environmentally responsible pharmaceutical ingredient (API) Especially powerful examples
manufacture of pharmaceutical manufacture is an efficient are carbon-carbon and carbon-
products. It is here that green synthetic route. Such a route heteroatom coupling reactions
chemistry can make an enormous should minimise the number of where two complex intermediates
impact to a companys triple bottom synthetic steps, while maximising can be efficiently coupled, thereby
line, as it is more cost-effective, safer atom economy. Each step should dramatically shortening the linear
for employees and better for the be as non-hazardous as possible synthetic route, and often greatly
environment (2). improving the overall yield
Figure 1: Greener synthesis
of API.
Green chemistry, formally defined maximising atom economy
as the design of chemical products
Traditional approaches
and processes that reduce or Waste

eliminate the use and generation of Waste O

hazardous substances, is arguably NH2 NH2 S


just good chemistry highly R


efficient, safe and cost-effective

(3). While gains can be made by Resolution/separation Organometallic addition

applying green chemistry principles

to an existing
Keywords pharmaceutical

manufacturing R
Greener approaches
Green technologies process, the far more
Continuous processing effective strategy Chiral catalyst, H2 Transaminase

is to build in green
Solvent waste
chemistry design
Process mass intensity NH2 O
principles early in
the development R
E-Factor life cycle. This

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In addition, traditionally problematic

areas of single enantiomer synthesis cooling

can often be overcome using

catalysis, thus circumventing the
need for non-atom economical Sample
Mixing T
chiral auxiliaries or resolution/ Relief Relief
separation approaches where half Filter
of the product is wasted (see Figure
1). Likewise, biocatalytic approaches Back pressure
are often used for single enantiomer regulator
Vent N2 #1 #2
Vent N2 Vent N2
synthesis. Recent advances in the Crystallisation Crystallisation
field allow for new genetically Feed 1 Feed 2

engineered enzymes to accomplish

a wide range of transformations,
with better enzyme productivity, in
higher concentrations and shorter reactor for a chemical reaction with cent of the total mass of material Figure 2: Integrated
continuous process for
cycle times. As an added bonus, mixed suspension-mixed product used in typical pharmaceutical intermediate and API
biocatalytic transformations most removals (MSPRs) in series for manufacturing processes (see production thermal
tube reactor and
commonly occur in water, thereby product crystallisation and isolation Figure 3) (5). In addition, a detailed
MSPRs in series
reducing their environmental (see Figure 2). In fact, Pfizer uses analysis was recently performed on
impact. As a result of the power a tube reactor-continuous stirred the benefits of recycling solvents in
of these green approaches, many tank reactor (CSTR) series for the the pharmaceutical industry and, in
companies have developed production of 400,000 kg/year of each case, reducing fresh solvent or
substantial in-house capacity the arthritis medicine Celecoxib (4). burning less solvent waste reduced
for traditional catalysis and total emissions for a process
biocatalysis research and numerous By far, solvents are the largest by more than 90 per cent (6).
US Presidential Green Chemistry contributors to pharmaceutical One of the main parameters that
Challenge awards have recognised process-related waste and can lead to reduced emissions is
achievements in these fields. emissions. A benchmarking study careful solvent selection. Thoughtful
by the American Chemical Societys selection of solvents that have
For many decades, traditional batch Green Chemistry Institute (ACS favourable azeotropes, and low
processing has been the modus GCI) Pharmaceutical Roundtable carbon footprints, can greatly Figure 3: 2010
pharma PMI
operandi in the pharmaceutical revealed that organic solvent and reduce overall emissions and energy composition data
industry, with the construction of water account for around 90 per usage. In addition, simplifying (per cent)
large facilities with reactors sized
up to 12,000 to 16,000 L to deliver
high-volume products. However,
operations at this large scale
often greatly restrict the type of
chemistries that can be performed
due to process safety constraints.
Over the past decade, pharma
Total solvents
has began to focus on continuous (excludes water)
processing which is inherently 35%
Total reactants
safer than batch processing and
can be run with a substantially
lower manufacturing footprint Total other process
(often >100x scale reduction) 54% materials

with significantly lower material

Total water
usage. In fact, many processes
considered too hazardous to run by
a conventional batch process can be 4%
operated safely and more efficiently 7%
in continuous mode. A common
continuous process configuration
is an integrated thermal tube

Innovations in Pharmaceutical Technology Issue 43 73

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processes to the minimum amount estimate life cycle analysis (LCA). developed a solvent selection
of required solvents also can A full LCA requires considerable guide that groups solvents into
have a large, positive impact more information, time and chemical classes and ranks their
on emissions reduction. resources. In an effort to quickly hazards with respect to safety,
estimate LCA in a cost-effective health and the environment
Green Metrics manner, a new version of the PMI (see Table 1) (8). The solvent
calculator is being developed to selection guide helps a chemist
The same benchmarking study estimate LCA based on the solvents make a more informed decision.
that found that solvents are the in the process (7). Another important tool which the
primary contributor to the process Pharmaceutical Roundtable has
mass intensity (PMI) of an API The benefit of tracking metrics is in development is a reagent
concluded that the mean PMI of to be able to drive improvements. guide that aims to identify the
the processes in the study was Companies have now begun to greenest possible reagents
120 kg/kg meaning that 120 kg set process development targets for the most used chemical
of raw materials were used to based on PMI. These targets are transformations.
manufacture 1 kg of API. By focusing generally internal guidelines that
on the inputs to a process, one can help communicate progress and Over the past decade, most
influence changes as the processes illustrate which processes need pharmaceutical companies have
and routes are being designed. improvements before moving adopted electronic lab notebooks
There are a number of green further into development. This (ELNs) as a means for recording
metrics to consider, but the two practice further integrates green and sharing experimental data.
most common in the industry are chemistry design principles early This paradigm shift has created
PMI and E-Factor (mass of waste in the development process. a unique opportunity to expose
per mass of API). It has been argued new scientists to green chemistry
that focusing on leading indicators Tools for Green Chemistry at the start of their professional
such as PMI will maximise value careers. Key green chemistry
and efficiency, with waste reduction One of the largest environmental metrics such as PMI, atom
a resulting benefit (5). impacts that can be made early economy and E-Factor can be
on in a drugs development life calculated and reported directly
PMI is not a perfect metric as it cycle is selection of as green a within the ELN without the need
does not include specific concerns solvent system as possible from to do secondary calculations (9).
regarding environment, health and the outset of development. In addition, an ELN is capable
safety of the materials involved or To encourage the greenest of linking to or launching a
the waste produced. However, it is possible solvent selection, the solvent selection guide. Thus,
an essential intermediate step to Pharmaceutical Roundtable has ELN technology has the unique

Table 1: Example of Pharma Roundtable solvent selection guide

Substance information Scoring information

Solvent class Solvent name CAS number Safety Health Environment (air) Environment (water) Environment (waste)
Acid Acetic acid 64-19-7 3 6 6 3 6
Acid Acetic anhydride 108-24-7 3 6 6 2 7
Acid Formic acid 64-18-6 2 6 5 4 7
Acid Methane sulphonic acid 75-75-2 6 6 10
Acid Propionic acid 79-09-4 2 5 6 4 6
Alcohol 1-butanol 71-36-3 3 5 5 5 3
Alcohol 1-propanol 71-23-8 4 4 6 2 6
Alcohol 2-butanol 78-92-2 4 5 6 3 5
Alcohol 2-methoxyethanol 109-86-4 4 9 5 3 7
Alcohol Benzyl alcohol 100-51-6 4 3 4 2 4
Alcohol Ethanol 64-17-5 4 3 5 1 6
Alcohol Ethylene glycol 107-21-1 3 3 5 1 7
Alcohol Isoamyl alcohol 123-51-3 3 4 5 3 4
Alcohol Isobutanol 78-83-1 3 5 4 3 3
Alcohol Isopropyl alcohol (IPA) 67-63-0 5 5 6 2 6
Alcohol Methanol 67-56-1 3 5 6 3 6
Alcohol T-butanol 75-65-0 3 5 7 2 6
Aromatic Benzene 71-43-2 5 10 6 6 2
Aromatic Toluene 108-88-3 5 7 6 6 2

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ability to provide green chemistry of pharmaceutical products. pharma manufacturers

metrics at scientists fingertips Regardless of the context, and suppliers alike
within their primary workspace. a holistic green chemistry 8. ACS Solvent Selection Guide,
approach to pharmaceutical ACS GCI Pharmaceutical
Green Chemistry Frontiers manufacturing through the use Roundtable website:
of green technologies, metrics
Green chemistry is a drive and tools will pay measurable portal/PublicWebSite/
for continuous improvement, and significant dividends to a greenchemistry/
and as such there continues to companys sustainability efforts. industriainnovation/
be opportunities for research, roundtable/CNBP_027158
engagement and collaboration. References 9. Kopach ME and Reiff EA, Use
Recognising that the 1. Nidumolu R, Prahalad CK of the Electronic Laboratory
fundamentals of green chemistry and Rangaswam MR, Why Notebook to Facilitate
are non-proprietary in nature, sustainability is now the Green Chemistry within the
the ACS GCI Pharmaceutical key driver of innovation, Pharmaceutical Industry,
Roundtable was developed in Harvard Business Review, Future Medicinal Chemistry
2005 as a partnership between September 2009 11: pp1,395-1,398, 2012
the industry and the American 2. Elkington J, Cannibals with
Chemical Societys Green Forks: the Triple Bottom Line Michael Kopach joined Eli Lilly and
Chemistry Institute to collectively of 21st Century Business, Company in 2001 and has led several
overcome challenges to green Stony Creek, CT, New Society multidisciplinary Phase 1 to Phase 3
chemistry integration. Consisting Publishers, 1998 R&D projects. Throughout his industrial
of 15 global pharma-related 3. Anastas PT and Warner JC, career, Michael has led research teams
corporations, the Roundtable Green Chemistry: Theory and applying green chemistry principles to
catalyses the implementation of Practice, New York, Oxford chemical process research and development, and has
green chemistry and engineering University Press, 1998 published several articles related to this topic. For the past
several years, he has represented Eli Lilly at the ACS Green
into the business of drug 4. Proctor L, Dunn PJ, Hawkins
Chemistry Institute Pharmaceutical Roundtable, where he
discovery, development and JM et al, Continuous
presently serves as Co-Chair. He earned a PhD in organic
production by informing and Processing in the
chemistry from the University of Virginia (Charlottesville,
influencing the research agenda, Pharmaceutical Industry, VA) and postdoctoral studies from Colorado State University
developing tools like the PMI Green Chemistry in the (Fort Collins, CO). Email:
calculator and solvent guide, and Pharmaceutical Industry,
educating current and future Eds: Dunn PJ, Wells AS and David Leahy has eight years experience
generations of scientists. More Williams MT, Weinheim, as a Process Chemist at Bristol-Myers
recently, the Innovative Medicines Germany, Wiley-VCH, Squibb in chemical development. He
Initiative (IMI) has been developed pp221-242, 2010 is engaged in BMSs green chemistry
and includes a green chemistry 5. Jimenez-Gonzalez C, Ponder effort and is currently a Co-Chair of
the American Chemical Society Green
component. These organisations CS, Broxterman QB and
Chemistry Institute Pharmaceutical Roundtable. He holds
demonstrate that companies Manley JB, Using the right
BS degrees in chemistry from Lebanon Valley College
can have a greater impact green yardstick: why process
(Annville, PA) and obtained a PhD at Indiana University
collectively than any one mass intensity is used in (Bloomington, IA). Email:
corporation could individually. the pharmaceutical industry,
Organic Process Research Julie Manley began her career at Abbott
While historically green & Development 15: Laboratories spending 10 years in the
chemistry efforts have focused pp912-917, 2011 manufacturing and environmental,
on the development and 6. Raymond MJ, Steward Slater health and safety organisations. She is
manufacturing of small molecules, C and Savelski MJ, LCA currently President of Guiding Green LLC
this view is ever evolving and Approach to the Analysis of (Sanford, MI), a sustainability consulting
firm, and Senior Industrial Coordinator for the American
expanding. Recent focus on Solvent Waste Issues in the
Chemical Societys Green Chemistry Institute where she
drug discovery embeds green Pharmaceutical Industry,
manages industrial partnerships including the ACS GCI
chemistry design principles even Green Chemistry 12:
Pharmaceutical Roundtable and its counterpart in the
earlier in the process, while the pp1,826-1,834, 2010
chemical manufacturing industry. Julie holds BA degrees
application of green chemistry 7. A tool to calculate PMI can from Northwestern University (Evanston, IL) and a
ideals into the biologics space be found at Master of Public Health from the University of Michigan
is beginning to benefit this gcipharmaroundtable and (Ann Arbor, MI). Email:
increasingly important class its use is encouraged for

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