GREEN

CHEMISTRY
BACKGROUND

ACTIONS

Chemistry is an integral part of our pharmaceutical business.

Green chemistry is understood to have minimal impacts on the
environment and on human health, but also to be cost effective.

Optimizing raw material use

and processes

Over the past decade, the pharmaceutical industry has been

moving toward the application of green chemistry principles,
mainly by introducing new production and analytical technologies,
using greener solvents, and emphasizing catalysis and enzymatic
chemistry.
Green chemistry focuses on making industrial chemistry safer,
cleaner, and on giving more consideration on how energy could
be use more efficiently while generating economic benefits. This
concept is driven by efficiency combined with environmental
responsibility, to offer enhanced chemical-process economics.
To quote the words of Paul Anastas, who introduced the term
green chemistry in 1991: Its more effective, its more efficient,
its more elegant, and its simply better chemistry!
The 12 Principles of Green Chemistry
To discover the 12 Principles of Green Chemistry, visit the ACS
Green
Chemistry
Institute
website:
http://portal.acs.org/portal/acs/corg/content?_nfpb=true&_pa
geLabel=PP_ARTICLEMAIN&node_id=1415&content_i
d=WPCP_007504&use_sec=true&sec_url_var=region1
&__uuid=3909fc08-40eb-485b-afc8-b1c663718151

POLICY
With a long history in active ingredient manufacturing, Sanofi is
committed to improving its drug manufacturing processes so that
it minimizes the impact on the environment.
Each development team involved in the design and improvement
of our chemical and biotechnical processes for producing our
active ingredients is intently focused on this goal. In support of
our corporate commitment, we have taken a number of tangible
steps to reduce our environmental footprintfrom the design of
our R&D synthetic pathways, to the production of active
pharmaceutical ingredients in our plants.

Throughout the chemical and biochemical product development

stages that are part of manufacturing drugs, Sanofi teams make
decisions about the processes they use based on criteria
designed to protect the health and safety of the employees while
preserving the environment.

Tracking the greenness of our

processes
Medicines are often produced using large amounts of input
materials to produce very small amounts of active ingredients,
which corresponds to low mass efficiency. Developing and
producing drugs this way is not only costly, but harmful tor the
environment.
Benchmarking shows that the pharmaceutical industry typically
uses about 100kg of raw material to produce 1kg of active
pharmaceutical ingredient (API). This 1% mass efficiency
compares to about 20% for fine chemicals and 50% for bulk
chemicals.
Also we face the trend of shifting towards biotechnologies based
on fermentation with micro-organism for the synthesis of active
molecules. This evolution means that less chemical steps are
necessary, but fermentation processes have other environmental
impacts (mainly biological COD load to waste water treatment).
Experts from within the industry, as well as health authorities
such as the U.S. Food and Drug Administration (FDA) and
European Medicines Agency (EMA), recommend that drug
companies focus greater attention on this issue. To this end, it is
essential to adopt a common metric to measure progress toward
more sustainable manufacturing.
For more information, please refer to the Green Chemistry
Factsheet published in May 2014, page 2 of 5.
To answer these requirements, the GCI-PR implemented the
Process Mass Intensity (PMI) indicator. PMI measures the mass
(weight) of the produced API compared to the mass (weight) of
substrates, reagents, solvents, and process water used to

Green Chemistry Factsheet

published in May 2015

Page 1 of 4

manufacture the API. As a member of GCI-PR, Sanofi uses PMI

as a key metric for process greenness.
The initial PMI assessments of our products reveal that our
figures are clearly within the pharmaceutical industry range.
However, the PMI alone does not enable a detailed view of
process improvement. In order to remedy this limitation, a set of
metrics has been elaborated in 2013-2014 by a working group for
the process research laboratoriesthe Key Process Performance
Indicators (KPPI). This tool consists of a simple Excel sheet
which
highlights
economical,
process
efficiency
and
environmental performance. In contrast with the PMI, the KPPI is
focussed on each chemical step, and enables every chemist to
visualize and evaluate the area requiring improvement for the
process under consideration, with the classical three-colour
codes (green, amber, red). For example, the solvents used in the
manufacturing process are flagged according to the solvent
selection guide of Sanofi, and the amount of solvent is considered
as an important environment metric. This KPPI tool is under
implementation. In Vitry, since June 2014, all Laboratory
Procedures transferred to pilot plant include the KPPI sheet.
To decrease the environmental footprint and reduce the costs
associated with the production of clopidogrel hydrogen sulfate
(trade name Plavix or Iscover), Sanofi set up an ongoing
green chemistry project that has led to improved synthetic
pathways, increased yields, and smaller quantities of solvents in
the manufacturing process. These important improvements meet
the expectations of both internal and external stakeholders.
Internally, a working group met several times in 2013 and 2014 to
investigate appropriate qualitative and quantitative indicators
including economic, process efficiency, and environmental criteria
at different development stages, such as:
research into industrial synthesis pathways at
laboratory scale;
process development and optimization; and
continuous process improvement at industrial level.
The aim of this investigation is to give better guidance to the
operating teams, based on relevant KPIs, and focus on the key
sustainable activities.

SOLVENTS
Making choices when it
comes to solvent use

after an active ingredient is in the production phase, industrial

development teams continue to optimize synthesis and
biosynthesis processes whenever possible. Choices made during
the industrial development phase are often difficult to change
later on, which is why it is important to make sustainable
decisions early in the development process, taking into account
future manufacturing and scale-up.
To choose substances and materials with the least environmental
impact, the Group has established processes designed to:
select the least toxic solvent;
reduce the quantities of solvents used in industrial
processes; and
recycle solvents whenever possible.
The guide that was developed, Sanofis solvent selection guide:
(1)
a step toward more sustainable processes , was published in
November
2013
and
is
available
at
http://pubs.acs.org/doi/abs/10.1021/op4002565.

Optimizing solvent
consumption
Solvents used in the production processes are either purchased
(consumed quantities) or regenerated at Sanofi sites.
To decrease the use of non-renewable raw materials, the Group
focuses on three areas:
process optimization;
recycling (when possible); and
incineration with energy recovery.
The continued conversion of chemical production to
biotechnology has led to a 3.3% decrease in the quantity of
solvents used by Sanofi. The solvent regeneration rate has arisen
very slightly as a result of the increase in solvents sent from the
sites of Sanofi located in Aramon and Saint-Aubin-ls-Elbeuf
(France) for regeneration.

(1) Prat, D., Pardigon, O., Flemming, H., Letestu, S.,

Ducandas, V., Isnard, P., Guntrum, E., Senac, T., Ruisseau, S.,
Cruciani, P. and Hosek, P. (2013). Sanofis solvent selection
guide: a step toward more sustainable processes, in
Organic Process Research and Development, 17(12), pp.
1517-1525.

From the earliest stages of product development, teams are

encouraged to use reagents and solvents that pose the least
possible hazard. One of their tools is a scale that assigns
compounds to one of five categories according to their potential
impact on health, safety, and the environment. To help teams
make decisions on a daily basis, Sanofi has developed an
internal guide on the appropriate use of solvents for the design of
drug-manufacturing processes.
The vast majority of energy, chemical reagent, and solvent
reduction occurs during scale-up and the manufacturing of
medicines, rather than during the drug-research phase. Even
Green Chemistry Factsheet
published in May 2015

Page 2 of 4

Weight of solvents used and percentage of regenerated solvents

2012

2013

2014

Variation
20132014

Solvents
used (tons)

178,968

168,397

163,595

-2.8%

Percentage
of
regenerated
solvents

59%

60%

64%

Promoting green chemistry

within the pharmaceutical
industry
Membership of learned societies
Sanofi is a member of several chemistry learned societies,
including the Socit franaise de chimie (SFC) and the
American Chemical Society (ACS), among others. Since 2011
Sanofi took an active part in a workshop organized by the Union
des industries chimiques (UIC) on Chemistry and Sustainable
Raw Materials, which focused on the importance of designing
green processes.

Our partnership with the ACS

GCI Pharmaceutical
Roundtable
In 2011 Sanofi joined the ACS Green Chemistry Institute (GCI)
Pharmaceutical Roundtable, which aims at catalyzing the
implementation of green chemistry and engineering throughout
the pharmaceutical industry globally.
Sanofi has launched various collaborative initiatives in line with
these general objectives, including:

assessment of PMI improvements for the production of

key active pharmaceutical ingredients;
contribution to the training program developed by the
GCI Pharmaceutical Roundtable in Europe; and
contribution to the current review of the solvent guide
with members of the GCI Pharmaceutical Roundtable.

For more information about the ACS GCI Pharmaceutical

Roundtable, please visit:
http://portal.acs.org/portal/acs/corg/content?_nfpb=true&_pa
geLabel=PP_TRANSITIONMAIN&node

Green Chemistry Factsheet

published in May 2015

The Innovative Medicines

Initiative (IMI)-CHEM21 project
in Europe
The discovery of green and sustainable synthesis methodologies
is a long-term endeavor. Today, collaborations between
academia and pharmaceutical companies provide an opportunity
to develop green, safe, and more effective processes to deliver
medicines for the 21st century.
The Innovative Medicines Initiative (IMI) is a pan-European
public-private partnership supported by the European Federation
of Pharmaceutical Industries and Associations (EFPIA). It was
created in 2007 to bolster the development of better and safer
medicines for patients in the European pharmaceutical industry.
To find out more about IMI, visit www.imi.europa.eu.
In 2011 Sanofi, together with other European pharmaceutical
companies (GSK, Janssen, Bayer, and Orion), suggested that IMI
launch a call for proposals in the field of sustainable chemistry.
Sanofi plans to contribute up to 5 million over four years to
support this project. Following a 2011 in-house workshop, the
IMI-CHEM21 project was initiated and started officially on
November 13, 2012, with a kick-off meeting gathering all the
participants in London. To find out more about IMI-CHEM21, visit:
http://www.chem21.eu.
Sanofi is participating as co-coordinator of the IMI-CHEM21
project, which aims at generating a range of technologies for
medicine manufacture that are demonstrably more sustainable
than existing methods.
Six working packages (Group) have been created and each of
them is co-led by a member of academia and a member of the
pharmaceutical industry (EFPIA). For each work package, a
Sanofi leader has been nominated for internal co-ordination and
for interfacing with the other members of the work package.
Sanofi will commit to a level of six full time equivalents employees
during the four years of the project, in the different work
packages.
In 2014 meetings were organized internally regarding IMICHEM21 initiatives, to share, inform, and brainstorm with the
Sanofi people involved in these working groups.
In working package No. 5 (WP5), Sanofi is working on medicinal
and process chemist education, with a goal of augmenting
internal employees awareness, as well as setting up a green
chemistry index. Sanofi participated in the IMI-CHEM21 General
Assembly in Graz in 2014. The aim of WP5 of IMI-CHEM21 is to
influence the next generation of chemists by exemplifying low
environmental impact chemistry, through the preparation and
delivery of high quality training and educational materials. In this
context, WP5 is working on the elaboration of a solvent selection
guide which will promote bio-derived solvents. Sanofi has a
leading role in this project. In 2014, a survey of solvent selection
guides has been published in Green Chemistry (Prat, D., Hayler,
J., Wells, A. Green Chem, 2014, 16, 4546-4551), which
constitutes the cornerstone of this guide.

Page 3 of 4

On April 1, 2014, our Vitry site Sanofi has welcome the ACS GCI
Pharmaceutical Roundtable and a joint meeting was organised
with IMI-CHEM21 topics. After a presentation of our commitments
to HSE and Green & Sustainable chemistry participants from
other pharmceutical companies have shared advances in this
topic.
ACS-GCI Pr has launched a benchmark inititaive among the
companies members in order to evaluate the use of PMI and LCA
tools. Sanofi has filed five processes fully analyzed with PMI &
LCA: one in clinical phase 1 and four in commercial phases.

Green Chemistry Factsheet

published in May 2015

Page 4 of 4