Green Chemistry Factsheet published in May 2015 Page 1 of 4

GREEN CHEMISTRY

BACKGROUND

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.

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: “It’s more effective, it’s more efficient,

it’s more elegant, and it’s 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 footprint—from the design of

our R&D synthetic pathways, to the production of active

pharmaceutical ingredients in our plants.

ACTIONS

Optimizing raw material use

and processes

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 2 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 laboratories—the 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

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

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, “Sanofi’s solvent selection guide:

a step toward more sustainable processes(1)

,” 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-lès-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). “Sanofi’s solvent selection

guide: a step toward more sustainable processes,” in

Organic Process Research and Development, 17(12), pp.

1517-1525.

Green Chemistry Factsheet published in May 2015 Page 3 of 4

Weight of solvents used and percentage of regenerated solvents

2012 2013 2014 Variation

2013-

2014

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 Société française 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

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 IMI-

CHEM21 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.

Green Chemistry Factsheet published in May 2015 Page 4 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.