This document discusses metrics for measuring green chemistry performance in the pharmaceutical industry. It notes that pharmaceutical processes are complex, involving multiple reaction stages and waste streams. The author advocates asking the right questions to define appropriate metrics, as there are many options. Key lessons are that analysis provides value and positive change is possible through establishing the right process measures from early stages of development.

1. Lessons learned through measuring
Green Chemistry performance:
The Pharmaceutical Experience
David J. C. Constable, PhD
Gaithersburg, MD 20878 DESCA - 2012
Telephone: 301-926-1402
e-mail: David.JC.Constable@gmail.com 5 March 2012

2. Carbon Efficiency
Reaction Mass Efficiency
Yield
Outline Atom
Economy
Stoichiometry
Mass Efficiency
First Challenges of the Pharma Context
Batch Chemical Operations
Second Metrics and Process
Ask the right questions
Total Water
Third Choose the Right Metrics
There are a lot of options
Fourth What did we Learn?
There is value in analysis
Total CO2
Fifth Conclusions
Positive change is possible Net Mass Excluding
Process Water
Energy
Solvent Recovery
Energy

3. The Pharmaceutical Industry is
Challenged by Complexity
O F OH
O HO O O
O S
H HO OH
O O O
O H NH N O O
N O O
H OH O H
OH O
F H N
O HO OH H
O
F HO
They are complex:
paclitaxel
F
fluticasone salmeterol atorvastatin
HN
• target molecules, reagents and reactants
• synthetic routes: 6+ stages
• processes and wastes: mixed aqueous and organic Cl
streams Cl
sertraline
Need for early and rapid definition of the synthetic route
But there is a high failure rate for target molecules
N O
N
N O N
O S N
N O
F H
N
O
esomeprazole
risperidone

4. The Pharmaceutical Industry
Regulatory Climate is Challenging
• Highly regulated by government agencies
• process changes
• use of recovered/recycled solvent
• Route and Process changes post-approval give the
appearance of being costly
• Regulatory / Legislative restrictions on solvent and
materials selection
• EU Solvent Directive, REACH, IPPC, ICH etc

5. Finding the Right Balance can be a
Challenge
Commercial
Focus on
Speed to
Market
Green process
Attrition
design early
when costs are lower

6. Green Chemistry and Metrics
WELCOME TO
Pine View, Colorado
Established 1872
“All he’s done is call it Green” Population 732
The person who sat behind me, GRC Green Elevation 5755
Chemistry Meeting, Oxford, 1999, as related by
John Hayler, GSK TOTAL 8359*
“If you don’t keep
score, you’re only practicing”
Jan Leshley, former CEO SB & GSK
*Audited by
3iDataCen
(Formerly, the Center
for
irrelevant, immaterial
and inconvenient
Data)

7. Key Message
Ask the right questions!
Avoid “the perfect uselessness of
knowing the answer to the wrong
question”
The Left Hand of Darkness
Ursula K. LeGuin
1969

8. ESTABLISH THE RIGHT
PROCESS

9. Develop a process that fits in with
existing ways of working
Highlight key
sustainability issues for Complete at known stages
materials and process of development
Document PRMR Identify and
information communicate
opportunities
Vehicle for discussion with chemists, engineers and management

10. Green Metrics Template
Compound Number Benchmarking data against
Route Designation A3 projects in the same phase
Campaign # and Date CDD4
Intended Purpose of Campaign Ph II, POC work
Amount made 4.8kg Life cycle impact (FLASC) &
Date of Assessment and Reference 2-Aug-06
Solvent Acceptability Score
YOUR DATA
AVERAGE VALUES FOR CS-
FTIH PROJECTS
• f(mass, number, type of
Number of Stages 6 solvent)
Number of Chemistry Steps 7
Number of Stages Outsourced 3
Overall Yield % theoretical 37.3%
Mass Intensity kg/kg API 207.57 691
Priority materials of concern
Aqueous Mass Intensity* 86.76 flagged according to the GSK
Mass Productivity % 0.48% 0.29
Reaction Mass Efficiency % 8.57% 5.5 Chemicals Legislation Guide
Total Number of Solvents 10 8.8
Number of Solvents per Stage 2.33 2.4
e.g. for Compound X
Total Mass of Solvents / Kg API
195.9
(94% of reaction wt)
591 • Route A – none
Current Material Cost / Kg API
(from B+)
• Route B – Dichloromethane
FLASC Score (1-5) 1.9 1.4
• Route C – 1,4-dioxane
Solvent acceptability score (1-5)
• Route D – Dichloromethane
1.2 0.5
Materials of concern none
THF 30.2%
Methanol 15.75%
Major Contributors to Overall Mass
Toluene 12.5%
of Materials
Ethanol 10.9%
Additional Comments

11. Green Metrics Template Page 2
Mass Productivity benchmarked
against current GSK data by
phase of development
FLASC score for your project
measures the environmental
impact of materials in a route
benchmarked against GSK
processes
General guidance to help
interpret the metrics values and
sources of further information

12. FIND THE RIGHT METRICS
• Make objective comparisons
• Benchmark progress
• Drive change
• Demonstrate improvement
• Increase transparency

13. Principles of Green Chemistry and
Engineering – Simplified*
• Maximize resource efficiency
• Eliminate and minimize hazards and
pollution
• Design systems holistically and using
life cycle thinking
*See: Green Chemistry and Engineering: A Practical Design Approach.
Jimenez-Gonzalez C, Constable DJC. John Wiley and Sons. 2011, p 35- 37.
http://www.amazon.com/Green-Chemistry-Engineering-Practical-
Approach/dp/0470170875

14. Key Metrics are Essential
Can we change
the chemistry?
• Yield
Telescope, maximise
• Reaction Mass Efficiency (RME) convergency, pay
• No. of stages and no. of attention to order of
side chain coupling
chemistry steps
• Total no. of solvents and solvents Recycle/reuse 80 –
90 % of the mass!
per stage
• Mass Intensity and Mass Focus on
Productivity (Efficiency) optimising
use of a few
• Materials of Concern key materials
• Process life cycle environmental
impact Starting
Materials matter!

15. Reaction Mass Efficiency (RME)
RME = efficiency of conversion of
reactants into product. It includes:
Yield
Atom Economy
Stoichiometry of the reactants

16. Reaction Mass Efficiency
For a generic reaction:
A+B C
m.w.of product C
RME yield
m.w.of A (m.w.of B x molar ratio B/A)
or more simply:
mass of product C
RME X 100
mass of A mass of B

17. Top 10 Chemistries Used 2004 - 2005
N-acylation
11%
N-alkylations
8%
others
39%
recrystallisation
8%
salt formation/salt swap
6%
hydrolysis (base)
6%
OH activation/functional
group change
3% S-alkylation
6%
O-alkylation Chlorinations
3% 6%
hydrogenation
4%

18. Solvent Use in Pharma is Significant
• In 2008, 10 solvents
Water 32% Solvents 56%
represented approximately
80% of all solvents used in
GSK
Other 5%
• Solvent use is the largest
contributor to: Reactants 7%
• Primary manufacturing process
mass intensity Composition by mass of types of
material used to manufacture an API
• Primary manufacturing life American Chemical Society Green Chemistry Institute
Pharmaceutical Roundtable Benchmarking 2006 & 2008
cycle environmental impacts
(e.g., ~80% mass, ~75% energy)

19. Process Water 50
38.9
40
Average wt% water
32.5
28.6 29.7
30
20
10
0
CS to FTIH FTIH to PoC towards
PoC to CP III full Phase III
scale
Pre-clinical commercialisation
Data shows that the amount of process water used in washings and
extractions per kg API could be optimised further

20. used
0
5
10
15
20
25
E
th IP No of stages 30
A
Solvents
y la
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ta
M t e
et
ha
IM no
S/ l
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th
a no
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ep
t an
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TH
F
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Top 10 Most Frequently Used
ne
ce
tic
ac
A id
ce
to
ni
tri
le

21. mass, %
Et
hy
la
0
2
4
6
8
10
12
14
16
18
ce
ta 20
t e
IP
A
D
ic
h lo TH
ro F
m
et
ha
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et
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To l
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IM uen
S/ e
Et
ha
Ac no
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Top 10 Solvent Use by Mass
et
on
itr
ile
H
ep
ta
ne
Ac
et
on
e

22. Solvent Use % Solvent Mass
100
80
mass %
60 2005
40 2006
20
0
CS to FTIH FTIH to PoC PoC to CP III Phase III
towards full scale
Pre-clinical commercialisation
• Solvent mass is ~90 wt% of reaction mass excluding water
• Dilution of reactions is consistent across all phases of development
• The type of solvent used does change; e.g., the majority of
dichloromethane is removed by Proof of Concept

23. Mass Productivity Headline Data
2.5
< 50 kg
per kg API
Mass Productivity %
2.0
100 kg per kg
1.5 API
1.0
0.5
0.0
CS to FTIH FTIH to PoC towards full III
PoC to CP III Phase scale
Pre-clinical commercialisation
API = Active Pharmaceutical Ingredient

24. What does it take to achieve MP > 1?*
RME > 25% for MP > 1%
RME 15 – 25% yields a 40% probability of MP > 1%
Having < 4 stages increases probability for a MP > 1%
% probability of MP
stages
>1%
2 85
3 75
4 50
5 50
>6 15
*Based on about 40 mature R&D processes

25. Materials of Concern
Chemicals for which there is evidence of probable serious effects to
humans or the environment
• carcinogens, mutagens or reproductive hazards (CMR’s),
• toxic and bioaccumulate or persist in the environment (PBT’s),
• very persistent or very bioaccumulative in the environment (vPvB),
• ozone depleting chemicals (ODC’s),
• endocrine disruptors (ED’s)
• those known to cause asthma (asthmagens)
Materials of Concern should be identified early to
develop strategies to eliminate or substitute.

26. Materials of Concern in 2006
Average mass % of materials of concern in processes
25
99.4% solvents
98.7% solvents
20
% by mass
15
100% solvents
10
65% Solvents
5
0
CS to FTIH FTIH to POC POC to PhIII PhIII
towards full scale
Pre-clinical commercialisation

27. Materials of Concern 2006 – top 6
90 81% dichloromethane
80
70
Mass %
60
50
40
30
20
10
0
ne
e
ne
P
CM
F
in
M
M
ha
xa
rid
D
N
D
et
o
Py
Di
xy
4-
ho
1,
et
m
Di
2-
1,
Finding alternative solvents to replace dichloromethane remains a key green
chemistry challenge

28. Are pharmaceutical processes
becoming greener?
If solvent mass is ~ 90% of the reaction mass and ~ 75% of
the life cycle energy and mass, what about the other 10% of
the reaction mass?
Are there correlations with current measures of greenness?
Reaction Mass Efficiency vs.
GSK FLASC Score vs. Chemical Mass
Reaction Mass Efficiency vs. Molecular Weight Added
Mass Intensity per Chemistry Transformation
60
RME vs MI per Step CS to FTIH
GSK FLASC score vs Chemical Mass
FTIH to POC
60 50
5.0 CS to FTIH
PoC to PhIII
FTIH to POC
PhIII
4.5
GSK FLASC Score
50 40 PoC CS to FTIH
to FTIH
4.0 PhIII FTIH to POC
RME RME %
40
3.530
PoC to FTIH
PhIII
%
3.030
2.520
20
2.0
10
1.510
1.0 0
0
00 100 50 200 300 100 400 150
500 600 200
700
0 50 100 150 Added200
MW 250 300 350
Chemical Mass kg
MI per step kg

29. Average Non-Solvent Mass
250
200
Non Solvent Mass kg/kg API
150 Cs to FTIH
FTIH to POC
PoC to PhIII
100 PhIII
50
0
0 2 4 6 8 10 12
No of Stages
Optimization of reagent and reactant mass during development will
have the biggest impact for complex syntheses

30. Assessing over 100 pharmaceutical
processes tells us something important
• No correlation between non-solvent mass and
several different measures of greenness.
• Mass based metrics do not appear to account
for the complexity of the chemistry.
• Mass based metrics do not account for the
nature and impact of chemicals.
• Is there more we should be doing to
influence the selection of reagents to
reduce the impact of solvents?

31. Life Cycle Assessment – The very big
picture Raw material and energy consumption
R&D:
Process Development
Resource Raw Material Intermediate Products Final Product
Material Selection
Extraction Manufacture
Hazard & Risk assessment
Sales and
Marketing
Ultimate
Ecological
Fate
Store Distribution
Final Consumer Use
Emissions to air, water and land

32. Using a Streamlined Life Cycle Tool is Key
FLASCTM - Fast Lifecycle Assessment of
Synthetic Chemistry)
• Web-based tool and methodology
• Simple to use (but not simplistic)
• Determines and benchmarks the relative
sustainability of chemicals
• Based on cradle-to-gate LCA impacts

33. Life Cycle Impact - FLASC scores
65% of the Life FLASC - all data
Cycle impact of the 27% of the Life
average GSK
5.0 Cycle impact of the
process* average GSK
4.5
process*
4.0 3.9
3.5 3.5
FLASC
3.0 ave
2.8
2.5 37% of the Life
Cycle impact of the
2.0
1.9 average GSK
1.5 process*
130% of the Life
Cycle impact of the
1.0
average GSK CS to FTIH FTIH to PoC PoC to CP III Phase III full scale
towards
process* Pre-clinical commercialisation
The environmental life cycle impact of all new processes
post-PoC is potentially much lower than for current
processes in manufacturing
* 25 GSK routes developed during 1990 to 2000 were assessed.
The average performance was assigned a FLASC rating of 2.3

34. Life Cycle Impacts can be Decreased
FLASC and Solvent Acceptability score Few years ago:
histogram
Most FLASC and Solvent
50% Scores in lower range
40%
FLASC score (medians 2.4 & 2.2)
SAS score
30%
20%
10%
0%
<2.5 2 - 2.5 2.5 - 3 3 - 3.5 3.5 - 4 >4 FLASC and Solvent Acceptability score
histogram
50%
FLASC score
Now: 40% SAS score
Most FLASC and Solvent 30%
Scores in middle range
(medians 3.0 & 2.7) 20%
10%
0%
<2.5 2 - 2.5 2.5 - 3 3 - 3.5 3.5 - 4 >4

35. Conclusions
• Biggest impact from solvents: ~90 wt% of
reaction mass
• Effect on mass efficiency / intensity from
replacing and substituting hazardous with
non-hazardous chemicals is unknown
• GSK’s life cycle assessment metrics suggest
that processes in development are
potentially getting greener

36. Summary
• The Strategy is to regularly influence during
product development
• Green Metrics help Project Teams
• Green Metrics should include life cycle
assessment
• Metrics should be collected for every pilot plant
campaign
• Metrics alone do not tell the whole story
• Assessment of “greenness” is, and should be, a
multivariate exercise

37. Future Challenges
• Less toxic alternatives for hazardous solvents and
reagents
• Integration of chemistry and technology
• Application of continuous processing, novel reactors, solvent
systems
• Bioprocessing
• Further
development of tools to objectively compare
bioprocesses with chemical processes
• Greater attention to downstream processing issues
• Integration of life cycle considerations
• Renewable feedstocks.
• New, cleaner, reactions and methodology.

38. Acknowledgements
Concepción (Conchita) Jiménez-González
Richard Henderson
GSK’s Sustainable Processing Team:
• John Hayler
• Clare Ruddick
• Graham Geen
• Jonathan Emeigh
• Mario Almi
• Tom Roper

39. ACS Webinar March 8th
Measures of Green Chemistry Performance
http://acswebinars.org/constable
Any Questions?