A Green Chemistry Continuum For A Robust and Sustainable API Supply Chain

Subscriber access provided by TRINITY COLL
Perspective
A Green Chemistry Continuum for a Robust and Sustainable API Supply Chain
Stefan G. Koenig, Cisco Bee, Alina Borovika, Christiana Briddell, Juan Colberg,
Guy R. Humphrey, Michael E Kopach, Isamir Martinez, Sudhir Nambiar, Scott
Plummer, Seth Ribe, Frank Roschangar, Jeremy P. Scott, and Helen F. Sneddon
ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/
acssuschemeng.9b02842 • Publication Date (Web): 19 Sep 2019
Downloaded from pubs.acs.org on September 24, 2019
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,

Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.
Page 1 of 51 ACS Sustainable Chemistry & Engineering
1
2
3
4
5
6
7
8
A Green Chemistry Continuum for a Robust and
9
10
11
12
Sustainable API Supply Chain
13
14
15
16
Stefan G. Koenig,*a Cisco Bee,b Alina Borovika,c Christiana Briddell,d Juan Colberg,e Guy
17
18
19 R. Humphrey,f Michael E. Kopach,g Isamir Martinez,d Sudhir Nambiar,h Scott Plummer,i
20
21
22 Seth D. Ribe,j Frank Roschangar,k Jeremy P. Scott,l and Helen F. Sneddonm
23
24
25 a Small Molecule Process Chemistry, Genentech, A Member of the Roche Group, 1 DNA Way, South San
26
27
Francisco, CA 94080, USA.
28
29
30
b Process Chemistry, Asymchem Inc., 600 Airport Blvd. Suite 1000, Morrisville, NC 27560, USA.
31
32
33
c Chemical and Synthetic Development, Bristol-Myers Squibb, 111 Squibb Dr, New Brunswick, NJ 08901,
34
35
36 USA.
37
38
39 d ACS Green Chemistry Institute®, The American Chemical Society, 1155 16th St NW, Washington, DC
40
41
20036, USA.
42
43
44
e Pharmaceutical Sciences – Worldwide Research & Development, Pfizer, 558 Eastern Point Road, Groton,
45
46
47 CT 06340, USA.
48
49
50 f Process Research and Development, Merck & Co., 90 E Scott Ave, Rahway, NJ 07064, USA.
51
52
53 g Small Molecule Design and Development, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN
54
55
56 46285, USA.
57
58
59
60 ACS Paragon Plus Environment
1
ACS Sustainable Chemistry & Engineering Page 2 of 51
1
2
3 h Research & Technology, Hikal, Plot No 3A, International Biotech Park, Phase 2, Hinjewadi, Pune 411057,
4
5
India.
6
7
8
i Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Ave,
9
10
11 Cambridge, MA 02139, USA.
12
13
14 j STA Pharmaceutical Co., Ltd., No. 589, North Yulong Road, Xinbei District, Changzhou, Jiangsu, 213127,
15
16
China. k Chemical Development, Boehringer Ingelheim Pharmaceuticals, 900 Ridgebury Rd, Ridgefield, CT
17
18
19 06877, USA.
20
21
l Process Research and Development, Pharmaron UK Ltd, Hertford Road, Hoddesdon, Hertfordshire, EN11
22
23
24 9BU, UK.
25
26
27 m GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts., SG1 2NY, UK.
28
29
30
31 Corresponding author: koenig.stefan@gene.com
32
33
34 KEYWORDS Green chemistry, Green engineering, Sustainability, Active Pharmaceutical
35
36
37 Ingredient, Pharma, Contract Research Organization, Contract Development and
38
39
40 Manufacturing Organization, Supply Chain.
41
42
43
44 ABSTRACT In an effort to improve sustainability and reduce the cost of goods for active
45
46
pharmaceutical ingredients (APIs), pharma companies have partnered on varying
47
48
49 portions of their supply chain with contract providers. This approach brings with it
50
51
52 numerous cost benefits but also logistical challenges. However, it also offers
53
54
opportunities to integrate sustainable science via green chemistry and engineering more
55
56
57
58
59
2
1
2
3
4
holistically into the entire sequence. The ACS Green Chemistry Institute Pharmaceutical
5
6 Roundtable (GCIPR) provides a multi-company industrial view on how to address the
7
8
9 challenges and best meet cost goals while enhancing the overall sustainability of the
10
11
global pharmaceutical industry.
12
13
14
15
16
17
18
19 Introduction
20
21
22
23 Delivering a life-saving medicine to patients is a tremendous undertaking. Drive and
24
25
26 coordination are required at every step of the way, from understanding disease
27
28 fundamentals, through discovery and development of the therapeutic, to manufacturing
29
30
31 and administration of the product. While established drugs address many recognized
32
33
34 afflictions, innovation remains essential to meet the challenge of growing unmet
35
36 medical needs.1 Moreover, the path to successfully developing new treatments has
37
38
39 become progressively more complex with a variety of factors contributing to this shift,
40
41
42 including: (a) increased pressure to curb the rising costs of medications; (b) increasing
43
44 regulatory requirements for drug approvals; (c) shorter exclusivity periods for certain
45
46
47 therapeutic areas; and (d) a reduced potential for success in the development of new
48
49
50
drugs, partially due to enhanced competition between innovator companies amid more
51
52 challenging drug targets, as well as the continued transition of previously pioneering
53
54
55 medicines into the generics realm. The accelerated loss of patent protection for
56
57
58
59
3
1
2
3
4
successful commercial drugs, in particular, threatens the income streams of innovator
5
6 companies that are the lifeblood of novel discovery and development activities.2
7
8
9
10 Figure 1. Representative Chemical Route to API
11
12
13
Continuum of API construction via CDMO or pharma company or combination thereof
14
15 Non-GMP: Raw mat to RSM GMP manufacturing: RSM to Intermed and ultimately API
16
17 Raw mat 1
18 RSM A Intermed
19 Raw mat 2
20
21 API = active pharmaceutical ingredient Raw mat 3
22 CDMO = contract development and RSM B
23 Raw mat 4 API
manufacturing organization
24
GMP = good manufacturing practices
25
26 Raw mat = commodity raw materials Raw mat 5 RSM C
27 RSM = regulatory starting material
28 Intermed = isolated intermediate
29
30
31 One significant strategic change that the industry has implemented to overcome these
32
33
challenges is the use of external networks to supply high value intermediates and/or
34
35
36 small molecule Active Pharmaceutical Ingredient (API) to support drug product (Figure
37
38
39 1).3 This partnership between pharmaceutical companies (“pharma”) and contract
40
41
research organizations (CROs) or contract development and manufacturing
42
43
44 organizations (CDMOs), represents a great opportunity to enhance the supply chain but
45
46
47 is far from a simple proposition. A large proportion of the organizations available to
48
49 pharma companies to deliver key intermediates and APIs have their operations located
50
51
52 in emerging market regions, and these now represent a crucial part of the industrial
53
54
55 supply chain. Some of the hurdles that the industry has encountered in the
56
57
58
59
4
1
2
3
4
implementation of this external sourcing approach include limited adherence to: (a)
5
6 intellectual property (IP) laws, (b) quality control compliance, (c) process safety concerns,
7
8
9 and (d) environmental regulations in manufacturing operations.4,5,6 These challenges
10
11
have led to increased scrutiny of practices at contract partners, particularly with regard
12
13
14 to the potential suspension of activities or even closure of facilities due to
15
16
17 environmental and regulatory infractions.7 As such, pharma companies assume a level
18
19
of supply chain risk and must take responsibility for this upstream production. These
20
21
22 various issues have begun to be addressed together by industry and public sectors via
23
24
25 new regulations and full enforcement of existing ones, joint training programs, and
26
27
educational initiatives to disseminate best practices in the relevant areas.8
28
29
30
31 There has been widespread recognition of the significant environmental footprint of
32
33
34 healthcare, and there are a number of initiatives to explore the supply chain from both
35
36
cradle-to-gate and cradle-to-grave perspectives.9 These initiatives include ReMediES10
37
38
39 and the NHS’ Sustainable Development Unit,11 both in the U.K., and, globally, the
40
41
42 Pharmaceutical Supply Chain Initiative (PSCI)12 and Walmart’s Sustainability Index13 via
43
44
The Sustainability Consortium (TSC)14 that includes membership from Johnson &
45
46
47 Johnson and chemical manufacturers DuPont, Dow, BASF, and DSM. However, these
48
49
50 initiatives focus on the adoption of sustainability and general EHS requirements within
51
52 manufacturing rather than integrating green chemistry and engineering into the
53
54
55 discovery and development supply chain.15 This paper sets out to explore the manner in
56
57
58
59
5
1
2
3
4
which the API R&D supply chain is evolving to become more sustainable, and ways in
5
6 which it could further improve. The authors expect that highlighting opportunities for
7
8
9 the supply chain to become greener will enable greater uptake and for commercial
10
11
products to be more sustainable in the long run.
12
13
14
15 As an important industrial sector of the rapidly evolving global business community,
16
17
18 pharma remains committed to improving the health and well-being of the world’s
19
20
population while adapting to the changing needs of society. With a view toward
21
22
23 maintaining this engine of innovation, GCIPR member companies are continuously
24
25
26 searching for more sustainable solutions to reduce their impact on the environment.
27
28
Part of the approach includes identifying sustainable practices in all operations, both
29
30
31 internal and external, to meet growing expectations.16 Likewise, motivation for the
32
33
34 effort comes from intrinsic drivers (higher quality for patients, improved efficiency, safer
35
36
workplace, etc.) as well as outside sources, such as the U.N. program of supply chain
37
38
39 sustainability, which declared that businesses should not outsource the responsibility for
40
41
42 their operations to suppliers and simply receive the benefits associated with low cost
43
44
operations.17
45
46
47
48 Table 1. 2016 EPA Toxic Release Inventory (TRI) Pharma Industry Waste Reporting
49
50
51
52 Releases Waste
53 Releases18 Waste
U.S Industry (as % (as %
54 (103 tons) (103 tons)
55 total) total)
56 All industries 1,722.1 100 13,899.3 100
57
58
59
6
1
2
3
4
Metal mining 758.8 44.1 810.2 5.8
5 Chemical industry 246.0 14.3 6,489.0 46.7
6 Primary metals 167.1 9.7 1,388.9 10.0
7
8
Paper 81.4 4.7 977.6 7.0
9 Food 61.2 3.6 715.6 5.2
10 Pharma
11 2.2 0.1 99.2 0.7
manufacturing
12
13
14
15
16
17
While the pharma industry nominally produces much less waste than other chemical
18
19 sectors according to the EPA’s Toxic Release Inventory (TRI) data (Table 1),19 any amount
20
21
22 should be considered a missed opportunity to be more sustainable. Much pharma
23
24
25
waste is not released but rather processed by wastewater treatment plants (neutralized
26
27 aqueous waste) or incinerated for energy recovery (organic waste stream). This is one
28
29
30 reason why GCIPR has put forth metrics to capture the quantity and identity of pharma
31
32
waste in a more detailed manner (vide infra). Lastly, as more manufacturing is now
33
34
35 conducted at partner organizations any relevant proportion of their waste should be
36
37
38 addressed as part of the pharma supply chain. While waste generated by the industry in
39
40
the U.S. (Figure 2) and other developed countries is relatively efficiently processed, the
41
42
43 situation in developing nations is likely not as exemplary,20,21 with the situation
44
45
46 untenable if companies in these countries are to form part of the supply chain for the
47
48
global industry.
49
50
51
52
53
54
55
56
57
58
59
7
1
2
3
4
Figure 2. Waste Handling in U.S. Pharma Industry by Type, 2016 Data (percentage of
5
6 99,243 tons).19
7
8
9 Rel eased /
Di s posed
10 2% Recycl ed
35%
11 Trea ted
38%
12
13
14 Energy Recovery
25%
15
16
17
18
19
20
21
22
23
24
In addition, recent years have seen the industry receive greater pressure from non-
25
26
27 governmental organizations (NGOs) around the world demanding that products are
28
29
30 delivered in an environmentally responsible manner.22 There has also been more
31
32
visibility and a greater number of queries from investors on company environmental
33
34
35 programs. Customers, stakeholders, and investors are demanding greater
36
37
38 environmental sustainability across the whole supply chain. It is therefore a paramount
39
40
objective and simply good business sense to make sure that CRO/CDMOs join pharma
41
42
43 in this journey.23 Through 2017, about 77% of global corporations communicated
44
45
46 expectations of sustainability to their supply chain yet less than 30% regularly monitored
47
48
performance and fewer than 10% verified remediation regarding water, carbon footprint
49
50
51 and waste generation.24 As pharma companies affirm public commitments to
52
53
54 sustainability goals, engagement by the industry to better address emissions of carbon
55
56
57
58
59
8
1
2
3
4
or greenhouse gases, the use of water, and waste to landfill or waste generated at
5
6 suppliers’ sites, will be critical. The external supply chain currently represents about 50%
7
8
9 of all pharma industry chemical operations across all phases of development (Figure
10
11
3).25,26
12
13
14
15 Figure 3. Proportion of Overall Externally Produced Pharma Waste by Stage26
16
17
18
19 100%
90%
20
80%
21 70%
22 60%
23 50%
24 40%
61%
25 30%
41% 44%
26 20%
27 10%
0%
28 Early Dev Late Dev Commercial
29
30
31
32
33
34
The American Chemical Society (ACS) Green Chemistry Institute Pharmaceutical
35
36
37 Roundtable (GCIPR) was created in 2005 to catalyze the integration of green chemistry
38
39
40 and engineering into the global pharmaceutical industry.27 Its mission is based on pre-
41
42
competitive collaboration to foster more sustainable science and engineering. To date,
43
44
45 the Roundtable is composed of 30 member, as well as associate and affiliate member
46
47
48 companies, representing a significant portion of the industry. As an increasing amount
49
50
of chemical research and development (estimated at ~50%, similar to the % external
51
52
53 waste production depicted in Figure 3)28 is now conducted outside of pharma
54
55
56 companies themselves through full-time equivalent (FTE) scientists, engineers, and
57
58
59
9
1
2
3
4
operators at CRO/CDMOs,29 this extended global supply chain will undoubtedly make
5
6 the pursuit of sustainable development in supplier operations grow in importance.30
7
8
9 Tackling it head-on today will mitigate larger disruptions in the longer term. While
10
11
some organizations have embarked down the path of holistically adopting green
12
13
14 chemistry,31 at a minimum, pharma and its partners need to ensure that growth in
15
16
17 external networks is managed responsibly to avoid damage to the environment. The
18
19
authors believe that investing in greener chemistry and the development and
20
21
22 implementation of sustainable practices in the supply chain is the only proven way to
23
24
25 meet pharma’s triple bottom line: people (patients, personnel, and the public), profit,
26
27
and planet.32,33 We hope that this publication illuminates the initiatives from pharma
28
29
30 and contract partners, and prompts greater uptake of green chemistry and engineering
31
32
33 throughout the global pharma supply chain.
34
35
36
Greener Thinking
37
38
39
40 The pharma industry has embraced new ideas as a means to deliver life-saving
41
42
43 medicines for decades, with innovation becoming ever more critical in recent years as
44
45
the low-hanging biological disease targets have been largely harvested. A collection of
46
47
48 forward-thinking firms started promoting more sustainable chemistry and engineering
49
50
51 with the advent of the ACS GCIPR over a decade ago.34,35,36 However, there is a
52
53 continuing need for the industry as a whole to marshal their collective resources and
54
55
56 fully leverage the opportunities inherent in more sustainable science. There exists
57
58
59
10
1
2
3
4
tremendous potential for companies involved in the global pharma supply chain to
5
6 share best practices in a non-competitive manner. The Roundtable is committed to
7
8
9 crafting clear and transparent guidance, as well as education and support to facilitate
10
11
the adoption of sustainability in science. Consequently, it engages in collaborations to
12
13
14 both promote and advocate for the implementation of greener business practices to
15
16
17 reduce the environmental impact of the industry.37
18
19
20
Change in Culture
21
22
23
24 It takes a tremendous amount of resources to design, evaluate, and develop a multi-
25
26
27 step synthesis to deliver a high-quality process. ACS GCIPR tools (Table 2)38 are
28
29
available for the assessment of greenness and efficiency (vide infra) and these should be
30
31
32 used throughout process development to track progress towards sustainability goals.
33
34
35 As a molecule progresses in the pipeline, it becomes more difficult to justify changing a
36
37
route once established for late-stage clinical production.39 In addition, it is often unclear
38
39
40 if further route scouting will result in an overall greener synthesis. It should thus simply
41
42
43 become second nature to develop sustainable processes from the beginning, so that
44
45
implementation does not rely on balancing resources to meet timelines. Early adoption
46
47
48 of green chemistry would improve awareness with scientists working in process
49
50
51 development. This enhancement is facilitated by integrating available tools, as well as
52
53 fostering a cultural shift in pharma R&D with incentives (or regulations) to encourage
54
55
56
57
58
59
11
1
2
3
4
scientists to use greener solvents, reagents, and conditions, starting with medicinal
5
6 chemistry investigations.
7
8
9
10 Table 2. Green Chemistry Tools
11
12
13
14
Tools & Metrics Description
15
16
77 commercially-available solvents evaluated on 3
17
Solvent Guide
18
criteria of safety, health, environment
19
20
User-customizable ranking based on principal
21
Solvent Selection
22
component analysis (PCA) of desired physical
23
Tool
24
properties
25
26
18 guides with over 150 reagents, background
27
Reagent Guides
28
information, literature links, Venn diagrams
29
30
Selection tool to help guide better choices with regard
31
Acid / Base Guide
32
to sustainability of various acids and bases
33
34
Free educational site of sustainable modules, created
35
36
Learning.Chem21.eu by the Innovative Medicines Institute, hosted by
37
38
GCIPR
39
40
Analytical method greenness score calculator to
41
Analytical Calculator
42
inform about better analytical selection parameters
43
44
Determination of mass of necessary materials for
45
Process Mass
46
production of API, establishing simple comparator
47
Intensity Calculator
unit
48
49
Process Mass Comparison tool of hypothetical process routes
50
51
Intensity utilizing historical data to determine most promising
52
53
Predictor strategies
54
55
56
57
58
59
12
1
2
3
4
Pharma Perspective: A key focus of green chemistry is the development and
5
6 implementation of new technologies to assist scientists with efficient process R&D and
7
8
9 use of greener solvents, reagents, or assisting with mass intensification in one way or
10
11
another (Table 3).40 The Roundtable hosts The Chem21 Learning Platform,41 an
12
13
14 extensive resource that features modules with instructions on how to craft greener
15
16
17 routes and processes to APIs. The Chem21 platform provides data, tutorials, and
18
19
presentations for key areas such as solvents, metrics, biocatalysis, etc. Overall, it is
20
21
22 understood that developing a “green mind-set” might be difficult in the dynamic
23
24
25 environment in which chemists operate. On top of that, it might be challenging to
26
27
develop the right approach to process design that would truly lessen environmental
28
29
30 impact of chemistries performed on scale. Yet, these challenges do not detract from the
31
32
33 overarching aspiration. In fact, several objectives are strongly correlated with efficiency
34
35
improvements and, ultimately, lower total costs.
36
37
38
39 Table 3. Combined Pharma and CDMO Concerns
40
41
42
43 Aim for aspirational “best” efficiency, e.g., minimal operations, reagent
44
45 equivalents, volumes, and solvent swaps, to enable more sustainable
46
47 outcomes
48
49 Target low Process Mass Intensity (PMI) values to develop greener syntheses
50
51 starting in process R&D to minimize impact, even in first clinical batches
52
53
54
55
56
57
58
59
13
1
2
3
4
Encourage technologies42 to reduce PMI and boost use of greener reagents,
5
6
especially with immobilized catalysts (e.g., supported enzymes) so reuse is
7
8
facilitated
9
10
Replace non-green solvents,43 where possible, to reduce toxicity and
11
environmental burden and demonstrate feasibility of a multitude of
12
13
chemistries in these solvents
14
15
Develop the “greener mind-set” in early career scientists to include awareness
16
17
of toxicology, process economics, and safety considerations
18
19
Incentivize greener approaches with both internal and external (CRO/CDMO)
20
21
awards to recognize scientific teams and foster further green innovations
22
23
Timeline compression via rapid approval pathways44 placing pressure on
24
25
chemistry, manufacturing, and controls (CMC) to stay off critical path through
26
27
development
28
29
Increasing complexity of chemical matter in development, leading to greater
30
31
sophistication of control strategies necessary to ensure quality and patient
32
33
safety
34
35
Governmental and other payer pressures, leading to price controls and
36
37
increasing use of generics, which translates to controlling supply chain cost of
38
39
goods (COGs)
40
41
Increasing global regulatory compliance to support higher quality
42
43
expectations, especially as it relates to data handling / integrity
44
45 Growing focus on environmental regulations,45 with a goal of meeting the
46
47 highest global bar to maintain industry competitiveness
48
49 Pressure to meet high bar of environmental stewardship, addressing risk of
50
51 CRO/CDMO site closure or temporary suspension of operation
52
53 Inclusion of sustainability goals within commercial contracts relating to
54
55 energy, waste, API discharges and other metrics
56
57
58
59
14
1
2
3
4
5
6
7 CRO/CDMO Perspective: Today’s players in the CRO/CDMO marketplace face enormous
8
9
10 demands to meet the challenges of developing new molecular entities from candidate
11
12
to commercially-approved products. In recognition of their role in the supply chain of
13
14
15 current and future medicines, global CRO/CDMOs must help set the standard for
16
17
18 sustainability in concert with pharma, a major point of this manuscript. In this context,
19
20
numerous trends impacting pharma also impact CRO/CDMOs and overarching
21
22
23 sustainability objectives (Table 3).
24
25
26
27 Mindful of these challenges, recognition of and involvement in green chemistry by
28
29
pharma contract partners is on the rise. As an example, one fifth of the current
30
31
32 membership of the ACS GCIPR is drawn from CROs, CDMOs, or those involved in
33
34
35 developing technology to support new molecular entity (NME) manufacture. Many of
36
37
these companies now have programs gathering sustainability metrics for both internal
38
39
40 use and to share with their commercial partners. Education also has an important role
41
42
43 to play in on-boarding green chemistry within the supply chain. The Roundtable has
44
45
collaborated on training with the Green ChemisTree Foundation46 and PCSI,12 among
46
47
48 other groups, in several developing countries.
49
50
51
52 Cost is a very significant driver for CRO/CDMOs for several of the reasons outlined in
53
54 Table 3. Green chemistry principles and practices are, however, well aligned47 with
55
56
57
58
59
15
1
2
3
4
delivering on COGs targets for commercial products as well as lowering the cost of
5
6 developing new medicines to the NDA stage (and, correspondingly, lowering the cost of
7
8
9 project termination, for example when therapeutic mechanisms of action prove futile).
10
11
Specifically, focusing on previously-mentioned improvement opportunities: (a) reduction
12
13
14 in solid and liquid waste through process intensification and corresponding reduction in
15
16
17 energy usage; (b) use of greener solvents and avoidance of ‘red flag’ reagents – a
18
19
“greener by design” approach; (c) use of continuous processing technologies;48,49 and (d)
20
21
22 use of biocatalysis and other technology areas such as photochemical- and
23
24
25 electrochemical-mediated synthetic transformations will be critical to delivering quality
26
27
APIs with safe and scalable processes to meet regulatory expectations and patient
28
29
30 needs.50,51 The model of CRO/CDMOs and pharma working in partnership to achieve
31
32
33 mutual goals should be encouraged to further the latter’s responsibility for the entirety
34
35
of the supply chain, not just starting at the regulatory starting material stage.
36
37
38 Integrating the capabilities and strengths of both will allow the industry as a whole to
39
40
41 better meet challenges.
42
43
44
Barriers
45
46
47
48 Pharmaceutical firms and their suppliers face a number of industry-specific barriers to
49
50
51 development of highly efficient and sustainable chemistry to late-stage intermediates or
52
53 APIs.52 One significant obstacle is the limited time available to discover and develop the
54
55
56 final manufacturing route of increasingly complex drug molecules. The average patent
57
58
59
16
1
2
3
4
exclusivity period of a launched drug in the U.S. is estimated at 11.5 years,53 so
5
6 pharmaceutical firms are motivated to minimize drug development timelines, which
7
8
9 exerts immense pressure on process R&D. In addition, as drug candidates progress
10
11
through development, changes to manufacturing processes become less desirable due
12
13
14 to a corresponding increase in regulatory requirements with respect to control of API
15
16
17 quality. Post-launch, any changes in technology, site, or manufacturing process require
18
19
a supplemental submission to regulatory authorities.39 However, pharmaceutical firms
20
21
22 cannot front-load chemical process R&D and heavily invest in speedy installation of the
23
24
25 most robust, green, and economic drug manufacturing process for every project,
26
27
because many drug candidates fail during development. Taking into consideration the
28
29
30 industry’s high attrition rates (spreading cost of all investigational therapies over
31
32
33 approved medicines), R&D costs for each approved drug can be as high as $3 billion, a
34
35
significant counter-argument to proactively optimizing process R&D.54,55 As a
36
37
38 consequence, drug manufacturing processes in many cases do not reflect the optimal
39
40
41 synthesis strategy and are therefore not often as green and environmentally-benign as
42
43
they could be. However, adoption of greener technologies by pharmaceutical firms and
44
45
46 their suppliers should enable design and development of greener and more robust
47
48
49 processes, even with limited resources.
50
51
52 As research organizations seek novel scaffolds and building blocks to incorporate into
53
54
55 drug substances, they increasingly rely on greener technologies in these efforts. In
56
57
58
59
17
1
2
3
4
particular, flow chemistry and continuous manufacturing have emerged as powerful
5
6 tools to run a variety of processes with an increased focus on green principles.56,57,58
7
8
9 Flow processes often allow for the elimination of unnecessary derivatization and the
10
11
development of more efficient routes.59 Hazardous reagents such as carbon monoxide,
12
13
14 diazomethane, and ozone are more safely handled under these conditions. Reactive
15
16
17 intermediates such as ketenes are more safely controlled, thus minimizing unnecessary
18
19
alternative stepwise processes to avoid such materials. Flow chemistry has also
20
21
22 provided an avenue whereby technologies such as photochemistry and electrochemistry
23
24
25 are made scalable and reproducible.60, 61 Lastly, flow technology is also ideally suited for
26
27
library synthesis and the screening of reaction parameters on small scale.62 Decreased
28
29
30 levels of solvents and reagents can thus be utilized for such studies when compared to
31
32
33 batch screening.
34
35
36
Alternate Modalities - Peptides and Oligonucleotides
37
38
39
40 Beyond the growing area of biologics63,64 and the associated antibody-drug
41
42
43 conjugates,65 another important area in pharma is the re-emerging concept of treating
44
45
disease with medium-sized molecules, primarily polypeptide66 and oligonucleotide67
46
47
48 (injectable) therapeutics (Figure 4).68,69 In contrast to small molecules and full-length
49
50
51 proteins or monoclonal antibodies (mAbs), these unusual modalities typically have a
52
53 molecular mass between 1,000-5,000 Daltons. A significant unmet need in these fields
54
55
56 is addressing the high volume of waste generated from current peptide and
57
58
59
18
1
2
3
4
oligonucleotide manufacturing processes, which typically generate PMIs between 3,000-
5
6 15,000 kg/kg API with multiple applications of hazardous reagents and solvents.70 Some
7
8
9 perspective on these new modalities is provided below.
10
11
12
Figure 4. Size Range of Therapeutic Pharmaceutical Compounds
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29 Pharma Perspective: With the knowledge gained from traditional small molecules over
30
31
32 the years, including in the realm of green chemistry, alternate modalities have a lot of
33
34
35
opportunity to improve their sustainability footprint. In particular, different synthetic
36
37 strategies beyond the linear construction on solid phase might be realized. Newer
38
39
40 inputs (solvents, reagents, and scaffolds) and technologies offer promise for further
41
42
43
improvements. Forging partnerships with specialized CRO/CDMOs provide additional
44
45 prospects to match different areas of expertise to arrive at greener overall outputs.
46
47
48 Some pharma areas of concerns are included in a shared list of interests in Table 4.
49
50
51
52
Table 4. Combined Pharma and CDMO Concerns for Alternate Modalities
53
54
55 Problems and challenges
56
57
58
59
19
1
2
3
4
Volume of solvent waste in oligo synthesis is a significant issue; other options
5
6
are needed beyond REACH-listed dipolar aprotic solvents71,72
7
8 Neither CRO/CDMOs nor pharma companies have traditionally collected
9
10 environmental metrics in this space so while there is no history, there is
11
12
opportunity
13
14 Solvents: dimethylformamide (DMF) and other dipolar aprotics as well as
15
16 dichloromethane (DCM) for reactions, acetonitrile/water for purifications
17
18 Cleavage of oligomer from resin occurs mostly with highly corrosive
19
20 trifluoroacetic acid (TFA)
21
22
23
24 Promising alternatives
25
26 Hybrid solid-phase and liquid-phase processes show promise to be greener,
27
28 offering solvent reduction, higher yields, and increased purity
29
30 Incorporating small fragment intermediates in more convergent syntheses
31
32 have potential to utilize greener solvents for couplings73
33
34 Pharma to share small molecule learnings with oligo CRO/CDMOs to facilitate
35
36 uptake due to limited green chemistry experience
37
38 Fundamentally better resins, which could operate in almost any solvent, are
39
40 needed in order to mitigate the impact and broaden the applicability
41
42 Incorporation of membrane technology could significantly reduce the overall
43
44 footprint as it could help obviate the need for chromatography74
45
46 Typical solid-phase and liquid-phase synthesis for production could be
47
48 augmented with membrane-enhanced synthesis or fermentation
49
50 Purification using reverse phase preparatory LC, ion chromatography, and
51
52 tangential flow filtration
53
54
55
56
57
58
59
20
1
2
3
4
Enzymatic approaches to synthesis of unnatural amino acid building blocks as
5
6
well as the assembly of intermediate sequences
7
8
9
10
11 CRO/CDMO Perspective: With growing interest in alternate modalities from clients,
12
13
14 more effective partnerships with CRO/CDMOs should be possible. These partners will
15
16
17
take pharma’s lead with regard to green chemistry and engineering to effectively
18
19 integrate these attributes into processes. As investments often follow projects out of
20
21
22 financial necessity, pharma can provide leadership to help direct best practices and
23
24
25
technologies, and enable further improvements in sustainability over time. Challenges
26
27 experienced by CRO/CDMOs on this topic include many of the same topics that pharma
28
29
30 finds important (Table 4).
31
32
33
34
Greener Tools and Practices
35
36
37 Implementation of more sustainable chemistry and engineering in the pharma supply
38
39
40 chain requires extra effort to shift the focus from an individual company’s traditional
41
42
43
way of operation, to a new model where green chemistry is part of the shared focus.
44
45 This cross-industry effort should involve collaboration between companies and pollution
46
47
48 control agencies to align on the contributions of green chemistry and engineering. ACS
49
50
GCIPR has developed the tools (vide supra),27 educational resources, and support for
51
52
53 newer technologies that help scientists and engineers develop greener chemical
54
55
56 processes. The multitude of approaches can be divided into four main areas: (1)
57
58
59
21
1
2
3
4
innovation in methodology and route planning, including discovery and development of
5
6 new reactions and catalysts (chemo/bio), utilizing the “greener by design” approach, and
7
8
9 targeting the ideal manufacturing route; (2) use of greener technologies, such as flow
10
11
chemistry, membrane applications for separations, etc.; (3) use of sustainable solvents
12
13
14 and reagents;75 and (4) leveraging metrics to understand and improve processes and
15
16
17 products (Figure 5).
18
19
20
Figure 5. Four Major Areas of Green Chemistry and Engineering
21
22
23
24 • Support grants • Highlight
25 to spur new advances (flow
26 chemistry in chem, etc.) to
27 areas of need drive interest
28
29
30
31 Innovation Technologies
32
33
34
35
36
37
38 Solvents /
Metrics
39 Reagents
40
41
• Encourage • Provide tools to
42
greener choices track data &
43
to reduce impact identify priorities
44
45
46
47
48
49 Innovation in Synthesis
50
51
52
53 The primary enabler in implementing greener chemistry is disruptive innovation that
54
55 allows chemical bonds to be made with an efficiency and selectivity that could otherwise
56
57
58
59
22
1
2
3
4
not be achieved. Successful synthetic organic chemistry in all industries is predicated on
5
6 discovering novel transformations and achieving the construction of evermore complex
7
8
9 molecules. A plethora of scientific journals have emerged to facilitate the sharing of this
10
11
information with the community, including several in the realm of green chemistry.
12
13
14 However, not all advances are favorable to more sustainable science as they continue to
15
16
17 utilize non-green inputs as well as wasteful practices. The GCIPR has demonstrated a
18
19
commitment to supporting sustainable science via green chemistry and engineering
20
21
22 through multiple avenues, including a long-running grant program.76 These academic
23
24
25 grants have funded innovative ideas that have translated into publications in highly
26
27
esteemed journals as well as being applied within pharma in service of API
28
29
30 production.77,78 GCIPR remains dedicated to advancing innovation as an imperative in
31
32
33 the service of sustainability in order to make the global pharma supply chain greener.
34
35
36
Greener Solvents and Reagents
37
38
39
40 It is necessary to pay attention to the nature of solvents and reagents that are used for
41
42
43 chemical transformations. ACS GCIPR’s free tools27 can assist suppliers in the design of
44
45
greener synthetic routes and processes. The Reagent Guides79 are a resource that
46
47
48 provide a general overview of useful chemical transformations in pharma and highlight
49
50
51 efficient transformations that are not just greener but demonstrated on scale with
52
53 citations for further information. In addition, the Roundtable has produced a succession
54
55
56 of Solvent Guides and Selection Tools, which rank solvents according to their
57
58
59
23
1
2
3
4
environmental, safety, and health impacts to influence the choice of solvent for a
5
6 synthetic route.80,81
7
8
9
10 Solvent and waste recycling can mitigate the impact of their application. While the
11
12
dramatic benefits of recycling – recovering useable solvent from large volumes of
13
14
15 process waste – accrue only on large-scale manufacturing scales, especially at
16
17
18 commercial levels post-validation,82 the output of development steps can be harnessed
19
20
in multi-purpose facilities that process many smaller operations from different partners,
21
22
23 which, in aggregate, provide larger volumes of solvents (Figure 6).83 The recovered
24
25
26 solvents should easily be implemented in cleaning operations more readily than in
27
28
active processing. In contrast, waste recycling with a third party might provide some
29
30
31 benefit where precious metals could be recovered from enriched waste streams
32
33
34 following application in reactions where these metals are used as catalysts.84
35
36
37
Figure 6. Solvent Impact across Lifecycle (origin / use / disposal)
38
39
40
41 Renewable
CO2
42 Resources
43
44 Recycle
45
46
47 Solvent
Distribution Application Disposal Incineration
Energy
48 Production Recovery
49
50
51 Recovery
52 Biological
53 Petrochemicals Persistance Environment
Degradation
54
55
56
57
58
59
24
1
2
3
4
5
6
7 Greener Technologies
8
9
10
11 Continuous flow processing,85 separation techniques (such as organic solvent
12
13
nanofiltration, etc.),74 and photoredox-86 / electro-87 / surfactant chemistry88,89 are some
14
15
16 of the new developments that could facilitate more sustainable chemical approaches to
17
18
19 intermediates and APIs. All require investment of dedicated resources (capital and/or
20
21
FTEs) and it is often difficult to assess return on investment before initiating work with a
22
23
24 new technology. Hence, oftentimes companies are hesitant to invest greatly in any
25
26
27 single greener technological development. This is where collaboration and partnership
28
29
of pharma with smaller companies that focus on specific technologies (e.g., flow,
30
31
32 separations, etc.) in process development can pay off with lower investment in
33
34
35 innovation, while retaining the potential of high reward. The IQ Consortium recently
36
37
published the results of a survey indicating that the pharma industry has been
38
39
40 increasing, and will continue to increase, the percentage of total manufacturing
41
42
43 executed in continuous fashion.90 The study also indicated that Plug Flow Reactors
44
45
(PFRs) and Continuous Stirred Tank Reactors (CSTRs) are common flow equipment to
46
47
48 which most pharma and CDMOs have access. An attractive option is the potential to
49
50
51 utilize portable flow carts containing these reactors in series which could be directly
52
53 transferred to internal pharma facilities or CDMOs as fully functional units. By
54
55
56 packaging the flow equipment on portable skids with transfer pump systems, this
57
58
59
25
1
2
3
4
should reduce barriers currently preventing company engagement in flow
5
6 development.91
7
8
9
10 Likewise, R&D organizations are placing an increased emphasis on biotransformations
11
12
for the production of chemical matter. As environmentally- and economically-attractive
13
14
15 processes, particularly when the enzymes are immobilized, they embody many of the
16
17
18 principles of green chemistry.92 These catalytic transformations are typically run under
19
20
energy-efficient conditions in a benign solvent (water). The use of biocatalysts
21
22
23 eliminates the need for endangered heavy metal catalysts, as well as wasteful
24
25
26 downstream scavenging steps to remove the toxic metals from the product stream.93 In
27
28
particular, biocatalysis has been employed for the construction of enantioselective
29
30
31 building blocks and drug substances in a sustainable manner. Pharma thus seeks CROs
32
33
34 and CDMOs with experience implementing this technology, as well as with the recovery
35
36
and reuse of the catalysts.94 It is recognized that access to clean water is not ubiquitous,
37
38
39 particularly in developing countries, and the best application of enzymatic catalysis
40
41
42 would involve in-house recycling of water for further application within the same facility.
43
44
45
Separation science departments within the pharma industry are also eager to partner
46
47
48 with CRO/CDMOs that have access to greener purification and separation techniques.95
49
50
51 In particular, research organizations are increasingly relying on Supercritical Fluid
52
53 Chromatography (SFC) as a means to separate compounds, especially racemic or
54
55
56 diastereomeric mixtures.96 As this method utilizes supercritical CO2 as opposed to toxic
57
58
59
26
1
2
3
4
and hazardous solvents (e.g., hexanes, dichloromethane), it is an ideal technique for an
5
6 enterprise seeking to maximize a green approach. Significantly less solvent waste is
7
8
9 generated via this technology as opposed to traditional flash chromatography with
10
11
disposable silica cartridges. Separation time and total workup time are also significantly
12
13
14 reduced via this method, thus making the approach more energy-efficient.
15
16
17
18 As research organizations seek to incorporate flow technologies, photoredox chemistry,
19
20
electrochemical processes, biocatalysis, SFC separations, etc., into their synthetic routes,
21
22
23 they are increasingly seeking CROs and CDMOs that have these capabilities. It is crucial,
24
25
26 however, that organizations maintain a focus on green principles97 while employing
27
28
these technologies. For instance, the incorporation of green technology does not
29
30
31 exempt synthetic chemists from the more basic practices of using sustainable solvents.
32
33
34 As always, new technologies have promise to improve productivity, but they need to be
35
36
assessed and implemented well to achieve the expected efficiencies.
37
38
39
40 Metrics
41
42
43
44 ACS GCIPR has been active over the years creating metrics to establish greener practices
45
46
and processes. One method espoused to benchmark and compare the environmental
47
48
49 impact of API synthesis is the aforementioned Process Mass Intensity (PMI, equation 1).
50
51
52 PMI, which is equivalent to complete E factor (cEF) plus the one normalized unit of
53
54 desired product,98 describes the amount of material (including all solvents) necessary to
55
56
57
58
59
27
1
2
3
4
create 1 kg of product – the lower the value, the lower the environmental impact of said
5
6 process.99 Lowering PMI values en route to producing API can be approached in a few
7
8
9 different ways: (a) process intensification of the existing route; (b) identifying enabling
10
11
chemistry to circumvent problematic steps; and, most ideally, (c) designing more
12
13
14 efficient processes from the outset. While the first two options emerge from traditional
15
16
17 process chemistry approaches, the third only arises based on shared knowledge of a
18
19
wide database of transformations and the innovation of new ones.
20
21
22
23
24
𝑃𝑀𝐼 = 𝑐𝐸𝐹 + 1 = [𝑚𝑎𝑠𝑠𝛴 𝑚𝑎𝑠𝑠
𝑜𝑓 𝑖𝑠𝑜𝑙𝑎𝑡𝑒𝑑 𝑝𝑟𝑜𝑑𝑢𝑐𝑡]
𝑜𝑓 𝑎𝑙𝑙 𝑖𝑛𝑝𝑢𝑡𝑠
(1)
25
26
27 As part of its mission to galvanize greener chemistry and engineering throughout the
28
29
30 industry, the Roundtable has recently assembled a sufficient amount of data to create a
31
32
33 PMI Prediction Tool100,101 that is available to the global chemistry community.102 This
34
35 user-friendly web application, which relies on real-world data and predictive analytics,
36
37
38 can help to prioritize the most efficient routes via their predicted PMIs prior to any
39
40
41 evaluation in the laboratory. Through prioritizing routes most likely to deliver low PMIs,
42
43 chemists and engineers can apply resources more judiciously to develop “green-by-
44
45
46 design” chemical syntheses. By bringing greater awareness of sustainability during the
47
48
49 ideation phase of route scouting the app should lead to reduced environmental impact
50
51 for pharmaceutical production related to the decrease in PMI.
52
53
54
55
56
57
58
59
28
1
2
3
4
Further application of PMI is also envisioned in a combined tool with Lifecycle Analysis
5
6 (LCA) to routinely evaluate products and API processes, as well as intermediates and
7
8
9 reagents. LCA allows for assessment of the environmental impacts of all stages of an
10
11
API’s life from the origin of raw materials through manufacture to end-of-life outcome,
12
13
14 evaluating energy, inputs, and releases along the way.103 The GCIPR streamlined PMI-
15
16
17 LCA tool, still under development, is also planned to be made publically-available and
18
19
would allow all members of the supply chain – those focused on raw materials, fine
20
21
22 chemicals, intermediates, and APIs and beyond – to prioritize the biggest challenges and
23
24
25 solve them with sustainable science in the form of green chemistry and engineering.
26
27
28
ACS GCIPR has still gone further, collaborating with the IQ Consortium Green Chemistry
29
30
31 working group and two academic institutions to unveil the innovation Green Aspiration
32
33
34 Level (iGAL) benchmark.104 iGAL (equation 2) sets an individualized, fixed target for each
35
36
small molecule API by relying on formula molecular weight – API molecular weight
37
38
39 excluding salt, co-crystal, or co-solvent – as a proxy for structural complexity.105 This
40
41
42 tool, visualized by a companion Green Chemistry Innovation Scorecard,106 represents the
43
44
first quantitative waste measure across the pharmaceutical sector. In addition, it allows
45
46
47 for a calculation of relative process greenness (RPG, equation 3) for any molecule via
48
49
50 development phase-adjusted comparison against industry averages. This evaluation
51
52 allows teams to improve their processes over time and communicate their contributions
53
54
55 in a quantitative manner. As such, it enables waste mass-based green performance
56
57
58
59
29
1
2
3
4
rating of pharmaceutical supply chain products as they move through the pipeline.
5
6 Pharmaceutical firms now have an opportunity to integrate the iGAL methodology into a
7
8
9 “Green Campaign Report” template that asks external manufacturers to provide waste
10
11
generation information relative to the iGAL goal as a tool to monitor and reward
12
13
14 external green chemistry process performance and improvements.
15
16
17
18
19
𝑖𝐺𝐴𝐿 = 0.344 × 𝐹𝑀𝑊 [ 𝑘𝑔 𝑤𝑎𝑠𝑡𝑒
𝑘𝑔 𝑑𝑟𝑢𝑔 ] (2)
20
21 FMW = API molecular weight excl. salt, co-crystal, or co-solvent
22
23 𝑖𝐺𝐴𝐿
𝑅𝑃𝐺 = 𝑐𝐸𝐹 × 100%, 𝑐𝐸𝐹 = 𝑃𝑀𝐼 ―1 (3)
24
25
26
27 Selection of reliable partners for externally procured molecules is a challenging task,
28
29 typically undertaken as a multidisciplinary effort within the sourcing pharma firm in
30
31
32 order to evaluate technology, quality, regulatory, and business criteria. However, while
33
34
35 the focus of external manufacturer evaluation, qualification, and management considers
36
37 a wide variety of aspects,107 it often does not explicitly include green chemistry criteria.
38
39
40 In order to fully appreciate the risks, opportunities, and value creation proposition of the
41
42
43 supply chain, and to implement the use of effective sustainability indicators, a pharma
44
45 procurement organization must consider the interdependencies of manufacturers with
46
47
48 their community and the environment.108,109,110 Since supplier management is
49
50
51 commonly the responsibility of the pharma purchasing or sourcing functions, a trend
52
53 towards a green procurement mind-set that is fully aligned with technical sustainability
54
55
56 goals would be prudent. ACS GCIPR metrics could be instrumental in helping guide this
57
58
59
30
1
2
3
4
endeavor. In addition, while many individual firms may be too small to exert great
5
6 influence over their supply chain, the Roundtable may be a suitable forum for
7
8
9 cooperative pharmaceutical industry action to drive shared sustainable goals and create
10
11
a “Supply Chain Collaboration.” This concept of “co-opetition,” based on the benefit of
12
13
14 cooperation among competitors, has already been suggested in this context.23 Such a
15
16
17 “co-opetitive” approach would have to be managed carefully with strict legal scrutiny,
18
19
but could offer the shared benefits of broad green chemistry implementation and
20
21
22 facilitate more innovation and medical advances to provide medicines to patients in a
23
24
25 more sustainable manner.
26
27
28
Conclusion
29
30
31
32 The small molecule pharmaceutical supply chain is a complex endeavor and has become
33
34
35 more diffuse due to business pressures. However, this expansion of the global footprint
36
37
shared between pharma companies and CRO/CDMOs has also unveiled some exciting
38
39
40 opportunities to share precompetitive green chemistry philosophies, tools, and
41
42
43 techniques. The authors believe that the publically-available tools (utilizing metrics:
44
45
PMI, etc.) and practices (selecting greener solvents, etc.) enumerated herein should be
46
47
48 readily adoptable by pharma and CRO/CDMOs, while other described technologies (flow
49
50
51 chemistry, etc.) would lead to further improvements. Working together, it will be
52
53 possible to craft a sustainable continuum to help meet the top priorities of the pharma
54
55
56 industry – high quality (for patients, regulators, etc.), manageable costs (payers, profit,
57
58
59
31
1
2
3
4
etc.), and forward-looking sustainability (employees, community, environment, etc.) – to
5
6 continue delivering life-saving drugs to patients.
7
8
9
10
11
12
13
AUTHOR INFORMATION
14
15
16
17 Corresponding Author
18
19
20
Stefan G. Koenig, Small Molecule Process Chemistry, Genentech, A Member of the
21
22 Roche Group, South San Francisco, CA 94080, USA, koenig.stefan@gene.com
23
24
25
26 Notes
27
28
29 This manuscript reflects the authors’ opinions and does not represent the official
30
31
position of any of their employers. It was developed with the support of the American
32
33
34 Chemical Society Green Chemistry Institute (ACS GCI) and the associated Pharmaceutical
35
36
37 Roundtable (ACS GCIPR, https://www.acs.org/content/acs/en/greenchemistry/industry-
38
39
business/pharmaceutical.html). The ACS GCI is a not-for-profit organization whose
40
41
42 mission is to catalyze and enable the implementation of green and sustainable
43
44
45 chemistry throughout the global chemistry enterprise. The ACS GCIPR is composed of
46
47
pharmaceutical and biotechnology companies and was established to encourage
48
49
50 innovation while catalyzing the integration of green chemistry and green engineering in
51
52
53 the pharmaceutical industry. The activities of the Roundtable reflect its members’
54
55
56
57
58
59
32
1
2
3
4
shared belief that the pursuit of green chemistry and engineering is imperative for
5
6 business and environmental sustainability. There are no conflicts to declare.
7
8
9
10 ACKNOWLEDGMENT
11
12
The authors would like to acknowledge other members of the ACS GCI and GCIPR, as
13
14
15 well as partnering organizations and individual member company management and
16
17
18 colleagues who support the collaboration.
19
20
21
22
23
24 ABBREVIATIONS
25
26 API, active pharmaceutical ingredient; CDMO, contract development and manufacturing
27
28
organization; CRO, contract research organization; COG, cost of goods; GCIPR, Green
29
30
31 Chemistry Institute Pharmaceutical Roundtable; iGAL, innovation Green Aspiration Level;
32
33
34 PSCI, Pharmaceutical Supply Chain Initiative; PMI, Process Mass Intensity; TRI, EPA’s
35
36
Toxic Release Inventory.
37
38
39
40 BRIEFS
41
42
43
In order for the global pharma industry to achieve a more economical and sustainable
44
45
46 position, it must work closely with its contract partners to integrate Green Chemistry
47
48
49 practices in the supply chain as a chain is only as strong as its weakest link.
50
51
52
53
54
55
56
57
58
59
33
1
2
3
4
5
6 REFERENCES
7
8
9
10 1Chin, W. W. A delicate balance – Pharmaceutical innovation and access. N. Engl. J. Med. 2015, 373, 1799–
11 1801,
12 DOI 10.1056/NEJMp1513227.
13
14 2Germann, P. G.; Schuhmacher, A.; Harrison, J.; Law, R.; Haug, K.; Wong, G. How to create innovation by
15 building the translation bridge from basic research into medicinal drugs: an industrial perspective. Hum.
16
Genomics, 2013, 7, 5, DOI 10.1186/1479-7364-7-5.
17
18 3 The schematic depicted in Figure 1 is a simplified graphical representation of the pharma supply chain
19
20 intended to educate those not familiar with how CDMOs fit into the paradigm that pharma companies
21 utilize to assemble its final API molecules. For any given API, one could imagine manufacture of some
22 components in one organization and others in another. As an example, RSM A could be synthesized at
23 one CDMO and RSM B at another CDMO, while RSM C and the final API are produced at the pharma
24 company itself. The reasons for a CDMO to run one intermediate may relate to a specific technology that
25 the pharma company does not have internally. An example would be a specific type of flow reactor. In
26 addition, the project requirements for a clinical phase differ from those for commercial manufacturing and
27 decisions have to be made as to where best place the production.
28
29 4Hartmann, J.; Moeller, S. Chain liability in multitier supply chains? Responsibility attributions for
30
31 unsustainable supplier behavior. J. Operations Management, 2014, 32, 281–294, DOI
32 10.1016/j.jom.2014.01.005.
33
34
5 Grimm, J. H.; Hofstetter, J. S.; Sarkis, J. Exploring sub-suppliers’ compliance with corporate sustainability
35 standards. J. Cleaner Production, 2016, 112, 1971–1984, DOI 10.1016/j.jclepro.2014.11.036.
36
37 6Foerstl, K.; Reuter, C.; Hartmann, E.; Blome, C. Managing supplier sustainability risks in a dynamically
38 changing environment – Sustainable supplier management in the chemical industry. J. Purchasing &
39 Supply Management, 2010, 16, 118–130, DOI 10.1016/j.pursup.2010.03.011.
40
41 7 Edney, A. How a tainted heart drug made in China slipped past the FDA.
42
https://www.bloomberg.com/news/features/2019-01-30/chinese-heart-drug-valsartan-recall-shows-fda-
43
44 inspection-limits (accessed May 14, 2019).
45
46
8The Globalisation of the Pharmaceutical Industry. Pharmaceuticals Policy and Law; Valverde, J. L.; Pisani, E.
47 Eds.; Vol. 18; IOS Press: Amsterdam, The Netherlands, 2016.
48
49 9Significant academic research exists supporting increased use of biorenewables (starting materials,
50 solvents, reagents, etc.) in chemical and pharmaceutical manufacturing. This topic will be the subject of a
51 separate ACS GCIPR publication. For a leading reference, please see: Meyer, H.-P. Sustainability and
52 Biotechnology. Org. Process Res. Dev., 2011, 15, 180-188, DOI 10.1021/op100206p.
53
54 10 https://remediesproject.com/ (accessed May 14, 2019).
55
56
57
58
59
34
1
2
3
4
5
6 11https://www.sduhealth.org.uk/policy-strategy/reporting/nhs-carbon-footprint.aspx (accessed May 14,
7
8 2019).
9
10
12 https://pscinitiative.org/home (accessed May 14, 2019).
11
12
13Walmart – Sustainability Index. Available from: https://www.sustainabilityconsortium.org/impact/case-
13 studies/walmart-sustainability-index/ (accessed May 14, 2019).
14
15 The Sustainability Consortium (TSC) homepage: http://www.sustainabilityconsortium.org/ (accessed
14
16 May 14, 2019).

17
18 15 The Green Chemistry and Commerce Council has issued a report examining barriers to green chemistry
19 in supply chains across a range of industries but not a particular focus on pharmaceuticals. See:
20
https://greenchemistryandcommerce.org/documents/Advancing-Green-Chemistry-Report-June2015.pdf
21
22 (accessed May 14, 2019).
23
24
16 ACS GCIPR has proposed use of Process Mass Intensity (PMI) as a method to capture the waste
25 categories and help guide chemists and engineers to address the largest contributions. As discussed later
26 in the paper, PMI data collection has led to further advances in metrics and methods to limit waste. See
27 for a further discussion on PMI: Jimenez-Gonzalez, C.; Ponder, C. S.; Broxterman, Q. B.; Manley, J. B. Using
28 the right green yardstick: Why Process Mass Intensity is used in the pharmaceutical industry to drive more
29 sustainable processes. Org. Process. Res. Dev., 2011, 15, 912-917, DOI 10.1021/op200097d.
30
31 17Establishing sustainability expectations for the supply chain. In United Nations Global Compact Supply
32
Chain Sustainability: A Practical Guide for Continuous Improvement, Second Edition 2015, 23-29.
33
34 18As defined by TRI, a “release” generally refers to a substance via emission to the air, discharge to water,
35
36 or placement in a type of land disposal.
37
38
19 https://www.epa.gov/toxics-release-inventory-tri-program (accessed July 10, 2019).
39
40 20Chapter 8: Industry: Producing more with less in A/42/427: Our Common Future: Report of the World
41 Commission on Environment and Development, UN Documents: Gathering a Body of Global Agreements,
42 http://www.un-documents.net/ocf-08.htm (accessed May 14, 2019).
43
44 21Mmereki, D.; Baldwin, A. Hong, L.; Li, B. The management of hazardous waste in developing
45
countries. Management of hazardous waste. Chongqing, China: INTECH. See:
46
https://www.intechopen.com/books/management-of-hazardous-wastes/the-management-of-hazardous-
47
48 waste-in-developing-countries (accessed May 14, 2019).
49
50 Hyderabad’s pharmaceutical pollution crisis: Heavy metal and solvent contamination at factories in a
22
51 major Indian drug manufacturing hub report. Nordea and the Changing Markets Foundation 2018, 1-80.
52
53 23Constable, D. J. C. “Differentiating yourself from the competition in the green chemistry supply chain”
54 April 2013, available online at IndustryMarketTrends (IMT):
55
56
57
58
59
35
1
2
3
4
5
http://news.thomasnet.com/IMT/2013/04/04/differentiating-yourself-from-the-competition-in-the-green-
6
7 chemistry-supply-chain/ (accessed May 14, 2019).
8
9
24https://www.unglobalcompact.org/docs/publications/UN%20Impact%20Brochure_Concept-FINAL.pdf
11
12 25Green chemistry in the pharmaceutical industry - Unification of green chemistry metrics & introduction of
13 the Green Aspiration Level. Roschangar, F. MBA thesis, Yale University, May 2014.
14
15 26Roschangar, F.; Colberg, J.; Dunn, P. J.; Gallou, F.; Hayler, J.; Koenig, S. G.; Kopach, M. E.; Leahy, D. K.;
16 Mergelsberg, I.; Tucker, J. L.; Sheldon, R. A.; Senanayake, C. H. A deeper shade of green: inspiring
17 sustainable drug manufacturing. Green Chem. 2017, 19, 281–285, DOI 10.1039/C6GC02901A.
18
19 27https://www.acs.org/content/acs/en/greenchemistry/industry-roundtables/pharmaceutical.html
20
22
23
28This proportion of externally-produced waste seems to correlate with the trend of decreasing industrial
24 chemical employment in the U.S. According to an ACS employment survey from 2015 (with data back to
25 1985 and covering different employment sectors), U.S. employment of chemists in the industrial workforce
26 decreased by 50% from 2005 to 2015 (19,300 to 9,800 for survey respondents), with many of these
27 displaced jobs potentially transferring to organizations in developing countries. See Table 6: Marchant, S.;
28 Marchant, C. ChemCensus: 2015. American Chemical Society ChemCensus 2015.
29 https://www.acs.org/content/dam/acsorg/careers/salaries/archive/salaries-2015.pdf (accessed July 10,
30
2019).
31
32 29 Contemporary contract development and manufacturing organizations (CDMOs) participate in activities
33
34 ranging from process R&D through to commercial manufacturing. While every pharma company differs
35 in how and when they engage CDMOs, the contract partners are driven to improve the chemistry so they
36 can more competitively provide intermediates and APIs to the pharma company.
37
38 30Koenig, S. G.; B. Dillon, B. Driving toward greener chemistry in the pharmaceutical industry. Curr. Opin.
39 Green Sustain. Chem., 2017, 7, 56–59, DOI 10.1016/j.cogsc.2017.07.004.
40
41 31Veleva, V. R.; Cue, Jr., B. W.; Todorova, S. Benchmarking green chemistry adoption by the global
42 pharmaceutical supply chain. ACS Sustainable Chem. Eng., 2018, 6, 2–14, DOI
43
10.1021/acssuschemeng.7b02277.
44
45 32Elkington, J. Enter the triple bottom line. In The Triple Bottom Line: Does it all add up? Assessing the
46
47 sustainability of business and CSR; Henriques, A., Richardson, J., Eds.; Earthscan: London, 2004; Vol. 1, pp 1-
48 16.
49
50 33Elkington, J. 25 years ago I coined the phrase “Triple Bottom Line.” Here’s why it’s time to rethink it.
51 Harvard Business Review [Online] 2018, https://hbr.org/2018/06/25-years-ago-i-coined-the-phrase-triple-
52 bottom-line-heres-why-im-giving-up-on-it (accessed July 15, 2019).
53
54 34Green Chemistry in the Pharmaceutical Industry; Dunn, P. J.; Wells, A. S.; Williams, M. T., Eds.; Wiley-VCH
55 Verlag GmbH & Co. KGaA: Weinheim, Germany, 2010.
56
57
58
59
36
1
2
3
4
5
6
Green Techniques for Organic Synthesis and Medicinal Chemistry; Zhang, W.; Cue, Jr., B. W., Eds.; John
35
7
8 Wiley & Sons: Hoboken, NJ, USA, 2012.
9
10
36Scalable Green Chemistry: Case Studies from the Pharmaceutical Industry; Koenig, S. G., Ed.; Pan Stanford
11 Publishing: Singapore, 2013.
12
13 37 In addition to awarding grants, creating tools, and hosting events, ACS GCIPR has partnered with
14 organizations to spread knowledge of green chemistry, such as with PSCI
15 (https://pscinitiative.org/partners, accessed July 15, 2019) since 2017 to incorporate green chemistry
16 training into their programming to influence behavioral change; with the IQ Consortium on training
17 (https://iqconsortium.org/events/green-chemistry-short-course-free, accessed July 15, 2019); or with the
18
Green ChemisTree Foundation at the Industrial Green Chemistry World Convention to reach out to
19
20 companies in India (https://communities.acs.org/community/science/sustainability/green-chemistry-
21 nexus-blog/blog/2017/08/17/igcw-2017-advances-green-chemistry-innovation-in-india, accessed July 15,
22 2019).
23
24 38 acs.org/GreenChemistryTools (accessed May 14, 2019).
25
26 39Pharma companies vary in their practices as to when it is too late to make changes to a manufacturing
27 process but all are likely to commit to a route prior to validation and commercial launch.
28
29 40Energy efficiency is a critical sustainability component, reflected in several of the Green Chemistry
30 principles. Most pharma companies track energy (along with waste and water) in their corporate
31
sustainability goals, however, energy is not as easy to assign to individual molecules / processes. For an
32
in-depth discussion about efficient and responsible energy usage, see: Quadrelli, E. A. 25 years of energy
33
34 and green chemistry: saving, storing, distributing and using energy responsibly. Green Chem., 2016, 18,
35 328-330, DOI 10.1039/C5GC90069G.
36
37 41 learning.chem21.eu/ (accessed May 14, 2019).
38
39 42 Examples discussed in this article include flow chemistry, catalysis, and biocatalysis, etc.
40
41 43Solvents are readily evaluated on many criteria, including physical properties, origin, safety, fate, etc.
42 Several organizations, including several ACS GCIPR member companies have devised solvent selection
43 guides with these criteria built into them. As a collective, we feel that greener solvent selection is
44
facilitated very well by GCIPR’s solvent selection tool. See the freely-available tool
45
(https://www.acs.org/content/acs/en/greenchemistry/research-innovation/tools-for-green-
46
47 chemistry/solvent-selection-tool.html, accessed on July 16, 2019) based on Diorazio, L. J.; Hose, D. R. J.;
48 Adlington, N. K. Toward a more holistic framework for solvent selection. Org. Process Res. Dev. 2016, 20,
49 760–773, DOI 10.1021/acs.oprd.6b00015.
50
51 44Including regulatory accelerated pathways for new drug application (NDA) / new molecular entity
52 (NME) filings such as Fast Track, Breakthrough Therapy, etc.
53
54 45A prominent example that many companies are following, and other countries are emulating, is the
55 E.U.’s Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH).
56
57
58
59
37
1
2
3
4
5
6 46 https://www.indiamart.com/green-chemistree/ (accessed May 14, 2019).
7
8
9
47Tucker, J. L.; Faul, M. M. Drug companies must adopt green chemistry. Nature, 2016, 534, 27–29, DOI
10 10.1038/534027a.
11
12
48Ott, D.; Borukhova, S.; Hessel, V. Lifecycle assessment of multi-step rufinamide synthesis – from isolated
13 reactions in batch to continuous microreactor networks. Green Chem., 2016, 18, 1096–1116, DOI
14 10.1039/C5GC01932J.
15
16 49Rogers, L.; Jensen, K. J. Continuous manufacturing – the green chemistry promise? Green Chem. 2019, 21,
17 3481–3498, DOI 10.1039/C9GC00773C.
18
19 50For an example of photochemistry for greener chemistry, see: Fu, N.; Sauer, G. S.; Saha, A.; Loo, A.; Lin, S.
20
Metal-catalyzed electrochemical diazidation of alkenes. Science, 2017, 357, 575–579, DOI
21
22 10.1126/science.aan6206.
23
24
51For an example of electrochemistry in pharma, see: Perkins, R. J.; Pedro, D. J.; Hansen. E. C. Electrochemical
25 nickel catalysis for sp2-sp3 cross-electrophile coupling reactions of unactivated alkyl halides Org. Lett., 2017,
26 19, 3755–3758, DOI 10.1021/acs.orglett.7b01598.
27
28 52Roschangar, F.; Sheldon, R. A.; Senanayake, C. Overcoming barriers to green chemistry in the
29 pharmaceutical industry – The Green Aspiration Level concept. Green Chem., 2015, 17, 752–768, DOI
30 10.1039/C4GC01563K.
31
32 53Rizvi, S. A. A.; Patents, exclusivities, and evergreening Strategies. In Social Aspects of Drug Discovery,
33
Development and Commercialization; Osakwe, O., Rizvi, S. A. A., Eds.; Academic Press: London, 2016; Vol. 1,
34
pp 245–254.
35
36
37
54DiMasi, J. A.; Grabowski, H. G.; Hansen, R. W. Innovation in the pharmaceutical industry: New estimates
38 of R&D costs. J. Health Econ., 2016, 47, 20–33, DOI 10.1016/j.jhealeco.2016.01.012.
39
40 55Paul, S. M.; Mytelka, D. S.; Dunwiddie, C. T.; Persinger, C. C.; Munos, B. H.; Lindborg, S. R.; Schacht, A. L.
41 How to improve R&D productivity: The pharmaceutical industry’s grand challenge. Nat. Rev. Drug
42 Discovery, 2010, 9, 203–214, DOI 10.1038/nrd3078.
43
44 56Newman, S. G.; Jensen, K. F. The role of flow in green chemistry and engineering. Green Chem., 2013,
45 15, 1456–1472, DOI 10.1039/C3GC40374B.
46
47 57Movsisyan, M.; Delbeke, E. I. P.; Berton, J. K. E. T.; Battilocchio, C.; Ley, S. V.; Stevens, C. V. Taming
48
hazardous chemistry by continuous flow technology. Chem. Soc. Rev., 2016, 45, 4892–4928, DOI
49
50 10.1039/C5CS00902B.
51
52
58Poechlauer, P.; Colberg, J.; Fisher, E.; Jansen, M.; Johnson, M. D.; Koenig, S. G.; Lawler, M.; Laporte, T.;
53 Manley, J.; Martin, B.; O’Kearney-McMullan, A. Pharmaceutical roundtable study demonstrates the value of
54 continuous manufacturing in the design of greener processes. Green Chem., 2013, 17, 1472–1478, DOI
55 10.1021/op400245s.
56
57
58
59
38
1
2
3
4
5
6 59Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. The hitchhiker’s guide to flow chemistry. Chem.
7
8 Rev., 2017, 117, 11796–11893, DOI 10.1021/acs.chemrev.7b00183.
9
10
60For an application of photochemistry in flow, see: Baumann, M.; Baxendale, I. R. The synthesis of active
11 pharmaceutical ingredients (APIs) using continuous flow chemistry. Beilstein J. Org. Chem. 2015, 11, 1194–
12 1219, DOI 10.3762/bjoc.11.134.
13
14 61For applications of electrochemistry in flow, see: Pletcher, D.; Green, R. A.; Brown, R. C. D. Flow
15 electrolysis cells for the synthetic organic chemistry laboratory. Chem. Rev., 2017, 118, 4573–4591, DOI
16 10.1021/acs.chemrev.7b00360.
17
18 62Bogdan, A. R.; Dombrowski, A. W. Emerging trends in flow chemistry and applications to the
19
pharmaceutical industry. J. Med. Chem., 2019, 62, 6422–6468, DOI 10.1021/acs.jmedchem.8b01760.
20
21
22
63Walsh, G. Biopharmaceutical benchmarks 2018. Nat. Biotechnol., 2018, 36, 1136–1145, DOI
23 10.1038/nbt.4305.
24
25
64Budzinski, K.; Blewis, M.; Dahlin, P.; D'Aquila, D.; Esparza, J.; Gavin, J.; Ho, S. V.; Hutchens, C.; Kahn, D.;
26 Koenig, S. G.; Kottmeier, R.; Millard, J.; Snyder, M.; Stanard, B.; Sun, L. Introduction of a process mass
27 intensity metric for biologics. New Biotechnol., 2019, 49, 37–42, DOI 10.1016/j.nbt.2018.07.005.
28
29 65Lambert, J. M.; Berkenblit, A. Antibody-drug conjugates for cancer treatment. Annu. Rev. Med., 2018, 69,
30 191–207, DOI 10.1146/annurev-med-061516-121357.
31
32 66Fosgerau, K.; Hoffmann, T. Peptide therapeutics: current status and future directions. Drug Discovery
33
Today, 2015, 20, 122–128, DOI 10.1016/j.drudis.2014.10.003.
34
35 67Khvorova, A.; Watts, J. K. The chemical evolution of oligonucleotide therapeutics of clinical utility. Nat.
36
37 Biotechnol., 2017, 35, 238–248, DOI 10.1038/nbt.3765.
38
39
68Zhang, M.Q. Medium-sized molecules – Fertile or futile ground for drug discovery? Drug Discovery
40 Today: Technol., 2010, 7, e95–e96, DOI 10.1016/j.ddtec.2010.11.008.
41
42 69 de la Torre, B. G.; Albericio, F. The pharmaceutical industry in 2016. An analysis of FDA drug approvals
43 from a perspective of the molecule type. Molecules, 2017, 22, 368–373, DOI 10.3390/molecules22030368.
44
45 70Isidro-Lobet, A.; Kenworthy, M. N.; Mukherjee, S.; Kopach, M. E.: Wegner, K.; Gallou, F.; Smith, A. G.;
46 Roschangar, F. Sustainability challenges in peptide synthesis and purification: from R&D to production. J.
47
Org. Chem., 2019, 84, 4615–4628, DOI 10.1021/acs.joc.8b03001.
48
49 71Lawrenson, S.; North, M.; Peigneguy, F.; Routledge, A. Greener solvents for solid-phase synthesis. Green
50
51 Chem., 2017, 19, 952–962, DOI 10.1039/C6GC03147A.
52
53
72Lopez, J.; Pletscher, S.; Aemissegger, A.; Bucher, C.; Gallou, F. N-butylpyrrolidinone as alternative solvent
54 for solid-phase peptide synthesis. Org. Process Res. Dev., 2018, 22, 494–503, DOI
55 10.1021/acs.oprd.7b00389.
56
57
58
59
39
1
2
3
4
5 73 Ferguson, J. R.; Frederick, M. O.; Kopach, M. E.; Seibert, K. D.; Strege, M. A. Technical and regulatory
6
7 strategies for synthetic peptides. Chimica Oggi – Chemistry Today [Online], 2019, 37, Article 12.
8 https://www.teknoscienze.com/tks_article/technical-and-regulatory-strategies-for-synthetic-peptides/
9 (accessed July 21, 2019).
10
11 74Szekely, G.; Jimenez-Solomon, M. F.; Marchetti, P.; Kim, J. F.; Livingston, A. G. Sustainability assessment
12 of organic solvent nanofiltration: from fabrication to application. Green Chem., 2014, 16, 4440–4473, DOI
13 10.1039/C4GC00701H. Membrane technology does not directly substitute for chromatography – removal
14 of related compounds based on differential adsorption to a solid phase – but it can assist in removing
15 certain dissimilar impurities (size, hydrophilicity, etc.) which can then allow better opportunities for
16
crystallization by avoiding impurities that cause oiling, out, etc.
17
18
19
75Bryan, M. C.; Dunn, P. J.; Entwistle, D.; Gallou, F.; Koenig, S. G.; Hayler, J. D.; Hickey, M. R.; Hughes, S.;
20 Kopach, M. E.; Moine, G.; Richardson, P.; Roschangar, F.; Steven, S.; Weiberth, F. J. Key green chemistry
21 research areas from a pharmaceutical manufacturers’ perspective, revisited. Green Chem., 2018, 20, 5082–
22 5103, DOI
23 10.1039/C8GC01276H.
24
25 76Koenig, S. G.; Leahy, D. K.; Wells, A. S. Evaluating the impact of a decade of funding from the Green
26 Chemistry Institute Pharmaceutical Roundtable. Org. Process. Res. Dev. 2018, 22, 1344–1359, DOI
27 10.1021/acs.oprd.8b00237.
28
29 77For an application of a grant-funded direct C-H functionalization to a phenol and application to
30
doravirine, a non-nucleoside reverse transcriptase inhibitor, see: Campeau, L.-C.; Chen, Q.; Gauvreau, D.;
31
32 Girardin, M.; Belyk, K.; Maligres, P.; Zhou, G.; Gu, C.; Zhang, W.; Tan, L.; O’Shea, P. D. A robust kilo-scale
33 synthesis of doravirine. Org. Process Res. Dev., 2016, 20, 1476, DOI 10.1021/acs.oprd.6b00163.
34
35 78For an application of oxidation of betulin with molecular oxygen based on work funded by a GCIPR
36 grant, see: Ortiz, A.; Soumeillant, M.; Savage, S. A.; Strotman, N. A.; Haley, M.; Benkovics, T.; Nye, J.; Xu, Z.;
37 Tan, Y.; Ayers, S.; Gao, Q.; Kiau, S. Synthesis of HIV-maturation inhibitor BMS-955176 from betulin by an
38 enabling oxidation strategy. J. Org. Chem. 2017, 82, 4958, DOI 10.1021/acs.joc.7b00438.
39
40 79 reagentguides.com (accessed May 14, 2019).
41
42 80http://learning.chem21.eu/methods-of-facilitating-change/tools-and-guides/solvent-selection-
43
guides/guide-tables/ (accessed May 14, 2019).
44
45
46
81https://www.acs.org/content/acs/en/greenchemistry/research-innovation/tools-for-green-
47 chemistry/solvent-tool.html (accessed May 14, 2019).
48
49 82Amelio, A.; Genduso, G.; Vreysen, S.; Luis, P.; Van der Bruggen, B. Guidelines based on Life Cycle
50 Assessment for solvent selection during the process design and evaluation of treatment alternatives.
51 Green Chem., 2014, 16, 3045–3063, DOI 10.1039/C3GC42513D.
52
53 Clark, J. H.; Tavener, S. J. Alternative solvents: Shades of green. Org. Process Res. Dev., 2007, 11, 149–155,
83
54 DOI 10.1021/op060160g.
55
56
57
58
59
40
1
2
3
4
5
6 84 Fröhlich, P.; Lorenz, T.; Martin, G.; Brett, B.; Bertau, M. Valuable metals – Recovery processes, current
7
8 trends, and recycling strategies. Angew. Chem. Int. Ed., 2017, 56, 2544–2580, DOI 10.1002/anie.201605417.
9
10
85Blacker, A. J.; Breen, J. R.; Bourne, R. A.; Hone, C. A. The growing impact of continuous flow methods on
11 the twelve principles of green chemistry in Green and Sustainable Medicinal Chemistry: Methods, Tools and
12 Strategies for the 21st Century Pharmaceutical Industry. The Royal Society of Chemistry: Cambridge, 2016;
13 pp. 140-155.
14
15 86Wang, C.-S.; Dixneuf, P. H.; Soule, J.-F. Photoredox catalysis for building C-C bonds from C(sp2)-H bonds.
16 Chem. Rev., 2018, 118, 7532–7585, DOI 10.1021/acs.chemrev.8b00077.
17
18 87Horn, E. J.; Rosen, B. R.; Baran, P. S. Synthetic organic electrochemistry: An enabling and innately
19
sustainable method. ACS Centr. Sci., 2016, 2, 302–308, DOI 10.1021/acscentsci.6b00091.
20
21
22
88Bryan, M. C.; Dillon, B.; Hamann, L. G.; Hughes, G. J.; Kopach, M. E.; Peterson, E. A.; Pourashraf, M.;
23 Raheem, I.; Richardson, P.; Richter, D.; Sneddon, H. F. Sustainable practices in medicinal chemistry: Current
24 state and future directions. J. Med. Chem., 2013, 56, 6007–6021, DOI 10.1021/jm400250p.
25
26 89Lipshutz, B. H.; Gallou, F.; Handa, S. Evolution of solvents in organic chemistry. ACS Sustainable Chem.
27 Eng., 2016, 4, 5838–5849, DOI 10.1021/acssuschemeng.6b01810.
28
29 90McWilliams, J. C.; Allian, A. D.; Opalka, S. M.; May, S. A.; Jornet, M.; Braden, T. M. The evolving state of
30 continuous processing in pharmaceutical API manufacturing: A survey of pharmaceutical companies and
31 contract manufacturing organizations. Org. Process Res. Dev., 2018, 22, 1143–1166, DOI
32
10.1021/acs.oprd.8b00160.
33
34 91May, S. A. Flow chemistry, continuous processing, and continuous manufacturing: A pharmaceutical
35
36 perspective. J. Flow Chem., 2017, 7, 137–145, DOI 10.1556/1846.2017.00029.
37
38
92Sheldon, R. A.; Woodley, J. M. Role of biocatalysis in sustainable chemistry. Chem. Rev., 2018, 118, 801–
39 838, DOI 10.1021/acs.chemrev.7b00203.
40
41 93Truppo, M. D. Biocatalysis in the pharmaceutical industry: The need for speed. ACS Med. Chem. Lett.,
42 2017, 8, 476–480, DOI 10.1021/acsmedchemlett.7b00114.
43
44 94DiCosimio, R.; McAuliffe, J.; Poulose, A. J.; Bohlmann, G. Industrial use of immobilized enzymes. Chem.
45 Soc. Rev. 2013, 42, 6437–6474, DOI 10.1039/C3CS35506C.
46
47 95Hicks, M. B.; Farrell, W.; Aurigemma, C.; Lehmann, L.; Weisel, L.; Nadeau, K.; Lee, H.; Moraff, C.; Wong, M.;
48
Huang, Y.; Ferguson, P. Making the move towards modernized greener separations: Introduction of the
49
50 analytical method greenness score (AMGS) calculator. Green Chem., 2019, 21, 1816–1826, DOI
51 10.1039/C8GC03875A.
52
53 96Galyan, K.; Reilly, J. Green chemistry approaches for the purification of pharmaceuticals. Curr. Opin.
54 Green Sustain. Chem., 2018, 11, 76–80, DOI 10.1016/j.cogsc.2018.04.018.
55
56 97 https://www.acs.org/content/acs/en/greenchemistry/principles.html (accessed May 14, 2019).
57
58
59
41
1
2
3
4
5
6 98cEF is the alternative common mass-based metric used in the pharmaceutical industry, and indicates the
7
8 amount of all co-produced waste (vs. the amount of all inputs for PMI) for 1 kg drug substance. See ref 52.
9
10
99 The statement about lower PMI values giving lower impact is generally found to be true. There are
11 obviously cases where one might use very non-green inputs to achieve a low PMI, however, all of these
12 hazardous or unsustainable inputs would make the approach undesirable. The onus is on the chemist to
13 find greener inputs based on the other guidance provided in this manuscript.
14
15 Li, J.; Simmons, E. M.; Eastgate, M. D. A data-driven strategy for predicting greenness scores, rationally
100
16 comparing synthetic routes and benchmarking PMI outcomes for the synthesis of molecules in the
17 pharmaceutical industry. Green Chem. 2017, 19, 127–139, DOI 10.1039/C6GC02359B.
18
19 101Li, J.; Albrecht, J.; Borovika, A.; Eastgate, M. D. Evolving green chemistry metrics into predictive tools for
20
21 decision making and benchmarking analytics. ACS Sustainable. Chem. Eng., 2018, 6, 1121–1132, DOI
22 10.1021/acssuschemeng.7b03407.
23
24
102 Borovika, A.; Albrecht, J.; Li, J.; Wells, A. S.; Eastgate, M. D.; Briddell, C.; Dillon, B. R.; Diorazio, J.; Gage, J.
25 R.; Gallou, F.; Koenig, S. G.; Kopach, M. E.; Leahy, D. K.; Martinez, I.; Olbrich, M.; Piper, J. L.; Roschangar, F.;
26 Sherer, E. S. The PMI predictor – A web app enabling green-by-design chemical synthesis, submitted.
27 https://doi.org/10.26434/chemrxiv.7594646.v1 (accessed May 14, 2019). See also: https://acsgcipr-
28 predictpmi.shinyapps.io/pmi_calculator/ (accessed May 14, 2019).
29
30 103Ott, D.; Kralisch, D.; Denčić, I.; Hessel, V.; Laribi, Y.; Perrichon, P. D.; Berguerand, C.; Kiwi-Minsker, L.;
31
Loeb, P. Life Cycle Analysis within pharmaceutical process optimization and intensification: Case study of
32
Active Pharmaceutical Ingredient production. ChemSusChem, 2014, 7, 3521–3533, DOI
33
34 10.1002/cssc.201402313.
35
36
104 A key component to utilizing iGAL is to trace each API target structure back to component building
37 blocks listed at or below $100/mol for commercially-available chemical inputs. For details, see:
38 Roschangar, F.; Zhou, Y.; Constable, D. J. C.; Colberg, J.; Dickson, D. P.; Dunn, P. J.; Eastgate, M. D.; Gallou,
39 F.; Hayler, J. D.; Koenig, S. G.; Kopach, M. E.; Leahy, D. K.; Mergelsberg, I.; Scholz, U.; Smith, A. G.; Henry, M.;
40 Mulder, J.; Brandenburg, J.; Dehli, J. R.; Fandrick, D. R.; Fandrick, K. R.; Gnad-Badouin, G.; Zerban, G.; Groll,
41 K.; Anastas, P. T.; Sheldon, R. A.; Senanayake, C. H. Inspiring process innovation via an improved green
42
manufacturing metric: iGAL. Green Chem., 2018, 20, 2206–2211, DOI 10.1039/C8GC00616D.
43
44 105In our evaluation, FMW turned out to be the best descriptor for drug complexity due to its higher
45
46 correlation of variation with complexity parameters. The constant 0.344 was determined from a detailed
47 study of 64 API processes from 12 participating pharma companies covering 703 production steps. See
48 reference 104.
49
50 106https://www.acs.org/content/acs/en/greenchemistry/research-innovation/tools-for-green-
51 chemistry/green-chemistry-innovation-scorecard-calculator.html (accessed July 17, 2019).
52
53 107Among the important criteria external partners are evaluated on are EHS, cost, delivery, quality
54 procedures, business risk, service, innovation and problem-solving, capability, capacity and flexibility, and
55 intellectual property protection.
56
57
58
59
42
1
2
3
4
5
6 108EPA, Framework for Sustainability Indicators at EPA. Available from:
7
8 http://www.epa.gov/sustainability/docs/framework-for-sustainability-indicators-at-epa.pdf (accessed May
9 14, 2019).
10
11
109Sikdar, S. K. Sustainable development and sustainability metrics. AIChE J., 2003, 49, 1928–1932, DOI
12 10.1002/aic.690490802.
13
14 110Sikdar’s framework from reference 109 was modified by: K. Beach, Edmond Oklahoma Info for Citizens
15 Planning to Survive Sustainability, 2010. Available from:
16 http://axiomamuse.wordpress.com/2010/12/30/edmond-info-for-citizens-planning-to-survive-
17 sustainability (accessed May 14, 2019).
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54 BIOGRAPHIES
55
56
57
58
59
43
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17 Stefan Koenig is a process chemist at Genentech (South San Francisco, CA, USA), where
18 he has contributed to several R&D projects, including small molecules, antibody-drug
19
20 conjugates, as well as novel modalities and delivery systems. He started his industrial
21 career at Sepracor (Marlboro, MA) after receiving his Ph.D. from Yale University (New
22 Haven, CT) and completing a post-doc at the ETH Zurich (Switzerland). Stefan has served
23
24 as Green Chemistry lead at Genentech/Roche and as co-chair of the American Chemical
25 Society (ACS) Green Chemistry Institute Pharmaceutical Roundtable (GCIPR). He remains
26 active within ACS GCIPR as well as with the IQ Consortium, and currently serves as
27
28
member-at-large to the executive committee of the ACS Division of Organic Chemistry
29 (DOC).
30
31
32
33
34
35
36
37
38
39
40
41 Cisco Bee obtained his B.Sc. in Biology from Acadia University in 1998, followed by his
42 Ph.D. in Chemistry from the University of Hawaii under Marcus A. Tius. In a postdoctoral
43
fellowship at the University of Texas at Austin, he worked on asymmetric hydrogenative
44
45 aldol couplings under Michael J. Krische. Subsequently, he joined Scynexis as a
46 process chemist where he worked for 9 years, after which time he joined Asymchem as
47
Director of Process Chemistry.
48
49
50
51
52
53
54
55
56
57
58
59
44
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15 Alina Borovika is a process chemist at Bristol-Myers Squibb Company (New Brunswick, NJ)
16 where she has been working on projects from IND-Tox deliveries through LTSS
17
18
campaigns. Experienced in both early and late stage process development including GMP
19 deliveries, tech transfer, technical writing, quality and risk assessment, impurity fate and
20 tolerance. Prior to Bristol-Myers Squibb, Alina received her Ph.D. degree at the University
21
22
of Michigan (Ann Arbor, MI). She has been representing BMS at the GCIPR for three years
23 and has been a leader and an active member ever since participating in numerous working
24 groups.
25
26
27
28
29
30
31
32
33
34
35
36 Christiana Briddell is the Communications & Outreach Manager at ACS GCIPR. She
37
38 received a B.S. with honors in Environmental Science from Dickinson College in 2001 and
39 a M.A. in Communication from Johns Hopkins University in 2016. After many years
40 working in sustainable agriculture, digital marketing and online education, she joined the
41
42 American Chemical Society Green Chemistry Institute team in 2012. As the
43 Communication Manager, she works to promote green chemistry and engineering
44 adoption in industry and academia across a variety of channels.
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
45
1
2
3
4
5
6 Juan Colberg is Pfizer’s Green Chemistry Program Leader and Sr. Director of Chemical
7 Technology for Process Chemistry. In his chemical technology role, he evaluates novel
8 ‘platform’ technologies suitable for small and large-scale manufacturing, partnering with
9
10 academic institutions, pharma and technology companies across the globe. Juan
11 graduated from the University of Puerto Rico with a Ph.D. in organic chemistry and has
12 been at Pfizer for 26 years. A former co-chair of ACS GCIPR and previous EPA Presidential
13
14 Green Chemistry Award winner, Juan was appointed by the EPA head in 2018 to serve at
15 the Board of Scientific Counselors (BOSC), a federal advisory committee that provides
16 advice and recommendations to EPA's Office of Research and Development on technical
17
18 and management issues.
19
20
21
22
23
24
25
26
27
28
29
30 Dr. Guy Humphrey received his B.Sc. (1st Class hon.) in 1982 from Brunel University, UK.
31
32 He undertook graduate studies with Professor Raymond Baker at the University of
33 Southampton, UK, where he received his Ph.D. in 1986. He joined the Merck process
34 research group in Hoddesdon, UK and subsequently relocated in 1990 to the Department
35
36 of Process Research in Rahway, USA where he is currently a distinguished scientist. Most
37 recently his group was responsible for the route design, development and regulatory filing
38 for several approved drugs including Letermovir (antiviral), Doravirine (HIV), and Zerbaxa
39
40 (antibiotic).
41
42
43
44
45
46
47
48
49
50
51
52
53
Michael Kopach earned a Ph.D. from the University of Virginia under Prof. W. D. Harman
54 and completed postdoctoral studies at Colorado State University with Prof. A. I. Meyers.
55 Mike began his industrial career at Roche, where he worked on nelfinavir, Xenical, and
56
57
58
59
46
1
2
3
4
5
6 enfuvirtide - the first synthetic peptides produced on tonnage scale. In 2001, Mike joined
7 Eli Lilly and Company and led several small-molecule phase 1 to phase 3 R&D projects.
8 Throughout his industrial career, Mike has led research teams applying green chemistry
9
10 principles and has published several collaborative articles in this field. For the past decade,
11 Mike has been active on the ACS GCIPR, including serving as co-chair from 2011 to 2013
12 and again from 2017 to 2019. After a 14-year career in small molecules, Mike now focuses
13
14 on synthetic peptides and led an internal infrastructure build to bring peptide synthesis
15 capability in house.
16
17
18
19
20
21
22
23
24
25
26
27
28
Isamir Martínez, Ph.D., PMP, is the Program Manager for Scientific Alliances and Business
29 Engagement at the ACS Green Chemistry Institute®. Isamir leads efforts at implementing
30 green and sustainable chemistry and engineering throughout the global chemical
31
32
enterprise by working with the ACS GCI Industrial Roundtables, engaging stakeholders
33 and other strategic collaborative programs. She has a wide scientific background in green,
34 organic, medicinal, process chemistry, biocatalysis, and chemical sourcing. Prior to ACS,
35
36
she worked at Neurogen Corporation, Pfizer Pharmaceuticals, and later at MAR
37 Consulting, where she built alliances between pharma and Contract Research
38 Organizations (CRO’s). Isamir obtained a Ph.D. in Organic Chemistry from the University
39
of Connecticut, a B.S. in Chemistry from University of Puerto Rico and a Master Certificate
40
41 in Applied Project Management from Villanova University. She served as a Dreyfus Post-
42 Doctoral research-teaching fellow at Connecticut College, is PMP-certified and has been
43
an ACS active member since 1994.
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
47
1
2
3
4
5
6 Sudhir Nambiar is President of Research & Technology at Hikal and has over 25 years of
7 experience in the area of process research and development of APIs, lifecycle
8 management of molecules, process safety, regulatory and technology across several
9
10 industries. He holds a Ph.D. in synthetic organic chemistry from the University of Louisville,
11 Kentucky, and did his post-doctorate at the University of Montreal. Dr. Nambiar
12 completed his Senior Leadership program from Harvard Business School. Prior to joining
13
14 Hikal, he worked at Dr. Reddy's Laboratories, AstraZeneca India Pvt. Ltd, Novartis / Sandoz,
15 among others. At Hikal, he is responsible for the Research and Technology initiatives with
16 a focus on driving innovation through chemistry.
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Scott V. Plummer is a member of the Chemical Technologies Synthesis unit within the
31 Novartis Institutes for BioMedical Research (Cambridge, MA). He is tasked with
32 formulating material enablement strategies with research teams, outsourcing, and the
33
34
introduction of emerging synthesis technologies to the project portfolio. He has a
35 particular interest in Green Chemistry, and serves as the leader of the grants sub-team of
36 the ACS Green Chemistry Institute Pharmaceutical Roundtable. He received his Ph.D. at
37
38
Indiana University (Bloomington, IN), and previously held positions within the Chemical
39 Development Unit of AMRI (Syracuse, NY) and Chemical Preparations Research at Alcon
40 (Fort Worth, TX).
41
42
43
44
45
46
47
48
49
50
51
52
Seth Ribe is a process chemist by training where he has just returned from a 7-year
53
54 adventure in China. While working there he spent time at Asymchem (Tianjin, China), STA
55 (a subsidiary of WuXiApptec at both sites, Chanzhou and Shanghai) and Novartis
56
57
58
59
48
1
2
3
4
5
6 (Changshu). Seth is currently working as an Associate Director of API at Entasis (Waltham,
7 MA, USA). After completing his Ph.D. at the University of Pittsburgh, he began his career
8 at Sepracor (Marlboro, MA). His focus has been devoted primarily to early phase GMP
9
10 manufacturing.
11
12
13
14
15
16
17
18
19
20
21
22
Frank Roschangar is Head of Global API Lifecycle Strategy in Ingelheim, Germany, and has 21 years
23 of pharmaceutical industry experience. Currently, he addresses complexity reduction for
24 commercial Human Pharma product portfolio and legacy APIs. Prior, he worked in early stage
25
26
development in Ridgefield, CT, USA. Notably, Frank led external chemistry activities for the
27 diabetes drug Jardiance during early development. As Boehringer Ingelheim’s global Green
28 Chemistry lead, Frank and a team of IQ and ACS GCI PR collaborators invented the iGAL
29
30
methodology that holds promise to standardize green chemistry analysis in the global
31 pharmaceutical industry, and is current co-chair of the ACS GCIPR. He received his Ph.D. in
32 synthetic chemistry from Rice University in 1996, completed a Deutsche Forschungsgemeinschaft
33
34
(DFG)-sponsored postdoctorate at Scripps Research Institute, and obtained an executive MBA
35 from Yale in 2014. Frank has co-authored 59 peer-reviewed journal articles, book chapters and
36 patents.
37
38
39
40
41
42
43
44
45
46
47
48
49 Jeremy Scott is Executive Director of Process Chemistry at Pharmaron and a Fellow of
50 the Royal Society of Chemistry. He obtained his Ph.D. at the University of Cambridge
51
52 and carried out post-doctoral training at the University of California, Irvine, working in
53 the fields of natural product total synthesis and synthetic methodology. Previously, he
54 was Director of Process Chemistry at MSD leading teams through complex route
55
56 definition, development and multikilogram delivery for dozens of drug substances as
57
58
59
49
1
2
3
4
5
6 well as supply chain and technical activities at the drug product interface. Dr. Scott has
7 contributed to bringing omarigliptin (Marizev™), relebactam, niraparib (Zejula™) and
8 elbasvir/grazoprevir (Zepatier™) to patients across the world.
9
10
11
12
13
14
15
16
17
18
19
20
21 Helen Sneddon obtained her Ph.D. in 2005 from the University of Cambridge under the
22 supervision of Professor Steven V. Ley. Following postdoctoral studies at the University
23
24 of California, Irvine with Professor Larry Overman, she joined GlaxoSmithKline in 2007. She
25 is a visiting professor of Sustainable Chemistry at the University of Nottingham and has
26 a particular interest in solvent and reagent selection and the development of more
27
28 efficient transformations.
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
FOR TABLE OF CONTENTS USE ONLY
50
51
52 Green Chemistry must be integrated in the pharma supply chain as a chain is only as
53
54 strong as its weakest link.
55
56
57
58
59
50
1
2
3
4
5 Desired state:
6 - Implemented Green Chemistry practices

- Consistent adoption across supply chain
- Exceeding regulatory expectations
7 Raw mat
supplier 1
RSM
supplier A
8
9
10 GMP
producer
API
11
12
Antiquated paradigm:
13 - Majority activities in-house
- Little regulation
Raw mat RSM
supplier 2 supplier B
14 - Wasteful practices
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
51

A Green Chemistry Continuum For A Robust and Sustainable API Supply Chain

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

A Green Chemistry Continuum For A Robust and Sustainable API Supply Chain

Uploaded by

Copyright:

Available Formats

Subscriber access provided by TRINITY COLL

is published by the American Chemical Society. 1155 Sixteenth Street N.W.,

16 May 14, 2019).

6 - Implemented Green Chemistry practices

You might also like