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Green metrics in Pharmaceutical Development

Conchita Jimenez-Gonzalez, Claire Lund

PII: S2452-2236(21)00120-6
DOI: https://doi.org/10.1016/j.cogsc.2021.100564
Reference: COGSC 100564

To appear in: Current Opinion in Green and Sustainable Chemistry

Received Date: 20 July 2021

Revised Date: 11 October 2021
Accepted Date: 12 October 2021

Please cite this article as: C. Jimenez-Gonzalez, C. Lund, Green metrics in Pharmaceutical
Development, Current Opinion in Green and Sustainable Chemistry, https://doi.org/10.1016/
j.cogsc.2021.100564.

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Green metrics in Pharmaceutical Development

Conchita Jimenez-Gonzaleza* and Claire Lundb

a
GlaxoSmithKline, 5 Moore Dr., Research Triangle Park, NC 27709, USA
b
GlaxoSmithKline, 980 Great West Road, Brentford, Middlesex, TW8 9GS, UK
* corresponding author, [email protected]

Abstract
This short review presents an overview of key metrics that have been used to assess the ‘greenness’ of
pharmaceutical processes in development in the larger context of environmental sustainability. The
green metrics cover areas of resource efficiency (mass and energy); environment, health, and safety

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considerations; and life cycle assessment. There is also a discussion of currently unmet needs in the area
that need enhanced focus.

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1. Environmental Sustainability: green metrics in context
‘We can’t manage what we can’t measure” is a reminder that in environmental sustainability it is critical
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to know where and how much impact or dependency a product has on the wider ecosystem services.
Positive action can then be taken and quantified to support the objectives of environmental sustainably,
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which is to mitigate climate change and nature loss which have been linked to negative impacts on
human health [1, 2].
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2. Green Metrics in Pharmaceutical Development

Much has been written about what constitutes a good metric for green chemistry or engineering. A
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general principle, metrics need to be clearly defined, simple, objective, and ultimately must drive the
appropriate actions. If decisions are not made based on the metrics, then there is no point on collecting
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them. For green metrics to be useful for strategic analysis, they need to provide an objective measure
of the progress towards the broader goal of sustainability, so the appropriate decisions can be taken. It
is therefore not surprising that many approaches about measuring ‘greenness’ have been developed.

Early attempts to establish metrics that could help quantify the environmental profile of pharmaceutical
processes followed the standard development of ‘green’ metrics, which initially centered either on
inherent properties the chemistry, or in waste. In the past 3 decades green metrics have moved beyond
waste to cover more extensively green chemistry [3] and green engineering [4] principles by
incorporating key attributes to measure sustainability [5].
 Resource efficiency (e.g., mass, energy)
 Environment, Health, and Safety (EHS) aspects (e.g., toxicity, waste, extreme process conditions)
 Life cycle assessment considerations (e.g., circularity, renewable feedstocks, biodiversity)

Since sustainability is a multivariable optimization exercise by nature, the challenge is to select the few
metrics that would drive the right behaviors towards more sustainable practices. In the next sections we
will discuss metrics on resources, EHS concerns, and life cycle assessment.
 2.1. Resource Efficiency – Measuring Mass and Energy in Pharmaceutical Processes
Although there have been a variety of green metrics proposed, the most used in the pharmaceutical
industry are mass metrics, a selection of these are shown in Table 1. The American Chemical Society
Green Chemistry Institute Pharmaceutical Roundtable (ACS GCI PR) has adopted PMI as its mass metric
[6], as PMI aligns philosophically and scientifically to sustainability by focusing on the increase of
resource efficiency and by having direct correlation with upstream supply chain life cycle impacts. To
that extent, the ACS GCI PR has developed tools for estimating PMI, and even developed a web-based
tool to predict PMI values to guide the design of more sustainable routes [7]. The ACS GCI PR has
performed PMI benchmarks amongst member companies for small molecule chemistry, [8] monoclonal
antibody production, including consumables in the definition of PMI [9, 10] and oligonucleotides [11].

Energy metrics as part of pharmaceutical process development have not had the same impetus of mass
metrics, with very few examples found in the literature. This may be driven by the fact that most of the
energy requirements in pharmaceutical settings are related to the energy needed to run the plant

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independently of the process. However, process energy requirements, measured by process energy
intensity, can be incorporated in the design of pharmaceutical routes to reduce the environmental

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profile of pharmaceutical processes, particularly when looking at novel ways of pharmaceutical process
development, such as process intensification, continuous processing, bioprocessing, and second

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generation optimization.[12, 13, 14, 15, 16, 17, 18] Pharmaceutical manufacturers have highlighted
both process energy intensity and energy integration as part of the key areas for green engineering [19].
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The list of metrics shown on Table 1 is not exhaustive, and one can quickly identify disadvantages of
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using only mass metrics. For instance, Atom Economy (AE) is simple to calculate, but excludes yield,
stoichiometry, solvents, and catalysts. Reaction Mass Efficiency (RME) is also simple to calculate and
incorporates AE, yield, and stoichiometry, but still exclude solvents and other materials. Initially E-factor
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and Process Mass Intensity (PMI) initially excluded water under the rationale that it may lead to
exceptionally large results that may make comparisons difficult. However, both metrics have evolved to
incorporate water given the increased importance of biological systems in pharmaceuticals and water
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scarcity impacts. PMI or E-factor are simple to calculate but do not account for complexity of the route.
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As a result of this, some efforts have been made to develop approaches to bridge some gaps. One
example is the Innovation Green Aspiration Level (iGAL) methodology, which developed a proxy for
molecular complexity to provide an aspirational goal for E-factor or PMI, and a relative process
greenness based on a statistical analysis [20, 21, 22, 23]. Another example is the adaptation of PMI for
route comparison at the discovery level with a specific methodology to ensure appropriate comparisons
at that early step in drug development [24]. Novartis has developed a Green Chemistry Process
Scorecard that is used to visualize an overview of the environmental impact of a complete product
portfolio. The scorecard acts an internal eco-label that includes PMI, waste and water intensity, a
estimation of carbon footprint, substances of concern, and number of chemical transformations [25].
Even with these efforts, it is evident that mass metrics alone are not sufficient to fully evaluate
sustainability, as they do not incorporate EHS or LCA considerations, although PMI does correlate with
LCA impacts.

2.2. Incorporating Environment, Health, and Safety concerns

Resource efficiency metrics provide a sense of how much of a given resource is utilized, but do not
incorporate the properties of the resources. Some semiquantitative approaches have been utilized to
incorporate EHS concerns such as human toxicity, eco-toxicity, and process safety. Given that solvents
have a significant mass contribution to PMI of small molecule synthesis, significant emphasis has been
invested on evaluating and communicating EHS concerns during solvent selection [26, 27, 28, 29]
including the ACS GCI PR developing an industry-wide tool as shown in Figure 1 [ 30] and successfully
working with key journal editors to change the publishing policy to discourage scientists from using
strongly undesirable solvents and strongly recommend considering environmental impact.[31, 32]

EHS concerns have also been the basis for reagent and biocatalyst guides [33, 34, 35], and metrics to
benchmark and compare the greenness of analytical methods supporting process development [36].
such as the ACS GCI PR Analytical Method Greenness Score (AMGS) [37, 38, 39], National Environmental
Methods Index (NEMI) [40, 41], and Green Analytical Procedure Index (GAPI) [42], amongst others [43,
44]. Additionally, EHS concerns are routinely used in the evaluation of different types of processes [45]

2.3. Life Cycle Assessment considerations

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A + B + Solvent + Energy + Catalyst + Reagents  C + Waste

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In the reaction above, the true environmental impact includes not only those related to resource
efficiency, waste, and EHS concerns of the reaction itself, but needs to include the impacts from

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producing all the materials and energy and disposing of waste. Chemists and engineering aiming to
apply green chemistry principles need to look beyond the reaction at the bench and expand its
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boundaries to evaluate the greenness of its entire life cycle.
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Life cycle assessment (LCA) helps to estimate the environmental impacts of a product or activity across
its entire life cycle. This includes quantifying the resource consumption (materials and energy),
emissions, and impacts across raw material extraction, manufacturing, transportation and distribution,
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use, and final fate (Figure 2). If one wants to measure the true ‘greenness’ during pharmaceutical
process development, the ideal is to have a set of metrics that include LCA impacts to best represent the
overall sustainability of a process or product. [46, 47]
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LCA capabilities in pharmaceutical development have undergone a steady evolution from the 1990s
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[48]. LCAs in pharma started from initial exploration with case studies [49], and then moved towards
chemical route comparison [50], material assessments [51, 52, 53], sub-system assessments [54],
footprints of formulated products [55], combination of LCA with other green metrics [56], and
enterprise-wide footprints [57]. Most recently, there have been proposals to harmonize the LCA
approaches in pharmaceuticals and established Product Category Rules [58, 59], and the exploration of
impacts specific to pharmaceutical compounds, such as antibiotic resistance [60]. LCA thinking and
related metrics will become increasingly important as they are key to understand the principles of
circular economy, particularly with a recent drive to explicitly integrate green chemistry principles in the
framework of circular economy [61, 62, 63, 64, 65].

Despite this increased incorporation of LCA considerations, LCA application is not a routine practice
within pharmaceutical product development. For instance, a literature review having found only about
30 LCAs human pharmaceutical products, processes, or precursors performed in or after the year
2000.[66] Performing an LCA consumes significantly more time and effort than estimating PMI, so there
have been some streamlined tools developed to help understand the LCA implications of decisions made
in product and process development [67, 68, 69]. Even though these tools have the potential to provide
useful insights, challenges remain regarding lack of available data of materials commonly used in
pharma and biopharma process development [70, 71], particularly as related to transition metals, bio-
derived materials, feedstocks, and biodiversity. Another challenge is the lack of consistent inclusion of
data quality indicators such as uncertainty and sensitivity analysis.

3. Current Needs and Future Focus

The number of different green metrics described shows that there is not one unified metric available
and widely accepted to measure the ‘greenness’ of a process. The green metrics one chooses must be
adapted for their context, but ideally need to incorporate LCA impacts if one aims to develop a fair
representation the overall sustainability of the process or product.

Green metrics need to be evaluated regularly to ensure that they are fulfilling their goal of driving
towards a more sustainable pharmaceutical process development. They must also be easily understood

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at the laboratory and pilot plant level and accepted by key stakeholders.

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Measuring the sustainability of pharmaceutical process during development needs to continue the
evolution towards a widespread use of LCA to ensure a more holistic approach. This can be challenging

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in the earlier stages of development given the limited data, but this challenge can be circumvented by
the further development and use of simple-to-use streamlined LCA tools, alone or in combination with
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metrics such as PMI and EHS attributes. In addition, focusing on the following aspects would help
improve the incorporation of LCA into pharmaceutical development:
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 Strategic assessment of key platforms and ingredients to identify insights and opportunities
 Enhanced data sets available with higher resolution for water, biodiversity, and land impacts
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 Availability of open source industry-average life cycle inventory data for common materials,
such as data from Plastics Europe.

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Better understanding of LCA impacts and ecosystem dependencies of bioprocesses and bio-
derived materials.

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Consistent inclusion of quality indicators such as sensitivity and uncertainty analysis.

Acknowledgements
The authors wish to thank the many colleagues in EHS and Environmental Sustainability within
GlaxoSmithKline for their dedication to a more sustainable future.

Conflict of interest statement

The authors are employed by GlaxoSmithKline (GSK). GSK is one of the pharmaceutical members of the
ACS GCI Pharmaceutical Roundtable that has published work on green metrics.
Tables

Table 1. Selected process green metrics

Metric Calculation Definition and comments References

Atom Economy (AE) 𝑚𝑤𝑃𝑟𝑜𝑑𝑢𝑐𝑡 Atomic percent of [72]
𝐴𝐸 =
∑ 𝑚𝑤𝑟𝑒𝑎𝑐𝑡𝑎𝑛𝑡𝑠 reactants incorporated
into product.
𝑚𝑤𝑎𝑠𝑡𝑒
Environmental-factor E-factor = Mass of waste produced [73]
𝑚𝑝𝑟𝑜𝑑𝑢𝑐𝑡
(E-factor) per unit mass of product.
Effective mass yield 𝑚𝑝𝑟𝑜𝑑𝑢𝑐𝑡 Percent mass of product [74]
𝐸𝑀𝑌 =
∑ 𝑚𝑛𝑜𝑛−𝑏𝑒𝑛𝑖𝑔𝑛 𝑖𝑛𝑝𝑢𝑡𝑠 to non-benign inputs
Reaction Mass 𝑚𝑝𝑟𝑜𝑑𝑢𝑐𝑡 Mass percent of the [75]
𝑅𝑀𝐸 =

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Efficiency (RME) ∑ 𝑚𝑟𝑒𝑎𝑐𝑡𝑎𝑛𝑡𝑠 reactants incorporated
into the product.

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Mass Intensity = Total mass of inputs per [76]
Process Mass ∑ 𝑚𝑖𝑛𝑝𝑢𝑡𝑠 unit mass of product

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𝑃𝑀𝐼 =
Intensity 𝑚𝑝𝑟𝑜𝑑𝑢𝑐𝑡
(MI or PMI)
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Mass Efficiency = 𝑚𝑝𝑟𝑜𝑑𝑢𝑐𝑡 1 Mass percent of the [75]
𝑀𝐸 = =
Mass Productivity ∑ 𝑚𝑖𝑛𝑝𝑢𝑡𝑠 𝑃𝑀𝐼 inputs incorporated into
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(ME = MP) the final product.

Energy Intensity ∑ 𝐸𝑖𝑛𝑝𝑢𝑡𝑠 Total energy inputs per [19]
𝐸𝐼 =
𝑚𝑝𝑟𝑜𝑑𝑢𝑐𝑡 unit mass of product
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Notation: mw: molecular weight, m: mass, E: energy

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Figures

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Figure 1 – Screenshot showing an example of solvent screening using the ACS GCI PR Solvent Tool,
version 2.0.0, Released Nov 2019.

Figure 2 – Representation of life cycle of a pharmaceutical product

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Declaration of interests

☐ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.

☒The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests:

The authors are employed by GlaxoSmithKline (GSK). GSK is one of the pharmaceutical members of the
ACS GCI Pharmaceutical Roundtable that has published work on green metrics.

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