iGAL 2.0: A Unifying Metric for a Greener Future

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By Frank Roschangar, Boehringer Ingelheim

More than ever before, pharmaceutical companies are expected to assess the impact of their sustainable development achievements.  However, the lack of a consistent metric system impedes the objective quantification and comparability of key sustainability indicators.  One of those indicators is Active Pharmaceutical Ingredient (API) manufacturing waste, which aligns with the United Nations Sustainable Development Goal (SDG) 12—Ensure sustainable consumption and production patterns.

While Process Mass Intensity (PMI) and complete E-Factor (cEF) are metrics that measure process efficiency, the innovation Green Aspiration Level (iGAL) 2.0 metric ([i]) builds on these metrics to help chemists compare their process efficiency to an industry average while accounting for molecular complexity of the API structure.  The comparability measure is called the Relative Process Greenness score or RPG (Eqn. 1 and Eqn. 2).  When comparing a first-generation API process to an improved process, the iGAL 2.0 Scorecard ([ii], Fig. 1) tells you how much waste you’ve eliminated—a number that indicates both a positive environmental impact (relevant to SDG 12) and a cost-savings for the company.  In addition, one can see which changes to the process led to the improved RPG score—these are grouped under percent yield and percent convergence improvements (converging processes being more efficient than linear processes).  Using the RPG score, one can quickly identify potentially underperforming and environmentally concerning processes early in the development cycle, and thereby proactively remediate those. 

Equation 1:  iGAL = 0.403 x FMW

FMW = salt - free Molecular Weight

Equation 2:  iGAL/cEF x 100% = 0.403 x FMW/cEF

cEF = PMI -1


Figure 1Figure 1

Fig. 1 displays the iGAL 2.0 Scorecard output for the 3rd Gen Dabigatran API process.  We can see that the scientists developed a process that is rated in the top 10% of commercial API processes according to our industry benchmarking.  The process has a Relative Process Greenness score of 284% and co-generates 2 times less waste than the FMW-normalized average commercial process.  With respect to SDG 12, waste is reduced by 163 kg per kg API or 65% compared to its Early Development predecessor.  In terms of innovation impact, the RPG was upgraded by 184%.  The calculated impact of Convergence improvements on the RPG upgrade is 9% and that of Yield optimization is 39%. 

It is noteworthy that we could not find a fit-for-purpose convergence formula in the literature, and so we developed a simple yet impactful formula (see Eqn. 7 in ref. 1).  We believe that this novel formula has potential applicability beyond iGAL 2.0 in Computer-Assisted Synthesis Planning (CASP) algorithms, where it could add sustainability consideration to retrosynthetic analysis.

In summary, implementing iGAL 2.0 across the entire API portfolio of a pharmaceutical company provides an opportunity to (1) report meaningful API manufacturing waste figures in the context of SDG 12; (2) establish “Target Sustainability Profiles” for API manufacturing and guide process development to identify environmentally potentially underperforming processes via their RPG scores, and subsequently focus resources on their optimization to deliver environmental and inherent economic value; and (3) reduce overall production costs.  We believe that the implementation of iGAL 2.0 across the pharmaceutical industry would stimulate fruitful competition in the spirit of SDG 12 by allowing for industry comparability.  This creates a win-win situation for businesses and the environment.

In addition (and related) to addressing waste, sustainable production must include a focus on climate change, from the energy needed to mine and process metal catalysts, to the energy used to manufacture an API, to the energy needed to incinerate waste solvents. The urgency of reducing waste and promoting sustainable processes has become even more visible after recent environmental events: In fact, there is reason to be seriously concerned about current developments. Just look at the recent flood disasters in Germany and the U.S., for instance. If we don't change anything now, we risk our future.  Therefore, promoting efficient sustainability practices is literally worth every penny.

[i] https://doi.org/10.1021/acssuschemeng.1c01940

[ii] https://www.acsgcipr.org/tools-for-innovation-in-chemistry/green-chemistry-innovation-scorecard-calc...