Sustainable and sustainability are terms applied to an increasing number of situations, but what do they really mean? Does introducing a renewable feedstock render a process sustainable? What if that feedstock is shipped across three continents to its point of use? What if one in every 10 manufacturing runs fails to deliver product?
Within Chemical Development in AstraZeneca, sustainability is integral to everything we do to stay in business. While no-one should be surprised that financial costs are a focus, the message from the highest levels of the company is that environmental impact should also be improved at a local and global level. How we do business is as important as what we deliver.
There is no escaping the complex, high waste nature of the pharmaceutical industry. Compared with the petrochemicals and bulk chemicals industries, pro rata waste production can be higher by two or more orders of magnitude. Coupled with high material costs, this could be viewed as the price paid for societal access to novel treatments for life-threatening diseases. However, resources are not limitless and the public expect increasingly higher standards for the environment.
In AstraZeneca, it is the responsibility of Chemical Development, based at the Macclesfield site in Cheshire, to improve the manufacture of drug active pharmaceutical ingredients (APIs). The work of this interdisciplinary team involves everything from optimising the synthetic route of manufacture through to API particle engineering. We promote a culture of introducing beneficial changes to a process as soon as is practicable rather than delay until late phase development.
Since 2006, AstraZeneca has been a member of the American Chemical Society Green Chemistry Institute Pharmaceutical Round Table (ACS GCIPR) alongside many other global pharma companies. We have adopted a metric from that organisation called Process Mass Intensity (PMI), which is a measure of the efficiency of using feedstocks.1 PMI is a variant of the Effluent Load Factor calculation used in ICI in the 1980s and 1990s, and now popularised as E-Factor:
Process Mass Intensity (PMI)=(Mass of all materials used in processing)/(Mass of API produced)
PMI is a core focus for activities in Chemical Development. It provides clarity to our scientists in driving their development programmes because it highlights inefficiencies in material consumption during processing. Are solvent washes too large? Can we reduce excesses of reagents? Is product lost to waste during phase separations?
The simple concept that ‘this much’ X leads to ‘that much’ Y is a powerful way to show the impact that we can have as an organisation, through the quality of our science and application of new technology. We also make use of PMI in simple, interactive exercises to educate senior management and non-technical colleagues in and outside the company on the benefits of process development.
We routinely track PMI for our development projects, particularly those in Phase 3 that are preparing for commercial launch. Each project has a PMI launch target, which is a function of the projected volumes used in planning models for commercial operations. A sliding scale allows a higher PMI target of say 500 for small volume products, such as typical oncology treatments, than for those in larger indications, for example, cardiovascular drugs. This recognises that processing in the latter may be at scales two or even three orders of magnitude larger and therefore likely to present a much bigger environmental impact.
In making this assessment, we make no concessions for perceived complexity or project challenges. We also include all materials as far back in the synthesis as we can exert influence – ie starting from materials that are available on the open market. This position is justified on the basis that pharma is a relatively small consumer, compared with other markets, and is unlikely to be able to change external behaviours independently before this point.
In the period 2010-2015, activities in Chemical Development delivered year-on-year reductions of >20% in PMI across our late phase portfolio. When extrapolated to peak year sales, this equates to a combined reduction in waste of >170,000 t/year for those products, several of which have now launched commercially.
Osimertinib is typical of newer approaches in small molecule cancer treatments, being a T790M-directed epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). It shows a high success rate in advanced non-small cell lung cancer patients with mutations of the cell surface receptor. In 2014, the drug was granted Breakthrough Therapy Status by the US Food and Drug Administration (FDA), after an accelerated development programme following positive results during early clinical trials. In an industry where development timelines of eight-plus years are viewed as the norm, osimertinib was launched as Tagrisso in the US in 2015 – within 32 months from the first patient being dosed in clinical trials. Launches in Europe and Japan soon followed.
With such an accelerated development programme, it would be easy to fixate on delivering materials to support clinical trials and marketing submissions with little concern for improvements. While this is an understandable viewpoint, it did not reflect our philosophy and an active programme was launched to deliver improvements to the osimertinib manufacturing process leading to greater robustness, increased throughput and better control of impurities. This resulted in a reduction of PMI by 70% during the development programme – without delaying clinical trials.
It is equally clear that there is no point in having the greenest manufacturing methods if they are too expensive or if batch failure rates are excessive. Successful delivery of a development programme also requires a robust manufacturing process that delivers an appropriate economic return. Healthcare providers place increasingly challenging price targets, which means that pharma companies must drive down costs. At AstraZeneca, environmental aspects are not regarded as a special condition, but are embedded in the core deliverables for our processes.
In 2010, AstraZeneca acquired the non-US rights to an antibiotic adjuvant called avibactam, which is combined with β-lactam antibiotics to counter resistance in Gram-negative bacteria. At the time of the licensing deal, avibactam had a PMI of 6450. To put this into context, the total daily dose of 1.5g of avibactam would require 9.75kg material to be processed during manufacture and a typical dosing duration of five to 14 days might consume 100kg resources. The financial cost of material was also massively prohibitive and beyond any viable commercial scenario.
Such a situation was untenable and work was begun immediately to address the problems. Scientists in Chemical Development rapidly identified a new synthetic route that offered much higher yields and robust large scale processes, while further development reduced both costs and PMI. Marketing approval for the combination of avibactam and ceftazidime – marketed as AVYCAZ – was obtained by Allergan in 2015 in the US, and by AstraZeneca in the EU – where it is marketed as Zavicefta – in 2016. At this point, the PMI for avibactam had been reduced from 6540 to 375, coupled with a 90% reduction in cost of goods, making the medicine economically viable.
The principles supporting the company’s view of sustainability are clear to see: critically ill patients get more rapid access to life changing treatments; AstraZeneca gets a commercial opportunity; and the impact on the environment of the treatment is substantially reduced. Coupling of PMI and reduced cost of goods, meanwhile, is a phenomenon we have seen repeatedly in our development projects and validates our approach of addressing both economic and ethical aspects.
In 2010, AstraZeneca promoted the PMI approach to a corporate objective in 2010, stating that 90% of products would achieve their PMI target at commercial launch during 2010-2015. In fact, 85% of projects met this very challenging objective during that time, with just a single highly complex API not meeting its PMI target. Process development on this API continues, while the same corporate target has now been renewed for 2016-2025.
PMI is not without shortcomings. It does not discriminate between different types of materials, for example, so that readily abundant iron is viewed as identical to platinum group metals, which require far more demanding and wasteful mining and processing. However, PMI does offer significant benefits that render it a useful metric. Our application of PMI has received plaudits for its simplicity and effectiveness from influential bodies such as the ACS GCIPR.
Meanwhile, an extension of PMI called Process Mass Intensity-Life Cycle Analysis (PMI-LCA) is now being introduced via ACS GCIPR that will allow us to demonstrate the impact of our activities on lowering our carbon footprint. Sustainability is not just a buzzword in chemical development; it is at the core of what we deliver.
1 C. Jimenez-Gonzalez, C. S. Ponder, Q. B. Broxterman, J. B. Manley, Org. Process Res. Dev., 2011, 15, 912.
AstraZeneca Environmental Sustainability 2015 report;
www.astrazeneca.com/content/dam/az/our-company/Sustainability/Sustainability Update 2015.pdf