Accelerate Pharma: The Solvent Debate

If we had to crystallize to an extractable conclusion from this fascinating discussion, it would be that clear regulation and guidance, with clarity about the long-term evolving economics and more deliberate and extensive collaboration are what will most strongly drive and facilitate industry to address the solvent dilemma.

When you bring knowledgeable and thoughtful people together to address a problem there is a strongly perceived risk. That is the risk of just further discussion, just more circular arguments, just more vacillation and no action. How valuable will it be? After all there were people in the room that in their own fields were already working very hard on these issues and had deep insight into it.

Forming new connections across a broad sweep of the whole ecosystems of solvent use in Pharmaceutical and Agrochemical manufacture seemed to create some new insights, clarity and catalyse future collaborations.

What is the solvent dilemma?

Solvents are used in large quantities in chemistry-based processing, their release to the atmosphere is climatically impactful, their waste streams are environmentally toxic, they represent a significant cost and risk in terms of treatment and regulation. There is a significant problem and no clear single path to addressing it. Some progress can be made intra-company, other parts require innovation in the supply and waste chains. Technological solutions need regulatory change, and other parts will need cross-sector collaboration.

To address the problem requires significant investment in capital and resources. In short, a complex problem and therefore there are dilemmas. Feedback from the participants demonstrated that the problem is seen as a priority within their business/sector. This is not ubiquitous, and, in some sectors, there is a lack of market demand and economic momentum.

 

Some parts of the industry are well advanced in their thinking and understanding of this emerging problem, while others are at the early stages.

What defines the dilemma, as much as any measure, are the multiple avenues being investigated to improve the situation.

 

What defines the dilemma, as much as any measure, are the multiple avenues being investigated to improve the situation.

 

 

Reducing usage through changing chemical pathways and process efficiency/intensification, combined with local, in-house recycling demonstrate how companies are looking within to solve most of the problem. Perhaps this represents a logical approach to reducing the demand for new solvent supplies as a precedent to finding new sources of biogenic¹ solvents.

Offsite re-cycling was deemed to have many complexities that reduced the focus on this course of action. Burning or oxidation remains a method of waste management which deals with the toxicity of the chemicals, however despite energy extraction it is perceived as very wasteful of high value chemicals.

Collectively it was felt that there were clear obstacles which slowed the changes and transitions. From the uncertainty of changing economics, the regulatory systems inhibiting change, and a backlash to sustainability without credible economics.

Despite these hurdles, there was agreement in the room that there was a vision across the industry and this was expressed as: -

■ All solvents bio-sourced and head-ache free (safe and compliant)

■ Use minimised

■ Recycling maximised

■ No burning

Maybe these could be summed up with the joint sentiment that an industry focused on health should not conspire to harm the long-term well-being of society.

 

So how do we accelerate?

The drivers for change in this arena need themselves to change, in reality and in dialogue.

With tough and uncertain trading conditions, drivers which do not put economics at the centre of things, risk becoming marginalised. The aims of efficiency, intensification, recycling and waste reduction, if applied correctly, are directly shared with improving today’s economics. In an arena where regulation and taxation will be aligned to carbon reduction, there is also a strategic necessity for long-term profitability. Framing the drivers in this way would chime much more favourably with shareholders, boardrooms, and in the political arena.

Economics are certainly the key driver in the generics manufacturers who operate in price-sensitive markets. Accounting for as high as 90% of prescription drugs, their strategies and business decisions have huge influence on the impact of the sector. They often do not carry the overhead of strategic teams, and there is an opportunity to share, promote and assist their move towards more efficient use of solvents through the sharing of insights and examples. The influence of the R&D led industry is hugely significant, providing the worked through case-studies and directly influencing their supply chain, including contract manufacturers.

Over the course of the discussion, there was a radical switch in the reflections on regulations and regulators. At the outset, regulators were seen as one of the significant barriers to moving forward at speed. There was some evidence for this as changing a drug registration can take three years and has a significant cost attached to it. However, it is unclear how many registrations do more than specify a solvent and list suppliers. If so, a change in source hypothetically is a small change. A biogenic source, meeting the specification, would require little or no change.

If only life was so simple. Current concerns about low level impurities exacerbated by issues like the discovery of nitrosamine impurities in medicines², have led to a higher sensitivity to change and the risk of unknown threats. Unknowns are inertial (hence regulations can be enablers); and there are also clear opportunities and support to try and test new ideas and processes e.g. MMIC ³.

A combination of developing science and clear and joined up regulation e.g. pharmacopeia and guidance, could help both the manufacturers and the biogenic solvent supply chain. Very clear and appropriate specifications and standards could help to accelerate the investment in and development of biogenic solvents, transitions, and approvals.

It was noted that there are streams of scientific development in Al models which can help predict the production of harmful impurities and detect these impurities cheaply at parts per billion and parts per trillion levels.

Standards are not just set by regulators. Any party that sets specifications helps to create a myriad of different standards. Consistent requirements across jurisdictions and customers could accelerate progress.

If the change to biogenic solvents can be made easier from a regulatory perspective, the next question is about the economics and supply Vs demand. If reducing usage and waste along with increased recycling can lead the way, then the unit cost of the solvent becomes less and less relevant.

Even now, the cost of solvent supply represents only 1% of Cost of Goods, although this amounts to $4bn globally. These numbers do not include the money spent by the industry to treat solvent waste, manage the safety risks, or pay any application of carbon tax.

It was noted that there are streams of scientific development in AI models which can help predict the production of harmful impurities and detect these impurities cheaply at parts per billion and parts per trillion levels⁴.

Even now, the cost of solvent supply represents only 1% of Cost of Goods, although this amounts to $4bn globally. These numbers do not include the money spent by the industry to treat solvent waste, manage the safety risks, or pay any application of carbon tax⁵.

If the market opportunity becomes clear and entry eased, there is an almost unlimited source of non-fossil organic materials from industrial waste streams e.g. food, drink, paper, fabric and agriculture. There is a huge effort ongoing to find replacement sources for aircraft fuel (SAF). A small amount of this could be diverted to the much more commercially valuable (margin-wise) supply of high purity solvents.

Waste recycling within plants is something many manufacturers are looking to increase. This does not come without quality and technical challenges. Local recycling, which is directly discouraged by some regulations, can increase batch-to-batch cross contamination. Recycling can concentrate impurities, an issue that requires monitoring and can drive the need for further processing. The technical issues are primarily around ensuring solvent waste is neither mixed with other solvents nor with other water-based waste streams. In fact, the segregation of waste streams in manufacturing is a very significant first step as this opens the possibility of multiple approaches to extraction, recycling and treatment.

Although there wasn’t a focus on recycling outside of the factory, there seemed to be many more potential solutions in this area. With the right segregation, there are opportunities for waste management companies to work with manufacturers to find both technically and economically sound solutions to recycle back into manufacturing and/or into other supply chains. Although not without issues, there was a strong sense that further conversations between manufacturers and the waste management industry to create new productive circular economies would be fruitful.

Strategy co-development to identify supplies of new solvents to support growing technologies – and growth in shared geographies – could foster new, efficient, and sustainable solvent supply and recycling routes.

Techno-economic modelling is seen as a vital component in guiding short-, medium and longer-term decision making on solvents.

As the chemical market changes alongside fiscal policies, understanding how to stay cost-effective and adaptable will be important. If this kind of analysis, or at least the insights from it, could be shared widely with the industry it could help accelerate interest and action, particularly in the generics ecosystem.

Problem solving in the room

Prompted by a thought that many players in this arena are waiting for engineering for technical solutions, there was a conversation about the complexity of the problem.

This is a multimodal problem to solve; even though we had suppliers, manufacturers, laboratories, regulators, waste management, academia and design engineers in the room, we accepted not everybody was represented who needs to be. To move more quickly continued multi-agency conversations and collaborations are needed.

Collaborative problem solving on this scale requires the right skills. Although some great engineers are coming out of universities, the curriculum has not adjusted quickly enough to emerging trends. Students are well-versed in chemical engineering skills; however, equipping them to work across boundaries within organisations, and across organisations to help change happen quickly, seems like a challenge for academia and industry. Creating courses which span traditional academic bastions seems important, while developing graduates into dynamic, collaborative and imaginative problem solvers is the key challenge for business.

A huge issue that is often ignored, but fundamental to the truism of “reduce” being the most important step in sustainability, is the enormous overproduction, supply, and wastage of drugs in the global ecosystem.

Some medicines are manufactured, prescribed, and sold which have little or no positive impact on human health. There is evidence that medicines commonly prescribed to women do not work⁶. There is a good deal of published research and perspectives on the oversupply of marginally beneficial, or even harmful, drugs.

If we could remove this demand for drugs along with severely reducing the waste of wrongly sold, wrongly prescribed, never-taken and out-of-shelf-life waste, this would have a significant impact on the environmental footprint of the industry.

One of the points raised was the lack of general knowledge about the impact manufacturing and delivery of medicine has on the environment. Greater public awareness may help to reduce some of this wastage through a reduction in demand.

Looking forward, there is a growing dilemma that new modalities may increase the diversity of solvents – acetonitrile, for example, may be of particular concern. The good news is that there is already some strategic collaboration happening in these areas.

As many new medicines are developed by start-ups, if we can ensure good guidance and information then we can get things right from the start. There are already collaborative groupings of start-ups, and linking these with the information flow on alternatives and economics could be highly beneficial.

 

Final thoughts

The group agreed that framing the driver for change around waste reduction and sustainable economics, together with greater public and business awareness and, would help to push the agenda in the right direction.

Regulators and regulations can be enablers for change, rather than inertial. The more consistent and proactive enablers, the better; they could create an environment where positive change can happen quickly within a clear, consistent economic playing field.

New technologies, including AI models to help predict the presence of harmful impurities alongside developments in impurity detection at parts per trillion levels, could be extremely useful. In conjunction with testing/development facilities, these technologies could accelerate problem finding and solving.

Fear, and the inertia of uncertainty, is lessened by shining a light on the technological and economic opportunities. This includes sharing insights from the R&D-led industry with contract manufacturers, generics and start-ups.

Start-up companies need investment to scale up quickly to support the pharmaceutical industry. While grants can help, they are not sufficient on their own – governments and industry stakeholders must actively identify and fund promising new developments. 

Keeping collaborations and conversations wide, while understanding there are solutions and opportunities still hidden away, will facilitate progress. The group agreed on the value of reconvening to continue this conversation and the interorganisational links it has initiated.

Preparation for the future: modelling, testing, trialling, planning, educating, informing, regulating, designing, delivering are all required to be progressed in a coordinated and joined up way to allow us to accelerate.

 

Our Accelerate programme brings together competitors and key players to debate and discuss the future trajectory of a sector and how to collectively overcome barriers to technology acceleration. Get in touch to join the movement.

 

^{1 Usually simple solvents (unhalogenated) derived from biomass.}

^{2 Nitrosamines demonstrate increase cancer risks in laboratory experiments and in 2018}

^{3 CPI Medicines Manufacturing Innovation Centre were discovered as impurities in some medicines.}

^{4 Post meeting research – University Cambridge & National University Singapore.}

^{5 Post meeting research – Yaseen et al., 2021, https://doi.org/10.1016/B978-0-12-821885-3.00015-3}

^{6 Invisible Women: Data Bias in a World Designed for Men Hardcover – March 12, 2019, by Caroline Criado Perez (Author) – Chapter on: - “When Drugs Don't Work”}