Engaging with EECO2, Quotient Sciences explores energy efficiency across its global network of locations and within the wider pharmaceutical outsourcing industry.

For many people, the current energy crisis has presented a significant challenge, with UK households seeing a 54% monthly increase in energy costs in April 2022 alone. In business, the lack of an energy price cap has hit many industries hard, with process manufacturing being one of the most severely impacted. For the pharmaceutical outsourcing industry, the reliance on high-intensity and complex systems, such as heating, ventilation, and air conditioning (HVAC), means that many organizations are beginning to explore means of offsetting this rise in operational costs, primarily through energy efficiency. Of course, the benefits of reducing energy consumption are not solely limited to cost savings, as these measures also reduce the amount of damaging environmental emissions produced by an organization.

Wanting to capitalize on the chance to both improve environmental sustainability as well as lessen operational expenditure, Quotient Sciences engaged with EECO2 on a series of site-based energy assessments. Quotient Sciences has an Environmental, Social, and Governance (ESG) group, which looks to monitor the organization’s impact on the planet, promote improvements, and reduce the consumption of energy and materials. As part of the ESG group's activities, Quotient Sciences engaged with EECO2 on energy assessments for two of its largest sites.

EECO2 help clients drive net-zero action within the life sciences industry to create a sustainable and healthy future. In doing this, EECO2 are trusted by many of the world’s largest pharmaceutical organizations to deliver cost and carbon reduction around the world. From site-level assessments to company-wide net-zero strategies, EECO2’s mission is to decarbonize the pharmaceutical industry, whilst maintaining and improving GMP compliance.

Quotient Sciences’ partnership with EECO2

Prior to this project, Quotient Sciences was aware of some potential opportunities for increasing on-site energy performance, such as introducing HVAC setbacks, but was keen to learn more about additional energy optimization and carbon reduction projects at its manufacturing facilities. Quotient Sciences asked EECO2 to assess two of its sites for energy optimization and carbon reduction projects, the learnings from which could then be shared across all Quotient Sciences sites.

EECO2’s successful track record in assisting many other pharmaceutical organizations to reduce their energy intensity and uncover new ways of decarbonizing operations was highly appealing, as identifying viable energy reduction projects that do not compromise compliance is an ever-present challenge in the life sciences sector.

To maintain compliant operations in pharmaceutical manufacturing, critical factors such as contamination control, temperature, and humidity need to be closely managed. Projects for energy optimization need to carefully consider the impact on operations, with a focus on the way proposed measures will impact processes, people, and products. Apprehension around energy improvement is common in the industry, but with EECO2’s deep technical knowledge, experience, and proven track record in the industry, they are well placed to provide appropriate solutions to meet the challenges in a safe and compliant manner.

The partnership between Quotient Sciences and EECO2 followed a collaborative approach in which EECO2 engineers surveyed Quotient Sciences’ Alnwick and Nottingham, UK, sites and met with the local site teams to share knowledge around engineering best practices.

In keeping with this collaborative approach, the team identified projects that were discussed with stakeholders, with clearly defined costs for project implementation. As a result of this joint effort between the two teams, new opportunities in HVAC optimization, sustainable lab practices, and innovative approaches in cleanroom control, such as demand-based airflow (ICCS^®), have been explored.

The outcome of EECO2's study

EECO2 were able to identify and quantify several opportunities for improving energy performance. From a sustainability perspective, these projects represent a sizeable improvement in carbon performance, reducing annual carbon emissions by 25% at Alnwick and Nottingham, avoiding 460 tons of CO₂ every year, equivalent to the emissions from 170 cars or 270 domestic homes.

In addition to this, the financial return of actioning these projects will be realized in approximately five years (on average), and with the continual rise in energy costs, this payback period is likely to shorten in due time. 

The predicted cost reduction has also been calculated by the EECO2 team, with the proposed measures set to cut energy costs by 33%. The report details EECO2’s final recommendations for implementing significant cost and carbon reduction at each site, with a roadmap showing when financial benefits will be first realized.

Keith Beattie, Director at EECO2, reflected on the recent partnership between the two organizations: "It is a privilege to partner with Quotient Sciences and assist in realizing the next stages of their sustainability journey. There is clear ambition and now a clear roadmap to make significant progress on site-based energy and carbon emission reductions. The recommended actions are good for business and the environment, and provide a competitive advantage as customers increasingly demand more sustainable products and services."

Michael Astle, Executive Director of Legal Affairs and Head of ESG at Quotient Sciences, added: "We are thankful for the support from EECO2 to improve the energy and sustainability performance of our sites. With the support of our owner Permira, this is just one of the initiatives Quotient Sciences is working on to reduce our impact on the environment. We have also introduced an electric vehicle leasing scheme for colleagues in the UK, with electric charging points at some sites, as well as providing guidance to colleagues on sustainable business travel. The roadmap provided by EECO2 has opened our eyes to the potential savings of carbon and cost, and we are now undertaking a more detailed feasibility assessment to enable us to implement as many of the changes as possible."

What does a day in the life of a chemist look like, and what do chemists do on a daily basis? Get insight from one of our team members about what his role is like as a chemist at Quotient Sciences.

Quotient Sciences’ Alnwick, UK, facility employs over 200 people across a range of scientific disciplines, including process chemistry, solid-state characterization, and radiosynthesis, to support the development and manufacture of drug substance programs at the site. In our latest article, we interview Max Critchlow, a Process Development Chemist on the Drug Substance team at the Alnwick site, to give those interested in exploring a day in the life of a chemist at Quotient Sciences.

What is your background in chemistry?

I studied chemistry at Bangor University in Wales, where I graduated with an MChem degree in 2020. Following my undergraduate degree, I began a PhD investigating direct enzyme prodrug therapy at XJTLU in September 2020. XJTLU is a leading international joint venture university in China, based on a partnership between Xi'an Jiaotong University and the University of Liverpool. Unfortunately, given the COVID-19 pandemic and travel restrictions, after 5 months of desk-based research, I had to stop my PhD. This led me to consider other options, the first being a laboratory technician role within a local school in 2021. During this time, I was able to think about my next move with regards to my chemistry career. During the school summer holiday, I was able to investigate various contract drug development and manufacturing organizations (CDMOs) and contract research organizations (CROs), as well as investigating an alternative PhD possibility. It was at this point I discovered Quotient Sciences’ Alnwick site.

What is your role at Quotient Sciences?

I began my career at Quotient Sciences’ Alnwick site in September 2021 as a Process Development Chemist within the Drug Substance department. My team is comprised of Process Development Chemists and Senior Process Development Chemists, in which we all report to a Process Chemistry Team Leader and the Head of Process Research and Development. We get additional support from our Laboratory Technician, who works closely with the team to ensure things run smoothly on a day-to-day basis.

Within my role as a Process Development Chemist, I primarily design and execute synthetic routes to target molecules, with a clear emphasis on developing safe, compliant, scalable, and economically viable processes for the downstream manufacture of intermediates and, ultimately, active pharmaceutical ingredients (APIs).

My responsibilities outside of the lab consist of typical desk-based work, such as maintaining laboratory notebooks and creating summary reports. I also present written and oral updates on project progress to clients and my colleagues.

What does a typical day at Quotient Sciences look like for you?

As I’m currently working a 4-day schedule, I usually arrive to work fairly early between 07:00 and 07:30. This is something offered by Quotient Sciences’ Alnwick site as a flexible work option.

I start my day by checking my emails, notifications, and meetings for the day. I usually run my analysis, such as high-performance liquid chromatography (HPLC), overnight as it’s automated, so I spend time in the morning reviewing this data from my desk. I then head into the lab to either sample or work up a reaction from the day before, and also set up a new experiment I have planned for that day. Once the whole team has arrived at site, we hold a quick meeting to touch base and raise any issues that have been encountered.

In addition to my lab work, I usually have various meetings throughout the day. This might include a Drug Substance team meeting, which typically involves a technical discussion on a particular project presented by the project chemists, a health and safety update, a briefing on the group/site and overall business performance, along with a general discussion of any other business. However, no two days are the same, and my role is ever changing with interesting new challenges each day. The one thing that stays consistent is the time I have my coffee and second breakfast! As PR&D chemists, we’re able to plan our time to what best suits us to get the relevant work done. This gives us the freedom and flexibility to perform our best work.

What typical challenges do you come across in your role, and how do you overcome them?
The main challenge within my role, and shared across the whole PR&D community, is the need to develop a synthesis and process that not only affords high-yielding and high-purity chemistry, but also avoid using traditional, small-scale organic synthetic techniques that are not suitable for scale-up.

For example, concentrating solutions to dryness is almost impossible to achieve on plant scale, where the vessels are fixed to the floor. Instead, distillation is commonly used to concentrate solutions, but there is a limit to the amount of solvent that can be removed. Usually, concentrating to dryness is for one of two purposes, to isolate your product or to swap to a different solvent. For the former, being able to crystallize your product is a huge advantage and will allow you to filter your drug substance relatively easily. For the latter, taking advantage of solvent azeotropes or a series of distillations can be used to swap from one solvent to the other without the need to go to complete dryness.

Column chromatography, which is a fundamental purification method, is almost entirely avoided when scaling up. It typically uses large quantities of solvent to purify modest amounts of material and requires a large quantity of solid support (silica gel), among other issues. In order to get around this, being able to crystallize your product is again the best option. This not only allows for simpler isolation, but crystallizations in the optimal solvent systems can realize high-purity drug substance, even for upgrading chiral purity in some instances.

Stability is also an important consideration. As we begin to scale up, the processing time of the reactions increases significantly, and understanding the representative holding points and stability of the reaction mixtures is vitally important.

Finally, it’s of paramount importance that before any large-scale process is undertaken, not only are the general chemical hazards assessed but also their inherent thermodynamic properties and reactivity are fully evaluated. With regards to general chemical hazards, reagent screening and route selection alternatives are considered to identify if certain high-potency, high-toxicity reagents or intermediates can be replaced with safer alternatives. With regards to thermochemical hazards, given that the cooling of a reaction vessel becomes less efficient as we increase scale due to the change in surface area-to-volume ratio, understanding the thermodynamics of the chemicals and reagents involved in these typically exothermic reactions is of upmost importance to avoid a thermal runaway and thus loss of containment.

What do you enjoy most about being a PR&D chemist at Quotient Sciences?

Overall, being a PR&D chemist involves facing new issues every day, which can be challenging but also satisfying, especially when I solve a problem. As a chemist at the forefront of PR&D, having a direct impact on the development of novel drug substances as APIs is very rewarding. I’m pleased that my work contributes to the company’s overall mission to develop new molecules fast.

In my role, there is also the opportunity to discover new chemistry, not only confined to new reactions, but new techniques, equipment, and methods too. Furthermore, I find it fulfilling to present my research and findings to not only my colleagues internally, but also externally to customers. This gives me a sense of pride and ownership with my work, which I think is important. I also appreciate the ability to collaborate with not only chemists on my project and within my department, but also with colleagues in other departments across the business, such as the analytical and manufacturing teams. This provides an authentic feeling of unity.

I’m lucky to find myself within a team of colleagues who are a pleasure to work alongside. Everyone is supportive and maintains a really positive culture, which breeds confidence in my role and my future career development. This culture is consistent throughout the Alnwick site and makes for a brilliant atmosphere and energy. I feel this site and its energy is a product of the people within, something I’m proud to be part of.

What would your advice be to chemistry students or chemistry graduates looking to start their careers in pharma?

It goes without saying, to establish yourself within the pharmaceutical industry and more specifically towards PR&D, it’s essential that you understand the basics and fundamentals of organic chemistry. Within the PR&D team, we often set monthly synthesis/process problems in order to develop and improve our knowledge. You also need to appreciate the problem-solving nature of this industry and understand the challenges of scaling up chemistry.

Other ways to begin developing your career within the pharmaceutical industry would be to investigate opportunities to gain work experience, such as summer placements, and it’s likely that your university tutors may have contacts or knowledge of a given opportunity. In addition, a year in industry as part of your degree course is an excellent way to gain work experience. At the Alnwick site, we offer industrial placements for undergraduate chemistry students, which you can apply for in the autumn for the following academic year.

Furthermore, keeping up to date with pharmaceutical companies, CDMOs, and CROs, along with relevant publications, can be a great way to understand how these businesses operate and what novel solutions are implemented to some intricate and complex problems.

It’s also worth investigating other areas of chemistry outside of PR&D. The pharmaceutical industry provides a huge variety of job opportunities for chemists in areas such as analytical sciences, formulation development, solid-state chemistry, and clinical or commercial manufacturing, to name just a few.

In this article, we talk to Gareth Jenkins, VP Science & Technology, about FlowInova, Quotient Sciences’ platform for continuous drug substance manufacturing developed in collaboration with the University of Nottingham. Quotient Sciences FlowInova platform offers a more sustainable and less wasteful manufacturing approach that can reduce the time and cost associated with new drug development.

What is the Quotient Sciences FlowInova platform?

Given that there is a growing trend towards more targeted drugs, small-molecule active pharmaceutical ingredient (API) candidates are becoming more potent. Consequently, the amount of drug substance required, both through the clinical development phase and at commercial launch, has reduced significantly, while the molecular complexity and demands on chemical manufacture have increased. This necessitates a radical rethink in terms of the technology required for manufacturing these drug substances. Continuous manufacturing facilities that can meet development and small-scale manufacturing requirements will be a critical solution to this problem. 

Quotient Sciences FlowInova platform started in 2018 as a research project when we set out to develop a data-driven methodology for process development and continuous manufacturing that enables efficient and intensive scale-up for early-phase development of API candidates. The novel approach combines high-throughput experimentation with process modeling and uses this to rapidly complete a number of plan-do-review cycles of process development. This leads to highly efficient and scalable processes that can produce kilograms of material within a laboratory environment, reducing the timescales for scale-up and the quantities of material required during development.

In collaboration with the Department of Chemistry at the University of Nottingham, the project was the first of its kind to be implemented by a UK-based contract drug development and manufacturing organization (CDMO). It enabled the development of innovative continuous processes and significantly reduces the time and cost associated with drug development, scale-up, and manufacture for customers across the globe.

The FlowInova project was the first to demonstrate that using automated reaction equipment and building models early in the process enables better decision-making for the next round of experiments. As more data is acquired and knowledge of the process increases, the process models become more predictive and allow for ‘virtual design of experiments’ to be carried out. This permits a greater focus on confirming and optimizing the predicted process parameters, leading to more robust and reliable scale-up.

What was it like collaborating with the University of Nottingham on this project?

Professor Michael George and Professor Martyn Poliakoff at the University of Nottingham have considerable research experience in fundamental understanding of reactions and applications of this understanding to build prototype reactors with optimal process conditions. With access to an engineering team that could make bespoke prototype reactors, our collaborators at the University of Nottingham were able to look at some challenging chemical processes and develop novel reactors that would be suitable for transfer and scale-up at our Quotient Sciences site in Alnwick. 

Some of the reactions we were interested in were poorly understood mechanistically and required the handling of corrosive or low-boiling-point reagents. While these reactions should be suitable for continuous processing, the reaction engineering skills at the University of Nottingham were critical to make this a reality. The Quotient Sciences team was involved in the review of the prototype reactors, providing guidance on the throughputs required to make them commercially viable and to ensure that we could transfer the knowledge to the Quotient Sciences Alnwick site to build a larger, kilo-scale system ourselves.

As a drug substance contract manufacturer, all of the chemistry we work on is on behalf of our clients. This means that we are constrained by the amount of time any process development project can run before we have to scale up and supply the product, which is often on the critical path during pre-clinical and Phase I clinical development. This insight helped our collaborators at the University of Nottingham focus on the most promising early prototypes, ensuring that both groups learned and developed skills from the other.

How has Quotient Sciences FlowInova platform been used?

We developed a continuous-flow approach to the kilo-scale manufacture of (2R,6R)-hydroxynorketamine based on the original literature route described in the 1960s. At the outset of the collaboration, we agreed that the University of Nottingham team would look at the bromination and ammonia reactions, which had no significant precedence and would need considerable reaction engineering. In parallel, the Quotient Sciences team focused on the thermal rearrangement and setting up our labs to be able to carry out continuous-flow chemistry using pumps, mass flow meters, membrane separators, and a commercially available plug flow reactor. This meant that we could quickly demonstrate some significant improvements in the overall process at our Alnwick site. Based on the literature, to produce 1 kg of the final product via a batch process would have required 18 kg of starting material to be processed through 24 batches (across all stages of the chemistry) at our 20 L laboratory scale. By running the thermal rearrangement in continuous flow, we improved the yield of that step from 60% to 95%, meaning that we could produce the first kilogram of the final product using only 10 kg of the starting material, and in less than 4 weeks.

Following this achievement, we transferred the work from the University of Nottingham team. We set up continuous-flow systems to carry out the bromination, amination, solvent swap, and thermal rearrangement stages using a combination of continuously stirred tank reactors (CSTRs) and plug flow reactors, daisy-chained together so that the output from one provided the input to the next and so on. We ran a full demonstration, bringing all of the reactors up to steady state and then running for over 24 hours before sequentially stopping each system. Over 1.2 kg of material was collected in 24 hours.

How has this project changed Quotient Sciences’ approach to drug substance manufacturing?

Continuous-flow chemistry is now embedded as a key tool in our process research and development offering for drug substance manufacturing. To be able to develop a continuous-flow chemistry process, there is a need to generate more information about the chemistry we take on as a drug development and manufacturing accelerator. This collaboration helped us to evaluate chemistry automation platforms, such as the EasyMax systems from Mettler Toledo and process modeling using Dynochem. With online process analytical technologies (PAT) giving time-course data on each experiment we run, we can more rapidly develop a greater understanding of the process and operating windows. This accelerates process optimization and de-risks scale-up, whether the process is better suited to continuous or batch reactors. All of our drug substance projects benefit from this approach, and its abilities to accelerate manufacturing. 

This success has prompted the construction of a flexible, modular, kilo-scale drug substance manufacturing facility at our Quotient Sciences Alnwick site, a £6 million investment that was opened in December 2022.

This has created 4 production suites, which can house a range of reactors, both continuous and batch, with the latter going up to 150 L in scale. Our data-rich approach to process research and development allows us to be much more material-sparing during the process development phase. We can get more information out of fewer experiments, while improving process robustness and our ability to deliver the 10s of kilograms our clients need on time and in full.

What are the benefits of Quotient Sciences FlowInova platform?

Quotient Sciences FlowInova supports faster, more reliable delivery of the first 10s of kilograms of a new drug candidate. This ensures that potential new medicines for unmet needs can accelerate through pre-clinical and early-phase clinical development by keeping API supply off the critical path. 

Additional benefits arise from our ability to efficiently evaluate and compare alternative chemistries to make the same new medicine. This can be applied to a single transformation in a synthetic sequence – for example, by evaluating different methodologies and catalysts used for a hydrogenation step. 

As well as optimizing for yield, our approach has allowed us to consider wider sustainability metrics, and we have successfully developed a conjugate reduction that scored 77 out of 100 using the Green Motion™ assessment tool, which considers all 12 Principles of Green Chemistry. 

As Quotient Sciences FlowInova helps capture and develop process understanding, we can embed efficient, scalable, and sustainable chemistry into the synthetic routes we develop. Demonstrating that continuous, process-intensive unit operations work at the kilo-scale allows us to supply API material to support critical Phase I and Phase II clinical studies without the need to re-develop the process. The transfer to Phase III and commercial manufacture can then be based on a comprehensive data package and removes the barriers often associated with introducing new technologies such as continuous processing in late-stage API manufacture.

What is the future of Quotient Sciences FlowInova platform?

With the emphasis on science and data-led experimentation, we are now starting to consider multiple criteria when optimizing any given process. As well as chemical yield, we include process mass intensity (PMI) and other green metrics as a measure of process development outcomes. Continuous processing lends itself to more automated ways of working, and we are now looking to bring automation into the earlier stages of process research and development. The success of this first collaborative innovation project led to an invitation to join an EU Horizon collaboration, Project ETERNAL, to develop future pharmaceutical products to be more sustainable by design and reduce their environmental impact throughout their lifecycle. 

Our focus within the project is on the early clinical development phases, where continuous processing can be more efficient and ‘on demand’, reducing the need to overproduce drug substance that then never gets used.

As a result, there is less overall waste, and the processes used to make the material can be optimized for sustainability. Building on our data-rich approach to process development, we plan to use digital manufacturing technologies for efficient chemical process transfer from lab to kilo scale and from one site to another. Other collaborators are looking at solvent reduction and recovery, removal of carcinogenic impurities, and intrinsically less environmentally harmful products.

Find out more about Quotient Sciences’ drug substance manufacturing capabilities.