Impact case study database

Context

Ligand-based drug design is a contemporary and exciting area of pharmaceutical R&D that aims to predict the affinity and selectivity of small molecules (candidate drugs) in the absence of the receptor 3D information. It relies on chemical and physical knowledge exclusively from small molecules that bind to the biological target of interest, such as small molecules 3D shape and flexibility. However, current methods of determining small molecule 3D shape and flexibility have limitations: protein co-crystallography is very expensive and time-consuming, small molecule crystallography suffers from non-physiological packing artefacts, computational modelling predictions of the 3D-shapes of small molecules and proteins needed to predict binding is inaccurate, and neither NMR methods nor crystallography can quantify small molecule flexibility.

The technology invented at UoM, Conformetrix (hereinafter referred to as “UoM Technology”) overcomes these shortcomings, producing accurate, experimentally determined 3D shapes in solution. Its accuracy and novelty stems from the fact that it can quantify the flexible (rather than time-averaged) shapes of small molecules in solution ( i.e., to effectively reproduce the Boltzmann distribution of conformations for a given molecule) to the atomic resolution needed for drug design [4]. These can then be used in traditional computer-aided drug design workflows, such as virtual screening, molecular docking, pharmacophore mapping and structure activity relationship models to improve the speed and accuracy of drug hit identification and lead optimization. C4XD have stated that, “ The patented [UoM] technology platform […] *is at the heart of the C4XD drug discovery engine enabling rapid progress in developing new and better drugs at a fraction of the cost compared to best industry practice.*” [A]

Pathways to impact

The UoM Technology was taken from the laboratory to a spin-out company by Almond and Blundell ( via research, translational and proof-of-concept funding and a secondment of Almond from the University to C4XD). A demonstration prototype was developed using BBSRC Follow-on-Funding and the drafting of a business plan was enabled by a BBSRC/RSE Enterprise Fellowship. C4XDiscovery was assigned IP from The University of Manchester and incorporated in 2007 (it was originally named Conformetrix Limited), hereinafter referred to as “C4XD.” Since 2013, C4XD has achieved significant growth and expansion into new technologies and therapeutic areas, by development and application of the UoM Technology. The appointment of Dr Clive Dix as CEO is particularly significant given his experience as a leading UK pharmaceutical R&D executive.

The impact of the UoM Technology falls into three categories: (i) accelerating drug discovery for C4XD and the associated benefits; (ii) economic impacts for C4XD; and (iii) creating new partnerships between C4XD and other pharmaceutical companies to take advantage of the UoM Technology.

Reach and significance of impact

(i) Accelerating drug discovery for C4XD

An example of the UoM Technology enhancing drug discovery at C4XD is its impact on their anti-addiction and substance abuse programmes. Abuse of tobacco, alcohol and illicit drugs costs the US alone over USD740,000,000,000 annually in healthcare, crime and lost productivity (according to the US National Institute on Drug Abuse, NIDA) and represents a substantial area of unmet medical need, forecast to be worth an estimated USD13,000,000,000 per annum in 2018 [B]. The UoM Technology enabled rational identification of multiple drug candidates that are highly specific to the Orexin G-protein coupled receptor (Orexin-1). C4XD estimates the development of their molecules, including the lead pre-clinical candidate drug C4X3256, has been achieved at less than 10% of the typical industry cost, and been delivered in a fraction of the time normally required [B, C(p15)]. Development of a drug candidate up until clinical studies costs industry on average circa USD1,000,000,000, and C4XD achieved this milestone using investment and revenues that totalled less than GBP100,000,000, while also progressing its other preclinical drug programmes. These candidates are substantially safer and have improved pharmacokinetic and pharmacodynamic properties compared to competitor best-in-class alternatives, which were discovered using traditional pharmaceutical methodologies.

The lead pre-clinical candidate drug, C4X3256, has highly desirable properties that had not previously been achieved through conventional drug discovery methodologies [B]. In particular, the compound has negligible off-target effects to a homologous receptor (Orexin-2), which causes insomnia, allowing rapid development into a therapy to tackle the craving associated with addictions to substances such as tobacco, opioid analgesics, and alcohol. Using the UoM Technology to study ligands that bind with varying affinities to the two receptor homologues, C4X3256 was able to be identified as having crucial specificity of C4X3256 for Orexin-1 over Orexin-2 [B]. C4XD had previously announced efficacy data of its lead compound, C4X3256, in in vivo models of addiction [D] and the pivotal pre-clinical and toxicology studies were completed successfully. In 2018 C4XD was awarded a grant of USD480,000 from the NIDA to support the pre-clinical development of C4X3256 in cocaine use disorder [B].

Alongside C4XD’s Orexin-1 antagonist programme, the UoM Technology has driven several other promising drug discovery programmes. For example, it was used to identify multiple drug leads that activate Nuclear factor erythroid 2-related factor 2 (NRF2), a human transcription factor associated with the cardiovascular diseases Pulmonary Arterial Hypertension (PAH) and Sickle Cell Disease, both of which are orphan indications [B]. In pre-clinical evaluation, several lead compounds identified using the UoM Technology show prolonged duration of action following low oral dosing, including in blood [B].

Another successful application of the UoM Technology at C4XD has been in targeting the signalling protein Interleukin-17 (IL-17), a high-value clinical target for inflammatory and auto-immune diseases with a ~USD13,000,000,000 p/a market [B]. The only clinically-approved drugs for IL-17 are injectable monoclonal antibodies. A goal of many companies is to identify orally-administered drugs for IL-17, in part because patients find oral pills preferable to injections. Using the UoM technology, C4XD has identified selective molecular inhibitors of IL-17, which maintain the pharmacokinetics properties of small, drug-like molecules [B]. C4XD say they “[continue] to receive strong interest from potential partners for this oral IL-17 inhibitor approach” [B].

(ii) Economic impacts from successful commercialisation and formation of C4XD

C4XD was the first BBSRC part-funded spin-out to be listed on the London Stock Exchange, following admission to AIM (Alternative Investment Market) in 2014 with a market capitalisation of GBP31,000,000 [E]. C4XD subsequently raised over GBP33,000,000 from public investors enabling the UoM Technology to be applied across strategic and opportunistic therapeutic areas to build a balanced pre-clinical portfolio of 11 discovery programmes, spanning immunology, inflammation, neurology, neurodegeneration and cancer. In 2016, C4XD acquired Adorial Limited for GBP1,700,000 using revenue and investment proceeds from the UoM Technology platform. The acquired technology, Taxonomy 3, is used to drive forward the search for novel gene targets and then the UoM Technology is used in tandem to enable hit identification, further enabling and expediting early-stage drug discovery.

The UoM Technology has resulted in significant new R&D growth in Manchester, and created high quality graduate and PhD jobs, as evidenced by C4XD’s financial results. FY2017: Revenue GBP143,000, R&D expenditure GBP6,100,000 (+16% YOY), employees 42. FY2018: Revenue GBP7,064,000, R&D expenses GBP6,992,000 (+15% year on year: YOY), employees 47 (+12% YOY) [F]. FY2019: In 2018, C4XD changed its business model to move away from service contracts and towards its own pharmaceutical development, and as such generated no revenue in FY2019 – however, it successfully raised GBP17,700,000 in funding from external investment, and spent GBP10,585,000 on R&D [F]. FY2020: R&D spend of GBP6,900,000, and raised a further GBP9,200,000 from external investment in two tranches [F].

(iii) Benefits for partnering organisations through use of the UoM Technology

By 2018 C4XD’s Orexin-1 antagonist drug discovery programme had met preclinical endpoints and entered clinical development as a novel addiction therapy via a license agreement with US-based Indivior (which markets Subutex and Suboxone, both substitution products for opioid addiction) [G]. C4XD received an upfront payment of USD10,000,000 (3/2018) and up to USD284,000,000 of development, regulatory and commercialisation milestones in addition to royalties [B]. Indivior has a global and exclusive license to C4X3256 and all other compounds in the same patent family and is responsible for the cost and execution of all further development. In September 2019, Indivior received a significant grant from the US National Institutes of Health to advance C4X3256 through clinical evaluation in the treatment of Opioid Use Disorder, which in 2018 affected some 10.3 million people over the age of 12 in the USA [B]. This grant is allowing C4X3256 to progress through Phase 1 clinical evaluation, and fund toxicological and metabolism studies to enable Phase 2 clinical evaluation [B].

In 2014, C4XD signed a research collaboration agreement to apply the UoM Technology across therapeutic projects at Takeda Pharmaceutical Company (Asia’s largest pharmaceutical company: ~30,000 employees, revenue USD16,200,000,000) to enhance lead discovery and hit identification [B, H]. The Senior Director of Chemistry at Takeda commented: " We are pleased to partner with C4XD and are excited about the potential of this collaboration. C4XD has a highly innovative platform technology [UoM Technology] which complements our strong research base to accelerate product development." [H] No financial terms have been disclosed.

In 2016, C4XD entered a collaboration with Hamburg-based Evotec AG (~2,000 employees, revenue EUR258,000,000) to apply the UoM Technology to co-develop new small molecule drugs across a range of targets, therapeutic areas and stages of development [B, I]. No financial terms were disclosed but Evotec indicated that the collaboration was beneficial because it would reduce near-term costs while increasing the potential output of C4XD’s drug discovery engine. Evotec’s Chief Operating Officer commented: " We are very pleased to continue and expand the broad-based drug discovery collaboration with C4XD. This integrated drug discovery deal showcases our broad target class expertise coupled with our industry leading platform, which perfectly complements C4XD's technology and expertise…" [I].

Recently, C4XD has entered into partnerships with e-Therapeutics (05/2018), Horizon Discovery (12/2018) and PhoreMost (7/2019) to use the UoM Technology to accelerate co-development of therapies for Parkinson’s disease and cancer. The CEO of PhoreMost said, “ We are thrilled to be joining forces with C4XD within this neurodegeneration collaboration, a therapeutic area that has a pressing need for new and better targets… C4XD’s [UoM Technology] is ideally suited to use the 3D biological shape information derived from SITESEEKER targets and convert this into small molecules starting points that will lead to the next generation of therapeutics” [A]. While the terms of the agreement were not disclosed, it is reasonable to expect that both companies agreed to share revenues on validated targets produced by the collaboration.

In 2017, C4XD collaborated with videogame developed Epic Games, developing their 4Sight virtual reality (VR) platform using the Unreal Engine [B]. This incorporates the UoM Technology, as well as C4XD’s Taxonomy3, to allow teams of drug developers to engage in “multiplayer”, real-time 3D molecular design in a VR environment [B].

Context

Nuclear magnetic resonance is one of the most important and powerful analytical tools used by chemists, and finds application in a wide range of other fields. It is able to determine, for example, the composition of a mixture, the structures of complex molecules, and the mobilities of these molecules in solution. However, to direct the complex and precisely-timed sequences of radiofrequency and magnetic field pulses that are used in an NMR spectrometer to measure these different properties of substances is a science in itself. The impact described in this case relates to the development and commercial exploitation of two such families of pulse sequences developed at Manchester, known respectively as DOSY and pure shift NMR, that are able to analyse complex mixtures in a unique manner. They have proved vital to industrial research and product development and has led to a significant shift in practice and capacity in industrial research.

Pathway to impact

The initial impetus for our developments came from an industrial collaboration with Pfizer Global Research, and led to dedicated processing software, which was initially shared widely but informally with other users. The subsequent development of DOSY software, both open source and licensed for the proprietary operating system of the major NMR manufacturer Varian (subsequently Agilent), gave both the opportunity to exploit the intellectual property generated, and an effective vehicle for disseminating the results to a wide range of users, including many industrial research organisations. Key contributors to this impact were the Department policy of maintaining shared high-resolution NMR facilities, and the assistance of UMIP (University of Manchester Intellectual Property management agent) in negotiating the licensing of DOSY software.

In parallel to licensing proprietary code, the researchers made open-source DOSY processing code available through the DOSY Toolbox (and very recently through the General NMR Analysis Toolbox, GNAT, which has had >1,200 downloads since its release in October 2018). UoM’s development of pure shift NMR, initially as an adjunct to DOSY but now very widely used in its own right, has been the subject of several workshops at international conferences (EUROMAR, SMASH); a September 2017 workshop held in Manchester attracted 66 delegates, 11 from abroad and 8 from industry. The workshop materials have been downloaded from the researchers’ website over 1,000 times.

In collaboration with the major NMR equipment manufacturer Bruker, the researchers integrated pure shift and DOSY experimental techniques into their commercial software, with the result that many of these experiments are now available on all Bruker spectrometers in a dedicated University of Manchester section of the Bruker user library. The researchers also assisted the other major manufacturer, JEOL, to implement our methods in their software.

Reach and significance of impact

This work has changed the way that NMR is used in the chemical industries, including pharmaceuticals, agrochemicals and food. It led to the discovery of a new flavour ingredient that generated sales well in excess of GBP100,000,000 in the REF period, was key to maintaining sales of a fungicide worth >GBP100,000,000, and has supported growth in a billion-dollar scientific instrument market.

The principal impacts associated with DOSY and pure shift NMR in this period are:

Driving growth and innovation at NMR instrument manufacturers

The integration of UoM’s DOSY and pure shift NMR techniques into major manufacturers Bruker and JEOL’s spectrometers has brought both companies significant benefits. Bruker and JEOL both include the techniques in their standard offerings of NMR experiments on current-generation, high-resolution spectrometers [A, B]. Bruker specifically highlight that “… processing software for diffusion experiments is now an essential part of our Dynamics Centre software suite”, and that “… pure shift methods have become an indispensable part of our standard experiment library and are used routinely by our customers” [A]. The improvements in analytical problem-solving for NMR spectrometer customers achieved by DOSY and pure shift methods have also brought financial benefits to Bruker and JEOL. Bruker confirm, “ *the wide uptake of usage will definitely have contributed to our global NMR sales (around $400 million per year)*” [A], whilst JEOL say that the techniques “ have contributed to our instrumentation global annual sales of $900M” [B].

Bruker and JEOL both acknowledge the significant advantages that adopting DOSY and pure shift techniques bring to their customers [A, B]. As Bruker note, these techniques “ have significantly improved the ability of our end users to analyse mixture samples efficiently, and in extremis to solve otherwise intractable analytical problems” [A]. For Bruker, DOSY NMR techniques have spurred them to further technical innovation including special probes (DiffBB and BBO) with 17 T m^-1 gradient strength and −40 to 150 °C temperature ranges, as well as a new amplifier (GREAT60), all of which further enhance the usefulness of UoM’s DOSY techniques [A].

Changing practice in the food, pharmaceutical, and agrochemical industries

UoM’s DOSY and pure shift techniques are now used widely across the chemical industries. They have made significant contributions to the way many companies in the food, pharmaceutical and agrochemical industries perform chemical analysis and characterisation. This change derives from the need in the chemical industries to solve analytical problems with increased speed, precision and detail. A Senior Technical Expert in Crop Protection at international agrochemicals giant Syngenta emphasises the importance of NMR to industry, saying “ Chemical analysis is important throughout the research and development process and this importance is growing because modern environmental and safety regulations demand identification and quantification of molecules at lower and lower levels. NMR remains Syngenta’s primary method of structure elucidation” [C]. Pharmaceutical company Arcinova’s Head of Drug Product and Scientific Direction confirms, “… it is evident that molecular level characterisation of both drug substances and drug products is pivotal throughout pharmaceutical development for optimisation purposes and also for reducing the time to commercialisation” [D]

DOSY NMR experiments are available to all researchers at Syngenta’s Jealott’s Hill International Research Centre, their largest R&D site, with >800 active researchers [C]. Specific impacts of DOSY and pure shift at Syngenta include:

• Identifying a xenobiotic metabolite in a highly impure sample, by separating metabolite resonances from contaminants; this was required to maintain multi-million pound sales of a key fungicide product [C]

• Measuring diffusion, in multiple solvents, of a fungicide with sales >GBP100,000,000, helping to “… *optimize and reduce waste from the production process of this fungicide.*” [C]

• “Understanding of how a crop protection product partitioned within a spray mix”, crucial to understanding the mechanism of action of the formulation and previously impossible [C]

Both large and small pharmaceutical companies have also embraced the use of DOSY and pure shift methods. Small pharmaceutical company Arcinova, for example, has fully integrated the techniques into their work, saying “ The techniques developed at Manchester are routinely implemented in our own Laboratories and, as a SME [Small and Medium-sized Enterprise] , we have recently invested >£200,000 in upgrades to our magnetic resonance instrumentation for enabling the highest quality data generation and processing”. [D] Specific impacts of DOSY and pure shift at Arcinova include:

• Characterising monomer, dimer and trimer impurities in a pharmaceutical product used for advanced cancer treatment, since commercialised and now used globally [D]

• Assessing physical stability of a liposomal product to determine whether it met technical requirements for use in humans; this product is now commercially available [D]

The international pharmaceutical giant AstraZeneca has also integrated DOSY and pure shift NMR techniques into their research, describing them as representing “… *a step function improvement in our ability to analyse our samples by NMR.*” [E]. The methods are widely used in the AstraZeneca analysis toolbox, and are “… *playing an important part in the development of both small and medium sized drugs (e.g. oligonucleotides)*” [E]. The benefits to AstraZeneca’s business are characterised by a Principal Scientist in Pharmaceutical Technology & Development, who says “ *…the understanding that is derived from these experiments helps expedite the drug development process, ultimately allowing us to deliver medicines to patients more effectively.*” [E].

Mestrelab Research, who produce the NMR processing software Mnova, illustrate the breadth of uptake across the chemical industries. Mestrelab‘s software, which has 150,000 users globally, incorporates specific processing algorithms for DOSY and pure shift NMR experiments [F]. Mestrelab‘s Managing Director credits the UoM NMR techniques with contributing to their software’s success, saying, “ *We have no doubt that incorporating processing for pure shift and DOSY methods has contributed to establishing a market-leading position for our Mnova software.*” [F]

Delivering financial benefits to the chemical industries

Alongside the more general benefits derived from the enhanced problem-solving that DOSY and pure shift techniques provide, companies have developed new products directly from their use. As an example, Givaudan, a major international flavours and fragrances company, used DOSY to discover a compound that only occurred in trace amounts in food extracts. This compound positively influences taste perception and is widely applicable to a range of flavour products; sales between 2014 and 2018 generated CHF120,000,000 (approximately GBP100,000,000) [G]. Givaudan emphasise the value of these NMR techniques for companies, stating “ We are optimistic that the newly developed DOSY techniques and the newly deveped (sic) processing toolbox will also help us in finding the next “golden bullet” and can give Givaudan a clear competitive advantage.” [G].

Development of chemical manufacturing processes using engineered biocatalysts

Pathway to impact

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Reach and significance

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Training the next generation of industrial biotechnologists – changing attitudes, behaviours and understanding

i) Changing practice in the chemical industries

The CoEBio3 researchers have created training courses in Industrial Biotechnology, based partly on their research . This includes a Continuing Professional Development (CPD) course on ‘Biocatalytic Retrosynthesis’, delivered to industrial chemists at AstraZeneca, GSK, Gilead, Novartis and Lonza. To accompany this, they produced a book, “ Biocatalysis in Organic Synthesis: The Retrosynthesis Approach.” (N.J. Turner and L. Humphreys, 2018), which has sold 500 units to date, as well as a computational tool (RetroBioCat: www.retrobiocat.com) which has received 557 downloads and has been read >1,600 times on chemrxiv.org (as of 23/10/20).

The CPD course developed and delivered to industrial chemists has proven remarkably successful. It has been delivered 10 times between 2013 and 2020 and over 500 participants have attended the course. The course has built the capacity of these participants to apply biotechnology, including CoEBio3’s engineered enzymes, in their industrial workplaces. Furthermore, RetroBioCat is now being used by many pharma companies for synthetic route design. Examples of this include (emphasis added):

• Gilead, who stated: “ *This training has resulted in an expansion of additional opportunities in the way our scientists work day-to-day with biocatalysis as part of their tool kit. It is now commonplace for our scientists to consider using biocatalytic transformations...*” [E]

• Bayer, who stated: “ as a direct consequence of working with the University of Manchester and the MIB, we have altered our working practices investing significantly in a new screening laboratory.” [A]

• AstraZeneca, who stated: “ *We are now also evaluating the computational tool RetroBioCat developed by the Manchester group and believe that this online tool has changed the way our synthetic organic chemists view biocatalysis”. [F]

• GSK, who stated: “ These courses have helped fundamentally changed (sic) the way both lab-scale and process-scale synthetic chemists at GSK Stevenage work. These chemists now routinely apply the concepts of biosynthetic retrosynthesis to their work. This has led to the more common use of engineered enzymes as biocatalysts in both lab-scale and process-scale synthesis.” and also: “ MIB represents by far the most fruitful source of talent in biocatalysis for GSK”. [G]

In 2018, in collaboration with AstraZeneca (GBP1,000,000 investment) and Prozomix, CoEBio3 established the Centre for Biocatalytic Manufacturing of New Modalities (CBNM) to develop new scalable biocatalytic technologies for the cost effective and efficient synthesis of new pharmaceutical modalities [F]. In 2020, CoEBio3 was selected by the Bill & Melinda Gates Foundation to develop new biocatalytic routes to global health drugs for treatment of HIV, COVID-19 and tuberculosis (GBP600,000). This programme of work has the specific aim of applying industrial biotechnology to the manufacture of medicines at greatly reduced cost, making them affordable to healthcare systems with severely limited financial resources.

ii) Shaping UK Government policy through an industrial biotechnology strategy

In 2008, by virtue of their research achievements and expertise, researchers from CoEBio3 were invited to join the UK Government-backed Industrial Biotechnology Leadership Forum (IBLF) [H]. The IBLF is formed of influential members drawn from industry, academia, finance, NGOs, funding agencies (BBSRC, EPSRC, InnovateUK) and government [H]. Through their participation with the IBLF, CoEBio3 researchers directly co-authored parts of our report “Growing the UK Industrial Biotechnology Base”, which was issued as a UK road map and strategy for Industrial Biotechnology to 2030. This report has directly shaped the UK Government’s policies in life science investment, and biotechnology and is foundational in the UK’s Bioeconomy Strategy that was formally launched by Government six months later in December 2018 [H]. This strategy is now the guiding document for UK bioeconomy policy – with a goal of creating a 2030 bioeconomy that has a GVA of GBP440,000,000,000 – double its size in 2018 [H].

iii) Inspiring the next generation of scientists to study industrial biotechnology

Alongside the specialist industrial course, CoEBio3 researchers designed and delivered a MOOC in Industrial Biotechnology (IB MOOC), available through the learning platform Coursera ( https://www.coursera.org/learn/industrial-biotech). This IB MOOC has made teaching that was traditionally available to students studying at a biotechnology specialist institution freely accessible to anyone with an internet connection. The course has had 47,465 total learners and [5,700] course completers, ~75% of whom are aged 18-34, from Africa, Asia, Europe and the Americas (1,795 ratings; average score = 4.7/5) [I]. 12% started a new career after completing the course and 17% got a tangible career benefit from this course [I].

The researchers also created and co-ordinate a programme of public engagement with research/researchers at the Manchester Institute of Biotechnology, which is delivered to younger, non-specialist audiences from underprivileged backgrounds. This CoEBio3 Public Engagement Programme has enabled over 100 researchers from our institute to engage locally and nationally with non-specialist audiences. This unique approach which has now been adopted by others, has included partnering bilingual researchers with ~400 young people from immigrant backgrounds. As of June 2020, 12 such community visits have been organised with engagement in some of the most widely spoken non-English languages in Manchester (Bengali, Arabic, Polish and Mandarin) as well as other minority languages (Greek, Spanish, Italian, Hindi and Tamil). This initiative has inspired participants into further study and influenced career ambitions. For example, one participant said, “I think this lesson has inspired me to pursue science as a future career”, whilst another said, “It was really nice to learn about the different aspects of chemistry and it has got me to want to know more about chemistry. I am now thinking to do Chemistry at university” [J]. Delivery of the lessons in non-English languages was also viewed very positively by participants, with one saying “ …I really liked how the session was in Polish because it meant we had more knowledge about science but in Polish” [J]. Teachers at these multilingual schools also greatly valued the classes, with one saying, “ The activity such as this gives children an opportunity to talk to the young scientists on interesting subjects in the language they are learning, which is a great encouragement to the children and a big help to the schools involved. This was clearly reflected in the highly positive feedback given by the participating children” [J].

Context

SIMS techniques have been applied to numerous industrial applications, including in the pharmaceutical and life science industries as a tissue and cell imaging technique, and particularly in the microelectronics industry for studying the structure of semiconductor devices. SIMS was previously limited in its utility, primarily to the analysis of inorganic materials. The aggressive nature of the atomic primary ion beam caused significant damage to the underlying surface of the material, restricting the amount of meaningful information that could be obtained to <1% of the sample surface, severely limiting the sensitivity of the measurement. In addition, the low yield of diagnostic secondary ions limited the spatial resolution available in SIMS imaging of molecular materials. Set against this background, UoM’s research and collaborations have aimed to overcome these limitations by using new, more gentle polyatomic ion beams, as described above.

Pathway to impact

The research underpinning this case study has been performed to a great extent in collaboration with UK SME Ionoptika Ltd, who provided in-kind support, engineering expertise and routes to commercialisation. This collaboration has been ongoing since 2000, when UoM researchers worked with Ionoptika to develop the first C₆₀⁺ primary ion beam source [B, C].

Reach and significance of impact

Changing practice in the scientific community and industry

Virtually all of the ~100 Time-of-Flight-SIMS spectrometers sold since 2013 include a polyatomic ion source, using either C₆₀, GCIBs, or both [B]. NPL characterise the importance of polyatomic ion sources in SIMS applications, saying “ These projectiles are critical in the application of SIMS across industrial sectors spanning manufacturing to healthcare and have been universally adopted by the worldwide SIMS community.” [B]. The Manchester group has been pivotal to the implementation and commercialisation of polyatomic SIMS allowing widespread access to these new measurement tools, which have changed analytical practice and capacity [A, D, E].

Industrial sectors including electronics ( *[text removed for publication]*), chemical (Dow Chemical, BASF), manufacturing (Dow Corning [a joint venture between Dow Chemical Company and Corning Inc.], Mitsubishi, Fujifilm) and pharmaceuticals (AstraZeneca, GlaxoSmithKline, Novartis) and governmental research labs (UK-NPL, USA-NIST, Korea-KRISS) rely on the enhanced sensitivity and 3D molecular imaging capabilities unique to these ion beams. The NPL stated, “ polyatomic cluster impacts together with novel analytical methodologies enable increased sensitivity of a 1000-fold for thick samples.” [B]. The NIST stated, “Work done by the group at Manchester has revolutionized the analytical capabilities and availability of this approach to the scientific community and industry. We have seen integrated signals improve by factors of 10⁵ for certain organic compounds when compared to atomic primary ion beams” [D].

At Dow Chemical Company, polyatomic SIMS provide unique depth-profiling capabilities to study chemical degradation and segregation on multilayer polymer-based materials *‘enabled experiments that have never before been possible’ [E]**.

Corning Inc. stated, “[Polyatomic SIMS] has changed the analytical practice and capacity within Corning Inc., enabling us to derive new levels of understanding regarding our products and their performance.” [A].

Leading analytical services company Tascon GmbH, serving customers in the automotive, chemicals, electronics, glass, life sciences, and pharmaceuticals markets stated, “ *(GCIB) has opened complete new applicational options. Not only depth profiling has become feasible, but also the reconstruction of the 3-dimensional composition (both elemental and molecular) has entered our daily analytical portfolio.*” [F].

The NIST stated, “ C₆₀ and GCIB ion sources are able to derive new chemical information on 3D micro-distributions within a wider range of materials (polymers, biological materials, drugs and semiconductors) than was previously possible with conventional SIMS using monoatomic ion beams” [D].

Economic benefits and capacity building for instrument manufacturers and industrial users

The co-development, with UoM, of polyatomic ion sources for SIMS, firstly C₆₀ and more recently GCIBs, are at the centre of Ionoptika’s business model and emergence into an international leader in SIMS technology [C]. Ionoptika stated, “ commercialisation of the J105 has led to Ionoptika moving to a larger manufacturing facility in 2014 and has resulted in the creation of 23 specialist manufacturing jobs since 1 August 2013, tripling our workforce.” [C]. The C₆₀ source is protected by three patents and the SIMS instrument developed to maximise polyatomic projectiles the subject of two more (2014).

Industrial users worldwide apply polyatomic SIMS measurements to derive new levels of understanding on products and their performance, leading to economic impact.

For example, at Dow this technology is used to develop new multilayer coatings and [text removed for publication] [E]. Corning Inc. state: “ I cannot say enough about the impact polyatomic ion sources have on industrial product development…. Since the introduction of the polyatomic ion beam source to Corning, there has been at least a 300% increase in sample volume.” [A].

Influenced new instrumentation products

As a result of UoM’s underpinning research since 2000, all three major manufacturers of time-of-flight SIMS, Ionoptika Ltd (UK), IonToF GmbH (Germany) and Phi Inc. (USA) supply C₆₀ and/or GCIB sources with their instruments with each ion source valued at GBP100,000‒400,000. The J105 instrument design results directly from our pioneering work with C₆₀ [B] which demonstrated for the first time a projectile beam combining high brightness, high molecular sensitivity and the capability to operate in a dynamic mode for full 3D-analysis [1]. These instruments (~GBP1,500,000 each) have sold across three continents, to industrial and academic labs [C]. The same principle of continuous bombardment has led to another instrument platform from Thermo/IonToF GmbH – the 3D orbiSIMS, launched in 2017 and selling 8 units worldwide [text removed for publication] [B].

Beyond SIMS, the rather gentle molecular erosion under polyatomic bombardment allows other 'surface analysis' methods including X-ray Photoelectron spectroscopy (XPS) to probe sub-surface chemistry. GCIB sputter-etch sources allow this highly-quantitative technique to measure buried molecular layers and clean-up contaminate surfaces. At Dow, product development was impaired by “ a gap of chemical analysis over the information depth of about 10 nm (usually thought of as the maximum depth for XPS) and a couple [of] microns (about the information depth of IR)…cluster beam etching coupled with SIMS and/or XPS analysis has eliminated this information gap… meaning the impossible is now possible” [E]. XPS market-leader Kratos Analytical stated, “ *Depth profiling with retention of chemistry was not possible before the development of GCIB technology. [text removed for publication]*”. [text removed for publication] [G].

Enhancing quality of life through new measurement capability

Polyatomic beams provide novel capabilities for chemical imaging in biomedical and consumer product fields. Examples include studies of drug distribution in single biological cells and drug release studies in biomedical implants [B]. A collaborative study between Novartis and Penn State University used a J105 instrument and micro-focused GCIB to image antimicrobials in single bacteria, shedding new light on the biological mode of action. Such studies demonstrate the downstream impact in personalised medicine and future healthcare. In a wide range of industrial applications, polyatomic beams provide answers to critical questions regarding product performance and failure which were simply not available previously [F].

At NIST polyatomic SIMS has opened several new application areas in healthcare and bioanalysis including (i) development of next generation drug delivery films, (ii) assessing potential health hazards associated with Homeland Security Application and (iii) public health and safety issues related to drug contamination and adulteration [D].

Corning Inc. stated, “ Polyatomic SIMS was used to understand the chemistries and failure mechanisms in our pharmaceutical vial coatings which are currently being employed for use in COVID vaccines [and] … has accelerated product development significantly and has led to improved quality of life for our global customers.” [A].