New technology to improve capability for clinical radiopharmaceutical production

This research will produce an operational prototype to make medical imaging drugs at, or near to, a hospital. Molecular imaging techniques (where a molecule is tagged with radioactive atom, injected into the patient and then tracked inside the body using a scanner) are increasingly becoming a key part of the clinical diagnostic pathway. They can detect a disease at an early stage and offer more precise information on how it will progress, also indicating the best possible treatment option in many cases.

The aim of this research is to develop devices improve the access to molecular imaging technologies that offer better diagnosis of disease.

These medical imaging techniques (particularly position emission tomography or PET) rely on radioactive atoms that are short lived (i.e. they decay away rapidly over hours or even minutes). This requires a small scale "drug factory", which in many cases must be on the same site as the patient due to the "feedstock material" decaying over time. Efficient conversion into the drug form is needed, it will be checked for purity and rapidly passed on for patient imaging.

These molecular imaging techniques are mainly applied to cancers but there are new applications for the diagnosis of cardiac disease and also dementia. This research work will focus on a particular molecular imaging agent to improve detection and understanding of prostate cancer, which is likely to be required at many hospital sites around the UK. The NHS is already developing a strategy for how it will be included in patient assessment pathways but will need to invest in infrastructure to achieve this. Reducing the cost (both of the production device itself and the required infrastructure) will increase the availability to patients.

The method we are using to deliver this, is to apply some of the latest advances in microfluidic technology developed by the University of Hull research team. This technology which deals with miniaturised devices handling low volumes to allow chemical synthesis of imaging drug molecules on a small scale with high efficiency. The Hull team are world leaders in this area. They have reported their initial results on at international nuclear medicines conferences and in scientific papers, and have also applied for five patents on this technology.

The key deliverables are the production and validation of an operational prototype device that can be taken into a clinical radiopharmacy and allow us to work along the clinical staff to show how this technology can be used to improve availability of diagnostic agents, particularly in cancer. All of these technologies are regulated to ensure their safe operation and we will engage and work with the regulators to ensure that the new technology can be safely used in the clinical setting (where clean rooms and standard operating procedures must be followed to ensure patient safety).

The project will be carried out between the University of Hull and the Hull and East Yorkshire NHS with the use of facilities on both the University of Hull site and the Castle Hill Hospital NHS site. It also involves King's College London as a project partner. We will work with collaborators in Uruguay and the USA, testing the imaging drug production unit in their clinical facilities to see how it fits in with their production procedures and regulations, which differ from those in the UK. We will also collaborate with Alliance Medical Ltd., the biggest supplier of positron emission tomography scanning services in the world and primary provider to the NHS, as part of the project.

The new technology will allow the production of the tracers in a more streamlined manner that will give clinicians access to a greater number of tools to assess and diagnose their patients. More effective tools will give improved outcomes and the technology will offer cost effective access to these technologies for the NHS and other healthcare organisations worldwide.

There is a roadblock in the availability of new molecular imaging agents for clinical use. The demand for enabling technology is driven by the expansion in agents that have been validated as gold standard in patient care but do not yet have sufficient clinical availability. There is a challenge in delivery of these new diagnostic drugs at an appropriate cost point with minimal impact on staff training and infrastructure. This is an issue affecting health service provision worldwide.

The key complexity in producing the radiopharmaceuticals is the infrastructure required on clinical sites (GMP facilities and highly trained staff on each site due to the short half-life of the drug). This increases cost above that incurred for routinely used agents in nuclear imaging such as fluorodeoxyglucose (FDG), a standard radiopharmaceutical used in positron emission tomography imaging.

The most important recent example is the development of gallium-68 PSMA imaging which has become a key driver in the expansion of the market. This agent offers unrivalled capability in the detection and therapy response of prostate cancers but only has limited availability. Most hospitals lack the infrastructure and trained staff to produce the agent. The gallium-68 generator has only recently been approved for routine clinical use (2014) and so this is an ideal time to enter the market with demand on a sharp upward trend. This may also link to theranostic developments that are expected to increase over the next 10 years.

The technology that we have developed is a microfluidic device that allows efficient processing of the generator eluent and brings synthetic capabilities to operate "at generator", increasing production efficiency with a strategy to provide tracer in a "patient ready" form for administration. This requires limited intervention by the radiopharmacist and can also produce the tracer in a "dose-on-demand" model that is a better fit with clinical need.

The clinical demand for positron emission tomography radiopharmaceuticals and molecular imaging agents is undergoing significant year on year expansion, which is likely to be further fuelled by the demand for theranostic approaches in the clinic. These exciting new diagnostic agents (and linked therapies) require an expansion in infrastructure that meets regulatory standards to effectively deliver them for patient imaging. As more agents are approved, the pressure on the infrastructure increases and miniaturised microfluidic technology can provide a solution to allow widespread clinical access.

The hands-on users of the technology developed in the proposed research are radiopharmacists involved in GMP radiotracer production for clinical diagnostic imaging. The technology developed in this work will facilitate more efficient and cost-effective production of radiotracers by using optimised microfluidic technology coupled with automation for more effective processing of gallium-68 generator eluent. This will offer access to the next generation of diagnostic and disease staging molecular imaging agents. It will improve the standard of patient care with more precise diagnosis, and potentially improved prognostic information, available for clinicians to assess patients.

The specific focus on gallium-68 technology was selected to have the greatest impact in the near term as there is a growing demand for PSMA targeted agents in prostate cancer. This is a key market driver as there is an unmet need in prostate cancer patients with metastatic castrate resistant prostate cancer (killing >300,000 men worldwide annually). This one agent is an excellent example of the potential for impact - a new gold standard of care is being defined (gallium-68 PSMA targeted agents) but the infrastructure and supply problems have not yet been addressed across the UK, Europe and the USA. There are currently >300 PET radiopharmacies across Europe and the USA which produce radiopharmaceuticals. However, a decentralised model based on the type of technology developed in this work may be the only way to meet future demands, not only in oncology but also in cardiac and dementia patient imaging.

The cost per dose of gallium based tracers is linked to both the cost and availability of generators and the need to use standard technologies/ infrastructure to synthesise and validate the radiotracers. There are challenges to the availability of this imaging agent in the NHS and it has been recognised as a priority for the future. Cost and health economic arguments are important for adoption of any new diagnostic method/ treatment hence reduction of production cost can increase access to the best possible treatment pathways.

The introduction of this technology into clinical radiotracer production that is approved by regulatory bodies will validate the approach and pave the way for next generation technologies. It will facilitate a move towards more efficient "dose-on-demand" technologies which could offer a revolution in molecular imaging technology as a greater number of imaging agents will be available for clinical studies and can be tailored to the patient. This precision approach will improve patient outcomes and allow more effective treatment pathways with improved access to molecular imaging. It will enable improvements in radiotherapy planning, chemotherapy selection and responsive changes to therapy.

The new technology could also be used to address some of the challenges in radiopharmaceutical production for the predicted expansion in theranostic isotope pairs in sequential imaging and treatment. Some hurdles to adopting these agents in routine clinical use are due to the complexity of production and handling of the agents. These can be overcome using microfluidic isotope processing, synthesis and quality control validation.