Tag: Drug Delivery

Respiratory Insights – Respiratory drug delivery systems

INSIGHTS

Industry Insights into the Future of Respiratory Drug Delivery

By Steve Augustyn • Deputy Head of Drug Delivery

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Advances and Opportunities in Respiratory Drug Delivery

Discover the exciting possibilities on the horizon for inhalation device design with our latest resource, “Breathing New Life: Industry Insights into the Future of Respiratory Drug Delivery”.

This e-book explores recent advancements and highlights innovative strategies crucial for developing significant new treatments.

Gain expert insights on:

The potential value of through smart inhaler technology.

Shifting away from high GWP propellants.

Maintaining drug stability and delivery precision across varied respiratory conditions.

Integrating innovation with user experience and sustainability in device design.

Developing customized devices for groundbreaking clinical research.

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By Cambridge Design Partnership
February 16th 2024

Exploring the potential (and pitfalls) in on-body large-volume injectors

In a recent Q&A with Healthcare Packaging, CDP’s Clare Beddoes and Stephen Augustyn discuss the latest trends in on-body large-volume injectors (LVIs) and what they expect to see in 2024.

READ THE FULL ARTICLE
LISTEN TO THE KEYNOTE
Clare Beddoes

Clare Beddoes

Head of Drug Delivery

Steve Augustyn

Steve Augustyn

Deputy Head of Drug Delivery

Here are their key takeaways:

There are a growing number of untapped disease states for on-body LVIs

“In terms of  large volume drugs that could be appropriate for delivery via an on-body LVI, conditions such as neurological disorders, oncology, and autoimmune diseases present promising opportunities.” 

On-body LVIs present both pros and cons when it comes to sustainability 

“Compared to traditional autoinjectors, the pros lie in enabling more patients to receive treatment at home, reducing travel and clinic resource usage. However, on-body LVIs are notably more complex than autoinjectors, involving adhesive patches, sterility barriers, intricate fluid paths, and often electromechanical drive systems.”

The two main hurdles to commercializing on-body LVIs are cost and risk

“Companies are understandably cautious about risk, often preferring to launch conventional devices initially, while avoiding adding risk on top of risk with a new device for a new drug product. Technical complexities, novel primary containers, device costs, and manufacturing for lower production volumes create hurdles.” 

Regulatory challenges have seen a significant improvement since 2022

“ISO 11608 Part 6 offers a clearer framework than before, when these devices were verified as infusion pumps, focusing on ‘rate accuracy’ and not ‘dose accuracy’. The regulatory route is much better understood and there are now products on the market, which gives confidence to device manufacturers.”

Device manufacturers are pushing to enhance automation for large and small-batch production

“In terms of assembly and packaging, high-speed automation rarely makes sense below 2m units a year, so below that, semi-automated or manual processes remain, adding to the device cost. However, some committed device manufacturers are pushing to enhance automation using well-considered device design and process monitoring.” 

In summary, the industry still favours established options like autoinjectors, with some pharma companies preferring to use two autoinjectors rather than deal with the complexity of an on body delivery system. However, as LVIs become more established, the anxiety around their use will diminish.

READ THE FULL ARTICLE

Missed our keynote at Pharmapack?

In their keynote session this year, resident experts in Combination Products, Head of Drug Delivery Clare Beddoes, and Deputy Head of Drug Delivery Steve Augustyn, asked: Where are all the on-body delivery devices?

Explaining the need to deliver innovation fast, they covered:

  • Barriers to market that on-body devices face and how to overcome them.
  • How to navigate relevant drug product pipelines, regulations and standards.
  • Future drivers for successful LVI development.

“The huge demand for high-volume biologics that was expected to drive on-body systems hasn’t materialized, or the devices are proving extremely complex and difficult to assemble. [But] as LVIs become more established, the anxiety around their use will diminish.” 

– Steve Augustyn

Innovations in Oncology|María|Antibody
By Cambridge Design Partnership
February 2nd 2024

Innovations in Oncology: Past, Present, Future

 

This article will explore five exciting developments in the field of oncology and how advances in diagnostics, data analytics, cell biology and delivery devices are enabling oncology companies to bring the hope of longer, healthier lives to a wider range of patients than ever before.

First, let’s look at the history of this field of medicine and the current state of play. It is a disease that has plagued us for millennia. The oldest known records date as far back as Ancient Egypt, when the great physician Imhotep described a “bulging in the breast” for which there was no therapy. Thankfully, we’ve come a long way since.

A history of oncology: a whistle-stop tour [1]

Doctor radiologist running CT scan for patient's body lungs from control room. Computed Tomography

Modern surgery (the 1800s):

Surgeons faced severe limitations until the discovery of anaesthesia and antisepsis in the late 1800s. By the early 1900s, sophisticated surgeries had become commonplace, and it was possible to treat a wide range of early-stage cancers by surgically removing solid tumours.

Radiation and chemotherapy (late 1800s-1900s):

The discovery of X-rays in 1895 ushered in the era of radiation therapy. Chemotherapy followed in the mid-1900s, with the first effective cytotoxic drug found in nitrogen mustard, a derivative of the mustard gas used as a chemical weapon in WWI.

Progress in the 1950s-60s:

A flurry of discoveries in the 1950s and 60s yielded gains in cancer prevention, detection, and treatment. Notable achievements include proving the link between smoking and lung cancer, the introduction of cervical cancer screening, and advancements in chemotherapy.

The knowledge revolution (1980s-present):

The 1980s marked a turning point in our understanding of cancer biology. What was once thought of as a monolithic disease, and then a collection of altogether disparate conditions, is now understood to be a group of related diseases. Underneath the heterogeneity of cancer lies a consistent pattern: mutated genes that typically sit at key junctions in cellular signalling pathways, granting the cell distinctive pathological capabilities (e.g., the ability to evade growth-curbing mechanisms).

With the discovery of proto-oncogenes, tumour suppressor genes, and an understanding of the ways in which they disrupt specific cellular pathways, came the promise of (molecular) targeted therapies. Herceptin was one of the first: a monoclonal antibody specifically engineered to target and block receptors encoded by the HER2 oncogene.

New insights also paved the way for better prevention and diagnostics, such as the development of preventative cancer vaccines and the use of cancer biomarker assays to improve clinical decision-making.

Oncology today: a global challenge

The knowledge revolution continues, with over 700 proto-oncogenes and tumour suppressor genes identified by 2018, providing a cornucopia of potential treatment targets. However, the focus has shifted from “finding a cure” to prolonging healthy life through better prevention and care. And it’s working: in the US, the age-adjusted cancer death rate dropped by 22% between 2005 and 2020 [2]. But challenges persist, including:

  • Detecting cancer early when it can be most successfully treated
  • Identifying the best treatment for each patient
  • Targeting treatments to kill cancer cells while minimising off-target toxicity effectively
  • Increasing equitable access to prevention and care 

Oncology tomorrow: a multidisciplinary solution

Opportunities that were previously unimaginable are now within our grasp – we have unprecedented insight into cancer and access to powerful new technologies. Here are five developments we’re excited about:

1. Investments in decentralised testing

In the world of oncology diagnostics, decentralised testing can help more patients get an earlier and more accurate diagnosis, improving their chances of survival.

Elsewhere in diagnostics – notably respiratory illnesses and sexually transmitted diseases – there has been a successful decentralisation of testing. An abundance of point-of-care tests are available, along with the infrastructure to support them. By speeding up diagnosis, these tests streamline the process from the appearance of symptoms to the patient receiving the correct medication.

In cancer diagnostics, this decentralisation hasn’t been possible to date. The vast majority of testing still requires a biopsy and subsequent analysis in a pathology lab; throughput is therefore constrained.

Ultimately, science is only part of the answer.
There is also a need to improve workflows across
the entire diagnostic journey, from sample collection
and preparation to data interpretation.

Emerging cell-free DNA methods, which use liquid biopsies, can potentially reduce the reliance on solid tumour biopsies, but limited sensitivity restricts their applicability. Ultimately, science is only part of the answer. There is also a need to improve workflows across the entire diagnostic journey, from sample collection and preparation to data interpretation. Here, too, progress is being made. For example, the UK has seen investment in Community Diagnostic Centres – vastly increasing computed tomography (CT), magnetic resonance imaging (MRI), and ultrasound scanning capacity to reduce the time to diagnosis [3].

A monoclonal antibody (yellow) blocks the interaction of PD-L1 with PD-1

2. Big data meets precision oncology

Once a diagnosis is made, clinicians must choose the most appropriate course of treatment. High-throughput sequencing technology and large-scale cancer genome studies have put a wealth of data at their disposal to aid in this decision. Precision oncology aims to harness that data to improve outcomes by using mutation analysis to guide treatment decisions for individual patients. However, making this a reality has turned out to be far more complicated than it sounds.

To be clinically useful, genetic or biomarker tests should be sufficiently predictive of treatment response from a targeted agent (e.g., HER2 positivity in breast cancer is predictive of susceptibility to Herceptin). Finding such test/treatment targets in the vast quantities of multi-omic data by brute force (and then developing or pairing with suitably matching drugs) requires immense computational power, which has so far been a limiting factor.

Because of its superior pattern recognition capabilities,
we’re excited about the potential for artificial intelligence (AI)
to change the game entirely.

Because of its superior pattern recognition capabilities, we’re excited about the potential for artificial intelligence (AI) to change the game entirely. For example, AI could leverage the ever-growing stores of data to more efficiently:

  • Identify driver mutations that may also be actionable drug targets
  • Generate and down-select potential drug candidates with in-silico screening
  • Identify predictive biomarkers that could be used to match patients with the most appropriate therapy

Of course, it’s early days for the application of AI for this purpose and making the best use of the data requires as much of it as possible to be publicly accessible, as well as the development of standard tools and conventions to improve cross-centre collaboration – so we’ll monitor developments with interest.

3. Foundational models of the cell

The promise of AI in oncology goes well beyond pattern recognition: just as foundation models have been developed for language (and are now used to power chatbots and generative AI), they could be developed for biological systems. Imagine general-purpose models of human cells of human cancers that could be adapted to represent specific patient cohorts or even individual patients (e.g., digital twins).

The models might be quite intricate, representing
a hierarchy of structure – from organ systems,
through tumours and their microenvironments,
to individual genes and the proteins they encode.

The models might be quite intricate, representing a hierarchy of structure – from organ systems, through tumours and their microenvironments, to individual genes and the proteins they encode. They could be adapted to assist in drug discovery, trial design and monitoring, and clinical decision-making. For example, to:

  • Simulate the effect of potential treatments on different patient populations
  • Evaluate treatment options in a specific cohort

Key to the successful implementation of such models is explainability: the ability to explain the model’s behaviour and its decisions in human terms. Additionally, to unleash their full potential, these models should not be static but rather learn continuously as new data is acquired – which will pose an interesting regulatory challenge.

4. The right device for the right patient at the right time

Once an appropriate therapeutic agent has been identified comes the challenge of delivering it safely and effectively. Here, the choice of administration route and delivery device are crucial.

In therapeutic areas such as rheumatoid arthritis, drugs that were previously delivered intravenously (IV) have long been available for subcutaneous (SubQ) self-administration – a transition made possible by improvements in formulation as well as device technology (e.g., autoinjectors).

A similar trend of IV to SubQ for in-home self-injection has been forecast for anticancer drugs for some time, with the promise of reducing the treatment burden for patients and healthcare systems [4]. It hasn’t quite materialised, and for good reason:

  • Most traditional cancer therapies are vesicant (i.e., known to damage subcutaneous tissue) and, therefore, fundamentally unsuitable for SubQ administration
  • Many are hazardous to handle: the risk of a leakage causing harm is high in a home or self-administration setting
  • Many patients need to be seen face-to-face by a clinician because their therapy requires variable dosing or close monitoring for side-effects

… there is certainly room for subcutaneous
delivery in oncology and even self-administration
– if the risk/benefit profile for a specific
patient and therapy warrants it.

As evidenced by the small but growing number of regulatory approvals (mostly in the form of pre-filled syringes or syringes prepared by the hospital pharmacy), there is certainly room for subcutaneous delivery in oncology and even self-administration – if the risk/benefit profile for a specific patient and therapy warrants it.

The solution, however, is not a push for wider adoption of any specific device technology but rather device selection that is underpinned by a thorough understanding of all stakeholder needs. Not just the immediate needs of the patient, clinicians, and formulation but also the wider context in which the therapy will be administered (care workflow, reimbursement pathways, etc.).

Interventional radiology. surgeon radiologist at operation during catheter based treatment with X-ray visualization.

5. Devices for targeted drug delivery

Cytotoxic chemotherapy has long been the mainstay of oncology treatment: it is versatile and effective. The problem is that off-target toxicity limits its tolerability. Targeted delivery aims to address this challenge by increasing drug concentration in cancerous tissues relative to healthy ones. This can improve efficacy while reducing side effects.

Drug-loaded nanoparticles, which are delivered systemically, have been investigated since the ‘90s as a way to achieve selective binding to tumour targets. However, despite extensive research, the number of such therapies available to patients is well below projections; promise in animal studies often fails to translate to success in humans [5].

We’re encouraged by the potential of targeted
delivery, for example, direct injection of cancer
drugs into tumours, as well as the use of
implantable pumps and reservoirs.

We’re excited about the potential of targeted delivery, for example, direct injection of cancer drugs into tumours, as well as the use of implantable pumps and reservoirs to access pharmacological sanctuaries such as the blood-brain barrier.

There is a robust pipeline of intratumoral therapies, with drugs for melanoma leading the charge – partly because the lesions are often superficial and, therefore, easier to find and inject into. Delivery to deeper tumours is more challenging and is currently conducted by highly skilled clinicians with imaging support – therefore requiring the development of delivery devices that provide a high degree of flexibility and control over the injection technique

Early diagnosis and targeted treatment offer hope of better outcomes

Oncology has come a long way and will continue to evolve with our growing understanding of the disease and the emergence of new technologies to prevent, detect and treat it. We’re excited to see innovations along the entire care pathway:

  • Investments in decentralised testing, including the development of cell-free DNA technologies, to allow faster and more accurate diagnosis
  • The potential of AI to revolutionise drug discovery and development and to help clinicians match patients to the most appropriate treatment
  • Improvements in delivery device technology to allow for safer, more targeted, and effective treatment


The journey continues, and hope prevails.

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References
  1.  The Emperor of All Maladies: A Biography of Cancer, by Siddhartha Mukherjee
  2. National Center for Chronic Disease Prevention and Health Promotion (U.S.). Division of Cancer Prevention and Control. An Update on cancer deaths in the United States (2022).
  3. https://www.gov.uk/government/news/government-to-deliver-160-community-diagnostic-centres-a-year-early
  4. Levêque, D. Subcutaneous Administration of Anticancer Agents. Anticancer Research 34 (4) 1579-1586 (2014).
  5. Mitchell, M.J., Billingsley, M.M., Haley, R.M. et al. Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov 20, 101–124 (2021).

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See our range of capabilities in developing drug delivery devices, diagnostics, and medical therapy solutions by visiting the below pages.

Drug Delivery
Diagnostics
Medical Therapy
Bespoke device for targeted intranasal delivery
By Cambridge Design Partnership
December 19th 2023

Taking a drug to first-in-human trials in a bespoke device for targeted intranasal delivery

Featured in ONdrugDelivery, Mark Allen, Andrew Fiorini, and Shai Assia discuss the need to develop delivery devices early when formulating nasally delivered drugs for systemic and local action, and a method by which the route to clinic can be made easier, faster and cheaper.

Systemic delivery has long been the mainstay of drug administration, whether via the oral, injectable, inhalable, nasal or another delivery route. There are, of course, many well-documented downsides of systemic delivery, including unintended side effects in locations beyond the drug target and reduced efficacy due to dose safety requirements to reduce those side effects. Targeted drug delivery can address many of those issues1 with targeted intranasal delivery, in particular, having the potential to treat many debilitating conditions, from as yet underserved conditions, such as cluster headaches, through to central nervous system (CNS) conditions such as Alzheimer’s disease. Indeed, there are currently many active studies on therapeutic delivery via this specialised route2. These targeted treatments have the potential to improve the lives of patients, their families and their carers immeasurably.

However, the key challenge lies in achieving the delivery of an accurate dose to a precise location within the nasal anatomy. A device that can enable that targeting is intrinsically linked to drug efficacy, meaning that it is necessary to consider device development earlier in the process than usual. In comparison, a drug intended for parenteral delivery has the well-trodden option of using a vial and syringe for administration by a healthcare practitioner during early development phases while proving basic safety and efficacy. A more complex drug delivery system can then be sourced or designed (if required) in parallel, ready for use in Phase III trials as part of a combination product development pathway.

“The key challenge lies in achieving the delivery of an accurate dose to a precise location within the nasal anatomy. A device that can enable that targeting is intrinsically linked to drug efficacy.”

This off-the-shelf-device approach, aimed at reducing the risk and cost associated with early-stage clinical studies, is not an option available to those developing highly targeted intranasal delivery – most of the currently available nasal devices are designed to coat as much of the nasal cavity as possible, making them unsuitable for delivery to a precise area. A nasal device with a broad spray pattern may even lead to the drug not reaching the intended target area at the required dose level.

So, how can a new, bespoke device be developed and made available for the initial Phase I and II trials? These are complex devices that need to be suitably well designed to ensure that patients or clinical professionals can use them during clinical trials to administer the drug accurately and repeatedly to the correct location, often deep in the nasal cavity.

To answer this, a minimum viable product (MVP) prototype device can be designed for the needs of the Phase I and II clinical trials. Designing for use within the controlled setting of a clinical trial and prioritising solely patient safety, spray geometry and usability (relating to holding and positioning the device) at this stage can considerably reduce the effort, cost and time required to reach the clinic. This MVP device will then allow the safety, efficacy and feasibility of the self-administered, targeted intranasal delivery method to be proven during these early clinical trials. The device performance and usability are critical to correctly delivering the drug, so learnings from this MVP device can be used in the further development and refinement of the device for Phase III trials, as well as the future commercial-scale device. Carrying out risk assessments and timely iterative testing (via formative studies) on the usability of the device is crucial; misuse or an inability to use the device could stop the patient from administering the drug to the intended location within the nasal cavity, or even cause harm, ultimately preventing the drug from achieving its intended therapeutic effect. Therefore, usability and human factors engineering must be incorporated into the design and development process from the start.

Defining a usable design

The challenge for the device development team is to successfully incorporate design for usability throughout a “lean” MVP device development process, meaning that a safe, usable device must be produced with reduced cost compared with traditional development processes. This can be achieved by careful adaptations to the typical design for usability process. When applying user-centric design principles, as outlined in ISO 9241-210, four steps should be followed:

  • Understand the context of use
  • Define the requirements
  • Build the design
  • Evaluate the design against the requirements.

Although this is not the only relevant ISO standard (others, such as ISO 62366, cover the application of usability engineering to medical devices), ISO 9241-210 provides a set of recommendations and requirements for applying user-centric design principles within design and development activities. These processes help to identify “real” user needs and usability challenges, which can then be used to establish a clearer framework for user interaction and interface design.

Understand the Context of Use

Consideration of the patient, including when and why they are receiving treatment, is essential. For example, if a new targeted nasal delivery device is to replace a healthcare practitioner-administered treatment, it is likely that the patient currently visits a clinic to receive their treatment, disrupting their schedule and placing an additional burden on the healthcare system. A self-administered device will naturally put the patient in control of their treatment and improve their quality of life – as has been witnessed through the advent of self-injection devices. However, targeted nasal delivery relies on the patient not only following the treatment regimen and using the device correctly, but also positioning the device accurately to ensure that the drug is delivered to the precise location intended.

“The best form of information gathering is to consult the patients themselves – they know their needs, and frustrations, better than anyone.”

Another key factor in the design process is predicting how a patient may interpret the device and, therefore, how they would go about using it. This is where the concept of mental models is useful, as it reflects the patient’s perception of how a device works and how to use it based on the patient’s experiences of similar devices. Perception is what a patient sees, hears, touches or smells, which, in turn, triggers mental recall and cognition, which then drives their actions.

The best form of information gathering is to consult the patients themselves – they know their needs, and frustrations, better than anyone. Clinicians and caregivers can provide additional information about patient behaviour and trends based on their experience across a wide range of patients, but their answers should take second place.

Speaking to patients is crucial to building an understanding of the context of use; however, care must be taken with the specific questions asked – they must be suitably phrased to avoid leading patients to give similar answers, but also to gather the information required to guide the device design via user needs. Working with experienced insight researchers and human factors experts can greatly increase the value gleaned from patient interaction throughout the design and development process.

Define the Requirements

Once the context of use is understood, the findings and needs of the patient must be converted from a range of opinions and perceptions into clearly defined requirements. It is essential to align patient needs with requirements in a format that can be validated. Similarly, technical requirements need to be verifiable, while also ensuring a cost-effective and usable device design.

User requirements should drive the technical requirements for the device. Requirements are living documents, so each set of patient interviews will typically lead to updates to the requirements throughout the design process. Equally, unknown parameters in the requirements documents can be used to drive patient interviews that can, in turn, be used to refine the requirements further or provide specific values for the device design team. These documents and patient interviews can then both be iteratively tested and updated as required.

Build the Design

The design stage is the point at which activities can be prioritised to reduce development time and costs by differentiating between a prototype device suitable for first-in-human testing and a fully developed and validated device. Here, the typical process of concept generation followed by down selection (via assessment against device requirements) is used to identify a suitable device design for further development.

Once initial prototype devices are available, engineering testing against the requirements can be performed to provide confidence in the design. Full design verification testing is not required at this stage, but sufficient evidence should be generated in the key areas, including safety and dose delivery performance. Development and evaluation of the important training materials, such as the instructions for use, should be started, but with a lowered risk assessment burden, in the knowledge that there will be clinicians available during initial trials.

“Once initial prototype devices are available, engineering testing against the requirements can be performed to provide confidence in the design.”

Focusing on the requirements of the MVP will accelerate time to clinic by concentrating on safety and usability. This MVP device is equivalent to a syringe and vial or prefilled syringe in injectable development for systemic treatments, so there will be future opportunities to refine the design for Phase III trials and commercial launch. This is an appropriate strategy, as the devices will only be used under supervision at this point. All learnings from the study can then be prioritised and incorporated into the final design as required, according to risks identified.

“Once a final prototype has been developed, it must be evaluated against the design requirements by design review, engineering testing and formative human factors studies.”

Evaluate Against Requirements

Once a final prototype has been developed, it must be evaluated against the design requirements by design review, engineering testing and formative human factors studies. This should incorporate a usability assessment for self-administration and simulate as many real functionalities as possible, including tactile, visual and auditory feedback from the device. This process should prioritise evaluating areas highlighted as high risk during previous activities, but also gather information on any additional learnings relevant to future design updates.

The Future of Targeted Intranasal Devices

The approach discussed here aligns with developing a bespoke prototype device suitable for first-in-human trials for targeted nasal delivery. The success or failure of this strategy depends on the nature of the collaboration between the pharmaceutical partner and the device design engineers, as well as in the experience of the insight researchers and usability engineers. Experience in the process required to develop a usable device is critical to the successful outcome of such a project and will pave the way for bringing a device to market in this new and exciting area of nasal drug delivery. It will be fascinating to see just how many new, life-changing improvements will be made possible by targeted nasal delivery.

References
  1. Hanson LR, Frey WH 2nd, “Intranasal delivery bypasses the blood-brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease”. BMC Neurosci, 2008, Vol 9(Suppl 3), S5.
  2. Hallschmid M, “Intranasal Insulin for Alzheimer’s Disease”. CNS Drugs, 2021, Vol 35(1), pp 21–37.

 

New frontiers in implantable neuromodulation therapies||Medical Therapy article|New frontiers in implantable neuromodulation therapies|||
By Cambridge Design Partnership
November 10th 2023

New frontiers in implantable neuromodulation therapies

Neuromodulation, where electrical signals in a patient’s nervous system are modified or stimulated to deliver a therapeutic effect, continues to be an exciting and evolving space within the healthcare sector.

There are many drivers contributing to its advancement. Ongoing clinical neuroscience research fueling new possibilities in neuromodulation therapies, the invention of new technologies, and the development of new product formats to meet unmet needs, are all notable factors.

Additionally, there has been increased acceptance and presence of established therapies for implantable devices – such as deep brain stimulation for Parkinson’s disease, spinal cord stimulation for chronic back and leg pain, and vagus nerve stimulation for epilepsy and depression – with Medtronic, Boston Scientific, Abbott, Nevro and others leading the industry.

In all, these factors have made the electrical-based neuromodulation space to become one of the fastest-growing medical device sectors, with market size expected to rise from $6.09 billion in 2021 to $14 billion by 20301.

The diversity of solutions is evident, with Figure 1 illustrating the current landscape of established and emerging implantable neuromodulation therapies.

Fig 1. Selection of established and emerging electrical neuromodulation technologies and their indications.

In this first article of a two-part series, we look at a few notable emerging therapies to illustrate how the implantable neuromodulation space is rapidly developing.

Bladder control: beyond sacral nerve stimulation

Addressing continence issues is a growing area in the healthcare sector, where neuromodulation is seeking to play a significant role in specific therapies.

Implant-based stimulation of the sacral nerve has relatively recently established itself as a way of addressing incontinence with the presence of Medtronic’s Interstim and Axonics’ product range. Alongside the sacral nerve, other nerves are being considered for implantable stimulation to address similar conditions and to respond to specific unmet clinical and patient needs.

One alternative is tibial nerve stimulation, which has a history of effectiveness for certain cases in its non-implantable form: percutaneous tibial nerve stimulation (PTNS). The implant-based approach seeks to address a patient and clinician inconvenience of PTNS, i.e., the need for repeated stimulation sessions and user steps2.

An example of such is the BlueWind Revi, which is part implantable (the electrode is placed near the tibial nerve) and, for minimizing invasive procedures, part wearable (a through-body power source). The device stimulates the tibial nerve which is connected to the sacral nerve plexus, containing the efferent and afferent nerve fibers that control the bladder and are responsible for bladder function. Here, the electrical impulses aim to modify the compromised activity of the detrusor muscle in patients with overactive bladder3. The company has recently achieved clinical results on their pivotal trial evaluating safety and efficacy (still under review by the FDA)4.

Similarly, Medtronic is seeking to develop an implantable tibial nerve stimulation system for incontinence which is currently undergoing clinical trials5.

Another nerve for addressing incontinence is the pudendal nerve. Amber Therapeutics is currently developing an implantable closed-loop therapy, Amber-UI,  for urge and mixed urinary incontinence. The therapy involves implanting electrodes that can sense, interpret, adapt and respond to individual patient signals, such as muscle contraction, in an attempt to restore normal bladder function. By accessing the pudendal nerve, it aims to treat both urge and stress incontinence episodes for the first time, not possible with existing neuromodulation devices, thereby expanding the overall addressable market. First-in-human clinical studies are expected to conclude by the end of 2023.

Emerging Vagus Nerve Stimulation (VNS) therapies

Along with established therapies for epilepsy and depression, VNS is also being explored for conditions such as Rheumatoid Arthritis (RA) to displace injectable and oral medication.

SetPoint Medical is currently evaluating a novel VNS treatment that activates the ‘inflammatory reflex’ pathway (neurophysiological mechanism by which the central nervous system regulates the immune system) that may decrease the type of excess inflammation that is the underlying cause of RA. Its multivitamin pill-sized MicroRegulator platform is currently an investigational device.

SetPoint Medical is progressing clinical trials not only for RA, but also for Crohn’s disease, and furthermore exploring the therapeutic effect, in animal models, to treat multiple sclerosis with VNS therapy.

Implantable VNS therapy is also being explored for other conditions such as sepsis, lung injury, stroke, traumatic brain injury (TBI), obesity, diabetes, pain management and cardiovascular conditions7. One example of cardio-based therapies include low stimulation of the vagus nerve to liberate the body’s own neurochemicals to improve heart function.

New pain indications

Neuromodulation has worked well in establishing itself to address specific intractable pain of the trunk and/or limbs and for diabetic nerve damage – both conditions treated by implanting electrodes in the epidural space using spinal cord stimulation. In light of this success and available product types, pain specialists are continually seeking solutions from neuromodulation to address different causes for different parts of the body.

This impetus was clearly illustrated in panel sessions and discussions with clinicians attending the American Society of Pain and Neuroscience 2023 conference in Miami. We heard testimonials of how specialists, using available stimulators, succeeded in treating a variety of new pain sources and anatomical locations in the wrist, joints, abdominal region and in one case, at the neck to relieve a patient’s sensation of being choked.

This dynamic led to some clinicians proposing that the future of neuromodulation should also consider the treatment of pain associated with oncology treatments, given the improved extended lives seen in cancer patients. This exploration and success could pave the way for the creation of more established therapies – which would be welcome given the prevalence of chronic pain in the general population and the initiative to deliver non-opioid alternatives.

Novel developments for spinal cord injuries

Along with surgical, drug and stem cell therapies, neuromodulation has also entered the frame for addressing spinal cord injuries.

ONWARD has seen success with its partial and fully implantable versions of its ARC Therapy™ product range, where electrodes are implanted in the epidural space to stimulate the lower portion of the spinal cord affected by the injury that fails to (properly) communicate with the brain. By stimulating these lower nerves, the system aims to help restore and optimize their functioning in connection with the brain. ONWARD indicated that for their ARCIM product, one study demonstrated the ability for long-paralyzed people to stand and walk again with little or no assistance using this therapy.

ONWARD’s products have been granted Breakthrough Device Designation status for a range of indications such as improving upper and lower limb function; bladder control and blood pressure regulation; and alleviation of spasticity in patients with such injuries8.

Also in ONWARD’s pipeline is a plan to integrate an implanted Brain Computer Interface (BCI) which senses the patient’s brain signals relating to the intent of leg/joint movement. In turn, these signals are wirelessly sent to its spinal cord stimulator which can activate nerves which are poorly connected to the brain due to injury. This aims to create a “digital bridge” between the brain and poorly connected nerves to enable and improve the patient’s walking ability. Much research and iteration is anticipated; however, this ambition is indicative of how neuromodulation can be innovative and transformational to people’s lives.

The road ahead for neuromodulation

The above examples only skim the surface of emerging therapies; neurostimulation, neuro-adaptive therapies and BCI technologies are attracting significant research and investment to create new therapies by leveraging the body’s physiological pathways.

We foresee continued progress in materials science, engineering, device design and biomedical research into neuro-physiological understanding of the human body to fuel the foundations for new, highly functional and patient-centered neuromodulation platforms.

We also foresee exciting developments in how targeting different nerves can potentially tackle similar medical conditions while the same nerve can be used to address various indications.

In our next article, we will explore the varied technology drivers and their considerations that are leading to the creation of new, innovative neuromodulation implants.

References 
  1. Strategic Market Research website https://www.strategicmarketresearch.com/market-report/neuromodulation-devices-market visited on 12/07/2023
  2. DOI: 10.1186/1471-2490-13-61
  3. DOI: 10.2147/RRU.S231954
  4. Clinical Study Results of the BlueWind System for Patients with Overactive Bladder Featured at the 2023 AUA Annual Meeting. https://www.prnewswire.com/news-releases/clinical-study-results-of-the-bluewind-system-for-patients-with-overactive-bladder-featured-at-the-2023-aua-annual-meeting-301811486.html 
  5. Evaluation of Implantable Tibial Neuromodulation Pivotal Study https://classic.clinicaltrials.gov/ct2/show/NCT05226286
  6. DOI: 10.1016/j.xjtc.2022.03.007
  7. DOI: 10.2147/JIR.S163248
  8. Website Onwards https://www.onwd.com/ visited 12/07/2023
Trends in Respiratory
By Cambridge Design Partnership
September 25th 2023

Trends in respiratory therapies: why pMDIs hang in the balance of new technology

In May 2023, RDD Europe returned to a real-world conference after years of pandemic-enforced online-only presence. The location was spectacular – Antibes on the Cote d’Azur – with the sparkling Mediterranean Sea providing welcome relief from a dismal British spring. 

The industry was well represented by device technology companies, CMOs, academics and pharma companies, and the presentations and workshops provided an engaging blend of research and practical advice.

Even though much of my time over the past ten years has been focused on parenteral device development, my career in combination products started in respiratory devices, working on a variety of dry powder inhaler (DPI) and pressurised metered dose inhaler (pMDI) devices, including the GSK Ellipta inhaler. This year at RDD, as I returned to my roots in this industry, three main themes struck me: preparing for the pMDI cliff edge; moving beyond traditional respiratory diseases; and implementing particle engineering for targeted treatment.

There were also two notable omissions: users and connectivity. More on those later.

Preparing for the cliff edge of pMDI propellants

The shift in pMDIs from using HFC propellants towards gases with a lower global warming potential (GWP) has gained momentum, with California imposing a ban on the sale and distribution of R227ea from the end of 2030, and R134a from the end of 2032, including for medical use. This means the end of the line for the sale of all current pMDI products in California, with other jurisdictions likely to follow suit as the world tries to move to a more sustainable solution.

The transition needs formulators, device designers, scientists, and other disciplines to collaborate to solve the challenges presented by the different physical properties of the new gases. Different thermodynamic and fluid dynamic properties can dramatically alter the plume geometry, droplet size and particle velocity, requiring careful redesign of the fluid pathways to compensate for the differences. These challenges were outlined in evidence presented by Recipharm (1), Proveris and Koura (2), and Healthy Airways LLC (3).

At Cambridge Design Partnership, we are receiving far fewer enquiries for pMDI products than DPIs and soft-mist inhalers. Obviously, an n=1 sample does not have a high degree of certainty, but it reflects a general sentiment among clients to focus future developments away from pMDI platforms.

Moving forward beyond traditional respiratory diseases

Asthma and COPD remain the biggest drivers in device and formulation development, much the same way that diabetes treatment has driven pen injector development. Two drivers that our drug delivery team have seen pushing device design in respiratory and the inhalation market are the need for home treatment, rather than hospital centered treatment; and platforms for biological drugs. The other significant drive is for vaccines that are stable at higher temperatures, which can be delivered without leaving behind copious volumes of blood-contaminated medical waste.

One challenge that comes with these new treatment regimens, beyond formulating drugs that will be stable in powder form, is getting the drug to the correct part of the body and making sure it remains present long enough to be effective. One paper from UCL and the University of Hong Kong (4) highlighted a promising approach to developing therapeutic antibodies against future SARS outbreaks. Some of these developments also require higher dose payloads, or API-only formulations; this presents a substantial challenge to device designers to make sure that the inhalation capabilities of different patient groups can achieve the required dose efficiency.

Aptar and Recipharm also shared their own device innovations to present novel spray and softmist technologies based on a syringe primary container. Targeting rapid treatment to the brain via the olfactory route is a much-neglected treatment option, in part due to the challenges of getting consistent behavior with users. At Cambridge Design Partnership, we’ve been working with a pioneering device company looking to exploit this pathway, and my colleague, Clare Beddoes, will be presenting information on this device development at PODD in October.

Enter: particle engineering for targeted treatment

In addition to the paper from UCL (4), particle engineering to target specific areas in the respiratory and nasal pathway was a topic that several posters and presentations addressed directly. Building on standard jet milling techniques, a paper from Aston University explained how isothermal dry particle coating (iDPC) can be used to create more potent formulations without increasing the volume of powder inhaled by the user (5). A third paper from Hovione and two Portuguese institutions focused on the characterization of different particle manufacturing techniques and how they affect deposition in nasal passages (6).

Closing the gap between the early stages of in vitro and in silico models, and the later stage in vivo performance, continues to receive a lot of attention. As the cost of computing power continues to fall, going into clinical or preclinical trials with greater confidence will accelerate time to market and reduce the cost burden on pharma companies looking to novel treatments.

Don’t forget user capability and connectivity

Two areas of development that received relatively little focus at the conference were human factors engineering (HFE) and connectivity – two concerns that are the subject of a great deal of effort in the parenteral sector. Recipharm presented a poster on the HFE advantages of their novel unit dose nasal spray when compared to a reference device (which bore a striking resemblance to an Aptar Unidose Liquid Nasal Spray). Research institution Solvias presented a paper showing how training users can lead to worse outcomes due to misperception of expertise using a device (7). This counterintuitive result demonstrated that patients with limited one-to-one training with a Handihaler showed more errors in use than patients who only had access to the device and IFU. 

While these insights were welcome, our in-house team knows that patients continue to struggle to use inhalers reliably and consistently, leaving even the most effective drug products showing variable results.

These challenges for patient use are also being seen in the parenteral market, which is why we are working so closely with our clients to find better ways to train patients and leverage connectivity to improve adherence to medication regimens. These connectivity solutions are often in direct conflict with cost and sustainability targets and finding a route to square this circle is a challenge with which CDP’s designers and engineers are actively engaging.

See you in Tucson?

RDD 2023 was the first RDD conference I have attended. It was great to reconnect with former colleagues and make new connections across the industry. The conference was very well run, and the standard of papers and presentations ensured there was plenty of fascinating material for industry and academia to engage with. I’ve already blocked out my diary for RDD 2024 in Tucson and I look forward to seeing you there.

References
  1. Albuterol Sulfate Metered Dose Inhaler Feasibility Using an Environment Friendly Propellant HFA152a and Novel Valves (Lei Mao, Sheryl Johnson, Nischal Pant, James Murray, Donald Ellis, Benjamin Zechinati, Johnathan Carr and Victoria Cruttenden)
  2. Comparison of Spray Characteristics of P-134a and Low GWP P-152a pMDIs With and Without Ethanol (Lynn Jordan, Sheryl Johnson, Ramesh Chand, Grant Thurston, Deborah Jones, Vanessa Webster and Sally Stanford)
  3. Accelerated Development of MDIs with Low GWP Propellants in a QbD Era: Practical, Regulatory and Scientific Considerations (Healthy Airways LLC and First Flight Pharma LLC)
  4. Inhaled Antibody Therapies: Enabling Prophylactic Protection against SARS-CoV-2 Infection with a Dual Targeting Powder Formulation (Han Song Saw and Jenny Ka-Wing Lam)
  5. Use of Isothermal Dry Particle Coating (iDPC) for the Development of High Dose Dry Powder Inhalers (Jasdip S. Koner, David A. Wyatt, Amandip S. Gill, Shital Lungare, Rhys Jones and Afzal R. Mohammed)
  6. Benchmarking of Particle Engineering Strategies for Nasal Powder Delivery: Characterization of Nasal Deposition Using the Alberta Idealized Nasal Inlet (Patricia Henriques, Cláudia Costa, António Serôdio, Ana Fortuna, and Slavomíra Doktorovová)
  7. Effect of Capsule-Based Dry Powder Inhaler User Training on In Vitro Performance (Oleksandra Troshyna and Yannick Baschung)

 

 

 

 

Care tech: exploring the latest trends in dementia care
By Cambridge Design Partnership
September 21st 2023

Care tech: exploring the latest trends in dementia care

We are witnessing important advances in the treatment of the most common cause of dementia, Alzheimer’s disease, most noticeably by the emergence of disease-modifying therapeutics. And this trend is only set to continue, with new innovations and technologies promising to help slow the progression of this devastating disease.

However, patients who do not yet have access to these treatments or are in a more advanced stage of the disease will continue to require significant care support. The caregiving sector is already under significant pressure due to the increasing demand for long-term care within aging populations [1]. As the disease progresses, family members, including elderly spouses, are often the main caregiver – but they may be left poorly equipped to do this without the right support.

With the cost of dementia care running to £32,250 per person per annum [2] technology innovators are finding new ways to make resources go further and give dementia patients independence for longer – providing reassurance to the caregiver and peace of mind to family members.

The challenge lies in making these solutions accessible to caregivers and usable for patients. In this article, we take a deep dive into the technologies available to support dementia care and explore emerging trends that are transforming the landscape by using the right technology at the right time.

 

Dementia care: the current landscape

Alzheimer’s disease is a progressive and irreversible neurodegenerative condition that primarily affects the cognitive functions of the brain, particularly memory, thinking and behavior. It is the most common cause of dementia, a broader term for a set of symptoms that impact a person’s ability to live independently.

In the UK, it is estimated that more than 900,000 people live with dementia, and this is projected to double by 2040 [3]. Of the people diagnosed, up to a third live alone [4]. With the aging population outpacing the rate of training and recruiting caregivers, the already significant caregiver shortage is set to increase [5].

Meanwhile, family members are taking on caregiver responsibilities, often with unsustainable and distressing consequences. This is in part because every patient journey is different and the rate of their disease progression can vary widely. Some patients may require discreet support at the early stages of the disease, while others may require constant care. Knowing when and how to intervene to provide the care support needed is crucial.

The care sector is increasingly looking to technology to maximize the impact of the professional and informal caregiver workforce. There is an increasing recognition that caregivers require ongoing support to make their role more manageable, especially following the pandemic.

An overview of innovations

Assistive technologies rarely exist in isolation. In fact, it is often the combination of these technologies that yields the best results. Here are some of the technologies available to support independent living and managing disease progression.

Personal alarms and safety tracking

Alarms and tracking technologies allow people to call for help if they need it – wherever they are – as well as providing peace of mind for caregivers and family members when they are not there. They are simple to use and can help patients stay independent for longer.

Location. GPS trackers such as Mindme, Ubeequee, and Angelsense consist of battery powered or rechargeable wearables that connect to a 24/7 monitoring support center to alert family members and emergency services if a vulnerable adult is outside designated safe zones. Direct-to-consumer devices, such as Medpage, work similarly, but the information links directly to family members and may not have predefined safety zones or raise an alarm. Connectivity is based on broadband and subject to subscription charges.

Alarms and calls. Technologies such as Tunstall’s MyAmie, Oysta, and Saga’s SOS allow patients to raise an alarm for relatives, caregivers or emergency services with the use of a single button. These technologies often come in the form of a pendant worn around the house and are connected to a hub via a radio signal. The patient can also use the hub to raise an alarm. The pendant must be within reach of the hub for it to work. Other technologies, however, work similarly to the GPS tracker and can rely on broadband for wider network reach. These technologies often also incorporate fall detection and GPS.

Fall detection. Wearables such as Buddi, Telecare, and Careline are designed specifically for dementia care. These use inertia measurement units, gyroscopes, and pressure sensors to detect falls and automatically send messages to caregivers, family members, and first-aid responders. These devices are often accompanied by an alarm button for the user and GPS tracking. Many of these technologies can also be connected to a 24/7 monitoring support team.

Reminders and medication adherence. There are a variety of technologies in this category which allow caregivers to set reminders for patients to take medication, drink water, eat, or  remember appointments or social events. Memory aid kits available include the MemRabel care alarm clock with a large screen, connected to a Pivotell Vibratime rechargeable wrist watch that vibrates for reminders. These can be in photo, video or audio format.

The challenge many of these technologies face is that they depend on a caregiver to ensure the patient remembers to engage with and wear the device, charge it when necessary, and crucially, press the button if in distress. In the case of some technologies, they must also be within reach of a hub.

These technologies are good for the early stages of the disease, but as cognitive decline continues, patients will rely more on caregivers to support them, thus limiting their advantages.

In other words, the longevity of these technologies can become incompatible with the patient’s journey, and this is one of the key hurdles to consider when designing and adopting technology in dementia care.

Remote monitoring

This is a fast-growing area for dementia care. Remote monitoring technologies share information on the patient’s daily living patterns with caregivers and family members. The purpose is to provide peace of mind to family members and enable caregivers to make informed care decisions in the short and long term.

Common functions include:

  • Movement monitoring. Generally delivered by several passive infrared (PIR) sensors installed around the house, and pressure mats in beds and sofas, connected to a hub.
  • House occupancy. Sensors on external doors to monitor whether an individual has left the house.
  • Appliance usage. Monitored by connected sensors placed between the mains inlet and the device plug.
  • Fall detection. Cameras or mmWave radar sensors to detect when an individual has had a fall, without the need for a wearable.

Many of these functions can be delivered by single systems, e.g. Taking Care Home Alert, with the more sophisticated fall detection systems generally targeted at professional care provider users, e.g. Hikvision and Vayyar Care.

It is also common for families to create their own solutions, especially when they feel no existing single solution works for them. This includes the use of consumer tech, such as smartphones, video doorbells, smart home speakers, and cameras around the house. Video doorbells, for example, can be valuable in preventing scams, while smart home speakers can set reminders, automate house functions, or call a relative. However, the use of cameras around the house does pose privacy concerns which need to be considered.

Although the overall objective is to monitor daily independent living, the information often requires interpretation by the caregiver. This can often be facilitated through a dashboard, although the information can be disjointed, and assessment of patterns may not be clear-cut.

Innovator Matt Ash from Supersense Technologies, however, believes we can do more to obtain valuable insights and monitor disease progression efficiently and noninvasively.

 

“There is a real need for technologies that support caregivers in their role and provide them with the confidence to take a break, knowing their loved one is safe. Though there are some credible assistive technologies out there, the unique needs of families living with dementia are not well served. Projects like the Longitude Prize on Dementia are investing in radical thinking to generate solutions with families living with dementia.”

 

Talking about some of the latest advancements being tested, Ash continues:

 

“Everyone’s journey with dementia is different. Right now, we are working on leveraging recent consumer developments in sensor technology, machine learning, and user experience to create personalized assistive systems that can evolve with the needs of an individual with dementia and their caregivers. It’s an incredible opportunity to provide the community with supporting technologies that serve their needs.”

 

Adopting the right intervention at the right time

If we want to empower those with dementia to live independently, maximize the impact of caregivers, and provide peace of mind to family members, we must enable the right type of intervention at the right time. Someone with early Alzheimer’s disease may feel overwhelmed or suspicious of new technology, while a person in later stages may be too vulnerable to learn how to use it.

The future of dementia care will center around collecting the right data and extracting the right insights from it to enable better care choices. By allowing technology to provide information on the progression rate of the disease for a particular patient, we can start building a profile of care by recognizing changes in patterns to a baseline. Emerging technologies such as remote monitoring platforms can support this and guide the longevity of other technological interventions to ensure that they align with the individual patient’s journey. At the heart of these technologies, privacy must be a top priority, which may include the use of AI and other methods to allow for patterns to be recognized quickly and with minimal need of human intervention.

We are entering a new era of therapeutics for Alzheimer’s disease, but there is still much to do, particularly in care. Although the use of technology can ultimately support patients, caregivers and family members, it is often incompatible with the individual’s stage of the disease, or inaccessible to caregivers. But as new technologies emerge, data and AI can unlock new insights to support a personalized care plan that scopes each patient to their individual needs – allowing caregivers and families to provide the best care at the right time.

References
  1. E. adult social care insight. The size and structure of the adult social care sector and workforce in England. Technical report, Skills for Care, Workforce Intelligence, 2023.
  2. Alzheimer’s Society, How much does dementia care cost? https://www.alzheimers.org.uk/blog/how-much-does-dementia-care-cost
  3. L. B.-A. A. R. Raphael Wittenberg, Bo Hu. Projections of older people with dementia and costs of dementia care in the United Kingdom, 2019–2040. Technical report, Care Policy and Evaluation Centre, London School of Economics and Political Science, 2019.
  4. B. W. Claudia Miranda-Castillo and M. Orrell. People with dementia living alone: what are their needs and what kind of support are they receiving? International Psychogeriatrics, 2010.
  5. E. adult social care insight. The size and structure of the adult social care sector and workforce in England. Technical report, Skills for Care, Workforce Intelligence, 2023.

 

 

 

 

Could oligonucleotide manufacturing advances redefine therapy
By Cambridge Design Partnership
June 20th 2023

Could oligonucleotide manufacturing advances redefine therapy? 

Oligonucleotides have the potential to address some of the most devastating diseases that remain stubbornly resistant to treatment. These include neurodegenerative, vascular, respiratory, and oncological illnesses. As exciting as this branch of science is, the oligo industry is still in its commercial infancy. Large-scale oligonucleotide manufacturing is not straightforward, and various challenges need addressing.

To understand these, Alejandra and Carla, two Consultant biomedical engineers at Cambridge Design Partnership (CDP), were invited to take part in the Innovation in Oligonucleotide Manufacturing Symposium hosted by CPI at their new facilities in Glasgow. After an intensive day of discussion between key stakeholders from industry, academia, government, and the regulatory sector, we present the main takeaways. For this to make sense, let’s start from the beginning.

How do oligonucleotides work?

Oligonucleotides are short DNA or RNA molecules, typically around 20  nucleotides (basic building blocks of nucleic acids) in length. They can modulate gene expression, the process by which information included in a gene informs the assembly of a protein molecule. They do this by binding to pre-mRNA and mRNA, the carriers of genetic information before the mature mRNA is translated into proteins. Because mRNAs carry code for all cellular proteins, oligonucleotides could be effective for targets and diseases not treatable by current drugs1.

What is their importance as therapeutic agents? 

Oligonucleotide therapeutics prevent or modulate the expression of almost any gene as part of highly targeted treatment. They aim to target the genetic basis of the disease rather than the symptoms. Compared to conventional therapies, oligonucleotides have a higher specificity with reduced side effects. They can target specific molecules that are currently difficult to target, such as RNA. Several oligonucleotide therapeutics are already on the market, with Novartis Pharmaceutical’s Vitravene, for treating cytomegalovirus retinitis in immunocompromised patients, being the first to be approved by the FDA in 1998. 

The list of diseases that oligonucleotides can target is ever-growing, with the market valued at USD 5.19 billion in 2020 and expected to rise to USD 26.09 billion by 20302. 

How are oligonucleotides manufactured? 

Oligonucleotides are synthesized chemically, where nucleotides are added stepwise, resulting in a growing chain. Each nucleotide is subjected to a series of chemical reactions to create a stable component allowing the chain to grow. 

The two different types of oligonucleotide manufacturing are solid-phase and liquid-phase synthesis. Solid-phase oligonucleotide synthesis is carried out on a solid insoluble object, such as polystyrene beads, placed in columns that enable all reagents and solvents to pass through freely.  

In liquid-phase synthesis, the oligonucleotides are grown on soluble polymeric support within a homogeneous media; the polymer-bound product is commonly recovered from the reaction mixture by precipitation, thus allowing the rapid elimination of excess reagent and soluble by-products.  

Solid phase allows high throughput synthesis and purification, with liquid phase taking longer to synthesize the oligonucleotides. However, liquid-phase has the advantage of being performed on a larger scale and typically being less expensive than solid-phase synthesis. Once the desired oligonucleotide has been synthesized, the material can be passed to the next processing steps, including purification, concentration and, commonly, lyophilization. 

What are the main challenges in the process? 

Oligonucleotide manufacturing is a complex process with many limitations, especially in scalability. The major problems researchers face are currently due to high expenses regarding the raw materials for oligonucleotide synthesis, a lack of funding for oligonucleotide therapies, and a shortage of skilled resources in the oligonucleotide synthesis field. These problems create substantial bottlenecks in the research required for therapeutic oligonucleotides and, ultimately, the clinical use of these therapies. 

Key takeaways on the manufacturing of oligonucleotides  

  • Moving towards liquid-phase oligonucleotide synthesis. Solid-phase oligonucleotide synthesis is a great tool for rapidly making lots of oligos in the lab. However, it has drawbacks when manufacturing hundreds of kg or even multi-ton quantities per year, which might be the case for emergent nucleotide products targeting more common diseases3.

    The major problems include:
    • As the oligo grows, the space for the fresh nucleotides to diffuse and react gets tight, leading to incomplete couplings. This results in an altered sequence of monomers and incorrect genetic information in the final product, which must be removed by extensive and expensive processes.  
    • It is hard to scale up the solid beds (insoluble particles to which the oligonucleotide is bound during synthesis).
    • The synthesis and purification steps generate large amounts of organic and aqueous waste.

 

  • Liquid-phase synthesis stands as a promising approach to increase the yield of the overall process while allowing the production of large amounts of oligonucleotides in, potentially, a more sustainable manner4.

 

  • New alternatives to current purification methods are under investigation. Promising approaches to simplifying the purification steps show good results in the investigational phase5. Examples are membrane-sieving technology and biocatalytic processes used for phase separation. In the biocatalytic process, oligonucleotides are synthesized in a single operation, with fewer impurities and by-product production, and in aqueous media. All these are promising features that target the current limitations of existing synthesis methods3.

 

  • New approaches come with new challenges: The development of novel and alternative technologies offers opportunities to address some of the limitations of solid-phase synthesis while also creating new challenges. For instance, using nanofiltration membranes to support the synthesis of oligonucleotides in liquid phase can present issues such as membrane stability and fouling. Another concern regarding the enzymatic approach is the availability of raw material with the right purity.  
    If we consider the bigger picture, another novel approach in the pharmaceutical industry is the adoption of digital manufacturing technologies. However, this up-and-coming tool may come with its own challenges due to lack of pharmaceutical manufacturing expertise and the high cost of initial funds. 

 

  • Raw materials suppliers are already working towards reducing the gap. Strategies to reduce the prices of chemicals and deliver sustainable solutions are already underway. For instance, Honeywell US, a major supplier of the raw material required for oligonucleotide production, recycles solvents and assigns dedicated chemical drums to individual businesses to avoid cross-contamination.

Big wins for early pioneers 

At CDP, we see every challenge as an opportunity, and we are pleased to know that governments and large industries have already recognized these problems.  Major efforts to accelerate research in the UK have been launched, not only as funding from governmental innovation agencies but also from pharmaceutical companies. In addition, the 18 oligonucleotide therapies already approved by the US Food and Drug Administration (FDA) for clinical use are leading the way6.  

There is a need for rapid adoption of next-generation processes that reduce risk, cut costs and save time while enabling on-demand therapies for every patient. However, regulatory-wise, standards in this industry are yet to be established. The risk around safety and efficacy remains a significant concern: How do we ensure we have the right sequence in each molecule? How do these molecules behave for a specific treatment? And what is the risk for the patient? These are just a few questions that still need to be addressed. 

The event at CPI highlighted the importance of bringing experts together to shape the path and accelerate innovation. Understanding the challenges in the oligonucleotide space and planning around them will allow us to drive successful manufacturing at scale. The moment to build the future is now!

References 
  1. Kole R, Krainer AR, Altman S. Nat Rev Drug Discov. 2012 Jan 20;11(2):125-40. doi: 10.1038/nrd3625. 
  2. Allied Market Research, Oligonucleotide Synthesis Market report, Code A08356, July 2021  
  3. Sarah Lovelock, “Biocatalytic approaches to therapeutic oligonucleotide manufacture” in “Enzyme Engineering XXVI”, Andy Bommarius, Georgia Institute of Technology, USA; Vesna Mitchell, Codexis, USA; Doug Fuerst, GSK, USA Eds, ECI Symposium Series, (2022). https://dc.engconfintl.org/enzyme_xxvi/37. Abstract: https://dc.engconfintl.org/cgi/viewcontent.cgi?filename=0&article=1034&context=enzyme_xxvi&type=additional  
  4. J. Org. Chem. 2021, 86, 1, 49–61 Publication Date: November 30, 2020 https://doi.org/10.1021/acs.joc.0c02291 
  5. Dousis A, Ravichandran K, Hobert EM, Moore MJ, Rabideau AE. Nat Biotechnol. 2023 Apr;41(4):560-568. doi: 10.1038/s41587-022-01525-6. 
  6. Martin Egli, Muthiah Manoharan, Nucleic Acids Research, Volume 51, Issue 6, 11 April 2023, Pages 2529–2573.  
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By Cambridge Design Partnership
March 8th 2023

Developing future drug delivery systems

WHITE PAPER

Developing future drug delivery systems

BY CLARE BEDDOES, AMY KING & JAMES HARMER

Here at CDP, we don’t think of the packaging as simply the container for the drug. We consider the whole delivery experience, from the device itself through to the accompanying materials such, as the instructions for use (IFU). While several factors must be considered in the selection of the right device and packaging materials for injectable drugs, including the drug rheology, how the drug is administered, and by whom and where, this document takes a high-level view of how specific consumer trends may impact the experience of self-injection devices.

In this paper, we explore:

  • The futuring methodologies needed to stretch strategic thinking
  • How consumer needs – and packaging – are changing 
  • The consumerization of healthcare
  • Improving drug delivery systems that benefit the patient, the planet and the manufacturer

Download the white paper

 

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By Cambridge Design Partnership
April 5th 2022

Reducing the carbon footprint and plastic waste of LFTs: Evidence-based opportunities

Billions of lateral flow tests have been used worldwide during the COVID-19 pandemic – over two billion have been provided in the UK alone. Debate has raged on social media about why the tests need to use so much single-use plastic and how they could be made more ‘sustainable’. The test strip caseworks is a particular source of dismay – why so much plastic to house such a tiny test strip?

With the UK government ending the free distribution of lateral flow tests for the general public – citing a transition from emergency response to longer-term management of the pandemic – now is the ideal time to look more closely at the sustainability of these lateral flow tests, and to seek the data to demystify some of the emotional assumptions being made. 

Familiarity with lateral flow testing has certainly increased, as has confidence in their clinical performance. It’s expected that lateral flow devices will be more present in our daily lives post-pandemic – not just for COVID-19 and pregnancy testing but to diagnose diseases such as seasonal influenza and sexually transmitted infections – all from the comfort of the home. 

We’ve carried out a high-level assessment to quantify the approximate environmental impact of lateral flow tests and identify evidence-based suggestions for improving their environmental sustainability. 

Why do COVID-19 lateral flow tests contain lots of single-use plastic in the first place? 

The emergence of COVID-19 was a global emergency, and vast quantities of lateral flow tests were needed urgently. Once developers could produce the right immunoassay chemistry to detect the virus (SARS-CoV-2), it required implementation in a low-cost, low-risk device, that has a mature supply chain – with proven, readily available materials that wouldn’t compromise analytical or clinical performance.     

This meant using existing plastic casework designs to retain and protect the nitrocellulose test strip. Plastic is robust, low cost, lightweight, easy to transport, and easily printed for QR codes and LOT numbers. Critically, it’s a consistent material proven for the highest volume manufacturing and won’t interfere with the immunoassay chemistry. 

From a performance, cost, and manufacturing perspective, redesigning the product with new materials would have been high risk. Material changes may also have needed significant R&D costs, new capital equipment as well as additional cost and effort needed to demonstrate equivalence and achieve regulatory approval – risking the ability to provide sufficient numbers of high-quality tests, at speed during the pandemic.  

Our results: The sustainability of lateral flow tests 

But how serious an environmental impact do these tests have? To find out, we broke down a test into its constituent components and weighed them to calculate the approximate environmental impact, using standard emissions factors to calculate the carbon footprint of a single test.

We focused on carbon footprint (the carbon dioxide and other greenhouse gases emitted during manufacture, transport, and disposal of the tests) and plastic waste (waste that would persist indefinitely if released into the environment) – the two issues that have attracted the most attention around lateral flow tests. A more comprehensive study should consider a broader range of environmental impacts, for example, the use of scarce resources and emission of other pollutants to avoid unintended consequences of any product changes. 

Our results reveal: 

  • The components needed to conduct the test account for around half of the carbon footprint and around two-thirds of the plastic waste. Packaging makes up most of the rest – as is often the case, a surprisingly high proportion of the total environmental impact. 
  • The test strip caseworks, which attracts the most comment online, is responsible for around 30% of the carbon footprint and 40% of the plastic waste. While it’s the most significant single contributor to the environmental impacts we evaluated, the large number of other small parts is also significant. Focusing on the caseworks therefore might not be the best strategy for improving the sustainability of the tests overall. 

Lateral flow tests a minor piece of UK healthcare’s environmental impact 

To put these numbers into context, we can compare the environmental impact of the two billion COVID-19 lateral flow tests distributed in the UK with the UK healthcare system’s overall environmental impact. We estimate the UK’s lateral flow tests have a carbon footprint equivalent to around 0.5% of the total NHS carbon footprint. This isn’t a trivial amount, but it’s also not the largest single contributor to the impact of the UK health system.

It’s also worth considering the positive environmental impact of a user-administered test on the health system. Conducting a test at home can eliminate the need for an individual to visit a test site, GP’s surgery, or hospital (assuming the clinical performance of the lateral flow test is adequate). Based on estimates from the Sustainable Healthcare Coalition, one lateral flow test has around 5% of the carbon footprint of a single GP appointment and produces a similarly low percentage of non-degradable (plastic) waste. 

And that’s before we consider travel. We estimate one lateral flow test has the same carbon footprint as driving 350 metres in an average UK car. So, if you’re driving yourself to a test site or GP surgery some distance away, at-home lateral flow tests compare even more favorably.

If a lateral flow test prevents an individual from transmitting COVID-19 to a vulnerable person, there’s a public health benefit – as well as an environmental benefit – to keeping people out of the hospital. We can all see the discarded waste from home tests, but the less visible impact from energy- and material-intensive medical interventions is often significantly higher. 

These approximate figures demonstrate why building an evidence base is vital during product development targeting sustainability objectives – because the results can be unexpected and non-intuitive.  

Quick ways to optimize today’s lateral flow tests  

Just because waste from lateral flow tests might not be the most urgent sustainability issue for UK healthcare, that doesn’t mean we can’t and shouldn’t do something about it.  

We used the ‘avoid/shift/improve’ model to find potential quick wins for lateral flow tests. These reduce the carbon footprint of each test by nearly a third and the plastic waste by almost a quarter – without impacting the fundamentals of how the test works. 

They include: 

  • Eliminate waste bags. There’s a case for quickly isolating contaminated waste (even given COVID-19 also spreads from infected individuals through the air), but the bags account for around 5% of the carbon footprint of the test. It’s not clear how widely used they are in a domestic setting – there may be a risk-based justification for not including them in the test kit. 
  • Package all the test strips in a single foil pouch. Using a single re-sealable pouch to protect the tests from ambient humidity (rather than individually packing each test in a pouch with desiccant) is common in packs of lateral flow tests designed for use by healthcare professionals. However, once opened, the stability lifetime of the remaining tests is affected. 
  • Reduce the size of paper instructions. These are important for the effectiveness of the tests and are a regulatory requirement, but account for 5% of the carbon footprint of a test – could they be reduced in size? 
  • Eliminate the cardboard sleeve. This packaging isn’t essential to the safe and effective functioning of the test, and it seems likely that the functions it does provide could be achieved with less material.
  • Prefill the extraction tubes with buffer solution. This is already done in some test kits, although manufacturers need to be conscious of moisture loss and the effect on shelf life. However, the separate plastic vial used in the test kit we studied accounts for around 5% of the carbon footprint and plastic waste.
  • Increase the size of the pack from seven to ten tests. This would mean less package waste per individual test. Including ten tests in one pack instead of seven reduces the carbon footprint by around 5% (depending on how many other optimizations are done at the same time). Perhaps a pack of seven tests was originally designed to cover a week of daily testing – but is that how tests are being used in practice? 

Redesign of the test strip caseworks 

Looking to the longer-term gets us into product redesign – creating a new generation of the product with sustainability in mind. Doing this can take significant investment since, for medical devices, it’s likely to require new regulatory approval, which is a lengthy and costly process.  

A popular idea circulating for lateral flow tests is to minimize the plastic test strip caseworks (without compromising the essential functions of providing a stable platform, and protecting the nitrocellulose test strip). It might be possible to halve the caseworks mass and reduce the overall carbon footprint and plastic waste by 15-20%. This would require significant investment in R&D, production tooling, and regulatory approval hoops to jump through – but could be worthwhile if future demand for tests stays high.

Longer-term options 

If we consider that the world may require billions more lateral flow tests over the coming decade, a more comprehensive redesign becomes commercially viable. This could involve stripping the design back to the fundamental requirements for a lateral flow test – flowing a sample through the test strip in a way that is controlled and free from contamination. Current designs take advantage of established components to collect, buffer, and dose the sample – but, at this production volume, it may be worthwhile designing a system from the ground up that is optimized for cost, usability, performance, and sustainability. 

Sustainability as a brand differentiator  

It’s clear there’s scope to optimize lateral flow tests to reduce their environmental impact – and a systematic analysis reveals options beyond those that might jump out to someone when they use the tests. But it’s essential to put the impact of lateral flow tests in the context of the wider healthcare system, to focus resources where they can have the most environmental impact – and to recognize that, sometimes, the plastic waste people can see helps to avoid more serious, but less visible consequences.  

On the other hand, while visible plastic waste from lateral flow tests may not be the most pressing environmental issue facing the healthcare industry, it highlights the growing influence consumer opinion is likely to have as diagnosis and treatment shift from hospitals to homes. And as lateral flow tests become (in the UK, at least) a product people buy with their own money, choosing from a range of options, there may be a competitive advantage for businesses that take note and optimize their products for sustainability. 

Featuring analysis conducted by Katie Williams, Mechanical Engineer

References

  • Prime Minister sets out plan for living with COVID [Internet]. GOV.UK. 2022 [cited 1 April 2022]. Available from: https://www.gov.uk/government/news/prime-minister-sets-out-plan-for-living-with-covid
  • The Sustainable Healthcare Coalition. Care Pathways Calculator. [Internet]. Sustainable Healthcare Coalition. 2022 [cited 1 April 2022]. Available from: https://shcoalition.org/