Design Verification for the Real World: Complex Drug Delivery in Uncontrolled Environments

September 11th 2026

Dr Matthew Roberts

Consultant Physicist

Andrew Fiorini

Senior Consultant Healthcare Devices Engineer

Featured in September’s issue of ONDrugDelivery, Dr Matthew Roberts and Andrew Fiorini, explore the key steps involved in building a successful design verification programme for ambulatory electromechanical infusion systems and share the lessons they have learned along the way.

Large-volume drug delivery is a rapidly growing industry, as more biologics, oncology therapies and treatments for chronic conditions move from hospital-administered infusion into home and self-administered settings. Many of these drug products require a subcutaneous infusion pump, changing the way infusion pumps are being used. This has resulted in increased regulatory scrutiny of how these devices perform once they leave controlled testing conditions (Figure 1).

Figure 1: The real-world performance of modern, complex drug delivery systems can differ significantly from that indicated by standard laboratory pump tests.

Design Verification Testing of Ambulatory Infusion Pumps

For electromechanical ambulatory infusion pumps, design verification (DV) typically begins with the International Electrotechnical Commission (IEC) standard IEC 60601-2-24. However, demonstrating safe and effective drug delivery in real-world use extends beyond the standard’s scope. The Association for the Advancement of Medical Instrumentation (AAMI)’s Technical Information Report (TIR) 101:2021 addresses this gap, with particular relevance to ambulatory, self-administered systems, where the gap is widest.

It is noteworthy that, although this report provides extensive guidance as to how to test and report system performance, it leaves manufacturers responsible for defining the conditions under which performance should be verified. Self-administration conditions introduce additional complexities, and success depends on understanding the delivery system before testing begins.

Beyond IEC 60601-2-24

IEC 60601-2-24 is the internationally recognised standard for electromechanical infusion pumps, syringe pumps and volumetric infusion controllers, providing a well-established framework for accurate and consistent drug delivery in both clinical and ambulatory settings.

The most complex pumps that the standard defines are Type 5 profile pumps that can combine basal and bolus delivery of drug products to manage symptoms that can fluctuate through the day. Insulin pumps for diabetes and apomorphine pumps for the management of Parkinson’s disease are two such products, delivering a basal rate for most of the day and patient-controlled boluses to manage mealtimes (for diabetics) or “off” episodes for patients with Parkinson’s disease. Whereas most pump testing described in IEC 60601-2-24 should be conducted with Class III water, pumps intended for use with a specific drug should be tested with that drug.

Water for injection behaves differently from many modern drug products, which may be highly viscous or exhibit non-Newtonian behaviour. At-home use introduces further variables that can affect performance and the dose received by patients:

Pronounced temperature swings that, compared with clinical settings, can affect both formulation properties and catheter behaviour
Delivery profiles often include patient-triggered bolus doses or variable flow rates, making transient performance important
Pumps may be worn at different heights, orientations and locations on the body throughout the day.

To address the gap between IEC60601-2-24 and real-world conditions, the AAMI published TIR101 in 2021, introducing test methods and reporting metrics that better reflect ambulatory and self-administered use conditions.

The sponsor is expected to define, justify and execute a statistically robust DV programme that demonstrates that the system performs as intended and the level of risk presented to patients is within acceptable limits. This flexibility is valuable but creates challenges: sponsors must consider which variables matter most for their drug-device combination and ensure that their testing strategy is both scientifically justified and regulatorily defensible.

DV testing of complex drug products using the AAMI TIR101 guidance can appear daunting, but it can be effectively managed by following three key steps:

Define the test matrix and reporting metrics
Design and de-risk the testing programme
Execute the DV testing.

From experience, more than 80% of the work lies in designing and de-risking the test programme itself – this is particularly true under AAMI TIR101. Unlike many traditional standards, with tightly defined test conditions, AAMI TIR101 leaves sponsors responsible for the test matrix, environmental conditions and acceptance criteria. Success depends heavily on the characterisation work performed before formal testing begins. Failure to prepare adequately can jeopardise a programme, resulting in repeated testing and delaying submissions by several months. However, with the right planning and a risk-based approach, even highly complex systems can be verified efficiently and with confidence.

Establish the Test Matrix and Reporting Metrics

Despite provision of details on how to measure, what to report and how to structure the data, TIR101:2021 does not contain acceptance criteria. It is up to the sponsor to justify which tests are applicable, what results are acceptable and how confidently those results can be trusted.

Establishing acceptance criteria starts with understanding patient dosage sensitivity, including minimum effective dose and clinically meaningful dose variation. Unlike IEC 60601-2-24, which focuses on pump performance, TIR101 views this through the lens of patient self-administration, evaluating drug concentration fluctuations using pharmacokinetic coefficient of short-term variation (PK-CV) methods. This should also drive the pump specification. TIR101:2021 requires testing at the lower and upper limits of pump flow rates – allowing the pump to operate outside clinically useful windows can significantly increase the complexity and timescales of DV (Figure 2).

Figure 2: In the PK-CV mode, drugs with a longer half-life will have a higher active volume in the patient and will be less sensitive to variance in pump flow rate.

The test matrix should reflect all clinically relevant operating conditions. Every claimed operating environment increases the DV burden; therefore, unnecessarily broad specifications can lead to significant additional testing. A pump with an established performance history and existing approvals can carry a smaller, better-understood test matrix than a newly developed platform, if its specifications are updated to meet the specific use case.

"A pump with an established performance history and existing approvals can carry a smaller, better-understood test matrix than a newly developed platform, if its specifications are updated to meet the specific use case."

Design and De-risk the Test Process

As with all DV processes, characterisation (or pre-DV) directly influences the efficiency of formal test execution. For ambulatory infusion devices dealing with complex formulations, unexpected behaviours arising during test execution can derail the entire programme. The following steps detail how to efficiently design and de-risk the DV protocol:

Risk identification
Risk elimination and mitigation
Define data analysis and integrity.

Risk Identification

For complex infusion systems, risks may often not be visible in product requirements or design documentation, so pre-DV activities should focus on uncovering underlying physical properties that may influence measurement performance (Figure 3).

Figure 3: Efficient testing begins before execution, with extensive pre-DV planning and preparation work.

Examples encountered during infusion pump verification programmes can include:

Trapped air bubbles created during cartridge assembly, including their presence and migration with pump orientation
Air bubbles becoming dispersed into catheters during fluid transfer
Non-Newtonian formulation properties (e.g. shear thinning) behaving drastically differently during infusion versus bolus delivery
Fluid evaporation through catheters and beakers.

These effects risk being misinterpreted as pump performance issues if the root causes are not fully understood. Flow-rate instability and end-of-dose issues could be incorrectly attributed to a pump’s drive mechanism, when the true causes are formulation – rather than pump-limited. For example, different air bubble locations along a catheter can produce distinct, repeatable flow signatures that closely mimic a mechanical fault, and separating the two typically requires careful analysis. Pre-DV activities should focus on identifying and understanding such mechanisms before they appear during formal verification.

Risk Elimination and Mitigation

Once identified, risks should be eliminated, controlled or characterised using targeted experimentation and engineering judgement. Effects such as balance drift, fixture design problems and temperature gradients can introduce significant measurement errors. For ambulatory pumps, this includes ensuring gravimetric balances have settling times long enough to resolve genuine flow transients without mistaking balance noise for a delivery event. Effective mitigation activities are those that eliminate sources of uncertainty.

Ambulatory pumps operate across broad parameter spaces, including temperature, viscosity, back pressure, orientation and start-up conditions, all of which affect performance. Design of experiments is an effective tool for systematically exploring these spaces, identifying interactions and sensitivities, and determining whether behaviour remains within acceptable limits across the intended operating range, thereby ensuring that an appropriate subset of testing conditions, representing potential worst-case scenarios, are chosen for the formal DV testing.

A recurring challenge in infusion pump verification is that the root cause can be misidentified. Formulation behaviour requires close attention and verification, as material properties on a certificate of analysis may be insufficient for predicting how a formulation behaves inside an infusion system. Shear rates and residence time can differ substantially from the conditions under which such data were generated – for example, density versus temperature.

"Formulation behaviour requires close attention and verification, as material properties on a certificate of analysis may be insufficient for predicting how a formulation behaves inside an infusion system."

As a result of investigations such as these, the mitigation strategy for a programme shifts towards understanding the physical mechanisms responsible and quantifying their impact. By the time formal DV commences, experimental signatures observed during the pre-DV phase can be accounted for and correctly assessed, reducing the risk of inefficient post-event root cause investigations and repeat testing.

Define Data Analysis and Integrity

During a DV programme, the characteristics of the data generated and how they are analysed are equally as important as the design of the physical test step. For example, a transient flow-rate disturbance may appear dramatic in raw data but have negligible impact on delivered dose, while a seemingly insignificant disturbance may accumulate into a clinically meaningful error over time. Distinguishing between the two requires careful analysis to identify clinically relevant issues from avoidable experimental artefacts.

This becomes particularly important with automated analysis workflows. Automation improves repeatability and processes large datasets efficiently, but introduces risks of incorrect data manipulation and interpretation. Validation should focus not only on software calculations but also on checks to ensure that the correct data are selected and analysed. Defining analysis, acceptance criteria and anomaly classification rules during characterisation ensure that formal DV answers meaningful questions about device performance as opposed to asking new questions of the data.

"Defining analysis, acceptance criteria and anomaly classification rules during characterisation ensures that formal DV answers meaningful questions about device performance, as opposed to asking new questions of the data."

Execute the DV Testing

Before executing the full DV matrix, teams must be trained, confident in procedures and clear on how to respond to unexpected results. Training should be documented, with the lab operating under a vigilance-driven, blame-free culture focused on catching issues early.

Planning how to respond to an out-of-specification (OOS) result beforehand is a key part of this culture, signalling to the reviewer that the process is robust and root cause analysis procedures are followed (Figure 4). OOS investigations all follow a simple logic:

If the behaviour reflects the real drug delivery performance, the failure must be accepted and included in the statistical analysis
If the behaviour reflects some aspect of the methodology, careful argument may justify the exclusion and retest of an erroneous result, if it can be proven as such
If the behaviour is ambiguous, capture evidence (e.g. environmental data, balance data, photographs), learn as much as possible and document it for further investigation. This will ultimately allocate the result to one of the first two categories.

Figure 4: Decision framework illustrating the primary categories of causes considered during investigation of an OOS result.

Following these guidelines significantly reduces the burden of root cause analysis and reporting, and, even where acceptance criteria are not met, the resulting understanding will support strong, evidence-based recommendations for product improvement.

A genuine product failure and a system effect may only be distinguishable after careful investigation, demonstrating why agreeing the OOS logic in advance is so important. The objective of characterisation is to ensure that formal DV contains no unexpected lessons so that execution focuses on demonstrating device performance rather than investigating previously unknown phenomena.

Conclusion

For ambulatory infusion systems, successful DV may not be limited by the ability to execute the required tests but by how well the underlying system is understood before testing begins. Modern delivery systems combine electromechanical pumps, consumables, complex formulations and patient-driven use conditions, meaning that performance is frequently governed by interactions between these elements rather than the pump mechanism alone. Trapped air bubbles, formulation rheology, start-up transients and fluid-path compliance can all generate behaviours that resemble pump failures, which, through characterisation work, can be correctly classified.

Successful programmes treat DV as a confirmation exercise by defining clinically meaningful metrics, identifying hidden sources of variability and establishing robust interpretation methods before commencing formal testing. By following these principles, sponsors can reduce programme risk while generating evidence that is both scientifically robust and regulatorily defensible.

ACKNOWLEDGEMENT:

With special thanks to Manuel Acha for his assistance with the article.

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De-Risking Post-Market Change Through Pilot Production for Drug Delivery Devices

July 17th 2026

Featured in ONdrugDelivery, CDP explores how pilot production drug delivery can be used to de-risk post-market change in drug delivery devices, and why this approach is becoming essential for manufacturers navigating change at scale.

Managing change in drug delivery device manufacturing post launch is inherently challenging. Whether driven by regulatory requirements, issues with an existing on-market device, supply chain disruption, or design evolution, even small modifications can introduce significant risk to product quality, cost, and supply continuity.

These challenges are compounded by the practicalities of generating statistically meaningful data from prototype designs without disrupting established, high-volume manufacturing operations.

This article explores how pilot production, delivered through an integrated design, development and manufacturing capability, can be used to de-risk change. It highlights how such approaches can improve confidence in decision-making while reducing overall time and cost.

What Drives Change in Drug Delivery Devices?

Even the most comprehensive design verification programmes cannot always accurately predict all failure modes that may emerge once a product is deployed at commercial scale. As production increases from hundreds to millions of units, variability in materials, processes, and real-world use conditions can reveal previously unobserved behaviours.

In addition to on-market performance considerations, manufacturers must also respond to external and internal drivers such as:

Regulatory updates
Material obsolescence
Supplier changes
Cost optimisation initiatives

Collectively, these factors make change management an essential element in the lifecycle of successful combination products.

However, implementing changes without disrupting supply presents a significant challenge. The commercial justification often requires data that can only be gained by transitioning from small numbers of lab-built prototypes to thousands of devices produced using representative manufacturing processes.

While guidance such as ISO 20069:2019 (Guidance for assessment and evaluation of changes to drug delivery systems) provides a framework for assessing and documenting changes, it offers limited direction on how exactly to generate the representative data efficiently without impacting validated production lines.

A Common Challenge

Consider an on-market drug delivery device that is manufactured at scale. The production system to make and assemble such a device will be highly optimised. Material handling, in-process quality controls, final packaging, labelling ‒ every step will be designed to reduce variation and ensure quality.

If such a device experienced an issue post-launch, the impact to the manufacturer could be enormous. The decision on how to proceed has significant consequences and could potentially trigger FDA (or other regulatory body) intervention.

This is reflected in the number of recalls and corrections reported by the FDA, underlining that the ability to implement changes to marketed products in a controlled way is a strategic need for manufacturers.

Examples from infusion and syringe-based drug delivery systems help illustrate this challenge. Table 1 presents a selection of recent product recalls and corrections affecting this class of devices. Whilst the specific failure mechanisms differ, the examples highlight recurring challenges associated with fluid handling and sensing functions, such as leak paths and occlusion detection.

Device	Failure mode	Patient risk	Date	Remediation
Cardinal Health, Monoject Luer-lock syringes	Recognition, compatibility and pump performance issues when used with syringe pumps and patient controlled analgesia pumps	Overdose, under dose, delay in therapy and delays in occlusion alarms	March 2024	Recall of specific product
B. Braun Infusomat Space Large Volume Pump	On certain models, occlusion alarm may sound when no occlusion exists	Interrupted or failed delivery of medication or fluids	September 2023	Correction of occlusion pressure sensor
Fresenius Kabi Ivenix Infusion System	Fluid leak that causes damage to the electrical system	Delay or interruption to treatment	March 2023	Urgent device recall letter sent to customers
Eitan Medical Sapphire Infusion Pumps	Failure to detect air in line when running on battery power	Serious injury or death from air embolism risk	September 2023	Recall and customer notification, software update

Design modifications to address issues such as these require large data sets to generate sufficient statistical confidence that the issue has been resolved. Where an issue is not fully understood or occurs on an infrequent basis, this can potentially run to tens of thousands of units.

The requirement for high numbers of finished devices exposes a gap in available manufacturing options:

Volumes too high for conventional prototyping approaches
Volumes too low, and timelines too short, to engage commercial-scale contract manufacturing organisations (CMOs)
Existing production lines may not accommodate the design without significant disruption

This scenario reflects a common industry challenge, where development teams must balance two competing priorities: minimising change to fit within existing manufacturing capabilities vs allowing sufficient design freedom to maximise the likelihood of technical success.

Contract Manufacturing can be Inflexible

In conventional outsourcing models, Contract Manufacturing Organisations (CMOs) are typically optimised either for low-volume engineering support or for stable, high-volume commercial manufacture. Small-scale engineering workshops prioritise flexibility and rapid iteration, whereas production facilities are designed around efficiency, repeatability and validated processes (see Figure 1). Projects that sit between these two models can create significant operational tension.

In the case of drug delivery systems, the challenge is often amplified by the combination of bespoke automation, tight tolerances and sub-assemblies containing both rigid and compliant parts. Even relatively small engineering programmes may require dedicated fixtures, custom tooling, automation development and specialised operator training. These investments can be difficult to justify when production volumes remain limited, and product designs are still evolving.

Furthermore, these engineering builds often involve a high degree of uncertainty. Device configurations may change frequently, process parameters may still be under investigation and build schedules can fluctuate as development priorities evolve. For a CMO operating under conventional production metrics, such variability can disrupt factory planning, reduce equipment utilisation and negatively impact operational efficiency.

There is also an economic challenge. Low-to-medium volume engineering programmes rarely achieve the economies of scale associated with high volume commercial manufacture, yet they may still demand significant engineering oversight and quality infrastructure. As a result, the commercial model can become unattractive for both the client and the manufacturing partner.

Many CMOs now advertise Design as a differentiator ‒ spawning the initialism “Contract Design Manufacturing Organisation” (CDMO) ‒ offering design services as well as more traditional manufacturing services. However, as design is often not a core skill, they can leave clients with a design that only works with their in-house manufacturing approach, or where the IP is no longer with the client.

For these reasons, many organisations may benefit from dedicated pilot production environments operating outside conventional commercial manufacturing structures, providing a more effective route for executing complex flexible manufacturing.

Conventional Prototyping Lacks Rigour

Traditional prototyping is typically focused on evaluating functional concepts and demonstrating technical feasibility. Prototype devices are often produced in small quantities using flexible, low-volume methods that prioritise speed and adaptability over repeatability. These builds are valuable during early-stage development, where the objective is to assess usability, confirm mechanical principles or explore initial design architectures. However, prototypes are rarely manufactured under conditions representative of commercial production. As a result, they may not fully reveal the interactions between product design, automation strategy and manufacturing variability.

Pilot manufacturing occupies a different position within the development pathway. Rather than simply proving that a device can function, pilot manufacturing aims to demonstrate that it can be assembled repeatedly, efficiently and robustly under production-representative conditions. This includes consideration of automation compatibility, process capability, quality inspection and operational throughput. The parts themselves are often manufactured by representative processes, for example injection moulded plastic housings rather than 3D printed parts.

The distinction is important because many challenges associated with drug delivery systems emerge only when products are built at scale. Tolerance accumulation, fixturing behaviour and automation interactions may appear manageable during low-volume prototyping but can become significant risks during industrialisation.

By bridging the gap between prototyping and commercial manufacturing, pilot production enables engineering teams to identify and resolve these issues earlier in development, reducing industrialisation risk and supporting more robust product and process design.

Why Existing Production Lines May Not Accommodate Design Changes

Many manufacturing systems for drug delivery devices rely on bespoke automation, tightly controlled tolerances and carefully sequenced assembly operations, developed specifically for a defined product configuration. Even relatively small design modifications, such as changes to component geometry, material behaviour or assembly orientation, can have cascading effects across the production process.

In automated systems, manufacturing equipment is often programmed around precise assumptions regarding part position, stiffness, insertion forces and component interaction. A seemingly minor design change may therefore require reconfiguration of robotic motion paths, vision system parameters, fixturing, feeding systems or inspection methods. In some cases, the modification can introduce variability that existing automation is simply unable to accommodate reliably.

These challenges are particularly acute in assemblies containing both rigid and compliant parts. Elastomeric tubes, adhesives or soft materials may behave differently during automated handling when adjacent components are modified, creating interactions that only become apparent at production scale. For example, a section of tubing may curl in one direction 98% of the time based on how it is presented. The low occurrence of the alternative behaviour means it may not be observed in small sample sizes, leading to assumptions during automation development that later prove unreliable.

Importantly, commercial manufacturing lines for medical and combination products are usually validated environments operating under strict quality and regulatory controls. Any significant modification to equipment, tooling or process parameters may trigger formal change control activities, revalidation requirements and production downtime. For manufacturers supplying commercial products, this introduces both operational risk and potential supply chain disruption.

As a result, manufacturers are often reluctant to trial experimental designs directly on operational manufacturing lines, particularly where product demand remains high.

Pilot production ‒ a hybrid of prototyping and commercial manufacturing ‒ provides a practical alternative. By replicating critical manufacturing operations outside the commercial environment, it allows design changes to be evaluated under production-representative conditions without interrupting ongoing supply, nor compromising validated manufacturing systems.

Developing a Hybrid Manufacturing Strategy

Replicating the full complexity of the existing high-volume manufacturing system when conducting pilot manufacturing is usually neither practical nor necessary. Instead, a targeted approach can be adopted to balance fidelity with flexibility and cost.

This hybrid strategy, illustrated in Figure 2, involves:

Mapping the device production process flow
Identifying critical-to-quality (CTQ) and critical-to-function (CTF) process steps
Assessing risk and applying suitable mitigations so each of these steps is replicated using appropriate technology. For example:
- A needle insertion step, which requires precise needle alignment (high risk), may require a controllable and repeatable automated system such as a Selective Compliance Articulated Robot Arm (SCARA).
- Non-critical processes (lower risk) could be conducted using manual or semi-automated methods.

As the pilot production system will be operating at a slower rate than a commercial line, a flexible approach to labour organisation and work balancing can manage uncertainties in the new, untested line. Even when simulating the new line with digital tools, the pinch points in production flows may not be known without running the system. The use of adaptable fixturing and work-in-process storage, which allows stations to build up inventories, is recommended to cope with these unknowns.

In addition, it may be possible to redeploy equipment from the existing production lines to maintain process fidelity without incurring unnecessary cost. These valuable pieces of process equipment may be unused spares or repurposed from obsolete lines. However, due care and attention must be observed when bringing them online: they may have different voltages, require repair or maintenance or translation of production documentation from other languages.

Implementation and Outcomes

The resulting pilot production line incorporates a combination of approaches that can be designed and implemented rapidly:

Automated assembly cells for critical processes
Manual and fixture-based operations for non-critical steps
Integrated inspection and functional testing capabilities

To give an example that puts this into context, a system such as this was designed, built and operated within a 12-week timeframe, including both factory acceptance testing (FAT) and site acceptance testing (SAT). This enabled rapid deployment into an engineering production environment while design activities continued in parallel.

In total, more than 14,000 devices were manufactured across seven design variants. These units supported:

Engineering performance evaluation
Accelerated ageing studies
Ongoing engineering verification testing to prove functional performance

The pilot production approach therefore provided both the scale and fidelity required to support robust, data-driven decision-making.

Conclusion

For established drug delivery devices, the pressure to change can be driven by performance data, regulatory evolution, supply chain disruption and the ongoing pursuit of improvement. Yet the tools available to generate the evidence needed to support those changes remain poorly matched to the task. Conventional prototyping lacks manufacturing fidelity; commercial-scale CMOs are structured around stability, not experimentation; and validated production lines cannot easily absorb the uncertainty of iterative design work.

Pilot production addresses this gap directly. By replicating critical manufacturing operations in a flexible, lower-volume environment, development teams can generate statistically meaningful data under production-representative conditions, without putting commercial supply at risk. Crucially, it is not a replacement for formal design transfer, but a means of arriving at that stage with greater confidence and fewer unknowns.

As drug delivery systems become increasingly complex, and as expectations for continuous improvement grow, such approaches are likely to play an increasingly important role.

By bridging the gap between concept and commercial manufacture, pilot production enables organisations to pursue innovation with greater confidence – while maintaining the reliability and supply continuity that patients depend on.

REFERENCES:

“Medical Device Safety Communications Database”. Web Page, US FDA, accessed 8th May 2026.

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For more on how pilot production can de-risk post-launch changes to drug delivery devices, contact Cambridge Design Partnership.

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From Impossible to Feasible: Using Theoretical, Synthetic and Tissue Models to Accelerate Novel Drug Delivery Development

May 18th 2026

Dr Karla Sanchez

Head of CNS Technology

Frances Pencliffe

Operations Lead – Drug Delivery

Introduction

Platform devices are often the preferred starting point for combination product development, and for good reason. A well-characterised platform offers a proven architecture, defined performance boundaries, and a clear path to market. However, an increasing number of therapies in development are pushing into territories where there is currently no existing platform to serve their needs.

Novel biologics are extending the boundaries of volumes and viscosities, cell and gene therapies are leading to ever-more tissue-targeted deliveries, suspensions and co-delivered (or sequentially delivered) therapies are among those demanding entirely new thinking about how, where, and whether a drug can be delivered. These formulations can all be gathered under the umbrella term “specialty delivery” and are united by a common challenge – where there is no existing platform device able to deliver the formulation, a delivery system becomes a core part of formulation development and testing. Where traditional developments are often able to rely on vial-and-syringe delivery to enable early clinical data to be gathered, these specialty delivery developments (especially those requiring tissue-targeted delivery) require more sophisticated devices to be available earlier in the therapy or formulation’s life cycle.

For these developments, feasibility work looks very different to what we expect when adopting a platform. Rather than asking “Can this platform device deliver our formulation?”, the question becomes “Is it possible to deliver this formulation at all?”, which could mean the difference between a few weeks of benchtop testing and months or even years of exploratory research. Answering this new feasibility question efficiently requires a structured, pragmatic approach that balances scientific rigour with the realities of early-stage development timelines and budgets.

The framework described in this article has been developed through more than a decade of feasibility work on some of the most challenging drug delivery developments we’ve encountered; projects where the answer wasn’t obvious, and where finding it efficiently made the difference between a development moving forward and stalling.

This article explores how theoretical, synthetic and tissue models can be combined to de-risk novel drug delivery developments, and how to deploy them intelligently to turn an apparently impossible challenge into a feasible one. While the worked example we’ll draw on throughout – a novel device for drug delivery directly to the brain – sits at the more complex end of the spectrum, the principles apply equally to any development where an existing platform doesn’t fit, or where it isn’t yet clear whether a device is a good match for the therapy. The approach scales to the necessary level of complexity.

What Does Feasibility Really Mean?

Feasibility for specialty delivery means different things depending on where you sit on the development complexity spectrum. At one end, it might mean confirming that an existing device can deliver a formulation that sits just outside its stated performance envelope, e.g., pushing the viscosity boundary and testing whether a longer injection time is still acceptable to users.

At the other end, feasibility might mean starting from scratch with a therapy that has never been delivered before, to a target site that has never been accessed in this way, using a device that doesn’t yet exist. Here, the risks are profound, and the unknowns are numerous, spanning therapy efficacy, navigation and targeting (including positional accuracy), tissue tolerability, usability, and many more.

The first challenge is therefore to understand where your development sits on this spectrum, which can be done by identifying the key risks to be addressed. This starts by understanding what the needs of the formulation are as compared to existing formulations on the market or in clinic. If, for example, you are targeting subcutaneous delivery, chances are navigating the device to the right area is not going to be a huge risk. But if you’re targeting a specific structure of the brain or a nerve within the nasal cavity, suddenly how the formulation is delivered to the right location is an unknown factor that’s critical to the efficacy of the therapy. The same principles apply for other aspects – are you targeting a new user group? Or a new use environment? Each area where you’re looking to push a boundary is a potential risk to be investigated during feasibility work.

The Model Landscape: A Brief Orientation

Once the key risks have been identified, the next step is to select the right tools -often models- to investigate them. In the context of drug delivery feasibility, models broadly fall into three categories.

In silico models – computational and mathematical approaches – range from simple physics-based calculations through to complex simulations such as computational fluid dynamics (CFD) or finite element analysis (FEA). At their best, they are fast, flexible, and low cost to iterate, making them well suited to early-stage exploration. Their limitation is that they are only as good as the inputs you give them, and at feasibility stage those inputs are often hugely uncertain.

In vitro models – bench-based physical testing – provide empirical data that computational models simply cannot. Synthetic tissue analogues, flow rigs, and bench prototypes all fall into this category. They offer a tangible way to test device and formulation behaviour under controlled conditions and are generally more accessible and affordable than animal or human studies.

Ex vivo models – testing in excised biological tissue – offer real tissue behaviour without the complexity and cost of full animal studies. For early feasibility work involving novel delivery routes or target tissues, ex vivo models are particularly valuable: they can provide rapid, biologically relevant data to characterise tissue properties and validate computational predictions at a stage where in vivo work would be premature.

In practice, the most effective feasibility programmes don’t rely on a single model type. The real skill is in knowing which combination to use, and in what order – and that starts with asking the right questions.

Framing the Right Questions: A Worked Example

Having the right models available is only half the challenge. The bigger risk in early feasibility work is asking the wrong questions of them, reaching for high-fidelity simulation before the problem is properly understood, or pursuing a level of detail that isn’t yet warranted. A multiphysics model of tissue mechanics or a full physiologically-based pharmacokinetic (PBPK) simulation might ultimately be the right tools but deploying them before the fundamental questions have been framed correctly is an expensive way to generate false confidence.

A more effective approach starts not with the model, but with the decision that needs to be made. At each stage of feasibility, it is worth asking: what do we need to demonstrate right now? What is stopping us from moving forward? Once that decision is clear, the next step is to identify the key drivers – what are the dependencies, and do we have reliable data for them? Only then can a model, or set of models, be properly selected, and the guiding principle should always be to choose the simplest approach that can answer the question with the necessary degree of confidence.

To illustrate how this plays out in practice, consider the development of a novel device for delivering drug directly to a target structure within the brain, a scenario that was once thought to sit firmly at the impossible end of the feasibility spectrum. There are many questions that could be addressed during feasibility, but we’ve selected three unrelated questions that have been posed to us in the past as examples of our approach to feasibility:

What is the delivery force?
Will the device achieve the required formulation distribution in tissue?
How will the device influence the clinical effect?

1. What is the delivery force?

The initial instinct may be to model the delivery force in full using a high-fidelity simulation incorporating device mechanics, friction, fluid dynamics, and tissue backpressure simultaneously. However, at this early stage, information about the conditions of delivery e.g. tissue properties, fluid interactions, variability (patient, user, device); may not be fully known. As such, reframing the question reveals a more useful starting point: the real need wasn’t to predict the exact force profile, but to understand whether the force required to deliver the drug would exceed what a typical user could reasonably apply. With that decision in mind, a more pragmatic model strategy emerges; ex vivo tissue characterisation to measure backpressure and understand fluid-tissue interactions, early bench testing with a simple prototype to assess injection force, and a low-order physics-based mathematical model to combine these inputs. Fast to generate, easy to iterate, and sufficient to answer the question that actually mattered at this stage.

2. Will the device achieve the required formulation distribution in the tissue?

The initial expectation might be a complex computational fluid dynamics (CFD) and fluid-structure interaction (FSI) simulation with a nonlinear, anisotropic tissue model and multiphase flow, an approach that would be computationally expensive and heavily dependent on tissue property inputs that aren’t yet fully known. Reframing shifts the question to something more tractable: can the device achieve the required distribution area (or volume) in tissue? This opens up a staged model strategy; simplified flow and porous media models for rapid screening, followed by testing in brain tissue analogues developed from published academic literature, allowing findings to be benchmarked against existing research. Targeted CFD is then reserved for where refinement is genuinely needed. Lower cost, easier to verify, and designed to work even when input data is uncertain.

3. How will the device influence the clinical effect?

Building a full PBPK model from preclinical data is an understandable ambition, but difficult at feasibility stage, where the biological inputs required are often unavailable or unreliable. Reframing the question from predicting clinical efficacy to “can the device achieve sufficient therapy exposure for target absorption?” enables a more practical, modular approach. Mechanistic models (which describe system behaviour) can be used to characterise device-to-delivery behaviour. Simplified transport models and targeted experiments address delivery-to-distribution as described above. And for distribution-to-exposure, findings can be bridged to existing pharmacokinetic and pharmacodynamic (PK/PD) models (the mathematical frameworks that describe how a drug moves through and acts on the body) making it straightforward to hand off to specialist teams when the time comes. This keeps the focus on the decision at hand and avoids reliance on uncertain biology.

In each case, the pattern is the same: resist the pull towards complexity, reframe the question to be asked around the decisions to be made, and choose the simplest model that can answer it. Models don’t just answer questions, used well, they help reveal the questions worth asking in the first place.

Conclusion

Even the most complex drug delivery challenges can be broken down into manageable pieces. The key is phase-appropriate pragmatism; understanding where your development sits on the feasibility spectrum, selecting models that are fit for the question rather than fit for the complexity, and knowing when you have enough information to make the next decision.

The worked example above illustrates how this plays out in practice. What was once considered an impossible development became feasible through the efficient combination of analytical, synthetic and tissue models, each chosen not for its sophistication, but for its ability to answer a specific, well-framed question at the right stage of the programme. It is an approach we have refined across many such projects, and one that we continue to apply wherever a development pushes beyond the boundaries of what existing platforms and precedent can answer.

To accelerate innovation, we need prompt decision making. Obtaining feasibility answers in weeks rather than years allows redirection of resource toward where it’s most needed (e.g. reframing of therapy or administration route), ensuring effective treatments reach patients faster. The framework works precisely because it is designed to find the answers that matter efficiently.

The tools are available. The challenge, and our experience, is in deploying them wisely.

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For more on how to accelerate novel and targeted drug delivery feasibility using computational, synthetic, and tissue models to de-risk combination product development, contact Cambridge Design Partnership.

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Sustainable pharmaceutical packaging without compromising safety or usability

February 24th 2026

Adrian Segens

Senior Sustainability Leader

Jon Powell

Head of Manufacturing

Steve Augustyn

Senior Consultant Mechanical Engineer

When people talk about “sustainable packaging,” they often picture quick material swaps and bold recyclability claims. But in pharmaceuticals, it’s rarely that simple.

Pharma packaging is a safety-critical system. It protects sensitive formulations, supports regulatory compliance, and helps patients take the right medicine in the right way, every time.

That’s why packaging teams are under a different kind of pressure: they are being asked to reduce environmental impact while holding the line on performance, patient safety, and supply resilience.

At Cambridge Design Partnership (CDP), we work with pharma and healthcare teams to make that trade space manageable. The goal isn’t sustainability as a side project. It’s packaging decisions that are evidence-led, patient-centered, and durable under regulatory scrutiny.

The structural tension at the heart of pharmaceutical packaging

In practice, pharmaceutical packaging exists inside tight constraints that are in place for good reason:

Validated moisture, oxygen, and light barriers (often with narrow stability margins)
Strict control of chemical interactions and leachables across materials, inks, adhesives, and coatings
Tamper evidence, traceability, and serialization requirements
Repeatable, audited manufacturing processes with controlled change management
Global regulatory alignment, long shelf-life assurance, long qualification cycles, and post-approval variation burden

However, here is another non-negotiable that is often underweighted in sustainability conversations: patient usability.

In effect, packaging is the interface between medicine and the person using it. It must enable patients to identify the correct drug clearly, complete any necessary inspection (for example, tamper evidence, integrity, or visual checks, where relevant), and access the drug product reliably. If a sustainability change makes a pack harder to open, harder to read, or easier to confuse, it creates a risk that overwhelms the environmental benefit.

As a result, progress is rarely about a single material substitution. Sustainable outcomes come from system decisions – barrier, labeling, usability, manufacturing, logistics, and end-of-life considered together.

Why the pressure is now unavoidable

1. Regulation is becoming a market access issue.

In Europe, the PPWR (Packaging and Packaging Waste Regulation) is now the anchor regime: it entered into force in February 2025 and will apply from August 2026, with recyclability tightening through 2030 and a formal review horizon in 2035 that is explicitly relevant to certain pharma pack exemptions. Here, the key challenge is timing: regulatory clocks move faster than pharma packaging platforms can change.

2. Stakeholder expectations are rising.

At the same time, payers, providers, investors, and patients increasingly expect credible action. Packaging is visible, measurable, and easy to compare – so it’s becoming a practical test of seriousness, not a marketing footnote.

3. The business case is shifting from “nice to have” to “must manage”.

Consequently, packaging decisions now touch cost, resilience, and speed to market: material exposure, waste fees, supply fragility, and late-stage redesign risk. In most cases, getting ahead of change is usually cheaper than reacting when options are already locked.

What we see in real programs

A few patterns show up repeatedly when teams try to move from intent to execution.

The biggest wins aren’t always in the primary pack.
In many cases, primary packaging can be the hardest part of the system to change quickly. By contrast, secondary and tertiary packaging (such as cartons, leaflets, protective elements, and shipping formats) often provide faster, lower-risk opportunities – especially when you design them to reduce total material use, improve transport efficiency, and avoid formats that create sorting and recycling problems.

“Recyclable” is not the same as “safe, compliant, and used correctly.”
For pharma, the right question is usually: What is the lowest-impact design that still delivers stability, compliance, and patient usability? That framing prevents false optimization.

Late redesign is the hidden cost.
When sustainability is added after packaging architecture decisions are made, you end up negotiating against a nearly fixed design. That’s when cost and time blow out – and when risk rises.

A practical framework for executive decision-making

If you’re leading packaging strategy, the most useful step is to turn sustainability into a structured decision process rather than a series of ad hoc requests. Here’s a framework we use with teams to keep work focused and defensible.

1. Define your non-negotiables up front

Before exploring options, align on what cannot be compromised:
Patient safety and correct use
Readability and differentiation (right medicine, strength, dose, expiration)
Access and openability under real-world conditions
Barrier performance and shelf-life confidence
Tamper evidence and traceability requirements
Validated manufacturing performance and supply resilience

This avoids “optimizing” a pack into something that fails in the field.

2. Establish a credible baseline, quickly

You don’t need a year-long study to find direction. A focused baseline – material flows, key pack components, manufacturing yield sensitivity, logistics assumptions, and end-of-life reality – usually reveals where the impact sits and where it doesn’t.

This is where we often apply lifecycle thinking and our Sustainability Cleansheet method: Quantify the big cost and environmental impact drivers early so you don’t spend months improving the wrong thing.

3. Build a short list of options and stress-test the tradeoffs

For each option, teams should be able to answer clearly:

What changes physically? (materials, structure, labels, coatings, inks, adhesives)
What risks move? (stability margin, E&L, usability, line performance, supply continuity)
What improves? (impact reduction, cost, simplification, waste reduction, data/traceability)
What evidence is needed? (bench tests, line trials, stability, human factors validation)

The aim is not perfect certainty. It’s the early elimination of weak options and disciplined focus on the few options that can scale.

4. Pilot to reduce uncertainty, not to signal virtue

In pharma, pilots only matter if they answer hard questions: manufacturability, patient behavior, stability confidence, and real end-of-life outcomes (not just theoretical recyclability).

We design pilots to generate decision-grade evidence, so teams can commit without gambling.

5. Use “smart print” technologies thoughtfully

Many teams want digital capability – traceability, anti-counterfeit protection, patient guidance, or better sorting instructions – without turning packaging into electronics.

That’s where smart print technologies can help: Printed features (from advanced QR codes and variable data to printed conductive inks and thin printed circuits) can deliver “DPP-style” benefits – linking the pack to verified product data, instructions, and chain-of-custody information – without adding bulky components.

But they still require end-of-life thinking. Even small amounts of conductive ink or functional layers can affect recycling behavior and material recovery if they’re used indiscriminately. The practical approach is:

Keep digital features as light as possible (often secondary packaging is the right home)
Avoid designs that contaminate or complicate recycling streams
Choose materials and inks with recovery pathways, where available
Be explicit about the end-of-life intent, not just the in-use feature set

Smart features can support compliance and patient outcomes – but only if they’re designed as part of the packaging system, not bolted on.

6. Build a roadmap that matches pharma timelines

Packaging change in pharma is slow by design: qualification, validation, supplier readiness, and stability programs all take time. That’s exactly why the gap between product development cycles and regulatory timelines matters. The right roadmap staggers effort:

Near term: Secondary and tertiary improvements and material reduction
Mid term: Architecture changes where stability risk is manageable
Long term: Platform shifts and primary packaging strategies aligned to the next regulatory horizon

How CDP helps

Clients bring us in when they need momentum without compromising on safety. What makes CDP different is the way we connect the disciplines that usually sit apart:

Packaging engineering and materials science
Human-centered design and real usability validation
Manufacturing realism (line performance, transfer to manufacture, scale-up)
Lifecycle thinking and decision-grade impact analysis
Digital and data capability to support traceability and future information needs

The result is packaging strategy that holds up: Lower-impact solutions that are still manufacturable, compliant, and usable – built on evidence rather than hope.

The opportunity

Sustainable pharmaceutical packaging isn’t about copying approaches from consumer goods. It’s about designing within the constraints that matter – stability, safety, usability, and supply assurance – while still making real progress on impact.

If you’re responsible for packaging strategy and you’re facing tighter timelines, rising expectations, and harder tradeoffs, we can help you move faster with confidence.

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For more on how to accelerate meaningful innovation in sustainable pharmaceutical packaging, contact Cambridge Design Partnership.

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Precision Delivery: The Missing Link In Cell & Gene Therapy

January 14th 2026

Emily Chang

Consultant Biomechanical Engineer

Jessica Alzamora

Consultant Mechanical Engineer

Dr Karla Sanchez

Head of CNS Technology

Featured in ONdrugDelivery News, Jessica Alzamora, Dr Karla Sanchez and Emily Chang discuss the necessity for precision when delivering cell and gene therapies, explore how this precision can be designed and demonstrated, then go on to describe how a minimum viable product approach to device development can act as a strong predictor of a successful drug delivery device.

Cell and gene therapies (CGTs) are at the forefront of precision medicine, with the potential to repair or replace faulty genes and cells to treat disease at its biological source. Despite this promise, the success of CGTs depends on one defining factor: precision. Every stage, from designing a vector to delivering it in the body, demands careful control to ensure that the treatment reaches the targeted region and/or cells, at the right dose and with minimal off-target effects (Figure 1).

Figure 1: Commonly targeted delivery sites for CGTs.

A clear example of this reliance on precision comes from a currently available gene therapy to help improve functional vision in patients with an inherited retinal disease due to a genetic mutation. The approved adeno-associated virus 2 (AAV2) gene therapy Luxturna^® (voretigene neparvovec, Spark Therapeutics, Philadelphia, PA, US) must be delivered via a highly targeted subretinal injection to ensure that the therapy reaches and acts on the exact layer of cells needed for vision. Even small variations in injection depth or placement can change how effectively it restores function, and incorrect placement can increase the risk of inflammation.¹ This shows that the success of a therapy depends as much on how it is delivered as what it delivers – the therapeutic effect is dependent on the accuracy of the delivery modality.

To unlock the full potential of CGTs, the industry must not only consider molecular innovation but also focus equally on the method of precision delivery to expand the pivotal link between discovery and patient benefit. Achieving reproducible precision will determine how effectively these breakthroughs translate from rare success stories into accessible, scalable therapies.

“This shows that the success of a therapy depends as much on how it is delivered as what it delivers – the therapeutic effect is dependent on the accuracy of the delivery modality.”

Where Precision Matters Most In CGTs

CGTs are not produced in the same way as small molecules or standard biologics. Many programmes are patient-specific or produced in small, labour-intensive batches, with customised biomanufacturing and strict cold chain to preserve vector integrity or cell viability. These constraints make products extremely costly: Luxturna®, for example, is priced at around US$850,000 (£650,000) per patient.² Given the resource-intensive nature of producing usable material, development teams must prioritise process efficiency and precision from the earliest stages of production.

Potency and safety are also tightly linked. Small deviations in target delivery or poor biodistribution control can provoke serious immune-mediated toxicities,³ among other serious side effects, which is particularly true in gene therapies.⁴ For instance, intrathecal delivery (administration into the cerebrospinal fluid, e.g. via lumbar injection, allowing direct access to the central nervous system) can have a biodistribution-associated risk that results in dorsal root ganglion inflammation and neuronal degeneration, particularly with higher doses, where neither the therapy’s tropism (affinity with specific cells) nor cerebrospinal fluid dynamics have been fully characterised.⁴

“Precision in where and how therapies are delivered determines how safely it can be dosed, how consistently it can be scaled and how much product is needed to achieve a therapeutic effect.”

Some therapies may only succeed when they are placed with millimetre-scale accuracy. For a rare neurological disorder called aromatic L-amino acid decarboxylase deficiency, the AAV2-based therapy Upstaza™ (eladocagene exuparvovec, PTC Therapeutics, Warren, NJ, US), is delivered through stereotactic neurosurgery, which delivers four small infusions into the putamen in a single session (two per hemisphere).5 The product label specifies the route, infusion sites and dosing parameters, as the efficacy of the therapy depends on reaching the correct brain region while avoiding wider systemic exposure. This is precision delivery built directly into the treatment’s design. Furthermore, for one-off or single-administration gene therapies, re-delivery may not be possible (e.g. due to pre-existing antibodies to AAV) or may be considered too risky to conduct (e.g. direct-to-brain administration).

Precision in where and how therapies are delivered determines how safely it can be dosed, how consistently it can be scaled and how much product is needed to achieve a therapeutic effect.

When Precision Becomes A Moving Target

Precision is easy to define, in theory, but difficult to achieve in practice. For many CGTs, location, distribution and dose must be defined long before clinical trials begin, yet each is influenced by complex and patient-specific variables (Figure 2). Precision is less critical for ex vivo approaches, such as chimeric antigen receptor T-cell therapies, where cells are modified outside of the body prior to intravenous administration. These treatments have demonstrated success, as seen with Kymriah® (tisagenlecleucel, Novartis) and Yescarta® (axicabtagene ciloleucel, Kite Pharma, Santa Monica, CA, US) in haematological malignancies. In contrast, precision becomes far more consequential for in vivo gene and stem cell therapies. What seems simple – such as targeting a specific organ for a rare disease – quickly becomes challenging when teams must decide what level of precision is sufficient in terms of which part of the organ and its diverse cell populations to target for the therapy to be effective.

Figure 2: Achieving the correct location, dose and distribution.

Location

This challenge is clearly visible in liver-directed AAV therapies, where defining location goes beyond reaching the organ itself. The liver’s intricate vasculature and cell diversity means that vector access and expression vary widely, while efficacy depends on transducing enough hepatocytes without excessive uptake by other cells that may trigger immune responses or reduce potency.⁶ Achieving this balance relies on optimising the route of administration, delivery site and dose flow control.

Distribution

Parameters such as vector concentration, infusion rate and device (e.g. cannula) geometry determine how the therapy is distributed through the tissue and how reliably it reaches target cells. To manage these interdependencies, computational and experimental modelling are integral throughout development of the therapy and delivery device. By modelling vector flow, convection and uptake in patient-specific anatomy, device developers can predict how a formulation or delivery approach will behave before starting animal studies, or they can refine it alongside these studies. These models enable the integrated team (composed of formulation/modality specialists, device developers and more) to optimise distribution patterns, reduce experimental uncertainty and accelerate iteration, allowing precise delivery to be engineered rather than inferred.

Dose

A clearer understanding of anatomical location and distribution also improves how the team defines and manages dose precision, which ultimately determines efficacy and safety. Dosing CGTs is about far more than volume; it reflects how much active vector or number/type of cells are needed to ensure the desired effect within the target tissue. Achieving precise dosages means controlling both potency and delivery conditions so that the administered quantity can translate into a safe and effective treatment. Advances in data analytics (e.g. vector analysis), flow-controlled infusion and real-time delivery monitoring are helping to define this relationship more accurately, enabling teams to move from empirical dose escalation to evidence-based dose design.

Although device design cannot completely negate biological variability, it can stabilise the physical conditions of delivery in terms of location flow and distribution, reducing the influence of external factors on therapeutic performance. In this sense, delivery systems are an integral and essential part of the therapy’s design; the therapeutic without the device is useless. A minimum viable product (MVP) delivery device is essential even in early-stage therapy development, as it underpins both the predictability and scalability of clinical outcomes, as well as reducing risk to both the patient and therapy programme.

How To Demonstrate Precision

If defining precision is difficult, demonstrating it under clinical conditions is even harder. Many CGTs show encouraging results in modelling and in vitro studies, only to encounter unexpected variability once tested in animals or humans. Translating a theoretical understanding of location, dose and delivery pattern into reproducible, in vivo performance remains one of the toughest challenges in the field.

The difficulty often emerges during the transition from therapeutic discovery to device-specific preclinical testing. Early studies may demonstrate vector bioavailability or device function separately, focusing on establishing foundational performance characteristics; however, this separation can limit understanding of how the two interact under physiological conditions. As a result, the first time the full system is tested, typically in animal models, teams may struggle to interpret poor outcomes. The question being: is the issue with the therapy itself or with how it was delivered?

If the delivery device or route is not well characterised before entering in vivo preclinical work, study design, surgical procedures and even success criteria can become ambiguous or have a lack of reproducibility.

Study Design

Preclinical study design therefore becomes the first true test of precision. The chosen route of administration determines not only how the therapy will be delivered, but also which model is appropriate for advancing an MVP approach to device design that supports overall therapy development. For example, a device that matches the therapy development stage and its requirements allows for evidence gathering on the control of delivery – isolating results for therapeutic effectiveness.

Anatomical and physiological differences, particularly in vascular structure, tissue density or organ size, mean that delivery parameters optimised in animals may not translate directly to humans. Building these constraints into the study design early on can help teams interpret results with greater confidence.

Procedural Control

Demonstrating precision also depends on procedural control. Every step, from therapy preparation and handling to administration and post-delivery care, can influence efficacy. For cell therapies, cell sedimentation during preparation or delays between thawing and delivery can alter dose consistency and viability. For gene therapies, infusion rate, device placement and user variability can all shift distribution patterns. Integrating human factors engineering into device and protocol design using procedural expertise helps to standardise these steps, thus improving reproducibility and safety.

Regulatory Scrutiny

Ultimately, preclinical and clinical studies are where precision delivery meets regulatory scrutiny. Demonstrating that a therapy and its delivery system consistently achieve targeted exposure is essential for proving both safety and efficacy. Without an early integrated approach to development of the device, formulation and route of administration, teams risk employing complex and expensive animal models or clinical studies only to discover that the delivery method itself limits their ability to assess therapeutic potential.

Incorporating delivery design and evaluation early in development is therefore not just good engineering – it is a strategic safeguard. Precision that is defined, engineered and tested in parallel with the therapy dramatically increases the chances of reproducible success in the clinic.

Conclusion: Precision Delivery Is The Next Frontier

The future of CGTs will not be defined solely by novel vectors or manufacturing breakthroughs, but by the industry’s ability to deliver these therapies with accuracy and consistency at scale. As CGTs move towards broader indications, the need for predictable, accessible delivery will only intensify. Achieving precision demands earlier integration of biological, engineering and human factors design, alongside continued investment in modelling and device innovation. Precision delivery bridges the gap between discovery and patient impact, turning theoretical efficacy into real-world benefit.

The lesson is clear: precision delivery is not a supporting technology, but the missing link that will connect scientific ingenuity with clinical and commercial success. Those who master it will define the next era of CGTs.

“The future of CGTs will not be defined solely by novel vectors or manufacturing breakthroughs, but by the industry’s ability to deliver these therapies with accuracy and consistency at scale.”

References

Patel MJ et al, “Surgical Approaches to Retinal Gene Therapy: 2025 Update”. Bioengineering, 2025, Vol 12(10), art 1122.
“Spark’s gene therapy price tag: $850,000”. News Article, Nature Biotech, Feb 6, 2018.
Morris EC, Neelapu SS, Giavridis T & Sadelain M, “Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy”. Nature Rev Immunol, 2022, Vol 22(2), pp 85–96.
Perez BA et al, “Management of Neuroinflammatory Responses to AAV-Mediated Gene Therapies for Neurodegenerative Diseases”. Brain Sci, 2020, Vol 10(2), art 119.
“Upstaza (eladocagene exuparvovec)”. Web Page, EU EMA, accessed November 2025.
Cao D et al, “Innate Immune Sensing of Adeno-Associated Virus Vectors”. Hum Gene Ther, 2024, Vol 35(13–14), pp 451–463.

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This article highlights how the right device can turn complex two-component injectables into simple, safe, and accessible treatments. If you’re exploring delivery challenges or want to design patient-friendly solutions for advanced formulations, we’d love to talk.

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Drug Delivery to the Brain: Engineering Precision Across Novel Modalities

December 2nd 2025

Dr Karla Sanchez

Head of CNS Technology

Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), motor neuron disease (MND, including amyotrophic lateral sclerosis, (ALS)), and frontotemporal dementia (FTD) remain areas with limited disease-modifying treatments. Therapeutic pipelines in this area are increasingly dominated by antisense oligonucleotides (ASOs), RNA interference (RNAi) molecules, monoclonal antibodies, and viral gene therapies such as adeno-associated virus (AAV). These modalities offer the potential to modulate genetic pathways, reduce toxic proteins, or deliver genes to modulate disease pathways.

However, the size, structure, and physicochemical properties of these modalities largely prevent them from crossing the blood–brain barrier (BBB) through systemic delivery routes. The brain’s protective architecture restricts where and how these molecules can be delivered, and their complexity introduces delivery demands that conventional administration cannot meet.

Drug development must therefore evolve in parallel with delivery system design.

Once a modality is defined, the delivery strategy and device architecture required to administer it safely, precisely and effectively must be developed alongside it.

Why New Modalities Require Bespoke Approach to Delivery

Many of the emerging central nervous system (CNS) modalities have delivery requirements that differ fundamentally from traditional therapeutics. ASOs and RNAi therapeutics, for example, require broad CNS exposure and are therefore commonly administered into the cerebrospinal fluid (CSF) rather than via more localised, parenchymal approaches. CSF flow is largely pulsatile and oscillatory, with a slow net movement along the spine. After lumbar intrathecal administration, for example, these transport dynamics together with limited diffusion and tissue uptake, usually cause the drug to stay concentrated near the injection site and to decrease progressively as it travels upward towards the brain. Because these molecules are highly charged and diffuse slowly, such gradients persist, limiting penetration into deep structures without controlled flow. Device requirements should therefore include precise catheter placement, controlled infusion, prevention of local pooling, and repeat dosing capability.

In contrast, large proteins such as monoclonal antibodies must reach cortical, subcortical, or deep-brain regions, necessitating intracerebroventricular or intraparenchymal delivery. Devices must incorporate many elements to ensure targeted delivery such as reflux-resistant geometries, strategies for targeted spatial coverage, controlled infusion profiles, and low-adsorption materials to prevent protein aggregation.

Viral gene therapies impose some of the strictest demands on delivery systems. AAV vectors are sensitive to shear forces, turbulence, surface adsorption, and pressure changes, and maintaining capsid integrity throughout preparation and infusion is critical. Delivery systems must include ultra-smooth internal surfaces, gentle and stable low flow rates, inert materials, and high-precision targeting of deep structures.

In these cases, the delivery device becomes an integral component of the therapeutic product.

Device Engineering as a Core Component of Drug Development

When delivery impacts therapeutic efficacy, the device effectively becomes part of the therapy. The mechanical, geometric, and material requirements of a delivery system must therefore be defined not only by clinical considerations, but by the physical and biological behaviour of the therapeutic agent and the tissue it enters. In the CNS, this means accounting for the poroelastic nature of brain tissue, how it deforms, absorbs, dissipates, and redistributes fluid under pressure. These properties vary markedly between grey and white matter, differ across deep nuclei and cortical layers, and evolve dynamically as disease alters cellular composition, extracellular matrix structure, and hydraulic resistance. Such heterogeneity means that a device designed for one anatomical context may not perform predictably in another, even at identical infusion parameters.

Because these biological factors directly shape how infusate spreads, engineers must design delivery systems around the interplay between modality constraints and tissue mechanics. This shifts the focus from simply handling the molecule to engineering the conditions under which it travels. Cannula-based systems, for example, are one way of addressing this focus and key decisions include selecting tip geometries that balance mechanical stability with minimal insertion trauma; choosing port architectures that control local flow vectors and prevent jetting or backflow; and tuning lumen dimensions and surface properties to reduce adsorption, shear-induced degradation, or clogging under clinically relevant conditions. Each of these choices dictates how the therapeutic is introduced into the tissue microenvironment and how reliably it follows intended distribution pathways.

Beyond the insertion device itself, infusion strategy becomes a critical engineering parameter in its own right. Flow rate, pressure control, and infusion timing must be optimised to avoid exceeding the tissue’s capacity to deform safely, a threshold that varies with pathology, age, and regional structure. In some contexts, a constant-pressure approach stabilises the infusion front, while in others, constant-flow allows more predictable volumetric spread. Incorporating features such as pressure-relief paths, multiport configurations, or dynamic flow modulation can further tailor distribution when a single port or monotonous flow profile is insufficient. The device, in other words, does not merely deliver the therapy, it shapes how the therapy propagates through complex biological substrates.

Thus, the therapeutic modality defines the device’s safe and effective operating window, from acceptable flow ranges to port geometry and infusion timing.

Integrating these constraints into device architecture is what converts a therapeutic concept into a deliverable intervention, shaping dosing, distribution, and clinical performance. This perspective anchors the subsequent design decisions and highlights why device engineering must evolve in parallel with emerging therapeutic modalities.

Research and Modelling: Validating Drug–Device Interaction

Ensuring a therapy reaches the right place (and not off-target), in the right amount, requires evidence. That evidence comes from a spectrum of approaches. In-silico modelling is often the first step, using first-principles physics, computational fluid dynamics, or finite-element methods to explore how a device, a therapeutic, and the brain’s microstructure interact. These models account for tissue porosity, elasticity, white–grey matter boundaries, fluids viscosity and dynamics, and pressure gradients to forecast how an infusion will spread before a single experiment is run.

But simulations are only as good as the worlds we build for them. Brain-mimicking hydrogels and 3D-printed phantoms provide physical testbeds where model-based predictions are challenged and refined. They make flow visible, enable rapid parameter testing, and allow researchers to probe failure modes without the constraints of animal work. These platforms narrow uncertainty and help translate computational insights into practical infusion parameters, helping guide device design.

Animal studies deliver the critical translational step, revealing how elements such as distribution, tissue response, device–tissue mechanics, and (for gene therapies) transgene expression play out in vivo. Here, the goal is not just to confirm spread, but to understand how biology responds to the physical act of delivery, a dimension no model or phantom can fully capture.

Together, these stages form an iterative design–test–refine loop, which is essential for reliable, modality-specific CNS delivery.

Collaborative Expertise and Scientific Frameworks

Because device-based delivery is integral to being able to achieve therapeutic effect of these modalities, progress depends on teams that can bridge biology, engineering, modelling, and clinical practice. Each discipline contributes a different piece: drug discovery teams define the therapeutic goal and target exposure; engineers translate those needs into device and flow-system architectures; modellers anticipate how an infusion will behave in complex tissue or fluid; neurosurgeons test procedural feasibility and targeting; imaging specialists verify where the therapy actually goes; and human factors experts ensure the device can be used safely and reliably in real clinical settings. Innovation emerges at the intersections of these disciplines, where insights are shared and refined.

To support this, many organisations draw on multidisciplinary scientific advisory boards (SABs) that span neurodegeneration, biomaterials, computational modelling, device engineering, neurosurgery, and regulatory science.

These boards provide an early-warning system for delivery challenges, shaping designs and validation strategies and ensuring that device performance stays aligned with biological and clinical requirements.

Complementing this are pre-competitive collaborations, modelling consortia, shared phantom libraries, device-testing networks, and harmonised imaging datasets, that give teams a common scientific language. These shared resources reduce duplication, improve reliability, and accelerate the path from concept to clinically deployable delivery systems.

Conclusion

Novel modalities, including ASOs, RNAi agents, antibodies, and viral gene therapies, represent the leading edge of neurodegenerative therapeutic innovation. But realising their full potential depends on delivery systems that are precise, reliable, and tailored to each modality’s unique demands.

Device design and engineering must therefore advance in parallel with drug development, supported by rigorous modelling, interdisciplinary expertise, and integrated scientific frameworks. By uniting therapeutic design with delivery system innovation, the field is laying the groundwork for meaningful progress in neurodegenerative diseases and accelerating the pace of CNS therapeutic innovation.

References

1. Yang HM. Overcoming the Blood-Brain Barrier: Advanced Strategies in Targeted Drug Delivery for Neurodegenerative Diseases. Pharmaceutics. 2025 Aug 11;17(8):1041. doi: 10.3390/pharmaceutics17081041. PMID: 40871062; PMCID: PMC12388969.

1. Gao J, Gunasekar S, Xia ZJ, Shalin K, Jiang C, Chen H, Lee D, Lee S, Pisal ND, Luo JN, Griciuc A, Karp JM, Tanzi R, Joshi N. Gene therapy for CNS disorders: modalities, delivery and translational challenges. Nat Rev Neurosci. 2024 Aug;25(8):553-572. doi: 10.1038/s41583-024-00829-7. Epub 2024 Jun 19. PMID: 38898231.

1. Wu, D., Chen, Q., Chen, X. et al. The blood–brain barrier: Structure, regulation and drug delivery. Sig Transduct Target Ther 8, 217 (2023). https://doi.org/10.1038/s41392-023-01481-w

1. Hunt MA, Hunt SAC, Edinger K, Steinauer J, Yaksh TL. Refinement of intrathecal catheter design to enhance neuraxial distribution. J Neurosci Methods. 2024 Feb;402:110006. doi: 10.1016/j.jneumeth.2023.110006. Epub 2023 Nov 13. PMID: 37967672.

1. Yuan T, Zhan W, Terzano M, Holzapfel GA, Dini D. A comprehensive review on modeling aspects of infusion-based drug delivery in the brain. Acta Biomaterialia. 2024 Sep 1;185:1-23.

1. Lonser RR, Sarntinoranont M, Morrison PF, Oldfield EH. Convection-enhanced delivery to the central nervous system. J Neurosurg. 2015 Mar;122(3):697-706. doi: 10.3171/2014.10.JNS14229. Epub 2014 Nov 14. PMID: 25397365.

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Delivering complexity: device considerations for two-component injectable formulations

October 8th 2025

María FM Balson

Featured in ONdrugDelivery, María FM Balson shares her expertise in device selection for two-component injectable formulations, and why this product area is becoming increasingly important.

Since the 1980s, when modern-day prefilled syringes (PFSs) and intravenous (IV) bags became prevalent, injectable drug delivery has steadily moved towards ready-to-use formats and integrated devices – as evidenced by the widespread adoption of self-injection devices such as autoinjectors and pen injectors.

Human factors considerations, now recognised as integral to safe and effective use of such drug-device combination products, have driven a clear trend towards simpler, more automated solutions with fewer use steps. This shift has enabled at-home care for more therapies than ever before – a key development given the growing strain on healthcare systems.

Nevertheless, the delivery of certain drugs, such as lyophilised injectables, often remains burdensome and dependent on administration by specially trained professionals. As injectable therapies evolve and become more complex, unique challenges and opportunities emerge.

Two-Component Injectables on the Rise

Let’s define two-component formulations as those consisting of two parts that, for stability or other reasons, must be kept separate throughout the product’s shelf-life, and are delivered together at the point of administration. The two constituent parts may be a solid drug and a liquid solvent or diluent (e.g. sterile water for injection) that must be mixed thoroughly before use. Alternatively, both constituents may be liquid, in which case they may either require mixing prior to delivery or be delivered sequentially (Figure 1).

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Figure 1: A simplified model of two-component injectables, classified according to the state of matter of constituent parts.

The Archetype: Solid/Liquid Reconstitution

Reconstitution is the process of adding a liquid solvent to a solid medication to dissolve it and form a solution. This may be required, at point of use, when a drug is unstable in liquid form and must therefore be stored dry. In such cases, the formulation is often filled as a liquid and then lyophilised (freeze dried) in situ. Alternatively, it may be manufactured and handled as a powder.

Freeze drying is an effective way to increase formulation stability. For small molecules, it can eliminate the need for cold-chain storage. For biologics (especially those that are large, complex or prone to aggregation) it can be a necessity in order to achieve an acceptable shelf-life.

“Lyophilised formulations now represent over 30% of all FDA-approved parenteral medications – and demand for lyophilised parenteral products is increasing.”

Lyophilised formulations now represent over 30% of all US FDA-approved parenteral medications¹ – and demand for lyophilised parenteral products is increasing, as evidenced by past drug approvals (~35 such drugs were approved by the FDA each year over the past decade, compared to ~12 per year in the decade prior²). Considering lyophilised parenterals approved in 2023, oncology and infectious disease indications represented the largest share, together accounting for ~75% of total approvals.²

As lyophilisation is on the rise, so too are devices to simplify reconstitution. A wide range of solutions are available beyond the well-established vial-and-syringe method – from primary container adaptors to dual-chamber systems.

Solid/Liquid Suspensions

Suspensions are a dosage form in which insoluble solid particles are mixed into a liquid medium. They enable delivery of insoluble drugs and can be used to formulate long-acting injections. Suspensions may be supplied as separate wet and dry components (in which case the liquid phase is added to the solid phase and mixed prior to administration) or in a single primary container that is shaken to resuspend.

While solutions can readily be reconstituted with gentle swirling, suspensions usually need a greater energy input to achieve even mixing – the required amount varies greatly depending on the chemical and physical properties of the formulation. In some cases, vigorous shaking is insufficient and benchtop equipment, such as a vortex mixer, must be used.

Given sufficient energy input, the particles will be uniformly dispersed within the liquid, however the resulting mixture will be heterogenous and unstable; it will eventually settle. Therefore, suspensions must be thoroughly mixed immediately before use. Inconsistent dispersion can lead to inaccurate dosing or needle clogging – persistent challenges for device integration.

Injectable suspensions are becoming more prevalent, particularly for severe chronic conditions such as schizophrenia and HIV,^3,4 where extended-release formulations are of particular value and which are often reliant on a suspension format to produce a long-acting depot. When formulated as separate wet and dry components, these products largely rely on vial-and-syringe or vial-adaptor workflows, with the occasional exception, such as Eligard’s reciprocating syringes, or the Abilify Maintena dual-chamber syringe.^3,4

Liquid/Liquid Mixtures

Injection of two-liquid mixtures is rarer but not unheard of. Two liquids may be mixed and delivered together out of:

Necessity: when a formulation consisting of two fluid phases is unstable in mixed form, but must be mixed prior to injection in order to achieve the intended therapeutic effect (e.g. API and polymer solutions that mix to form a long-acting depot).
Convenience: if two liquid formulations are frequently administered together, such as in combination vaccines, pharma companies may choose a dual-chamber presentation over developing a coformulation, such as with Vivaxim.⁶ In this case, mixing isn’t necessary but rather a side effect of leveraging mature dual-chamber systems (which mix the two liquids prior to administration) rather than betting on more niche sequential delivery technology.

Sequential Delivery of Two Liquids

Sequential delivery of two different liquids through a single needle or injection port has been proposed for combination therapies, as well as for IV drug administration through a vascular access device (with the drug preceded, or followed, by a catheter flush).⁷

While there are several delivery technologies in development that might enable these use cases, only one combination product in this category is on the market at the time of writing, according to data from PharmaCircle. The DuoDote emergency-use autoinjector, based on a custom primary container, sequentially injects atropine and pralidoxime chloride. It is approved for treatment of nerve agent or insecticide poisoning.

Choosing the Right Device

Choosing the right device for a two-component injectable is often an exercise in trade-offs, highly dependent on the properties of the formulation itself, indications for use and the stage of development. Hereafter, this article will assume that a two-component injectable consists of separate wet and dry constituents that are reconstituted prior to injection, unless otherwise stated. This section will briefly cover the range of available technologies, and factors to consider when it comes to device selection.

“Choosing the right device for a two-component injectable is often an exercise in trade-offs, highly dependent on the properties of the formulation itself, indications for use and the stage of development.”

Vial and Syringe: Trusty but Burdensome

Two-component injectables are often supplied in vials, with off-the-shelf (OTS) needles and syringes used for fluid transfer and subsequent injection (Figure 2). By leveraging mature primary containers and fill-finish technologies, this approach benefits from low unit cost and a robust supply chain. It is also extremely versatile, with fewer restrictions on formulation volume and viscosity compared with alternatives, the ability to accommodate different doses in a single stock keeping unit, and no need for device-specific training.

On the other hand, the process is onerous and a high degree of technical expertise is required to perform all steps correctly. Dose accuracy is highly dependent on the user, and there is a greater risk of contamination and sharps injury compared with other methods, meaning that this type of system is typically limited to trained staff in clinical settings. Moreover, some drug wastage is inevitable, with vials often overfilled by 10–20% to ensure that a full dose can always be drawn.

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Figure 2: A summary of steps required for manual reconstitution using vials and syringes.

Devices to Simplify the Reconstitution Process

Given the growing prevalence of two-component injectables and the limitations of the established vial-and-syringe method, it is no surprise that a wide range of specialist devices have been developed to aid reconstitution. Figure 3 illustrates some of the solutions available.

Primary Container Adaptors: Co-packaged with standard prefilled primary containers, these allow for drug components to be accurately pre-dosed during manufacturing, while maintaining low device and fill-finish costs.
Integrated Manual and Automated Systems: Some of these leverage standard OTS containers, while others are designed around bespoke primary containers (e.g. dual-chamber cartridges).

- Integration of device components reduces the number (and sometimes complexity) of use steps, reducing the burden of use and the likelihood of errors.

- Automated devices take this further by incorporating mechanisms in the design (such as springs or electronics) to enable reconstitution and/or delivery with minimal user input.

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Figure 3: Examples of reconstitution devices for intravenous, intramuscular and subcutaneous administration. Devices marked with an asterisk are in development at the time of writing; the others are on the market. Note that prefilled dual-chamber systems can fall within the “integrated manual” or the “automated” categories, depending on device function.

Horses for Courses: Different Drugs Have Different Needs

When choosing a device, key trade-offs include cost, time to market, dose accuracy and ease of use. Consider:

Properties of the Formulation: All reconstitution devices have their strengths and limitations; the choice of device must be compatible with the needs of the formulation. For example, dual-chamber PFSs are limited to products with relatively low volumes that reconstitute readily.
Use Case and Dose Accuracy: The choice should be made with the final user in mind; integrated and automated systems greatly simplify usage, making accurate reconstitution accessible to users with less technical expertise (e.g. patients in the home setting).
Supply Chain Implications: The choice of primary container is the single most important factor influencing development timeline and manufacturing cost of the device. Dual-chamber fill-finish is highly complex; expertise is rare and CMO capacity limited.
Stage of Drug Development: Priorities differ depending on the stage of development. For example, a novel drug in clinical trials may benefit from the use of vials, since they offer flexible dosing and use only OTS components, whereas more integrated systems may be introduced post-launch to encourage wider adoption.

Dual-Chamber Delivery Systems

Prefilled dual-chamber systems (DCSs) are “all-in-one” devices built around bespoke primary containers, designed to simplify the reconstitution and delivery of two-component injectables. This final section delves deeper into this device category – strengths, limitations and key design considerations.

Anatomy of a Dual-Chamber System

In a DCS, the primary container consists of a barrel (typically made of glass) divided into two chambers by a central stopper. This barrier keeps the drug components separate from each other throughout storage. Once the DCS is activated, a bypass mechanism allows fluid to flow from the back (wet) chamber into the front (typically dry) chamber (Figure 4).

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Figure 4: Use steps and function of a typical DCS embodiment. Note that the linear application of force causes the bypass mechanism to activate, opening a fluid path that connects the two chambers.

DCSs vary in type of closure and bypass:

The closure can be PFS-style or cartridge-style (Figure 5).
The bypass is usually external (a blister bypass), but can also be internal (such as the multi-groove design of the Genotropin MiniQuick – Figure 5, Device 5). Note that an internal bypass allows the use of standard syringe or cartridge tubs, which is advantageous for manufacturing. Emerging designs, such as Credence MedSystems’ fenestrated needle bypass, also have the additional benefit of being compatible with OTS syringes.

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Figure 5: Approved DCS products (all marketed, bar Tanzeum, which has been discontinued). Left: dual-chamber prefilled syringes. Right: integrated injection devices built around dual-chamber cartridges. Device 1 contains a lyophilised suspension; Devices 2, 4, 5 and 6 contain lyophilised solutions; and Device 3 contains two liquids for co-administration.

Bespoke Primary Containers: A Double-Edged Sword

Like other specialist reconstitution devices, DCSs make administration of two-component injectables accessible to a wider range of users and care settings. They require less technical expertise to use accurately and consistently, with fewer and simpler handling steps, pre-measured drug components and reduced sharps exposure.

“Thanks to this design, DCSs can readily be integrated into devices with enhanced usability and/or advanced features.”

However, their unique strength lies in their form factor – the single barrel with a bypass that can be activated with a co-linear application of force (so both mixing and delivery are done by pushing on the rear plunger in a straight motion). Thanks to this design, DCSs can readily be integrated into devices with enhanced usability and/or advanced features. For example:

Xyntha Solofuse, an easy-to-use device with a simple finger flange (Figure 5 Device 2).
Caverject Impulse, an integrated manual system with dose selection capability (Figure 5 Device 4).
The reusable Skytrofa Autoinjector, pictured in Figure 3 with the green needle guard.

The flip side of the form-factor coin is that complexity is pushed into the manufacturing and filling process. Fill-finish for these devices requires specialist equipment and know-how (as noted above, expertise is rare and capacity is limited) and lyophilisation is inherently less efficient in the dual-chamber geometry compared with vials (smaller batches, poorer energy transfer, longer cycle times⁶). It all adds up to greater up-front investment and time-to-market, higher unit cost and a restricted supply chain.

For this reason, DCSs have so far been limited to premium value products, such as those used to treat rare diseases (e.g. haemophilia, growth hormone deficiency) or those that solve complex or critical clinical challenges (e.g. unmet needs, home care).⁶

Design Considerations

Current marketed DCSs have inherent technical limitations that impact formulation compatibility and device design. For example:

Capacity is limited to ~4 mL total reconstituted volume: Headspace in the front chamber must be sufficient to accommodate the initial plunger stroke required to open the bypass, both drug components, and additional room for swirling and mixing. Therefore, there is a limit to how much can be delivered with these devices before they become too large to be practical.
Venting and orientation are important: There usually needs to be a path to atmosphere during mixing to avoid pressure build-up in the front chamber (if there is a large amount of headspace in the powder chamber, this may not be required). In all cases, excess air must be vented prior to injection, which can be challenging and requires careful handling, as the device must be kept upright whenever there is a path to atmosphere to avoid drug spilling through the needle.
Plunger motion must be well controlled: When the bypass opens, the pressure in the system drops sharply. Unless the plunger’s forward motion is well controlled, there is a risk of prematurely locking out the fluid path, which would prevent the liquid in the back chamber from being fully incorporated into the mixture. To prevent this, many devices incorporate a screw mechanism that enforces a slower twist-to-mix action.
They are best suited to lyophilised formulations that are readily reconstituted with gentle swirling: Suspensions can only be delivered if the energy required to suspend is low. In addition, sequential delivery is not possible without specialised valve design (some mixing will always take place with the currently marketed DCSs). Finally, very particular considerations apply to the delivery of liquid/liquid mixtures – space is at an even greater premium, venting becomes critical and mixing performance varies widely depending on the specific device and formulation.

Looking Ahead

Meeting the next generation of injectable delivery challenges will demand the best of device innovation, alongside advances in formulation and process development. As therapies grow more complex, the need for close cross-functional collaboration becomes increasingly critical.

Developers of combination products will continue to face trade-offs between usability, flexibility, cost and manufacturability. To navigate these successfully, device and formulation experts must work hand-in-hand with clinical, regulatory, commercial and access stakeholders. Working together, we can deliver medicines that are fit for purpose today, and ready to meet the needs of tomorrow.

References

Kumar S et al, “Application of lyophilization in pharmaceutical injectable formulations: An industry and regulatory perspective”. J. Drug Deliv. Sci. Technol., 2024, Vol 100, article 106089.
Gray J, “LyoHUB 2024 Annual Report”. 2024. Available from: https://pharmahub.org/resources/1112
“Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations”. Web Page, US FDA, accessed Jul 2025.
“Purple Book: Database of Licensed Biological Products”. Web Page, US FDA, accessed Jul 2025.
“DailyMed: Prescription drug labeling and information.” US National Library of Medicine, accessed Jul 2025.
Werk T et al, “Technology, Applications, and Process Challenges of Dual Chamber Systems”. J Pharm Sci, 2016, Vol 105, pp 4–9.
Sousa et al, “Brief Report on Double-Chamber Syringes Patents and Implications for Infusion Therapy Safety and Efficiency”. Int J Environ Res. Public Health, 2020, Vol 17(21), art 8209.

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Designed to deliver: How collaboration created an award-winning device that puts patients first

July 16th 2025

Frances Pencliffe

Operations Lead – Drug Delivery

When Credence MedSystems set out to build on the capabilities of their Dual Chamber Syringe System (DCSS), they weren’t just looking to adapt it – they wanted to expand its potential. Together, we set out to create a new platform for at-home, sequential-drug delivery: one that combined human-centered design, deep technical know-how, and the power of partnership. Over the course of the project, our teams worked together to bring that vision to life. The result? A Red Dot 2025 award-winning demonstration autoinjector that not only showcases the functionality of the DCSS, but also reimagines how two drugs can be delivered at home in one simple injection.

Three Ingredients for Award-Winning Device Design

1. End-to-End Expertise

This project brought together two areas of specialist knowledge. Credence brought the core technology: a dual-chamber syringe system with automatic needle retraction that uses standard glass components, designed for sequential delivery of two formulations. Our team contributed deep experience in autoinjector design, usability, and manufacturing engineering. We translated complex drug delivery requirements into devices that are safe, manufacturable, and easy to use.

2. Close Collaboration

This was a shared, iterative development process built on close collaboration. From the outset, the teams worked together to define key requirements and align on a shared vision. By combining Credence’s knowledge of their container system with our insight into autoinjector mechanisms and user experience, This allowed us to accelerate from concept to working demonstration.

We shaped the engineering and design direction through regular feedback loops. Both teams were actively involved in decision-making throughout. When the Credence team visited our site in Cambridge, UK, we held a hands-on working session to evaluate both functional prototypes and industrial design handling models. Together, we assessed the feel of device activation, form factor, and visual cues. We blended technical and aesthetic considerations to arrive at the perfect overall experience.

The feedback was immediate. One mechanism was described as “smooth as butter”. This was a clear signal that we were on the right path.

3. Built-in User-Centered Thinking

While the request was to develop a reloadable, robust model for demonstration purposes. The long-term goal was always to support at-home use. We designed the experience to closely emulate the familiar, two-step workflow of a single-chamber autoinjector, while delivering the additional benefit of dual-drug administration. In addition, we made the demo unit reusable and resettable for hands-on use. We developed it with a clear development pathway towards a single-use, commercial device.

We also considered communication and clarity from the outset. Exploring iconography, leaving space for regulatory labeling, and ensuring the device visually conveyed key aspects of the user benefits.

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From initial sketches…

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…through concept renders…

…to the real thing

Platform Flexibility

What makes this device stand out isn’t just the sequential delivery of two formulations. It’s the fact that the same primary container can be used across both prefilled syringe and autoinjector formats without changing any drug-contacting components. This flexibility helps reduce development burden. It simplifies supply chains and makes it easier for pharmaceutical partners to scale and adapt their delivery format over time. There’s also a clear benefit for patients. Fewer injections, simpler instructions, and added confidence that both parts of the treatment are delivered, every time. Beneath it all lies a sustainability advantage. With a sequential delivery device, there’s only one autoinjector to manufacture, ship and dispose of. This can make a meaningful difference at scale.

As a result, this wasn’t just a concept exercise. It was a real-time demonstration of what’s possible when two expert teams bring their strengths to the table. We developed a fully-functioning demo platform and in doing so, also laid the groundwork for future commercial evolution, including a clear view of what it would take to move from demo model to single-use device.

Our shared focus, technical excellence, and momentum powered this collaboration. We’re proud to see this work recognized with an industry award.

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For more on how to turn patient-centred thinking and collaborative engineering into award-winning drug delivery devices, contact Cambridge Design Partnership.

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EXCLUSIVE INSIGHTS

Advancing Injectable Drug Delivery Systems

Increase the chance of commercial success

By Clare Beddoes • Head of Drug Delivery

Featuring exclusive interviews from industry leaders and pharma innovators

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Tell us a bit about yourself and we’ll email the guide directly to you.

Each article provides exclusive insights on different aspects of injectable drug delivery, offering valuable perspectives on design, usability, and market trends

Expert Perspectives and Innovations

As more complex injectable drugs move from clinic to home, are devices keeping pace with patient expectations and healthcare system expectations?
What does it take to make drug delivery safer, simpler, and more effective, especially when every second counts?
What role does user-centered design play in making advanced therapies more accessible and effective?
Looking ahead, how can delivery technology help unlock access to life-changing treatments?

To answer these questions, this downloadable PDF explores the future of injectable drug delivery, spotlighting innovations that are transforming patient care. Furthermore, through real-world examples, we dive into how device design, patient-centricity, and pharma-device collaboration are reshaping the landscape.

Download the guide to access the full interviews and explore these insights in detail:

Epinephrine injectors for pediatric use
Improving usability for effective emergency treatment

Ocular drug delivery
Advancing sustained release to ease the burden of acute therapies

User-centered infusion pumps
Enhancing patient comfort and convenience

Advanced Parkinson’s Disease treatments
Strategies to overcome regulatory challenges

platform technologies|Figure 1: Platform devices are designed to support delivery of multiple formulations.|Figure 2: Example platform test plan (for each precondition) to provide confidence in the performance envelope.|Figure 3: Example bridging test plan for injection device.

Analysis

Healthcare

From platform to product: Accelerating time-to-market for platform technologies

29th January 2025

Fran Pencliffe of Cambridge Design Partnership explores the benefits of platform devices for parenteral delivery and outlines the challenges, risks and best practices when bringing a combination product to market in this way.

Analysis

Drug Delivery

Healthcare

Pump It Up: User-Centered Infusion Pumps on the Rise

14th November 2024

The pharma industry’s move towards larger volumes of subcutaneous (SC) therapeutics and home-based care is increasing the demand for self-administration devices. We recently partnered with KORU to explore innovations in infusion pump technology aimed at enhancing patient comfort and convenience

Therapy assistant for parenteral drugs

21st April 2020

Patients suffering from chronic diseases such as rheumatoid arthritis or multiple sclerosis often follow a complicated treatment regimen at home. They sometimes need to store their drugs in the fridge, warm them up to the correct temperature for injection, prepare their auto-injector for use and finally dispose of the used device safely.

Navigating new frontiers: Bringing Parkinson’s treatments to new markets

February 6th 2025

Krai Chatamra

Steve Augustyn

Senior Consultant Mechanical Engineer

Advances in drug delivery and strategies to overcome regulatory challenges for global patient access

Patients with Advanced Parkinson’s Disease (APD) face significant challenges in managing their symptoms and maintaining their quality of life. Effective, continuous dopaminergic stimulation treatment options are critical, as conventional oral therapies no longer offer adequate relief with advancing disease state. Advanced device-aided therapies that provide consistent symptom control are essential for improving patient outcomes and enabling a more independent lifestyle.

However, bringing these innovative treatments to market is challenging. Adequate control of APD via continuous treatment can require a combination of drug products, delivered with an infusion pump that is flexible enough to meet the needs of different patient groups yet simple enough for home use.

When deciding on a pump solution, companies must choose whether to adapt existing technologies or develop new solutions from scratch; each path requiring different developmental strategies and involving differing levels of investment and risk. They must then navigate an often-changing regulatory landscape with distinct requirements across regions, adding complexity to the development and approval process.

This article, authored by Steve Augustyn, Deputy Head of Drug Delivery at Cambridge Design Partnership, featuring insights from Krai Chatamra, Vice President of Clinical Development at Intrance Medical Systems Inc (Intrance), explores the necessity of advanced therapies that provide consistent symptom control to improve patient outcomes and enable a more independent lifestyle.

Krai Chatamra has decades of experience in the pathology and treatment of APD. In this article, Steve Augustyn spoke to Krai about the process of bringing a new treatment for APD to the market.

To clarify some of the terminology used in this article;

a drug substance is the active pharmaceutical ingredient
a drug product is the final dosage form that includes the drug substance
a combination product (in this instance) is the drug product working with the specified infusion pump.

Intrance Medical Systems, Inc. is developing a next-generation therapy for patients with APD. The lead product combines a proprietary gel formulation of carbidopa, levodopa and entacapone delivered by an ambulatory infusion pump. The pump delivers the medication directly to the jejunum via a percutaneous endoscopic gastrostomy (PEG) tube, enabling continuous treatment for patients with APD, removing the burden of managing complex oral dosing regimens and preventing the complications associated with the unpredictable motor fluctuations.

Cambridge Design Partnership (CDP) recently supported Intrance in the verification of its selected infusion device, clearing the way for a Phase III clinical trial as part of the company’s marketing application for the US. The verification required hundreds of delivery profile tests to meet the latest requirements in AAMI TIR 101:2021 (Fluid delivery performance testing for infusion pumps) to demonstrate the safety and accuracy of Intrance’s combination product.

Challenges and innovations in APD therapies

Complexity of APD

Krai: Parkinson’s Disease is a vast field. Currently, we are concentrating on the advanced stage of the disease, which is uniquely complex. As the disease progresses, it becomes increasingly multifaceted. Conventional oral therapies are ineffective at this advanced stage.
In APD, patients experience motor fluctuations between two highly disabling states: OFF, where they are unable to move, and hyperkinetic [dyskinetic], where they move uncontrollably. Patients typically spend at least 50% of their waking hours oscillating between these two states. Our goal is to thread the plasma level of L-dopa into the narrow therapeutic window, thereby avoiding patients experiencing such disabling OFF and dyskinetic states.

The challenge of maintaining levodopa levels

Krai: The plasma level of levodopa must be maintained within this very narrow therapeutic window, which continues to narrow as the disease progresses. Therefore, we need a drug delivery system that can precisely regulate the plasma levodopa levels within this narrow synaptic window. This is our biggest challenge.

Our current product, Lecigon, is an investigational drug in the US. However, it has already been approved in multiple European countries. So, the challenges we face are distinct from those encountered by other companies developing drugs or devices for different stages of PD.

“We need a drug delivery system that can precisely regulate plasma levodopa levels within a narrow synaptic window.”

Krai Chatamra | Vice President of Clinical Development at Intrance Medical

Identifying a suitable device platform

Multifaceted challenges

Krai: The challenges are multifaceted. Firstly, there is a constantly changing regulatory landscape. Secondly, each regional governance has its own requirements, which are not necessarily aligned. Lastly, we had to weigh the availability of existing pumps versus the invention of a completely new device, both of which require different developmental pathways. Before deciding on the final infusion device, we had to go through numerous qualifying steps in great detail.

We initially targeted the European market. We are now moving to the US, and ultimately Japan.

“There is a constantly changing regulatory landscape, and each regional governance has its own requirements, which are not necessarily aligned.”

Krai Chatamra | Vice President of Clinical Development at Intrance Medical

Differences in verification and validation: drug products vs. medical infusion pumps

Distinct development pathways

Krai: The developmental pathways from a regulatory perspective for a drug product and a medical device are quite different. While there are some common themes, such as ensuring safety for patients, the requirements, especially in the US, differ significantly between the drug and the device.

We are dealing with different administrative arrangements, review procedures, and guidelines. Collectively, these differences mean that the paths to take a product – whether it be a drug, device, or combination of both – from development to market are distinct.

For those new to drug-device development, whether developing products independently or as combination products, it’s important to understand that the process, in the US, ultimately depends on which center (e.g. CDER, CBER or CDRH) your product is filed with.

“The requirements, especially in the US, differ significantly between the drug and the device.”

Krai Chatamra | Vice President of Clinical Development at Intrance Medical

Advice for developing a combination product for neurological conditions

Do your homework

Krai: The single most important piece of advice I would give [when developing a combination product] is to do your homework thoroughly. This may sound simplistic, but it involves several critical steps. First, understand the disease you are targeting.

Second, know the region [you plan to seek marketing approval in]: Understand the regulatory and market conditions. For example, if you are targeting the US, you need to be aware of the existing availability of infusion pumps, which can help you navigate the requirements for pump testing. (Using an infusion pump that is already approved for use in the US can substantially reduce the amount of testing and risk in the process.)

Third, decide on the product approach: Determine whether you want to use an existing device that is already in use elsewhere, or develop something new yourself.

These three elements are crucial prior to committing additional resources to your program.

“Determine whether you want to use an existing device that is already in use elsewhere, or develop something new yourself.”

Krai Chatamra | Vice President of Clinical Development at Intrance Medical

Future trends and developments in APD therapies

Promising advances in drug administration

Krai: The future looks promising. Over the past ten years, many companies have recognized that different methods of drug administration are not only useful but are also safe and effective. There are now multiple ways to introduce drugs to patients. Oral treatment is now considered the least effective for APD due to the inability to completely overcome the issues associated with gastric complications of the stomach, e.g. erratic discharge, interaction with amino acids etc. The only way to overcome this is to bypass the biggest culprit, the stomach.

Several companies are exploring alternative methods of administration for PD therapies, such as enteral, subcutaneous, or sublingual routes. These methods, combined with advancements in drug formulation, have significantly improved treatment options. Levodopa, for example, is recognized as notoriously insoluble until recent advancements enabled it to be dissolved in a suitable medium.

Advancements in formulation, pump technology, and alternative methods of administration have contributed to the development of multiple new products. It is an exciting time to be involved in this field.

Opportunities for continuous blood serum monitoring

Krai: It would be remiss of us in PD therapeutic development not to recognize how other fields have successfully approached similar problems. For example, in diabetes management, continuous monitoring is crucial, and the ability to intervene as needed has been a significant success.

For PD, the challenges are similar. If we could monitor patients’ symptoms – both motor and non-motor – and adjust the treatment dosage accordingly, it would be highly advantageous. There are ongoing developments in this field, particularly with various wearables that are being developed rapidly and are becoming more prevalent.

The future I envision involves the combined use of infusion treatments and continuous monitoring. Imagine if we could detect when a patient’s plasma levodopa level is dropping, accompanied by certain symptoms, and then automatically adjust the drug delivery. That would be ideal.

“Imagine if we could detect when a patient’s plasma levodopa level is dropping, accompanied by certain symptoms, and then automatically adjust the drug delivery.”

Krai Chatamra | Vice President of Clinical Development at Intrance Medical

PD therapy is rapidly advancing, marked by significant advances in drug delivery technologies. These innovations are already providing significant improvements in patient outcomes and quality of life. Navigating the distinct regulatory environments across different markets is crucial. Understanding these differences is essential for successfully bringing new treatments to the market. CDP helps clients address this challenge by providing expert guidance on all aspects of drug delivery device design and verification.

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If you would like to discuss the content of this article, please get in touch with Steve Augustyn, Deputy Head of Drug Delivery at Cambridge Design Partnership:

Steve Augustyn, Deputy Head of Drug Delivery
steve.augustyn@cambridge-design.com

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Design Verification for the Real World: Complex Drug Delivery in Uncontrolled Environments

Design Verification Testing of Ambulatory Infusion Pumps

Beyond IEC 60601-2-24

Establish the Test Matrix and Reporting Metrics

Design and De-risk the Test Process

Execute the DV Testing

Conclusion

ACKNOWLEDGEMENT:

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De-Risking Post-Market Change Through Pilot Production for Drug Delivery Devices

What Drives Change in Drug Delivery Devices?

A Common Challenge

Contract Manufacturing can be Inflexible

Conventional Prototyping Lacks Rigour

Why Existing Production Lines May Not Accommodate Design Changes

Developing a Hybrid Manufacturing Strategy

Implementation and Outcomes

Conclusion

REFERENCES:

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From Impossible to Feasible: Using Theoretical, Synthetic and Tissue Models to Accelerate Novel Drug Delivery Development

Introduction

What Does Feasibility Really Mean?

The Model Landscape: A Brief Orientation

Framing the Right Questions: A Worked Example

1. What is the delivery force?

2. Will the device achieve the required formulation distribution in the tissue?

3. How will the device influence the clinical effect?

Conclusion

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Featured Insights

Precision Delivery: The Missing Link In Cell & Gene Therapy

Drug Delivery to the Brain: Engineering Precision Across Novel Modalities

CNS Drug Delivery – Precision delivery for complex therapies

Sustainable pharmaceutical packaging without compromising safety or usability

The structural tension at the heart of pharmaceutical packaging

Why the pressure is now unavoidable

1. Regulation is becoming a market access issue.

2. Stakeholder expectations are rising.

3. The business case is shifting from “nice to have” to “must manage”.

What we see in real programs

A practical framework for executive decision-making

How CDP helps

The opportunity

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Precision Delivery: The Missing Link In Cell & Gene Therapy

Where Precision Matters Most In CGTs

When Precision Becomes A Moving Target

How To Demonstrate Precision

Conclusion: Precision Delivery Is The Next Frontier

References

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Featured Insights

Medical Device R&D: How to Focus Your Team on What Matters Most

Prioritize Innovation and Commercial Viability in Surgical Robotics with Intelligent Architecture

Design Verification for the Real World: Complex Drug Delivery in Uncontrolled Environments

Drug Delivery to the Brain: Engineering Precision Across Novel Modalities

Why New Modalities Require Bespoke Approach to Delivery

Device Engineering as a Core Component of Drug Development

Research and Modelling: Validating Drug–Device Interaction

Collaborative Expertise and Scientific Frameworks

Conclusion

References

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Delivering complexity: device considerations for two-component injectable formulations

Two-Component Injectables on the Rise

The Archetype: Solid/Liquid Reconstitution

Choosing the Right Device

Vial and Syringe: Trusty but Burdensome

Dual-Chamber Delivery Systems

Looking Ahead

References

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Designed to deliver: How collaboration created an award-winning device that puts patients first

Three Ingredients for Award-Winning Device Design

Platform Flexibility

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EXCLUSIVE INSIGHTS

Advancing Injectable Drug Delivery Systems

By Clare Beddoes • Head of Drug Delivery