Delivery-device constraints, including volume, viscosity, injection force, and administration time, increasingly shape formulation strategy.
High-concentration, low-volume biologics and lower-concentration, larger-volume products present different formulation, manufacturing, and usability tradeoffs.
Primary containers, contact materials, and device components can affect stability, compatibility, dose delivery, and product quality.
Human-factors engineering should inform formulation and device decisions before the final product configuration is fixed.
Integrated formulation and device development can identify incompatibilities earlier and reduce the risk of costly late-stage changes.
The Delivery System Is a Product-Design Input
Formulation development is often described as the process of creating a stable, manufacturable drug product and then identifying an appropriate container and delivery mechanism. That sequence may be workable for some conventional presentations, but it becomes increasingly difficult to sustain when the delivery system places tight limits on volume, viscosity, administration time, user interaction, or dose accuracy. In those cases, the device cannot be treated as a downstream packaging choice. Its capabilities become inputs to the formulation strategy.
This does not mean that developers should select a device in isolation and force the formulation to conform to it. Formulation and device requirements influence each other. A device may establish the available fill volume, acceptable delivery force, dosing rate, contact materials, and administration procedure, while the formulation determines whether those requirements can be met without compromising stability, manufacturability, or clinical performance. Development therefore needs to account for both parts of the system early enough that a change in one can still inform the other.
Regulatory expectations increasingly reflect this integrated view. Essential drug-delivery outputs include the characteristics needed for a device to deliver the intended dose accurately and reliably under expected conditions of use. Those outputs must be established, verified, and validated for the finished product rather than assumed from the performance of a device considered separately from the drug it will deliver. The same principle applies to interactions among the formulation, primary container, device components, manufacturing process, and user interface. Each can influence the quality, safety, or performance of the final combination product.
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The practical implication is that delivery objectives should begin shaping formulation development before the dosage form is fixed. Route, dose, dosing frequency, administration setting, intended user, and target delivery time can all narrow the formulation space. By identifying those constraints early, development teams can select formulation and device strategies that are compatible with the intended product rather than discovering late that a technically sound formulation cannot support the desired method of administration.
Beginning with the Target Delivery Experience
A formulation cannot be optimized meaningfully without a clear definition of how the product is expected to be used. The same molecule may require very different formulation attributes depending on whether it will be administered in a hospital, infused in a clinic, injected by a healthcare professional, or self-administered by a patient at home. These settings differ not only in convenience but also in the acceptable complexity of preparation, the level of training available, the time permitted for administration, and the ability to manage an incomplete or interrupted dose.
The intended user is equally important. A device designed for self-administration must account for the physical and cognitive capabilities of the people expected to operate it. Grip strength, dexterity, vision, hearing, health literacy, familiarity with the treatment, and disease-related limitations may all affect whether users can complete critical tasks correctly. Those considerations can translate directly into formulation requirements. A highly viscous product may demand greater actuation force or a longer injection time. A product requiring reconstitution may add preparation steps that increase the opportunity for error. A formulation that produces discomfort, irritation, or another immediate reaction may affect whether the user can complete administration as intended.4,5
The target delivery experience should therefore be defined alongside the target product profile. This includes the route, dose, frequency, intended setting, expected administrator, acceptable preparation burden, desired delivery time, and the type of feedback needed to confirm that dosing has started and finished. These choices help establish what the formulation must accomplish and which device concepts remain realistic.
Patient centricity should not be reduced to choosing the smallest device or the presentation that appears most convenient in isolation. Patients may value home administration, shorter treatment time, fewer preparation steps, or less discomfort, but preferences vary across populations and products. A device that performs well for one group may be difficult for another to operate, and a preferred presentation may not be compatible with the dose, formulation, or stability profile. Development decisions must balance preference with dose accuracy, product quality, compatibility, manufacturability, and safe use.4,6
Beginning with the intended delivery experience does not predetermine the final device. It defines the problem that the formulation and device must solve together.
Dose, Volume, Concentration, and Device Capacity
Subcutaneous biologics illustrate the relationship between device selection and formulation strategy particularly clearly. The therapeutic dose determines how much protein must be administered. The available delivery volume influences the concentration needed to provide that dose. Device capacity, route-specific constraints, administration time, and patient tolerability then determine whether that formulation can be delivered as intended.
One option is to concentrate the protein sufficiently to fit the dose into a relatively small volume. This approach can support compact delivery formats and may preserve a familiar injection procedure, but it can intensify viscosity, stability, and manufacturing challenges. Another option is to use a lower-concentration formulation delivered in a larger volume through a system designed for slower or extended administration. That strategy may reduce some of the pressure associated with very high protein concentrations, but it can introduce a larger device, a longer wear or injection time, and a different set of usability and performance requirements.7,8
Neither approach is inherently preferable. The appropriate choice depends on the molecule, dose, dosing frequency, intended use setting, user population, manufacturing process, and commercial presentation. A formulation intended for a compact autoinjector must operate within the container volume and force capabilities of that device. A formulation intended for a larger-volume system may have more concentration flexibility but must remain suitable throughout a longer delivery period and under the mechanical conditions created by the selected system.
This tradeoff demonstrates why device selection can change the formulation problem rather than merely determine how an already finished formulation will be administered. Choosing a small-volume presentation places more emphasis on concentration, viscosity, injectability, and high-concentration stability. Choosing a larger-volume presentation may shift attention toward delivery duration, device attachment, dose completion, residual volume, and the behavior of the formulation during extended administration.
The expanding range of large-volume subcutaneous products and clinical programs shows that developers are no longer limited to a single delivery model. Compact injectors, prefilled syringes, larger-volume autoinjectors, on-body systems, pumps, and formulation-enabling approaches can address different combinations of dose, volume, viscosity, and administration time. This broader design space increases flexibility, but it also makes early coordination more important because each presentation establishes a different set of formulation requirements.9
When a Compact Device Demands a High-Concentration Formulation
Fitting a large biologic dose into a limited volume often requires a high-concentration formulation. As protein concentration rises, interactions among molecules can increase viscosity substantially, although the magnitude and mechanism vary by molecule. High viscosity can then affect nearly every stage of product development, from mixing and filtration to filling, storage, and administration.7,10
During manufacturing, highly viscous solutions may be more difficult to transfer, homogenize, filter, and fill consistently. These challenges can affect processing time, equipment selection, yield, and the ability to maintain uniformity. During administration, viscosity influences the force required to move the formulation through the primary container, needle, and delivery path. A formulation that is stable in bulk and can be filled successfully may still exceed the mechanical capabilities of the intended device or create an injection experience that is too long or demanding for the target user.
The relationship among viscosity, needle dimensions, injection force, and delivery time creates a set of interdependent design decisions. A narrower needle may reduce the perceived invasiveness of injection but increase resistance to flow. A faster injection may shorten the user experience but demand more force. A slower injection may lower the force requirement but extend the period during which the user must hold or wear the device correctly. These parameters cannot be optimized independently from the formulation.
High concentration can also affect physical stability and other product attributes. Protein–protein interactions may contribute to aggregation or other forms of instability, and the excipient strategy used to manage viscosity may have consequences for osmolality, tonicity, pH, chemical stability, or tolerability. Formulation development must balance these attributes rather than treating viscosity reduction as an isolated objective.8,10
As a result, representative testing is critical. Bulk measurements can identify promising candidates, but they do not fully reproduce the stresses and interfaces present in the finished presentation. Formulations should be evaluated in the intended primary container and, as development progresses, in representative delivery systems. That testing can reveal whether plunger movement, break-loose force, glide force, pumping behavior, residual volume, or delivery time changes over shelf life or under expected storage conditions.
The device requirement can therefore serve as an early screening criterion. A formulation that cannot be delivered within the device’s force, time, or volume limits should not advance solely because it performs well in conventional stability studies. Recognizing that incompatibility early allows the team to adjust concentration, excipients, container components, needle geometry, device mechanics, or the delivery concept while options remain open.
When a Larger-Volume Device Changes the Formulation Problem
Larger-volume delivery systems offer a conceptually straightforward alternative to continually increasing protein concentration. By expanding the volume available for administration, developers may be able to deliver the required dose at a lower concentration. This can reduce viscosity pressure and may provide greater flexibility when optimizing stability, excipients, and manufacturing performance. It may also avoid some of the processing challenges associated with highly concentrated protein solutions.7,8
The formulation challenge does not disappear. It moves into a different part of the system. A larger-volume device may require the product to remain attached to the body or otherwise engaged with the user for a longer period. The formulation must remain homogeneous and deliverable throughout that interval. The device must maintain contact, control flow, avoid interruption, and deliver the intended dose under realistic conditions of posture and movement.
Longer delivery times also elevate questions that may be less prominent in a rapid injection. Developers may need to examine the effects of partial dosing, flow interruption, occlusion, residual volume, temperature exposure during use, and the stability of the formulation after activation. Feedback mechanisms become important because users must know whether delivery has started, is progressing, and has finished. The risk analysis may also need to address what happens if the device is removed too soon or loses adhesion before completing the dose.
These systems can change the user experience in ways that are neither uniformly positive nor negative. A slower administration may reduce the need for extreme concentration or high injection force, but a wearable or on-body device may be more visible, require longer interaction, or impose different preparation and disposal steps. The acceptability of those tradeoffs depends on the disease, treatment frequency, duration of therapy, and patient population.
The distinction between high-concentration, low-volume and lower-concentration, higher-volume development is therefore not merely technical. It affects manufacturing, clinical use, human factors, product positioning, and the evidence required to support the finished presentation. The device defines which formulation pressures can be relaxed and which new system-level requirements must be controlled.9
The Primary Container and Materials Are Part of the Formulation Environment
The delivery system begins with the primary container. Vials, cartridges, syringe barrels, stoppers, plungers, seals, lubricants, needles, tubing, reservoirs, and other components create the environment in which the formulation will be stored and delivered. Their materials and interfaces can influence product quality long before the device is activated.
Device and container materials may introduce extractables or leachables, contribute particles, adsorb the active ingredient, or alter the effective dose. Lubricants and surface treatments may interact with proteins or other formulation components. Seals and elastomers must maintain container-closure integrity throughout storage and use, while also allowing the mechanical movement required for administration. These interactions can change over time and may be affected by temperature, orientation, transport, sterilization, and repeated mechanical stress.2,3
The interaction is bidirectional. The device material can affect the drug product, but the formulation can also affect the device. A formulation may cause swelling, degradation, loss of mechanical strength, or changes in the performance of materials along the fluid path. A system that appears mechanically suitable with water or a simple placebo may behave differently when exposed to the actual formulation over the intended shelf life.
This creates a strong argument for assessing compatibility in the finished configuration rather than relying exclusively on data from individual components. The formulation, primary container, delivery path, and device should be evaluated under the conditions expected during manufacturing, storage, shipping, and use. Sterilization methods and assembly processes also require attention because a method suitable for one constituent may alter another. The stability of the final combination product may therefore differ from the stability of the formulation or device assessed separately.2
A late change in primary container or device can have consequences beyond mechanical fit. It may alter extractables and leachables, adsorption, particulate risk, container-closure integrity, delivery force, fill–finish operations, or stability. Depending on the development stage and the extent of the change, it may also raise comparability, bridging, human-factors, and regulatory questions.11
Treating the container and device as part of the formulation environment helps prevent the assumption that a stable bulk drug product will remain unchanged once placed into its final presentation.
Beyond Injectables: Formulation and Device as a Single Performance System
The influence of device design on formulation requirements extends well beyond parenteral products. Nasal and inhaled therapies provide a clear example because the clinically relevant dose is created through the interaction of the formulation with the delivery system at the moment of administration.
For these products, viscosity, density, surface tension, rheology, particle or droplet characteristics, and suspension behavior can affect metering, atomization, plume geometry, spray pattern, and emitted dose. Pump and actuator design determine how the formulation is drawn, pressurized, and dispersed. Priming, repriming, orientation, actuation force, and the interval between uses may also affect performance. A formulation cannot therefore be evaluated independently from the pump, actuator, container, or nebulization mechanism intended to deliver it.12
Changing the delivery device may alter performance even when the formulation remains nominally unchanged. A different pump can produce different droplet sizes or spray characteristics. A change in formulation viscosity or surface tension can affect how an existing device meters and atomizes the dose. These interactions influence where and how much product is deposited, making device and formulation controls inseparable from clinical delivery.
This principle also clarifies why product specifications must include system-level performance attributes rather than relying only on conventional chemical assays. Potency and purity remain essential, but they do not establish that the device will emit the correct amount, produce the intended particle or droplet distribution, or perform consistently throughout its use life.
In such products, the device does more than dispense a prepared dosage form. It participates in generating the dose that reaches the patient. Formulation development must therefore account for the mechanical and aerodynamic conditions created by the selected system from the beginning.
Designing for the User Without Oversimplifying Patient Preference
User needs can influence both device design and formulation strategy. A device may function correctly in engineering tests yet remain unsuitable if intended users cannot prepare, activate, hold, monitor, or dispose of it reliably. Human-factors engineering helps identify those risks before the design is fixed.
Formative evaluation should occur iteratively during development. Early studies can reveal whether users understand the instructions, apply enough force, maintain the required orientation, recognize feedback, or complete the full administration sequence. These findings may lead to changes in the device, labeling, packaging, training, or formulation. A longer injection time caused by viscosity, for example, may require clearer progress feedback or a different activation method. A multistep reconstitution process may indicate a need for a simplified presentation or additional error controls.4,5
The complete user interface includes more than the device housing. Packaging, instructions, labels, preparation steps, accessories, feedback signals, and disposal procedures all shape whether the product can be used safely. The formulation contributes to that interface through injection duration, actuation force, preparation requirements, sensory effects, and the consequences of interruption.
Patient preference should inform these decisions, but it should not be treated as uniform or self-evident. Many patients value at-home administration, yet preference varies by disease, prior experience, device design, treatment burden, and confidence in self-administration. Studies comparing devices also show that specific attributes, such as ease of activation, feedback, discomfort, and injection pain, can influence preference.6 These findings support direct research with representative users rather than assumptions about what patients will choose.
The goal is not simply to produce the most convenient-looking presentation. It is to design a product that intended users can operate correctly while preserving dose accuracy, formulation stability, manufacturing control, and acceptable treatment burden.
An Integrated Development and Control Strategy
Designing around a delivery objective requires closer coordination among formulation scientists, device engineers, analytical teams, clinical pharmacologists, human-factors specialists, manufacturing experts, quality functions, and regulatory teams. Each discipline controls part of the same product system, and decisions made in one area can create constraints elsewhere.
Development should begin by defining the dose, route, use setting, intended users, and target administration experience. Those goals can then be translated into preliminary formulation and device requirements, including volume, concentration, viscosity, delivery time, force, primary-container format, material compatibility, preparation steps, and essential delivery outputs.
Formulation candidates should be screened against realistic device constraints rather than evaluated only for bulk stability. Device concepts should likewise be tested with representative formulations rather than idealized fluids that do not reproduce actual viscosity, interfacial behavior, or material interactions. Compatibility, stability, device performance, manufacturing feasibility, and formative usability work should proceed with enough overlap that findings can inform each other.
This iterative approach does not guarantee a shorter program, and the available evidence does not support a universal claim that early device integration reduces development time or cost by a defined amount. Its principal value is that it exposes conflicts while the development team still has options. A mismatch among dose, concentration, volume, force, delivery time, stability, and usability is easier to address before the formulation, device, and manufacturing process have all been locked.
Changes introduced later may require additional comparability work, stability and compatibility studies, device verification, human-factors evaluation, manufacturing development, regulatory documentation, or pharmacokinetic and clinical bridging. The active molecule may remain unchanged, but the finished presentation can create new questions about how the product performs and how patients use it.
The most effective development model is therefore built around the intended delivery outcome. The formulation, primary container, device, manufacturing process, and user interface should be developed as parts of a single product, with requirements flowing in both directions. As delivery systems become more specialized, the formulation can no longer be finalized first and handed off to device development without risking avoidable incompatibilities. The device helps define the conditions the formulation must meet, and the formulation determines which delivery concepts can ultimately succeed.
