Expanding The IV → SC Framework: What Reformulation Really Means

By Monika Sharma, fractional CMC & program leader, CDO, EOSPA LLC

In Article 1, I made a simple point: IV → SC is not a formulation problem or a device problem. It is a system design decision.

Here, I will go deeper into what that means in practice, where programs start to strain, what teams consistently underestimate, and how to tell early if a design will hold up.

Dose: Where The System Gets Set

Dose is one of the most important design decisions in IV → SC transitions because it is often set outside the delivery discussion and then inherited as fixed. I see teams lock it early, and that is usually where flexibility starts to narrow.

Dose is not just a clinical parameter. It defines how much protein must be delivered, which drives volume, concentration, formulation stress, device feasibility, manufacturing demand at scale, and ultimately the cost structure of the product.

Strong teams treat dose as a design variable. That means investing early in dose optimization, regimen modeling, and exposure-response relationships, and using flexibility where it exists, whether that is fixed versus weight-based dosing, loading versus maintenance structure, or exposure margin, before the system is pushed to its limits.

I have seen programs carry forward a high-dose IV regimen to preserve the clinical profile, only to find that this one decision tightens everything downstream, including formulation, device, manufacturing, and comparability. Once dose is locked, the rest of the system has far less room to move.

What follows is usually predictable, even if it is not obvious early. As dose pushes concentration or volume beyond typical ranges, it affects not just formulation and device feasibility but also analytical strategy, process performance, and comparability expectations. Higher protein loads and more aggressive formulations change how teams handle process-related impurities, host cell protein clearance, and viral clearance robustness. These might not always be full redevelopment efforts, but they are also not trivial.

The risk is not that these constraints exist. The risk is assuming they will not need to be revisited.

Volume: What It Really Drives

Volume is often discussed with surprisingly little nuance, as if the question is simply whether the subcutaneous space can accommodate a given amount. I see teams reduce it to a number, such as 2 mL versus 10 mL, when in reality it reflects system behavior.

The real issue is not whether a target volume can be administered, but how that volume interacts with rate, time, tissue response, device design, and user experience. A 2 mL injection delivered quickly is not the same problem as a 10 mL administration delivered over several minutes through a wearable system.

As large-volume SC delivery becomes more common, expanded capability can be mistaken for flexibility. Larger volumes are not neutral. They increase dependence on the surrounding system, including where administration occurs, how long it takes, what happens if dosing is interrupted, and whether the experience is realistic outside a controlled setting.

This is often where programs lose alignment. The technical feasibility is there, but the-use model is not fully thought through. There is also a tendency to assume that upstream administration changes do not affect downstream handling assumptions. In several programs, I have seen IV bag compatibility and in-use assumptions carried forward without reevaluation after an SC transition, creating a hidden comparability and stability risk that only surfaces later.

Volume, concentration, and presentation are tightly linked. When one changes, the others rarely remain untouched.

Concentration And Formulation

High-concentration formulation is often where teams go next because it looks like the cleanest answer to the volume problem. If the same protein mass can be delivered in less liquid, SC feasibility appears to improve. In practice, this shifts pressure onto formulation behavior, device performance, process robustness, and downstream analytical and comparability expectations.

As concentrations rise, solution behavior becomes more difficult. Viscosity increases, stability margins narrow, and processing becomes more sensitive. Fill/finish becomes more challenging, and product quality becomes more exposed to temperature excursions, shear, container interactions, and hold conditions.

The formulation challenge therefore extends beyond concentration itself. Teams need to consider:

• colloidal stability
• interfacial behavior
• aggregation risk
• syringeability or reservoir behavior
• container closure interaction
• hold-time sensitivity
• transport robustness
• compatibility with the device.

Excipient strategy, presentation, and intended use are tightly linked and cannot be developed in isolation.

These constraints often become more visible over time. A composition that looks promising in early screening may behave differently under storage, agitation, freeze-thaw, pumping, or fill/finish conditions. The gap between a technically acceptable formulation and a commercially durable one can be significant, especially once real handling and device use conditions are applied.

What is often underestimated is how much of the downstream CMC package may need to be revisited. At higher concentrations, prior assumptions do not always hold around viral clearance, host cell protein profiles, process-related impurities, and analytical methods across extended concentration ranges.

This shows up in the questions regulators will ask:

• Are viral clearance studies still representative at the new concentration and process conditions?
• Do host cell protein and impurity profiles change under higher load or different processing stress?
• Are analytical methods still accurate, precise, and linear at the higher concentration range?
• Does stability data still support shelf life under more sensitive conditions?
• Are in-use and handling conditions, including dilution, hold times, or container interactions, still valid?

These are not always full redevelopment efforts, but they are also not trivial.

From a regulatory standpoint, the question is not whether each component works on its own. It is whether the overall product, at the selected concentration and in the selected presentation, remains consistent, stable, and clinically reliable. If these questions are not addressed early, they tend to surface later, when options are more limited and changes affect multiple parts of the program at once.

Device And Use: Where Design Meets Reality

Device strategy is often reduced to format selection, such as prefilled syringe, autoinjector, or wearable system. I see teams start with what can deliver the required volume rather than what they are actually trying to build.

The better question is what the delivery experience needs to look like in real use. The right device is not simply the one that can deliver the dose. It is the one that can be used correctly, delivers the full dose reliably, and fits into the intended care setting.

A common failure mode in IV → SC thinking is treating injection experience as a downstream topic, when it is often where the design either works or starts to break. In practice, administration may take longer than expected, the device may be harder to use than intended, or it may not be clear whether the full dose has been delivered. When that happens, dosing becomes inconsistent and product performance follows.

Regulatory expectations reflect this. Guidance from the FDA makes it clear that usability is part of the product and cannot be addressed at the end. The product has to be designed with intended users, environments, and use risks in mind from the beginning. For IV → SC transitions, this directly affects device choice, instructions for use, packaging, and feedback on dose completion.

Regulatory Expectations

Regulators do not evaluate the drug and device separately. They evaluate whether the combined product works as intended. For IV → SC programs, that translates into a practical set of expectations that can be answered by these questions:

• Can the intended user prepare and administer the product correctly?
• Is dose delivery consistent across users and settings?
• Does the device support reliable completion of dosing?
• Are product quality attributes maintained in the final presentation and under real use conditions?

Guidance from the FDA on human factors and combination products reinforces this. Device, instructions for use, packaging, and administration workflow are part of the evidence package and not just supporting elements.

This is why deferring device and usability decisions creates rework. In practice, teams may need to revisit usability late, device assumptions may not hold in real use, or questions may arise during review around dose delivery, user error, or consistency across settings. These issues become more pronounced when the SC strategy depends on higher concentrations, longer administration times, or more complex delivery formats.

Comparability

Comparability is often treated as something to evaluate after an SC strategy is defined. In practice, it is where earlier decisions are tested.

Changing route affects absorption, variability, and exposure. The expectation is not identical PK but a clear demonstration that clinical benefit is preserved.

This raises practical questions:

• Does the SC profile support the same exposure-response relationship?
• Are variability and peak-trough differences clinically acceptable?
• Does the delivery approach introduce new immunogenicity risk?
• What level of clinical bridging is required?

When comparability is treated as a downstream check, it often leads to rework. By that point, flexibility is already limited.

Manufacturing And COGS

Manufacturing is where many IV → SC concepts stop looking as clean as they did on paper. When dose stays high and concentration increases, more material has to be pushed through the process, and it becomes harder to handle. Solutions are more viscous, filtration slows down, mixing becomes less efficient, and hold steps become more sensitive to time and temperature.

These changes show up quickly. Batches take longer to process, losses during filtration and transfer increase, and yields become less predictable. Fill/finish becomes more difficult, especially at higher viscosities, and batches take longer to run and overall timelines extend.

Device integration adds another layer. The product is no longer just filled into a vial. It has to work within a specific delivery system, which introduces additional constraints around fill volumes, container closure, assembly, and release.

These requirements carry through to cost. More batches may be needed to supply the same number of patients, processing takes longer, and material losses increase. Device, assembly, packaging, and cold chain requirements all add to the overall burden.

At that point, this is no longer just a development question. A clinically strong SC design can still be difficult to sustain if manufacturing becomes slower, less predictable, or more resource intensive. The goal is not to minimize cost but to understand what the design requires before it is locked.

Where Does The Value Actually Come From?

One reason IV → SC transitions are pursued so aggressively is that the value extends beyond administration mechanics. For some products, SC can shift care from infusion centers to home or lower-cost settings, reduce scheduling friction, and create a more manageable experience for patients and caregivers.

That value only materializes when the use case is clear. A technically feasible SC regimen that still feels logistically heavy often delivers less real-world advantage than expected.

This is why site-of-care strategy needs to be considered alongside device and formulation, not after them. If the goal is at-home use, then training, confidence in dose completion, support model, and packaging all need to reflect that reality. If the goal is differentiation through convenience, then convenience has to be defined in practical terms, not assumed.

One useful question is simple: what will make patients, providers, and payers see this SC option as meaningfully better? If the answer is unclear, the design usually is, too.

How Do Teams Actually Execute This?

IV → SC transitions are inherently cross-functional, so execution depends heavily on how decisions are made. Weak programs allow each function to optimize locally and only later discover that the design does not hold together. Strong programs force trade-offs into the open early.

A key discipline is distinguishing between working assumptions and true constraints. Dose becomes fixed because no one wants to reopen the clinical discussion. Device format becomes fixed because early vendor input looked promising. Formulation direction becomes fixed based on early data. When these assumptions harden without alignment, flexibility is lost without anyone making that decision explicitly.

Strong teams take a different approach. They treat formulation, device, manufacturing, and clinical strategy as one conversation. When concentration shifts, device and process implications are reviewed at the same time. When device constraints narrow, dose or administration goals are revisited. Human factors is used early to define what a credible experience looks like, not just to validate it later.

They also evaluate feasibility in context. A design is not viable just because it works technically. It has to work for the intended user, at scale, within a realistic manufacturing and cost structure.

This does not eliminate trade-offs. It makes them visible and deliberate.

What Happens When This Goes Wrong?

Late-stage IV → SC corrections are expensive because they do not stay contained. Reformulation can trigger additional stability, analytical, and process work. Device changes can reopen human factors, packaging, and regulatory strategy. Dose changes can affect clinical bridging and program positioning. Manufacturing adjustments can alter supply plans and cost assumptions.

Even when recovery is possible, the cost is paid in time, flexibility, and confidence.

There is also a less visible cost. When teams continue trying to rescue a strained design through incremental fixes, effort shifts from improving the system to defending earlier assumptions. That is often where programs slow down.

A Different Way To Think About It

The question is not whether an IV therapy can be made subcutaneous. The better question is what subcutaneous system is being built, and whether it still works when real constraints are applied across dose, user experience, device performance, manufacturing, supply, and economics.

Once that becomes the working mindset, trade-offs become clearer. Dose can be challenged without undermining the clinical case. Device strategy can shape the design rather than react to it. COGS can inform decisions before they harden. Human factors becomes part of design rather than a checkpoint.

Conclusion

IV → SC is not fundamentally about convenience. It is about whether the drug product, device, administration experience, manufacturing, and economics function together as one system. Programs that succeed recognize that early. Programs that struggle usually realize it later than they should.

The teams that do this well are not the ones that push concentration the furthest or adopt the most advanced device. They are the ones that manage interdependencies honestly and make trade-offs visible early enough to design around them.

The earlier teams treat IV → SC as a system problem, the fewer times they have to solve it twice. I look forward to hearing what others experiences are.

About The Author

Monika Sharma, M.Sc., is an executive leader with 25+ years of experience across large and emerging biotechs. Sharma brings integrated expertise across asset strategy, clinical development (early through late stage), CMC, and program execution, enabling programs to progress from IND through BLA and into commercialization. Her background spans roles from formulation scientist to vice president of product development, along with adjunct faculty positions, all of which have equipped her with the expertise to excel as an executive consultant. In her current role, as a leader at EOSPA Consulting, she serves not only as an advisor but as an embedded leader, ensuring execution goes beyond planning to deliver real results.