ADC vial stability isn’t enough

Why your ADC’s IND or IMPD needs proof that it survives the journey from pharmacy shelf to patient, and what clinical administration studies catch before regulators do.

Why clinical administration studies?

Most stability data describes a drug product sitting in its vial. Patients never receive it that way. Between the pharmacy shelf and the vein, an ADC is reconstituted, withdrawn, transferred, diluted into an IV bag, held, pushed through lines, filters and pumps, and finally flushed. Each step brings new materials, new surfaces and new stresses.

Successful IND/IMPD and BLA/MAA filings need empirical evidence that critical quality attributes (CQAs) hold across that whole clinical administration window. Where they don’t, regulators expect you to say so, often with exclusionary language such as “PVC-derived IV bags and lines must not be used”.

Three things regulators want to see

Compliance comes down to three objectives. Each has its own failure modes, and ADCs are exposed to all of them.

Product stability

Soluble and insoluble aggregation
ADC payload shedding
DAR and heterogeneity shift

Material compatibility

Surface adsorption
Leachable-induced reactivity
Extrinsic contamination

Process integrity

Mechanical shear
Interfacial shear
Volumetric loss (hold-up)

The vial to vein journey, in 12 steps

Pharmacy preparation

Steps 1–5

Vial retrieval, reconstitution, withdrawal, dose transfer, bag mixing. High-shear reconstitution and the silicone oil lubricants in closed system transfer devices (CSTDs) are primary sites for protein aggregation and contamination.

Clinical setup

Steps 6-9

Hold time, spiking, priming, pump integration. Dilution into IV bags and priming the IV set can trigger degradation through “dilution shock” and surface adsorption.

Patient administration

Steps 6-9

Venous access, infusion, flush. The high surface-area-to-volume ratio of IV lines and filters drives drug loss through adsorption. Pump mechanics and the final flush add late, shear-induced aggregation risk.

Every ADC meets these risks differently.

The only way to know how yours behaves is to simulate the journey with your drug product, your intended materials, and analytical methods sensitive enough to see the change.

What case studies found

Both studies used a client’s final ADC drug product, developed by a third party, with administration materials supplied by the client. We measured sub-visible particles (SVP) by light obscuration (LO) against pharmacopoeial limits: fewer than 6,000 particles ≥ 10 μm and fewer than 600 particles ≥ 25 μm.

Case 1: IV set compatibility (mean SVP count, LO)

IV set

≥ 10 μm, high dose

≥ 10 μm, low dose

≥ 25 μm, high dose

≥ 25 μm, low dose

Brand 1

Non-compliant

Compliant

Non-compliant

Compliant

Brand 2

Non-compliant

Brand 3

Compliant

Brand 4

Compliant

Case 2: CSTD compatibility (mean SVP count, LO)

CSTD

≥ 10 μm

≥ 25 μm

Brand 1

Non-compliant

Compliant

Brand 2

Compliant

What it meant for the filing.

Both studies found non-compliant particle counts across several common brands. None of this would have shown up in vial stability data. Both results required exclusionary language in the final regulatory submission. Found at IND stage, that’s a line in the label. Found later, it can mean protocol changes or a clinical hold.

Your challenge during study setup

Identifying and accounting for possible drug product (DP) manipulations by patient or healthcare providers are crucial for your specific API and its stability expectations.

Where problems show up most often

Infusion media compatibility
PVC/DEHP material incompatibility
Storage stability: hold time after reconstitution and dose transfer
Adsorption that increases from one administration step to the next
Particulate matter introduction
The effect of dilution during dose simulation

What we test, and how

Administration variables we explore most: syringe; vial adapter or CSTD; spike (vial or bag); IV bag (empty or pre-filled); IV line and line extension; in-line filter; IV filter.

Four takeaways

Vial stability is not enough

Filings need proof that the drug product stays a stable, potent monomer from the pharmacy shelf to the patient’s vein.

De-risk early

Finding CQA deviations at IND/IMPD stage prevents costly protocol changes and clinical holds.

Optimise recovery

Accurate hold-up volume measurement ensures the patient receives the intended dose, protecting the therapeutic window of an expensive ADC.

Choose materials on data

A hypothesis-driven approach to selecting CSTDs and IV lines avoids failures such as silicone oil interference or shear-induced aggregation.

Frequently asked questions

Clinical administration and in-use studies can significantly impact filing timelines if not properly considered for your DP and API. These questions could help in your study design.

Questions about the topic

What did the IV set study show?

Bring us in when your injectable needs a formulation or process that holds up to diligence:

During lead candidate nomination,
Fixing a stability problem, or
Adding to internal capacity.

We’ve completed 270+ formulation, process and CMC projects for pharma and biotech clients.

What did the CSTD study show?

Usually within 2 to 4 weeks of agreeing the scope, so your programme doesn’t sit in a queue.

Once your material arrives, our scientists go straight into the lab.

Why aren’t the brands named?

No.

We focus on development and transfer your formulation and process to the GMP manufacturer you choose, with 170+ technology transfers completed to date.

Planning your clinical administration or in-use stability studies?

Our calls veer technical fast, usually more useful than another month of internal debate. If we’re not the right partner, we’ll say so.

See what the studies found

In one ADC study, two of four common IV set brands failed sub-visible particle limits at high dose. One failed at every dose tested.

Unlock the full results, the administration variables we test most, the analytical methods behind them, and the full poster PDF.