Biosimilar Manufacturing Complexity Demands Mastery, Not Mimicry

By Mei-Chun Yang, Ph.D., CEO, GlycoNex

Biosimilars are now an essential counterpart to originator biologics. They broaden patient access, introduce price competition, and make health systems more resilient. Yet developing and scaling them is anything but simple. Unlike small molecule generics, biosimilars must demonstrate high similarity to a living, evolving reference product across a matrix of analytical and functional attributes, while also competing under intense price pressure. That combination elevates one factor above all others: manufacturing sophistication.

At GlycoNex, we’ve confronted this reality directly with SPD8, our denosumab biosimilar currently in a Phase 3 clinical trial in Japan. Denosumab is an IgG2 antibody, a subclass defined by distinct disulfide isomers (IgG2-A, IgG2-B, and IgG2-A/B) that subtly shift stability, binding, and function. Reproducing the originator’s distribution of these isomers at scale, lot after lot, is a scientific and technical challenge. Add the thicket of originator process patents around cell culture, purification, and formulation, and it’s clear why “just copy it” is not a meaningful strategy in modern biomanufacturing.

The Comparability Fulcrum: Analytics Plus Process Control

For biosimilars, analytical comparability is the core of development. Precise orthogonal methods are required to characterize critical quality attributes (CQAs) and maintain alignment with the reference product. Practically, this includes:

• ultraviolet-visible spectroscopy (UV/Vis) for accurate concentration (a parameter that directly influences potency),
• high-performance liquid chromatography (HPLC) for glycan profiles and aggregate assessment,
• capillary electrophoresis-sodium dodecyl sulfate (CE-SDS) for detecting fragment species and non-glycosylated heavy chain,
• capillary isoelectric focusing (cIEF) for resolving charge variants,
• mass spectrometry (MS) for detailed post-translational modification (PTM) mapping, and
• cell-based assays to confirm functional activity.

These data collectively guide process design and critical process parameter (CPP) control, ensuring that analytical expectations are reliably translated into consistent manufacturing performance at scale.

On the process side, we rely on continuous monitoring of CPPs — pH, dissolved oxygen and carbon dioxide, glucose and lactate, temperature, feed rates — supported by both real-time sensors and disciplined offline measurements. Appropriate CPP control is what translates analytical intent into manufacturing reality. Without it, even a well-constructed comparability plan can drift at scale.

Cost Is A Science Problem, Too

Market dynamics add a second constraint: cost. Denosumab’s pricing leaves limited headroom for discounts. That doesn’t change the scientific bar, but it does force development teams to treat cost as a design parameter from day one. For SPD8, we optimized feed strategies to push volumetric productivity, increased batch sizes to amortize fixed costs, and streamlined unit operations where possible, always within the guardrails set by CQAs. The goal is not “cheap”; it’s high-similarity product at sustainable cost, with no compromises on quality.

Design of experiments (DoE) helps here, especially in high-throughput systems (e.g., small-scale bioreactors like Ambr-250). DoE accelerates understanding of factor interactions, so we can dial in process ranges that are both robust and efficient. It also shortens the path from lab to plant by clarifying which parameters truly matter at scale.

From Clone To 2,000 L: Scaling Is A Continuum

Scale-up is a continuum, not a handoff. We start with CQA-driven clone selection, preferring clones whose product quality profiles align with the reference early, not just those with high titer. Process development is then integrated into cell-line work so that clones are pre-adapted to downstream conditions. We validate and refine performance at 1 L, step through 50 L single-use systems, and ultimately confirm reproducibility and control in 2,000 L validation runs. At each step, analytics confirm that CQAs remain within the predefined similarity window. This reduces surprises, de-risks technology transfer, and keeps timelines tractable.

Patents, Pathways, And Practical Strategies

Originator process patents complicate route selection across media, upstream, downstream, and formulation. There is no shortcut here. The practical approach is to build alternate pathways that achieve the same product quality without infringing protected methods. That demands creativity from process scientists and close alignment with regulatory expectations. A strong paper trail — documenting why each process decision was made, how it was verified analytically, and how it performs under stress — becomes a strategic asset during review.

Lessons For Innovators: Complexity As A Defensible Advantage

For originators, advanced manufacturing is not just a means to supply, it’s a durable differentiator. Sophisticated conjugation chemistries, finely tuned process windows, and deep process knowledge raise the bar for would-be biosimilar competitors. Even after patent expiry, a mature, tightly controlled process can act as a competitive moat. The message is straightforward: invest in manufacturing intelligence early. It pays dividends long after exclusivity lapses.

Lessons For Biosimilar Developers: Master, Don’t Mimic

For biosimilar developers, the lesson is complementary: success depends on mastering complexity, not merely mimicking it. Prioritize CQA alignment in clone selection. Build analytics that are sensitive to the attributes regulators care about. Embed process development at the cell-line stage. Treat scale-up as an iterative confirmation of similarity, not a last-mile exercise. And regard cost as a design constraint that must be solved scientifically, not shaved administratively.

Why This Matters For Next-Generation Biologics

These manufacturing lessons map directly onto newer modalities, including antibody-drug conjugates (ADCs). ADCs bring added layers such as linker selection, drug-to-antibody ratio control, and conjugation site specificity, each with its own impact on safety and efficacy. Our work in glycan-directed oncology illustrates the point. While SPD8 has strengthened our large-scale biologics manufacturing, our glycan-targeted ADC program (GNX1021) benefits from the same discipline: CQA-anchored design, rigorous analytics, and process control that maintains a stable therapeutic window. GNX1021 targets branched Lewis B/Y, a tumor-associated glycan enriched in gastric and other epithelial cancers and is advancing toward IND submissions in Taiwan and Japan in Q1 2026, with a first-in-human study anticipated in Q2 2026. The common thread is simple: innovation and manufacturing are inseparable.

A Pragmatic Path Forward

Biosimilars will continue to expand access; originators will continue to innovate. The competitive ground in between is manufacturing. For developers on both sides, the advantage goes to teams that can connect analytics to process, process to scale, and scale to sustainable cost, without losing sight of the product’s clinical purpose. That’s where complexity stops being a barrier and starts being a moat.

If our experience with SPD8 has taught us anything, it’s that the hard work behind the scenes — methodical analytics, disciplined process control, thoughtful scaling — makes the difference between theoretical similarity and practical success. In an era where margins are thin and expectations are high, that discipline is not optional. It is the strategy.

About The Author:

Mei-Chun Yang is the CEO of GlycoNex, a biotechnology company specializing in glycan-directed cancer therapies. With over 20 years of experience, she drives innovation in antibody-drug conjugates, advancing targeted treatments that improve patient outcomes globally.