When an analytical development team has a biosimilarity assessment strategy established early in a program, it can shape decisions throughout biosimilar development. Deep analytical characterization gives development teams the evidence needed to understand complex biologics, guide process optimization, assess biosimilarity and comparability, and build a robust package for regulatory review.
Yet analytical characterization is often viewed primarily as a regulatory requirement rather than a decision-enabling discipline that can guide biosimilar development throughout a program.
This article draws on Dr. Barbara Fedejko-Kap’s extensive experience in NBE and biosimilar development as Associate VP Development at Rezon Bio to explore analytical characterization approaches that can strengthen a CMC strategy, from establishing biosimilarity to managing process changes and supporting NBE development.
Analytics is not only a supporting activity, but is actually the core of biosimilars development.
Key Takeaways
- Analytical characterization is a decision-enabling discipline, not simply a regulatory requirement. Early analytical understanding can guide decisions throughout biosimilar development.
- Analytical biosimilarity and analytical comparability answer different questions. Biosimilarity compares a proposed product with a reference medicine, while comparability assesses the impact of changes to the same product or process.
- “Sufficiently comparable” does not mean identical. The goal is to determine whether introduced changes are meaningful and could affect product quality, safety, or efficacy.
- Deep product and process understanding creates more flexibility for optimization. Well-characterized processes are easier to improve, explain, and assess when changes occur.
- The analytical discipline developed through biosimilar programs can also strengthen NBE development. Deep characterization, functional understanding, and comparative analysis provide a stronger foundation for managing product and process changes.
What’s the Difference Between Analytical Biosimilarity and Analytical Comparability?
“Analytical biosimilarity” and “analytical comparability” describe different comparison contexts in biologics development. Analytical biosimilarity compares a new version of an existing biologic directly with the licensed reference product. In other words, how similar is this independently developed product to the originator biologic? In contrast, analytical comparability usually refers to demonstrating that a biologic manufactured before and after a process change remains comparable. For instance, did this particular manufacturing change alter the critical quality attributes (CQAs) of the product?
The terms often get used interchangeably, but they answer different questions within a biosimilar program throughout its development cycle from clone selection through commercial scale-up, as Dr. Barbara Fedejko-Kap indicates:
Biosimilarity and comparability are sometimes mixed, especially in discussions around biosimilar products, but they address different questions. Comparability assesses the same product before and after a process change, while biosimilarity evaluates a proposed biosimilar against an already-authorized reference drug product.
What Does “Sufficiently Comparable” Mean to CDMO Analytical Development Teams?
For analytical development teams, “sufficiently comparable” does not mean analytically identical. Biological products naturally exhibit some degree of variability, even when manufactured using the same process. The challenge, then, is not to eliminate every detectable difference, but to determine whether the observed differences are meaningful. Barbara explains why two biologics from the same process are likely only ever to be sufficiently comparable, and why it’s crucial to assess this:
“Biologics do show some tendency for variability. Even when produced using exactly the same process, two batches will not have exactly the same quality profiles. Therefore, when a change is introduced to the process, the products will never be completely identical. The objective of such a study is to show that if there are differences, and there will be, they do not affect the quality, the safety, and the efficacy of the biosimilar.”
As Barbara states, this exercise requires analytical development teams to provide a comprehensive, coherent scientific narrative built for a reviewer who might be unfamiliar with the process alterations:
It’s all about the so-called totality of evidence, and the package needs to tell one coherent scientific story. First of all, the change should be clearly and well described, so that any reviewer can readily understand what changed and why. The potential risks should be assessed, and based on those risks, a proper study is designed using material considered representative of the pre-change and post-change batches. The package of methods should, of course, be sufficiently sensitive to detect relevant differences, with orthogonal methods in place for the assessment of critical quality attributes.”
For CQAs, orthogonal analytical methods can provide independent lines of evidence, reducing the risk that a conclusion depends on the limitations of a single assay. In practice, a comparability package compares equipment, process parameters, in-process controls, release data, extended characterization and functional assays, and stability and degradation profiles. This must be pre- and post-change, side by side.
When Does Biosimilar Process Optimization Become a New Process?
Biosimilar development often requires continued optimization as the manufacturing process matures. However, at some point, excessive process optimization could increasingly look like a new process altogether and might trigger a re-evaluation. Barbara indicates that there’s nuance in determining when a process has become too dissimilar to the original:
There is no single numerical boundary that defines when process optimization becomes a new process. If the fundamental process architecture, such as the cell line or drug presentation, remains unchanged, and the quality profile of post-change batches stays within an understandable and justifiable range, we consider it optimization. But when, for example, the change introduces new impurities, involves a new drug presentation, important CQAs results move outside historical experience, or the previous control strategy no longer explains how product quality is maintained, then we consider it a new process.
Also, analytical development teams must establish whether the scientific knowledge built on the old process is still valid for the new one, but this largely depends on how well the process was characterized to begin with. As a minimum, teams should understand the baseline variability of the process, the operating ranges, what the current process performance is, and how much it fluctuates to lay the groundwork for successful optimization:
A well-understood process, developed based on a robust platform, is easier to optimize and to explain to regulatory authorities than a product coming from a poorly characterized process, or one developed around highly molecule-specific requirements.
Together, this highlights the value of a team’s deep analytical knowledge of both the products and the processes used to manufacture them. The sooner and more thoroughly a product is characterized, the more room a program has to subsequently improve its process without re-validation risks, limiting the costs and potential timeline risks that come with it.
Five Lessons from Rezon Bio’s Analytical Development Experience
Asked what she’d tell sponsors, biotechs, or other CDMOs about to start comparability or biosimilarity studies, Barbara says a clear target paired with rigorous product characterization and analytics is key. She highlights five principles that can strengthen biosimilarity and comparability studies:
- Characterize the product thoroughly from the outset
“The first recommendation I would give is to really characterize your product. If it’s a biosimilar product, characterize the originator thoroughly. Establish your target product profile and clearly define what you want to achieve. And then, as the product moves through the different phases of clinical development, aim to maintain the quality profile you have established.”
- Use analytics to drive development decisions
“The second point is that analytics is not a supplementary activity. Analytical capabilities and the data they generate are fundamental to making informed development decisions.”
- Develop relevant functional assays early enough
“The other thing I would strongly recommend is to develop the functional assays that reflect the product’s mode of action — these methods are often among the most technically challenging, but if delayed, the program may lack the evidence needed to interpret physicochemical differences.”
- Plan the comparability strategy before implementing changes
“Design comparability before making changes, and make sure representative pre-change batches and samples will be available for testing.”
- Manage process changes strategically and collaboratively
“Avoid changing too many things at the same time, and cooperate with regulatory and quality teams throughout the process.”
Why Biosimilar Analytical Characterization Helps NBE Development
Biosimilar development requires analytical teams to characterize a molecule against an external reference product with exceptional depth. While NBE programs do not need to demonstrate biosimilarity to an originator, the analytical discipline developed through biosimilar programs can still help teams establish a deeper understanding of product quality, recognize meaningful sources of variability, and build the evidence needed to assess comparability as manufacturing processes evolve, as Barbara indicates:
Developing biosimilars is much trickier than developing an NBE, especially at these initial stages of process and product development. However, the depth of product and process understanding gained through biosimilar development can be highly valuable and applied to the development of NBEs.
The analytical discipline required for biosimilar development can also strengthen CMC strategy across an NBE portfolio, and it’s why Rezon Bio’s integrated analytical and process teams treat characterization as a decision tool from the outset.
Explore how integrated biologics manufacturing connects process development and analytical development around a shared program and CMC strategy from the outset.
About Dr. Barbara Fedejko-Kap
Dr. Barbara Fedejko-Kap is Associate VP Development at Rezon Bio, where she leads the technical, strategic and operational planning of development programs. Her focus lies in optimizing value, time, resources and risk across the biologics lifecycle.
With a strong academic foundation and 15 years of industry experience, Barbara combines scientific expertise with a strategic development mindset to accelerate the delivery of biologic medicines from concept to patient. She focuses on translating science into product value by incorporating manufacturing, quality, and regulatory perspectives to development processes to enable successful and efficient product realization. Her experience spans the full biologics development lifecycle, from early-stage development and technology transfer to commercialization and lifecycle management
Barbara holds a Ph.D. in Biotechnology from the Gdańsk University of Technology and is currently expanding her business expertise through participation in an Executive International MBA program, strengthening her leadership perspective and strategic insight within the life sciences industry.
