Prioritize Speed And Precision In Biosimilar Development By Aligning With The Latest FDA Guidance
By Life Science Connect Editorial Staff
A rapidly evolving biosimilar landscape is taking shape as the industry approaches its next major patent cliff — a wave of recently expired (trastuzumab, denosumab) and soon-to-expire (pembrolizumab) patents for high-demand biologics. In October 2025, the FDA released draft guidance proposing that rigorous analytical data be used in place of clinical efficacy studies when appropriate. Draft Revision 4 of the FDA’s biosimilar Q&A, released in March 2026, also introduced new strategies to cut pharmacokinetic study costs in half and eliminate the need for three-way switching studies.
Although these regulatory shifts create faster, lower cost pathways to market, they place increased pressure on process development (PD) and chemistry, manufacturing, and control (CMC) teams, intensifying the unique burden for biosimilar developers: to balance creativity and agility with the need to meet highly specific targets. However, with advancements in cell line engineering alongside analytical innovation, companies pursuing biosimilars are well positioned to meet the quality and biosimilarity profiles of their originator molecules and take advantage of rapid approval pathways.
In a recent Bioprocess Online Live event, “Process Control’s Increasing Role In Biosimilar Approval,” an expert panel discussed how this latest guidance is reshaping the landscape:
- Cecilia Michel, Managing Director and Head of R&D Strategy and Devices, Alvotech Sweden
- Diana Colleluori, Ph.D., Principal CMC Consultant, Biologics Consulting
- Vincent Narbut, Principal Consultant, Biologics Consulting
Will Bioassay Characterization Replace Clinical Efficacy Studies?
As the biosimilar industry has expanded, the FDA has gained greater insight into what approaches verify biosimilarity. The agency concluded that comparative analytical assessments (CAAs) can, in certain scenarios, sufficiently demonstrate biosimilarity and, in turn, reduce the need for clinical efficacy studies. Prior to this latest guidance, CAAs were still critical to the success of biosimilars; nevertheless, their value has only increased.
So, what constitutes a robust CAA? Per Colleluori, “CAAs must conduct the necessary risk assessments to determine product quality attributes, which requires leveraging the right quantitative assays on the analytical panel, including potency and functional tests. Without clinical efficacy proof, we’re relying solely on analytics. “
Despite these FDA updates, clinical efficacy studies are not being eliminated. Their necessity depends on the strength of the analytical data; when data are insufficient, such studies may still be required. Yet, there are no fixed rules in biosimilar development — only best practices that must be thoughtfully applied to each unique molecular scenario.
Michel asserted that CAAs will be effective in demonstrating biosimilarity even for complex proteins with heavy post-translational modifications: “The same standards and thinking apply to all molecules. With over 80 approved biosimilars in the U.S., we have a good database of different protein formats, mechanisms of action, and indications. Regulators have scrutinized this data to determine it is sufficient to reach approval.”
Although less data exist for highly complex proteins, advanced analytical methods have demonstrated their ability to effectively characterize their structure and mechanisms of action. By using cutting-edge analytical tools paired with pharmacokinetic studies, effective process controls, and thorough process understanding, developers can save time and avoid clinical efficacy studies, even with highly complex proteins.
What Is An Effective Process Control Strategy For Biosimilars?
The pathway to effective process control is largely consistent between biosimilars and originator molecules, with one critical addition:
- Analyze the originator product over time to account for lot-to-lot variability and manufacturing changes, applying statistical analysis to establish acceptable biosimilarity.
- Identify a biosimilar’s critical quality attributes (CQAs) and each CQA’s criticality, i.e., whether they directly impact a drug’s immunogenicity, function, activity, and/or mechanism of action.
- Establish the critical process parameters (CPPs) necessary to control upstream and downstream manufacturing processes.
- Determine the relationship between the CPPs and CQAs via single-factor and multivariate experiments.
- Evaluate critical raw materials and the lot-to-lot variability they could introduce as part of a quality control strategy.
- Optimize media and feed strategies, along with bioreactor parameters, such as pH and temperature, to procure high-titer cell culture material that meets the target product profile.
When it comes to biosimilars, developers must also meet the CQAs specified in the analytical data for the originator drug. “Custom designing a process to meet the originator drug’s range of specifications is a detailed, iterative effort that requires tweaking the parts of the process you can control,” Narbut expounded. “The primary impact is during upstream process design, where glycan profiles and charge variants are adjustable. On the downstream side, chromatography steps can be modified.”
Are There Strategies For Minimizing The Need For Clinical Efficacy Studies?
The key is designing a strong analytical comparability package using orthogonal assays to evaluate physical and chemical attributes, potency, and binding. Per Colleluori, “If your product exhibits multiple functional activities, sponsors need to assess those multiple functional activities, whether it’s effector, target, or receptor. The focus should be on having orthogonal methods to assess many quality attributes.”
The goal is to match the reference product’s mid-range for each CQA rather than the extremes, and analytical assays should define these target ranges. Michel also emphasized early and ongoing FDA engagement. “We have found it beneficial to engage with the FDA at an early stage and continue discussions throughout development,” she said. “We meet with them as early as possible to align on the strategy and data necessary to support a specific product.” The FDA has made clear its willingness to discuss potential strategies to minimize the need for clinical efficacy studies and mitigate risks or failures down the road.
How Can Biosimilars Reach Patients Sooner?
To capitalize on the biosimilar surge, developers must design well-understood manufacturing processes that are aligned with the originator molecule’s CQAs. With thorough analytical panels and an effective process control strategy, biosimilars may be on track for faster regulatory approval and improved patient access.