Overcoming Formulation Challenges for Biosimilars

Despite the inherent variability of recombinant proteins and antibodies, biosimilars must be comparable to their corresponding branded counterparts with respect to safety, efficacy, and pharmacokinetic and stability profiles.1,2 Trends in the sector, including an increasing focus on patient centricity, such as in the form of citrate-free buffer systems, and the move to high-concentration formulations that allow subcutaneous (SC) administration, present growing challenges for biosimilar formulators as they seek to demonstrate comparability through analytical and functional characterization, particularly in the face of complex intellectual property issues. 1,2

What Are the Main Biosimilar Formulation Development Challenges?

Biosimilar formulation development requires navigating around scientific, regulatory, and legal challenges, according to Sung Keun Chang, drug product team leader for Samsung Bioepis. One of the main challenges he highlights is the thicket of patents for reference products that are designed to extend patent protection.

Such patents not only include the core molecule, but also excipients or a class of excipients in the drug formulation, manufacturing processes, and delivery devices, Chang notes. “Due to such protection, buffers, stabilizers, or surfactants that are included in biosimilar formulations need to be re-optimized or replaced with alternatives. In extreme cases, excipients such as buffers cannot be utilized at all if there is patent protection for the class of excipients,” he says.

The industry shift toward high-concentration protein formulations (HCPF) primarily designed to enhance patient convenience through SC delivery is making biosimilar formulation optimization even more difficult. Maintaining the stability of high-concentration formulations and managing their higher viscosities during manufacturing and administration can be challenging.1,2

“A key issue is the constraints placed on formulators of SC formulations by proprietary-based excipient systems, which creates bottlenecks to demonstrated comparability with reference products,” observes Venkat Reddy Sunkara, global head of Regulatory CMC at ICON.

Recent regulatory trends around waiving comparative efficacy studies (CES) in biosimilar development do provide additional opportunities to develop biosimilars. However, with analytical comparability replacing clinical proof of efficacy because biologic products are process-defined, not composition-defined, it is even more essential to define uncertainties analytically in a manner that is aligned with regulatory requirements, according to Kimberly Salgado, head of ICON’s Center for Biosimilar Drug Development. Chang agrees that the new regulatory flexibility poses challenges to biosimilar formulators with respect to meeting the rigorous, comprehensive requirements for analytical characterization. Demonstrating comparability of post-translational modifications can be particularly challenging.2

What Are the Implications for Biosimilar Commercialization?

Surmounting these scientific, regulatory, and legal hurdles is a prerequisite for approval and commercialization of a biosimilar product. “In many cases, formulation-related patents can evolve into a family of patents that minimize the possible design space for biosimilar formulations during the life cycle of the product. As a result, biosimilar companies need to navigate around a moving and evolving target when developing biosimilar formulations,” Chang comments.

In addition, for biosimilars being designed for improve patient convenience (eg, SC delivery), it is necessary to demonstrate not only therapeutic equivalency, but improved performance attributes, such as lower local irritation and better tolerability, according to Salgado.

How Can Biosimilar Developers Demonstrate Analytical Comparability?

The first step, says Salgado, is to identify tiered, risk-based critical quality attributes (CQAs) that are likely to impact clinical safety and efficacy and link them to the product mechanism of action (MoA) and clinical relevance.

Equally important is the need to account for the inherent lot-to-lot variability of reference products and regional sourcing differences using high-resolution sensitive techniques that can detect subtle differences, according to Sunkara.

Demonstrating analytical similarity is, therefore, often achieved by analyzing a large number of batches of the reference product over an extended period of time to determine the acceptable variability range for the biosimilar product, Chang observes. “Using an insufficient sample size may result in a similarity range that is too narrow to be met,” he adds.

Finally, both Sunkara and Chang emphasize the importance of using orthogonal analytical methods that are complementary and based on different scientific principles to ensure that target CQAs are robustly met.

Overcoming Challenges in High-Concentration Formulations

High-concentration formulations can pose multiple challenges, Chang observes, including an increased propensity for aggregation and particle formation due to dense protein concentrations, as well as difficulties in manufacturing and drug delivery because of higher viscosities.

In addition, Sunkara notes that most of these formulations use proprietary excipient systems for which establishing analytical comparability can be difficult.

Some of these challenges can be overcome through optimization of pH, ionic strength, or the excipients during formulation development, according to Chang. Indeed, using innovative excipients may be necessary to achieve stable formulations that can be administered using “patient-friendly” delivery mechanisms.1

“For example, altering the pH away from the isoelectric point can reduce electrostatic-driven interaction,” Chang comments. “Certain amino acids can also effectively mask the hydrophobic patches on protein surfaces, thereby preventing protein-to-protein interaction. In addition, viscosity can be further controlled by minimizing or avoiding the use of certain stabilizers that increase viscosity, or by adding excipients that disrupt self-association,” he says.

Biosimilar formulations must also meet product shelf-life expectations and support device functionality, and properties such as syringeability, injector performance, and patient usability must also be considered, says Salgado. The latter issues can be managed by fine-tuning formulations for pH, osmolality, and using advanced filtration techniques to reduce particle seeding. Container closure systems must also be optimized to ensure minimal silicone oil use.

Underlying all these solutions for overcome challenges to the formulation of high-concentration biosimilars, contends Sunkara, is using advanced characterization techniques to offset any risks.

Are There Best Practices for Overcoming Regulatory Hurdles for More Patient-Friendly Biosimilars?

Biosimilars provide benefits to patients and healthcare systems through affordability, expanded patient access, and innovation. One of their key benefits emphasized by Chang is to enhance usability of the reference product by adding innovative features. He highlights the removal of citrate in biosimilar formulations because it is now known to be a potential cause of injection site pain (ISP) during subcutaneous delivery. Biosimilar developers also often provide a wider choice of drug delivery devices than available for the reference product, such as autoinjectors or other advanced drug delivery devices in addition to existing vials and prefilled syringes.

During formulation development, Sunkara emphasizes following International Council for Harmonisation’s (ICH) Q5E principles for comparability strategies and using orthogonal analytical and functional assays that are relevant to the MoA to mitigate potential risks.3 Equally important, he notes, are conducting device and drug product formulation development in parallel and employing human factors/usability studies to demonstrate dose accuracy, implementing controls for extractables and leachables, and assuring container closure integrity.

Developers of more patient-friendly biosimilar formulations may also need to establish a robust bridging strategy to demonstrate that the improvements do not impact the quality, safety, or efficacy of the product, according to Chang. “As part of the bridging strategy, it is important to build a robust data package along with a comprehensive risk assessment to justify such changes,” he adds. Engaging with regulators early in the development stage to determine whether proposed analytical and clinical bridging strategies will be sufficient for justification is also highly recommended by Chang.

Overcoming Challenges Created by Shrinking Timelines

Biosimilar developers are under intense pressure to shorten development timelines while still meeting ever‑higher regulatory and scientific expectations. “To meet these objectives,” contends Salgado, “it is necessary to adopt a combination of scientific, regulatory, operational, and strategic solutions to compress timelines without compromising approvability or commercial viability.”

Examples highlighted by Salgado include the following:

• early and iterative regulatory engagement to avoid rework triggered by post‑submission questions
• reference product procurement strategies
• platform-based approaches to process and analytical method development that are backed by accumulated knowledge
• parallelization of chemistry, manufacturing, and controls (CMC), nonclinical, and clinical activities
• leveraging advanced analytics to de-risk clinical programs
• ensuring access to ready-to-use manufacturing capacities/capabilities.

Formulation development can also be accelerated using high-throughput screening technologies that enable parallel testing of a wide range of buffers, stabilizers, and surfactants in a short timeframe, adds Chang. He also points to the use of automated equipment for sample preparation and analytical testing as a means for further shortening development timelines.

All of these efforts must be pursued while maintaining compliance with regulatory expectations. Salgado notes that biosimilar developers should focus on the totality of evidence of similarity generated from their analytical data, followed by a more abbreviated clinical trial for confirmation of this similarity if needed. She adds that using final formulations in pharmacokinetic similarity studies can reduce risk and ensure stronger demonstration of comparability, which is important because if similarity can be demonstrated through a strong CMC and nonclinical package, CES can potentially be avoided.

Impact of FDA’s Proposed Changes for Demonstrating Biosimilarity

The FDA in October 2025 introduced several proposed changes to its requirements for establishing the comparability of biosimilars to reference products.4 The draft guidance eliminates the need for comparative human clinical studies if biosimilar developers can provide sufficient analytical testing data to demonstrate similarity.5 In a separate initiative, the agency has elected to stop recommending that “switching studies” be conducted to show interchangeability between different biosimilars.4

These regulatory updates from the FDA, as well as streamlined pharmacokinetic requirements and the expanded acceptance of non-US-licensed comparator products, are expected to significantly reduce biosimilar development costs by up to 25% while shortening timelines, according to a Celltrion official. “In this evolving environment, biosimilar developers are increasingly focused on enhancing efficiency across the entire development process while maintaining robust analytical comparability and regulatory compliance,” the spokesperson remarks. “These changes are meaningful and are expected to accelerate pipeline expansion, including into small and mid-sized markets that were previously less accessible due to high development costs,” the Celltrion official also contends.

Are There Any Emerging Challenges to Biosimilar Formulation Development?

With innovator companies increasingly launching line extensions (eg, high‑concentration, citrate‑free, device‑enabled, longer shelf life, room‑temperature stable), biosimilar developers often still chase original reference products. However, observes Salgado, “future commercial relevance and clinical acceptance will depend on matching (or at least not falling behind) the latest reference product attributes.” Successful biosimilar developers will need to find a way to eliminate these gaps.

Using novel excipients is one way to do so, but there remains no separate regulatory pathway for approval of such excipients. Consequently, novel excipients are considered high-risk and often are avoided in biosimilar formulations (especially in SC products), particularly where switching/substitution is expected, according to Sunkara. He also notes that regulatory expectations are increasing with respect to particle analysis, with data now typically required on not just particle counts, but particle morphology, composition, and immunological relevance.

Newer technical challenges with increasing relevance for biosimilar developers highlighted by Sunkara include the inability of current screening tools to fully predict non-linear behaviors such as self‑association, shear sensitivity, and viscosity jumps, of high-concentration formulations; the increasing role of autoinjectors and other advanced delivery systems in dictating formulation limits, including maximum viscosities, injection forces, and dwell times; and the rising ability to detect minor formulation‑related differences previously invisible to older, less-sensitive analytical methods.

What Will Matter Most for Future Biosimilar Formulation Development?

Given the current trend in biologics development to more patient-friendly, convenient products, biosimilar developers will need to balance innovative formulation approaches with regulatory compliance, quality assurance, and cost management to ensure commercial success.1 Selecting optimal formulations will require input from cross-functional teams of experts, incorporation of patient-centric formulation innovations, comprehensive characterization and establishment of comparability, and the use of quality-by-design approaches, process analytical technologies, and artificial intelligence tools. This strategy will ensure cost-effective development, product performance (quality, safety, efficacy), regulatory compliance, and avoidance of patent-based legal restrictions.

In this vein, companies such as Celltrion are strengthening competitiveness through integrated capabilities spanning development, manufacturing, and direct sales, while driving formulation innovation that reflects the needs in clinical practice, according to a spokesperson from Celltrion. “The launch of differentiated formulations—such as liquid intravenous and SC options—demonstrates how biosimilar developers can improve patient convenience and operational efficiency in real-world settings,” the Celltrion official concludes.

References

1. Bas TG. Innovative formulation strategies for biosimilars: Trends focused on buffer-free systems, safety, regulatory alignment, and intellectual property challenges. Pharmaceuticals (Basel). 2025; Jun 17;18(6):908. DOI: 10.3390/ph18060908
2. Leukocare Editorial Team. Biosimilar Formulation Development: Navigating the Delicate Balance. Blog, July 7, 2025. https://www.leukocare.com/blog/biosimilar-formulation-development
3. ICH. Q5E Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process, Step 4 version (2004).
4. FDA. FDA moves to accelerate biosimilar development and lower drug costs. Press Release, October 29, 2025. https://www.fda.gov/news-events/press-announcements/fda-moves-accelerate-biosimilar-development-and-lower-drug-costs
5. FDA, Draft Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product: Updated Recommendations for Assessing the Need for Comparative Efficacy Studies (Rockville, MD, Oct. 2025).