Overcoming Biosimilar Scaling Challenges

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Demand for biosimilars is predicted to be expanding at a compound annual growth rate of nearly 18% from $9.4 billion in 2023 to $66.9 billion in 2028 (1). This strong growth reflects both higher acceptance and adoption rates and increasing numbers of approvals in multiple regions. By mid-2024, 40 biosimilars had been approved by FDA in the United States, with 25 products launched to the market. While this growth is attracting new entrants, hurdles to developing cost-effective and competitive biosimilars remain. In addition to the need to clearly demonstrate biosimilarity to reference branded products, manufacturing complexity, including scaling challenges, must be overcome.

Developing a biosimilar starts with characterization of the reference product. That information is used to develop a cell line capable of producing the desired product with comparable post-translational modifications and other important product quality attributes. Process development and optimization, including upstream cell culture and downstream purification comes next. Comprehensive product characterization, formulation development, fill/finish, final product release, and packaging round out the activities.

Successful scaling of upstream, downstream, and fill/finish operations while ensuring high yields of high-quality product that is comparable to the reference molecule requires consideration of many factors. The best approach is to use a holistic strategy that takes these factors into account from the outset.

Growing modality diversity

Biosimilars approved to date are largely recombinant proteins and monoclonal antibodies. The past decade has witnessed a rapid rise in approvals of more complex modalities, such as bi- and tri-specific antibodies, fusion proteins, antibody-drug conjugates, and cell and gene therapies. In a recent analysis, the Boston Consulting Group estimated that new modalities represented $168 billion in pipeline value in 2024, an increase of 14% from 2023 (2). Many products in these new drug classes will soon lose patent protection, according to Patrick Meyer, global head of business development and alliance management at Rentschler Biopharma.

“These modalities present greater challenges in development, manufacturing, and analytics compared to conventional antibodies. They often necessitate advanced cell-line development techniques, additional downstream processing steps, and sophisticated formulation and analytical methods,” Meyer says. This greater complexity means that developing scalable processes is often more difficult. Importantly, the different modalities often have specific manufacturing requirements and thus require tailored and customized development, optimization, and scaling solutions.

Meyer therefore anticipates the growing diversity of modalities will further drive the need for contract development and manufacturing organizations (CDMOs) with the willingness and flexibility to adapt to new modalities and markets.

Several technical challenges

Although it may not seem like a specific scaling challenge, Meyer argues that the need to demonstrate biosimilarity is indeed a scaling challenge because of the nature of biologics. “Ensuring biosimilarity is a multifaceted challenge because biological systems are inherently variable, and thus achieving comparability with the reference product requires addressing several important aspects throughout the development and approval process,” he observes. One crucial success factor in biosimilar process scaling, therefore, is maintaining cell growth and productivity without introducing variability when transitioning from small-scale to large-scale bioreactors.

Achieving product and process consistency from batch to batch and across scales is a notable challenge as well. Realizing this goal must start at the cell-line development stage, where all differences from the reference product must be minimized, according to Meyer. Development of highly controlled processes is then essential to ensure stringent product quality as processes move through development phases and scale-up to commercial production. “Application of advanced analytical techniques that enable comprehensive comparison of the biosimilar’s critical quality attributes (CQAs) to those of the reference product is key,” he says. Biosimilar developers therefore must have experience and expertise in the analysis of biologics and access to well-equipped, state-of-the-art analytical labs.

Successful scale-up of biosimilar manufacturing processes also requires access to a stable supply chain affording consistent supply of high-quality raw materials and up-to-date knowledge of regulatory requirements, Meyer notes. Process scaling must also be practically achievable with reasonable process economics without compromising product quality.

Recent innovative solutions

Fortunately, the biopharmaceutical industry is, although conservative, also highly innovative, with constant investment in new technologies geared to improving productivity and quality while reducing risk and cost. Biosimilar developers have benefited from many recent advances.

Notable examples highlighted by Meyer include single-use bioreactors, which reduce the risk of cross-contamination across all scales; process analytical technology, which allows for real-time monitoring and control of critical process for streamlined scale-up and consistent performance from lab to commercial production; and innovations in cell-line development such as clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing and high-throughput screening, which have led to more productive and robust cell lines that, in turn, support streamlined scaling.

Of course, introduction of new technologies inevitably brings new sets of challenges. For instance, new technologies cannot be integrated into complex biomanufacturing frameworks without a transition period, according to Meyer, which can include, among other things, reconfiguration of systems and processes and significant training of personnel.

The implementation of new technology also brings about new challenges regarding data management and security, Meyer comments. “As biopharmaceutical manufacturing becomes more automated and digitized, it is the responsibility of CDMOs to ensure the safe and compliant handling of client and product data,” he contends.

Overall, Meyer concludes, it is essential to balance the benefits and challenges of innovative technologies to realize the successful and sustainable scale-up of biosimilar manufacturing processes.

Adopt a holistic strategy and platform processes

Given the multiple steps involved in biosimilar process development and scale-up, planning is essential and, according to Meyer, should take into account several key factors: process consistency and robustness, analytical excellence, and regulatory compliance.

At Rentschler Biopharma, success in biosimilar development hinges on providing robust processes that deliver material of highly comparable quality to the reference product, and doing so in a manner that supports submission timelines and ensures reliability, according to Meyer. That is achieved by taking a holistic approach and considering multiple factors from the outset of a biosimilar development project, including cell-line development, analytical needs, and regulatory compliance.

Establishing state-of-the-art cell lines that ensure biosimilarity early on and provide consistent performance across scales, including high titers to lower overall cost of goods, is crucial for biosimilar market success, observes Meyer. Use of state-of-the-art analytical techniques for thorough characterization and real-time monitoring of CQAs also supports successful process development and scaling. Rentschler Biopharma leverages these approaches combined with a quality-by-design approach, which enables early identification of CQAs and process parameters, leading to greater process understanding and the ability to develop robust, scalable processes. Meanwhile, use of scalable bioreactor systems, including multiple 2000-L and 3000-L bioreactors, makes it possible for Rentschler Biopharma to optimize conditions for large-scale production.

Staying abreast of regulatory changes is also crucial to ensure ongoing compliance. Rentschler Biopharma has a dedicated regulatory affairs team with extensive experience in biosimilar development that engages with regulatory authorities early on in the development process and maintains open communication to align on expectations and requirements, according to Meyer. “By anticipating additional data requests from regulators, we prepare comprehensive data packages in advance,” he adds.

Access to modular and flexible manufacturing facilities is also essential to ensuring easy scale-up of biosimilar processes given that each molecule has unique attributes and often requires custom solutions to ensure consistent performance across scales. With its sites in Laupheim, Germany, and Milford, Massachusetts, in the United States, which leverage similar equipment and manufacturing platforms across lab to commercial scale, for instance, Meyer notes that Rentschler Biopharma can provide tailored development and manufacturing support for many different biosimilar candidates from early to late-stage through commercialization.

References

1. MarketsandMarkets. Biosimilars Market by Drug Class (Drug Class (Monoclonal Antibodies (Adalimumab, Infliximab, Rituximab, Trastuzumab), Insulin, Erythropoietin, Anticoagulants. rhGH), Indication, Region–Global Forecast to 2028. Marketandmarkets.com (accessed Dec. 23, 2024). https://www.marketsandmarkets.com/Market-Reports/biosimilars-40.html.
2. Chen, L.; Bush, B.; Brochu, M.; and King, G. New Drug Modalities 2024, Boston Consulting Group. BCG.com. Sept. 24, 2024. https://www.bcg.com/publications/2024/new-drug-modalities-report

About the author

Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology^®.

Article details

Pharmaceutical Technology®
Vol. 49, No. 1
January/February 2025
Pages: 20–22

Citation

When referring to this article, please cite it as Challener, C.A. Overcoming Biosimilar Scaling Challenges. Pharmaceutical Technology 2025 49 (1).