The biopharmaceutical sector is the fastest-growing segment of the pharmaceutical industry, accounting for approximately 20 percent of the global market.1 With an annual growth rate exceeding eight percent1 – twice that of conventional pharmaceuticals – bio-based medicines are rapidly reshaping the landscape of drug development. This rapid expansion is driven by the unique molecular complexity of biotherapeutics, which enables highly targeted and effective treatments for previously untreatable diseases, often with fewer side effects than traditional drugs. Among these innovations, protein-based biologics – such as fusion proteins, recombinant proteins, cytokines, hormones, and enzymes – are becoming increasingly central to modern medicine. These therapies are not only advancing treatment options but also improving access to effective medical care for patients across the globe.
This rapid progress does not come without challenges, and biomanufacturers face several critical obstacles in the development of novel protein-based products. The complexity of these molecules, coupled with the technical demands of scaling up production, can create significant barriers to efficient and cost-effective manufacturing. Proteins are highly diverse, characterized by unique amino acid sequences, complex three-dimensional structures,2 specific post-translational modifications3 and, at times, specific cofactor requirements.4 This variability demands a highly tailored approach to protein production, often resulting in extended development timelines and higher costs, which complicates the journey from discovery to commercial production.
Key Challenges in Biopharma
Navigating the complexities of bioprocess development becomes increasingly crucial as the biopharmaceutical market continues to expand. Some of the most significant hurdles faced by biomanufacturers are low yield, poor stability, and issues with purity or solubility.
Low yield
Achieving high outputs from recombinant expression systems is critical for biotherapeutic protein production. However, many proteins exhibit poor expression levels, limiting the amount of product that can be generated in a single production run. Factors such as the choice of expression system – bacterial, yeast, or mammalian – protein folding and stability, and the efficiency of post-translational modifications all play a role in determining yield. For example, aggregate formation or misfolding can lead to the production of low amounts of functional protein, hindering the scalability of the process. Low yields mean that more resources – including raw materials, time, and labor – are required to produce the same amount of therapeutic product, driving up the cost of goods. Time-to-clinic can also be affected, as biomanufacturers must dedicate more time to overcoming these hurdles. Optimizing yield is a complex and iterative process that demands advanced bioprocessing techniques and a high level of expertise.
Instability
Stability is another key consideration in biopharmaceutical production, particularly as many proteins are prone to aggregation, degradation, denaturation, or structural changes. Protein instability can occur at various stages of the biomanufacturing process, from fermentation to final drug formulation. Loss of structural integrity can render proteins biologically inactive or cause them to trigger immunogenicity in patients, reducing their therapeutic effectiveness.5
Additionally, instability often leads to a shorter shelf life, limiting the window in which biologics can be safely administered to patients. A range of strategies – such as optimizing the cell line or expression conditions, modifying the protein’s amino acid sequence, or incorporating excipients and stabilizing agents6 – can help to address this issue. While these measures are essential for ensuring efficacy and meeting regulatory standards, they add complexity and costs to the manufacturing process.
Poor purity and solubility
High levels of purity and solubility are also critical for ensuring the therapeutic effectiveness and safety of biological drugs. Proteins used in drug formulations must meet high purity standards to avoid contamination with common impurities, such as host cell proteins and DNA, endotoxins, or unwanted byproducts from the production process. These contaminants can compromise product safety and efficacy, and even cause harmful immune responses. In addition, certain proteins tend to aggregate or precipitate, making them difficult to dissolve in solution. Insufficient solubility can impact the bioavailability of the drug, reducing its effectiveness and making it harder to formulate for clinical use.7 Rigorous purification and filtration processes are needed to address purity and solubility challenges. Techniques such as chromatography, depth filtration, and tangential flow filtration (TFF) can be used to isolate the desired protein from impurities and enhance solubility. These processes add significant operational expenses and can extend production timelines, making large-scale biomanufacturing more difficult and costly.
The CRDMO Solution
Addressing the complex challenges of bioprocessing often requires substantial resources. Many biopharmaceutical companies lack the time, space,e and expertise needed to efficiently develop new cell lines or manufacturing technologies in-house, so they are increasingly turning to contract research, development, and manufacturing organizations (CRDMOs) for support. These specialized partners offer advanced knowledge and tools spanning all aspects of the biopharmaceutical production pipeline, from initial host selection to rigorous quality control.
Expertise in host selection
Host selection is a critical first step in the biomanufacturing process, and significantly influences the efficiency of therapeutic protein production. The choice of host organism directly impacts several bioprocessing outcomes, including protein expression levels, solubility, and overall yield. Although biomanufacturers have traditionally relied on well-established hosts – such as mammalian cell lines or Escherichia coli – CRDMOs can offer a broader array of options, including Gram-positive bacteria like Bacillus subtilis, and yeasts like Pichia pastoris. These alternative expression systems offer faster growth rates, require simpler and more cost-effective growth media, are often easier to genetically manipulate, and can produce high yields of recombinant proteins with proper post-translational modifications. A well-equipped CRDMO will bring additional value to biomanufacturers by offering advanced cell line and strain engineering capabilities to ensure that the selected host system is fully optimized for maximum productivity. This includes offering a library of superior genetic elements and expression vectors designed to enhance the expression and solubility of specific proteins.
Streamlining process development
Following host selection and engineering for recombinant expression of the desired biologic, CRDMOs can further enhance the biomanufacturing process through careful and tailored strain or cell line optimization. This involves iterative cycles of modifying the host organism to improve the stability, folding, and expression of the target protein. For instance, genetically engineering the host species can prevent the expression of unwanted proteins – like proteases that might degrade the target protein – or enhance the production of chaperones that are crucial to ensure proper protein folding and stability. Additionally, CRDMOs apply the design of experiments (DOE) approaches to optimize critical parameters in both upstream and downstream bioprocessing. This may include improving fermentation processes, enhancing growth media, and adjusting purification methods. This meticulous fine-tuning ensures process scalability and robustness. Refining these variables enables CRDMOs to establish a robust manufacturing process that can easily be transferred back to the customer, streamlining the production of clinical trial material.
Harnessing innovative technologies
Modern CRDMOs integrate cutting-edge technologies, such as machine learning algorithms, into their workflows to enhance bioprocess development and enable real-time monitoring and control of various protein production variables.8 For example, in cases where traditional codon optimization tools fall short, advanced machine learning models can help to improve the translation of DNA into proteins. These algorithms can help to address the unpredictability between RNA and protein expression, leading to improved yields and more efficient production processes.
Advanced analytics and quality control
Finally, collaborating with a CRDMO grants biomanufacturers access to advanced analytical tools, offering reassurance that the biologics they produce meet the highest standards of quality and consistency. One example is quadrupole time-of-flight liquid chromatography-mass spectrometry (Q-TOF LC-MS), an innovative technique used to separate, identify, characterize, and quantify biopharmaceutical compounds. This analytical tool provides detailed information about the composition, integrity, and biological activity of complex protein products to ensure that quality standards – such as purity, solubility,y, and stability – are consistently met. It also allows CRDMOs to quickly detect issues in biotherapeutic production and make real-time adjustments, ensuring product consistency, safety, and regulatory compliance.
Integrated Platforms to Streamline Biopharmaceutical Production
A CRDMO partnership offers end-to-end benefits that can greatly boost the efficiency and scalability of biomanufacturing. To streamline this process even further, some CRDMOs have adopted platform technologies that combine various stages of production – including host selection, process development, and quality control – into a single integrated framework. They ensure that modern CRDMOs can quickly adapt to new projects, enabling rapid and precise process development and optimization.
Platform technologies offer biomanufacturers the flexibility to effectively explore a range of host organisms and expression systems, providing tailored solutions for producing even the most complex biopharmaceuticals. In addition, some systems integrate machine learning algorithms and advanced data analytics, enabling easy automation and optimization of bioprocesses. This allows for quicker iteration cycles, real-time adjustments, and seamless scalability from early-stage development to full commercial production. Centralizing biologic production to an integrated platform therefore offers biomanufacturers a faster, more reliable pathway to market, while reducing the costs associated with in-house development and manufacturing of novel complex proteins.
Conclusion
Protein-based biopharmaceuticals are quickly becoming an essential component of modern healthcare systems worldwide. However, the complexity and diversity of these products present significant challenges to biomanufacturers, often resulting in prolonged development timelines and increased costs. Biopharmaceutical companies are therefore increasingly turning to CRDMOs to access advanced technologies and the specialized expertise necessary for efficient and cost-effective biologic production. These partner companies provide a broad range of services – including cell line development, process optimization, and advanced analytics – to streamline recombinant protein production. In addition, many modern CRDMOs offer platform technologies that integrate all stages of development and manufacturing into a cohesive framework. The result is a fantastic and efficient production pipeline that supports biomanufacturers in bringing their innovative therapies to market faster while minimizing risks and reducing production costs.
References
- Otto R, Santagostino A, Schrader U. Rapid growth in biopharma: Challenges and opportunities. In: From Science to Operations: Questions, Choices, and Strategies for Success in Biopharma. McKinsey & Company.
- Sun PD, Foster CE, Boyington JC. Overview of protein structural and functional folds. Current Protocols in Protein Science. 2004;35(1).
- Ramazi S, Zahiri J. Post-translational modifications in proteins: Resources, tools and prediction methods. Database. 2021;2021.
- Marchetti M, Puglisi R, Cellini B, Dindo M, Marchesani F. Editorial: The role of cofactors in protein stability and homeostasis: Focus on human metabolism. Frontiers in Molecular Biosciences. 2023;10.
- Yasir M, Tripathi AS, Shukla P, Maurya RK. Immunogenicity of therapeutic proteins. Protein-based Therapeutics. 2023:251-273.
- Vulto AG, Jaquez OA. The process defines the product: What matters in biosimilar design and production? Rheumatology. 2017;56(suppl_4):iv14-iv29.
- Stielow M, Witczyńska A, Kubryń N, Fijałkowski Ł, Nowaczyk J, Nowaczyk A. The bioavailability of drugs—the current state of knowledge. Molecules. 2023;28(24):8038.
- Khuat TT, Bassett R, Otte E, Grevis-James A, Gabrys B. Applications of machine learning in antibody discovery, process development, manufacturing, and formulation: Current trends, challenges, and opportunities. Computers & Chemical Engineering. 2024;182:108585.
Author Details
Leonardo Magneschi, Vice President of Research and Technology Development
Masha Kononov. Director of Business Development (North America)
Dr. Leonardo Magneschi holds a PhD in Plant and Microbial Biotechnology, with over 15 years of experience in microbiology and genetic engineering of alternative hosts. He also has 17 publications in peer-reviewed journals and was granted inventorship on five international patents. Leonardo joined Ingenza in 2016 as a Senior Scientist and was promoted to Vice President of Research and Technology Development in May 2024 to strategically advance Ingenza’s development of world-class biotechnology solutions.
Masha Kononov has a successful track record of over 25 years in life sciences business development and R&D in the biotechnology and pharmaceutical sectors. Before joining Ingenza, she held senior business development roles at prestigious companies like Leukocare AG, Arcinova/Quotient Sciences, and Catalent Pharma Solutions. She became the Director of Business Development (North America) at Ingenza in 2023, responsible for developing new territories, businesses, and market-focused strategies to achieve the company’s strategic and commercial goals.
Publication Details
This article appeared in Pharmaceutical Outsourcing:Vol. 25, No.4 Oct/Nov/Dec 2024Pages: 30-32