Biologic Manufacturing: Process, Steps, and Challenges

Biologic manufacturing describes the process of producing medicine by the means of living organisms. Biotech and pharma companies make use of this approach to produce biologics like mAbs (monoclonal antibodies) or mRNA vaccines both at small and large scale, bringing several advantages over traditional small-molecule drug products.

Central practices in biomanufacturing encompass various stages of production, from upstream processes involving cell culturing and harvesting to downstream processes focusing on purification and formulation. In this article, we will take a look at the most distinctive steps and challenges, and discover how they can be mastered.

An introduction to biologic drug development

Pharmaceuticals produced via biomanufacturing

Biomanufacturing plays a crucial role in the production of various pharmaceuticals, particularly biologics and biosimilars. This process involves harnessing living cells, microbes, or genetically engineered systems to produce a wide range of healthcare bioproducts.

Some common types of biomanufactured products include:

• Vaccines (e.g. mRNA vaccines)
• Viral vectors
• Blood products
• Cell and gene therapies
• Antibodies (e.g. monoclonal antibodies)
• Recombinant proteins
• Growth factors
• Hormones
• Gene therapies

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Mammalian cell lines are often preferred for their ability to produce complex proteins with human-like post-translational modifications. These cell lines are maintained in cell banks, ensuring their long-term viability and reproducibility throughout the manufacturing process.

Upstream processing also includes extensive process development and optimization to maximize protein yield, purity, and quality, e.g. via seed train intensification, where the cultivation process of a certain cell line can be increased in speed. Successful upstream processing lays the groundwork for downstream processing.

Downstream processing in the production of biologics

Downstream processing is a crucial phase in biologics manufacturing, where harvested proteins undergo purification, formulation, and final product manufacturing. This stage ensures the production of high-quality biopharmaceuticals ready for drug development and therapy.

Purification

During downstream processing, biotechnological techniques are employed to purify the drug substance, removing impurities and contaminants to meet stringent quality standards. This phase is particularly important for manufacturing biosimilars and biopharmaceuticals, with purity and consistency of the final product being paramount.

Techniques involved in this process include chromatography, filtration, and centrifugation, among others, allowing for the separation and purification of target proteins from cell culture supernatants.

Formulation

Formulation involves composing the final product with excipients to enhance its stability, solubility, and shelf-life. Buffer systems, crucial for maintaining pH within optimal ranges, are selected based on the biologic molecule's properties.

Stabilizers may be incorporated to shield the drug substance from degradation due to various factors like temperature and oxidation. These additives safeguard the structural integrity of the biologic, preventing denaturation.

Filling of biologics

Filling processes are to be encountered in several upstream and downstream phases of biomanufacturing, when either intermediates or finished biopharmaceuticals are transferred (e.g. into bioprocess containers). Additionally, further substances, such as buffer solutions and media, may be added. These processes demand close attention to filling precision and sterility in order to minimize the risk of batch-to-batch inconsistencies and product loss.

Throughout the manufacturing process, stringent quality control measures are implemented, and validation protocols are followed to monitor each step of production. Aseptic techniques are employed to maintain sterility during every step.

Fluid management solutions for biologics, such as Single Use Support’s RoSS.FILL, are developed to cater to these specific requirements, able to perform efficient fluid transfer while providing highest accuracy.

Freezing of biologics

Freezing biologics ensures the preservation of product integrity and efficacy. Biologics, such as monoclonal antibodies and other proteins, are often sensitive to temperature, making it necessary to follow individual freezing protocols for different product classes.

Freezing involves cooling biologics to sub-zero temperatures using controlled freezing methods to regulate the formation of ice crystals, which can damage protein structures. Cryoprotectants are added to the formulation to protect biologics from freeze-induced damage and ensure their stability during storage.

An increasingly popular approach in freezing biosimilars and biologics is plate freezing. The drug substances, filled in primary packaging options like single-use bioprocess containers, are covered by secondary packaging solutions, such as Single Use Support’s RoSS® Shell. These will have direct contact with the cooling plates of RoSS.pFTU or another plate freezer, leading to efficient heat transfer and maximum control over freezing rates.

Storage and cold chain logistics of biologics

Once frozen, storage of biologics requires specialized ultra-low temperature storage freezers to maintain protein stability over extended periods. These storage facilities are equipped with temperature monitoring systems to ensure that biologics remain within specified temperature ranges.

One of the most crucial strengths of ULT storage freezers like Single Use Support’s RoSS.ULTF is their high storage density thanks to a modular interior shelving system. Furthermore, as temperature variations and fluctuations may be detrimental to product efficiency and safety, these devices provide stable temperatures via reliable air temperature conformity, offering safe storage space for valuable biopharmaceuticals.

Challenges in biomanufacturing

Challenges in manufacturing biosimilars and biologics span worker safety, product integrity, and scalability. These challenges for the biotechnology industry are tied to regulatory compliance, the complexity of the manufacturing process, and evolving possibilities and demands in biotechnology.

• Product safety: Maintaining the safety, efficacy and integrity of biologic drugs throughout the manufacturing process is critical. Challenges arise in establishing proper freeze thaw processes for biosimilars and biologics, minimizing contamination risks, and reducing other risks associated with product loss.
• Regulatory compliance: Biomanufacturing is subject to rigorous regulatory oversight from agencies. Compliance with regulations governing manufacturing processes, quality control measures, and Good Manufacturing Practices (GMP) is vital to ensure the safety of new drugs, therapies, and vaccines – in preclinical and clinical trials as well as in the commercial manufacturing of biologics.
• Worker safety: Ensuring the safety of workers engaged in biomanufacturing processes is unnegotiable. Risks such as exposure to hazardous materials, ergonomic strains, and potential accidents during manual handling or when working in ATEX zones (explosive atmosphere) must be addressed through comprehensive safety protocols and ongoing training initiatives.
• Quality control: Implementing robust quality control measures throughout the manufacturing process aid in delivering safe and effective biologic drugs. While regulatory standards are the baseline when designing pharmaceutical manufacturing processes, establishing specific measures to monitor CQAs (critical quality attributes) depends on individual biomanufacturing environments. Here, traceability, standardization, and transparency are key to establish process control and quality systems.
• Scalability: Scale-up of biomanufacturing processes to meet increasing demand while maintaining product quality presents significant challenges. Balancing scalability with process efficiency, resource allocation, and cost-effectiveness requires careful planning and investment in infrastructure and technology.

In order to face these challenges, manufacturers are increasingly focusing on implementing technologies based on single-use technologies. Coupled with automated workflows, these are able to increase both reliability and cost-effectiveness.

Single-use solutions as provided by Single Use Support offer enhanced flexibility and enable scalability, allowing for rapid process development and easy scale-up. This is facilitated by the modular design of Single Use Support’s product portfolio – be it RoSS.FILL as a fluid management solution for biosimilars and biologics with its elevated efficiency and filling precision, or the plate freezing platform RoSS.pFTU.

RoSS.pFTU is able to freeze and thaw different volumes of drug substances – from a few mL to hundreds of liters –, able to meet individual freezing rates and protocols while reaching temperatures as low as -80°C. RoSS.LN2F provides equal control over freezing rates. However, this cryogenic freezer is designed for even lower temperatures (down to -170°C) without direct exposure to liquid nitrogen.

All these systems streamline operations, reduce downtime and enhance overall productivity. And as the biopharmaceutical industry continues to evolve, embracing single-use technologies enables drug manufacturing facilities to meet a growing demand while maintaining the highest standards of safety and quality.