Biomanufacturing: Process, steps and challenges in manufacturing biologics

micheal-eder

Michael Eder

May 13, 2024

Table of contents

Show

Biomanufacturing describes a production process where biological systems are used outside their regular context for the synthesis of goods. 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.

Still, manufacturing biosimilars is a multistep process with more than one hurdle to overcome. In this article, we will take a look at the most distinctive steps and challenges, and discover how they can be mastered.

 

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

Source: 1 2 

Manufacturing biologics step by step

Manufacturing biologics involves a series of distinct process steps, each crucial in ensuring the production of high-quality biopharmaceuticals. These steps encompass various processes, from initial cell line development to final product formulation and distribution.

Throughout the manufacturing process of biologics, stringent quality control measures and adherence to regulatory standards are paramount to ensure the safety and efficacy of the biologic drugs. Let's dive a bit deeper!

Upstream processes: Cell line development and culturing

In the initial stages of biologics manufacturing, upstream processes such as cell line development and culturing (e.g. in bioreactors) set the foundation for producing therapeutic proteins. These processes involve utilizing techniques like genetic engineering, microbial fermentation, and cell culture to establish cell lines capable of expressing the desired biologic drugs. Researchers may employ genetic engineering to modify the genome of host cells, optimizing them for protein production.

Microbial fermentation manufacturing

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 and biosimilars

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.

Success Story RoSS.FILL: Aseptic Aliquoting in Bioprocessing Applications

A Success Story of the RoSS.FILL Automated Filling Solution that Connects Upstream, Downstream and Fill & Finish. The major technology gaps are filled by automated aseptic dispensing platforms that transfer drug substances from one process step to another, such as from downstream to fill & finish. But the proven record of aseptic filling with RoSS.FILL goes into more areas of application, including seed train intensification, bacterial fermentation, media perparation and fill finish of small volumes in single-use bags.
Filling of drug substance: 5 threats you should know

Freezing biologics and biosimilars

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 transport 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.FRDG 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.
 

Biomanufacturing – safety and efficiency gains with single-use technologies

In biomanufacturing, the adoption of single-use technologies heralds an elevated level of safety and efficiency. By replacing traditional stainless steel systems with disposable components, biopharmaceutical manufacturers mitigate the risk of cross-contamination and ensure product integrity. Furthermore, automated systems reduce the need for manual handling and thus the risk of human error.

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.

Read more about Biomanufacturing

In biomanufacturing, the adoption of single-use technologies heralds an elevated level of safety and efficiency. By replacing traditional stainless steel systems with disposable components, biopharmaceutical manufacturers mitigate the risk of cross-contamination and ensure product integrity. Furthermore, automated systems reduce the need for manual handling and thus the risk of human error.

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.

Optimizing pDNA production using advanced single-use technologies

How to optimize biomanufacturing efficiency

There are several parameters to be considered in the attempt to maximize efficiency in biomanufacturing. In this article, we will discuss different areas that have an impact on process efficiency, including ways to improve them.

Freezing biologics: best practices

Freezing biologics – best practices

There is more than one way to prepare biologics for long-term storage under temperature-controlled conditions – in this article, we will explore some of the main freezing methods.

storage-biologics

Safe storage of biologics: Requirements & solutions

Once biologics are produced, they need to be stored for shorter or longer periods of time, with dedicated storage requirements to be met. Here, we will uncover these requirements, along with solutions to fulfill them.

Automated aliquoting system: From small volume aliquoting to bulk filling with RoSS.FILL

Aseptic filling & processing of biologics

Many drug products require aseptic conditions along their entire production process. In this article, we will discuss essential considerations on aseptic filling in the biopharma industry.

  1. Biologics vs. small molecules: Drug costs and patient access, http://dx.doi.org/10.1016/j.medidd.2020.100075, Published 2020-11-23
  2. Biomanufacturing and Synthetic Biology, https://www.cdc.gov/niosh/topics/advancedmnf/biomnf.html, Published 07.2019
micheal-eder

Michael Eder

Senior Marketing Manager

Michael Eder, MA, is Senior Marketing Manager at Single Use Support. He is expert in pharma and health communication with his 8+ years experience in pharma. After completing his master's degree in International Healthcare Management at MCI The Entrepreneurial school in Innsbruck, he has gained experience in the pharmaceutical field. Michael creates articles about Freeze Thaw applications and Platform solutions from Single Use Support and is the author of current news with Single Use Support worldwide. 

More from Michael Eder

Vaccines

The development process of biosimilars

The development process of biosimilars slightly differs from the one of their reference biologics. In this article, we will discuss each phase in detail.

micheal-eder

Michael Eder

May 13, 2024

Vaccines

Efficient strategies for manufacturing biosimilars

Establishing both efficient and safe manufacturing processes for biosimilars requires planning, expertise, and state-of-the-art equipment. In this article, we will shed light on different steps in the manufacturing process and discuss ways to improve them.

micheal-eder

Michael Eder

May 8, 2024

Read more about Vaccines

Vaccines

Fluid management solutions for biosimilar production

In biosimilar production, fluid management takes on an overarching role, as it is encountered at several manufacturing steps. This is all the more reason to deal with efficiency in fluid management – which we will do in this article.

BRMO

Brian Moloney

May 14, 2024

Vaccines

Challenges in manufacturing biosimilars

The manufacturing process of biosimilars is a complex endeavor, accompanied by several challenges. We will discuss some of the biggest hurdles in this article, along with solutions to overcome them.

BRMO

Brian Moloney

May 14, 2024

Vaccines

How to optimize biomanufacturing efficiency

There are several parameters to be considered in the attempt to maximize efficiency in biomanufacturing. In this article, we will discuss different areas that have an impact on process efficiency, including ways to improve them.

michael-muehlegger

Michael Mühlegger

May 13, 2024

Vaccines

The development process of biosimilars

The development process of biosimilars slightly differs from the one of their reference biologics. In this article, we will discuss each phase in detail.

micheal-eder

Michael Eder

May 13, 2024