Bioprocess and quality: the production of biological molecules

Bioprocessing paves the way for the future of biotechnology

Drug development has undergone a radical transformation since the early 2000s, with the growth of the biotherapy market replacing traditional pharmaceutical drugs. It is estimated that "biologics" will account for 70% of approved drugs by 2025.

Bioproduction refers to the production of these biological molecules, which are proteins, antibodies, membranes or other glycolipids. The very great complexity of the composition and structure of these macromolecules requires manufacturing in living systems; the chemical approach to synthesis has generally reached its limits.

What are the advantages of using a service provider for the production of proteins, antibodies or other biomolecules?

Access to services best suited to the specificities of the molecules to be produced


Save time in the production phase

Discover bioproduction services and exchange with the best service providers.

Challenges regarding antibody development

Antibody production expertise and techniques have grown for the creation of tools for biological research and clinical diagnostics. Methods that use antibodies include ELISA, flow cytometry, immunohistochemistry, immunoprecipitation and Western Blot. Antibody development is typically achieved by injecting antigen into a small animal (immunization step) or by using phage display methods. The challenges associated with the development of antibodies are typically their specificity, initial quantity produced, and future production required.

A rapidly growing area of antibody development is that of therapeutic monoclonal antibodies, i.e. used in the treatment of diseases. In 2017, 61 mAbs and 11 Fc-Fusions were in clinical trials. These new drugs hold the promise of treating multiple classes of diseases, particularly cancer and chronic inflammation. This class of antibodies faces multiple challenges specific to biomolecular and drug development.

Toxicity

The antibodies initially produced in an animal must be humanized to reduce the immune responses specific to the presence of exogenous constant domains, resulting in recombinant chimeric antibodies. The reference humanization technique is CDR-grafting. Significantly reducing the toxicity of the therapeutic mAbs, a humanitarian response is still observed in about 9% of patients.

Efficacy

Although therapeutic antibodies are successful against diseases with more severe or no treatment, they are subject to internal resistance mechanisms. This results in a loss of attachment to the surface of the target cells, a process called "modulation". To overcome this, constant domain Fc engineering is implemented, resulting in targeted mutations.

Specificity

Because of the detection limits of an antigen, biotech companies have developed bispecific antibodies, i.e., that recognize multiple targets. The advantage of these bispecific antibodies or bispecific antibody fragments is, depending on the strategy, to increase selectivity for a given target cell, or to recruit both target and effector cells.

Production capacity and costs

The production of mAbs is done by expression via immortalized hybridomas. However, the low production yields of these cell lines and the genetic modifications that can be introduced have led to the development of new production models. These methods include the use of mouse ascites (with regulatory limitations in terms of application), and recombinant expression through high production efficiency lines.

Types of providers

Bioproduction, since it concerns a vast field of competences, can call upon different types of service providers:

Academic structures

Academic platforms are very regularly solicited by research laboratories for the production in small and medium volumes of recombinant proteins and enzymes.

Service companies

Many service companies produce antibodies for research or clinical diagnostic purposes. They have the capacity to produce small and medium scale batches.

Specialized companies offer antibody engineering services, particularly for the development of therapeutic antibodies, or the production of more atypical biomolecules, such as lipopolysaccharides or exosomes.

Development and production companies (CMO & CDMO)

For the large-scale production required when a molecule enters the clinical phase, only a few structures can follow the project. These companies, called Contract Development and Manufacturing Organizations (CDMOs), may themselves be specialized in certain productions of biotechnological molecules or solutions.

The history of bioproduction

The production of biological molecules has undergone three major revolutions in terms of products and production techniques. At the beginning of the 20th century, production was limited to primary metabolites such as butanol, acetone, ethanol or citric acid, produced by bacterial fermentation (acetone production by EBA fermentation or Weizmann process).

The second revolution came with the Second World War and the discovery of antibiotics. Using mutant strains and aerobic submerged liquid fermentation, the industry is now able to produce secondary metabolites (penicillin, streptomycin...).

The third revolution was made possible by the appearance of recombinant DNA technology and the optimization of cell culture parameters. Biological systems can produce complex biomolecules including proteins, molecules that cannot be synthesized by chemical synthesis.

Whereas until the middle of the 20th century bioproduction was based on the opportunistic use of biological systems producing molecules of interest, the third revolution made it possible to express molecules to an organism that is not naturally capable of doing so. Today, bioproduction is based on an expression based on the construction and design of the biological system (synthetic biology revolution to come...!).

Technologies used for bioprocess

Cell culture: Microorganisms and eukaryotic cells

Preparative chromatography

Cloning, sequencing, recombinant expression

In silico modeling

ELISA, Western Blot, SPR

Animal facility

Estimated rates for this type of service

It takes a few hundred euros to produce a polyclonal antibody (i.e. produced for a rabbit).

The production of a batch of monoclonal antibodies for research can cost € 3,500 - € 7,000.

The production of a therapeutic antibody varies considerably depending on the number of steps required, starting at around €12,000 and reaching several hundred thousand euros.

GMP (good manufacturing practice) productions can also be very expensive, depending on the complexity of the molecule to be produced and the quantity.

The cost of producing recombinant proteins varies depending on the host organism, starting at around € 1,500 for production in bacteria.

Need help?