Bioproduction: the big challenge for biotechnologies

July 20th, 2020, by Labtoo's team

Bioproduction refers to the production of biological molecules (proteins, antibodies, hormones, membranes and other macromolecules) by a living system in order to cure diseases that are difficult to treat by classic chemical molecules: degenerative, rare or chronic diseases, cancers, etc. These innovative therapeutic strategies involve for example vaccines, gene therapy or cell therapy.

The history of bioproduction

La production de molécules biologiques a connu trois révolutions majeures en termes de produits et de techniques de production. Au début du 20ème siècle, la production était limitée à des métabolites primaires tels que le butanol, l’acétone, l’éthanol ou encore l’acide citrique, produits par de la fermentation bactérienne (production d’acétone par la fermentation ABE ou process de Weizmann).

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 relies on an expression based on the construction and design of the biological system (and the synthetic biology revolution has yet to come).

Biodrugs: what are the differences with chemical molecules?

A biodrug (or biopharmaceutical) is a medicine whose active substance has a biological origin and is not produced nor obtained by chemical synthesis like most of the current pharmacopoeia’s molecules. Biodrugs, by being macromolecules, differ from small chemical molecules on many aspects.
Small molecules are composed of 20 to 100 atoms and are typically produced by chemical synthesis. Biodrugs range from a few hundred atoms (e.g. hormones) to 25,000 atoms for antibodies. They are typically produced by a living cell system.

As for the delivery system, small molecules are administered orally. They have a higher cell permeability and can reach intracellular regions through cell membranes. In some cases, they can even cross the blood-brain barrier (BBB). Biodrugs, being larger in size and sometimes more unstable in structure, are administered by injection. Many therapeutic targets are not accessible to biomedical drugs because of the BBB or the plasma membrane for example. This difference between the two types of drugs affects the mode of delivery: by blood circulation for small molecules, and by blood and lymphatic route for biomedical drugs.

As for the targeted pathologies, small molecules address a wide spectrum of pathologies. This is also the case for biopharmaceuticals, but these drugs dominate in oncology, inflammation, infections, metabolic and cardiovascular diseases.

From a medico-economic standpoint, small molecules benefit from low prices thanks to their simpler and cheaper development process. However, they suffer from greater competition, largely linked to the generic’s economy. Biodrugs undergo a much more complex and expensive development process, resulting in high prices when it comes to marketing. The equivalent of generics for biodrugs is called biosimilars. However, demonstrating the bioequivalence between two biodrugs is practically impossible, given the physicochemical complexity of these products and the high technicity of their bioprocess. The goal here is to prove that the drugs are comparable on their therapeutic usage, their structure and bioprocess.

The issues of bioproduction in France

Vaccine production is the most developed bioproduction activity in France. Representing around 8,500 employments, the French bioproduction offer is globally polarized between SMEs that mainly produce clinical batches and big companies producing clinical and commercial batches. Despite an acknowledged pool of societies, skills and scientists, the French bioproduction network is still considered as insufficient. The about-thirty bioproduction sites set up in the country are not enough to counter the erosion of the pharmaceutical production that France has been going through over the last fifteen years.

Among the 11 main countries that produce medicines in Europe, only France and the United-Kingdom have experienced a decline of their production between 2004 and 2014, with France moving from being number one to number four in terms of production capacity, surpassed by Switzerland, Germany and Italy. France has missed the chance to engage itself in synthetizing the first therapeutic antibodies in the early 2000s; and Sanofi and Novartis are now the only stakeholders sufficiently dimensioned on the territory to support a worldwide production of commercial batches of monoclonal antibodies.

Struggling to keep pace with other European countries to produce biological medicines, France suffers from a cruel lack of links between industrials and biotech societies, mainly represented by startups. Startups, often lacking technical and financial means, are facing an unstructured ecosystem that is missing manufacturers who can produce their clinical batches: offshore pharmaceutical production becomes then a bigger threat, even though the French Government has recently declared its willingness to recentralize production in France.

To deal with such threats, the Government wishes to establish a coordinated policy to foster collaborations between stakeholders working on similar innovative technologies (cell and gene therapies), and to avoid competition between regional players and their service offering. Networking between startups and the industrial fabric has to be facilitated too, in order to increase the visibility of French bioproduction capabilities on an international level. France has still many challenges to overcome concerning its bioproduction offer; it is now just a matter of time to see whether the country will be able to become a European reference in this field, or not.

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