Summary
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- Microbial Monitoring RABS Gloves: Unravelling the Implications of Directional Use
- General Considerations on Bacterial Endotoxins & USP Approach to Developing GC <86> Bacterial Endotoxins Test Using Recombinant Reagents
- Bacterial Spore Formers in Disinfectant Efficacy Testing
- Avoiding product oxidation by H2O2 in isolators. It all depends on the right analyses!
Outsourcing bioproduction of biomedicines in France
Bioproduction. … a vast subject that merits detailed study. Highlighted by the health crisis associated with the Covid-19 pandemic, the strategic importance of having production capabilities on their own territory became a central concern for countries all over the world. But what do we understand by bioproduction? Is it the same process whether producing a therapeutic antibody, cell therapy, gene therapy or vaccine. Unfortunately … no.
1.Let us begin at the beginning
To retain or even restore independence in health, it is essential to think in terms of the whole chain, from the R&D phases of a biomedicine through to bioproduction. A biomedicine is very often produced in the country in which it was developed, provided that it has adequate capabilities. France has two key assets. Our country is in fact very advanced, with 898 therapeutic biomedicine projects in development, the fruit of the historic and lasting strength of our academic sector. At the same time, the French innovative services sector can support the development phases of a drug candidate over the entire value chain.
So we have the fertile environment that is essential for completing this chain with bioproducers capable of producing for themselves on proprietary sites, as well as sites owned by CDMOs (Contract Development and Manufacturing Organizations), capable of producing for others as service providers!
It might be simplistic, however, to refer to bioproduction in the singular, as there is not one but indeed very different types of “bioproductions”. Producing a therapeutic antibody that targets a broad population in 20,000 L tanks, with a highly structured production process, has little to do with producing a cell or gene therapy that most often targets a limited population. Making a choice implies giving up on some possibilities, yet France must invest, with its European partners, to endow itself with the capabilities for each of these different biomedicines with very different production processes. But let’s rejoice, the State is aware of the stakes and specific EAA have been created to help our national champions, that are playing the game to the full and investing to grow and to give us the bioproduction capacities that we lack.
Since 2023, CDMOs and other bioproduction players have announced increases in capacity. These have included LFB and Yposkesi which are doubling their production capacities respectively for antibodies and viral vectors, GTP Bioways which is increasing its microbial systems production capacities, R&D Biotech which has opened its new plasmid production unit and Just Evotec, which should also be launching its new production site in the near future. Add in those companies developing innovations to optimize bioproduction, and the observation that France wishes to regain its former place in drug production is no longer in doubt. Although the need is great and France wants to position itself, however, the competition is stiff and Asia arrived in force several years ago.
Samsung Biologics or WuXi Biologics to cite just them, are constantly winning market share and making many French and European CDMOs suffer (the American Senate recently took measures targeting WuXi in particular, to limit American dependence on this strong new player). The takeovers and mergers currently in progress are clear proof of this. The sector must organize and structure itself while remaining agile to absorb reduced volumes when times are hard, and take account of the increasingly complex special features of the biomedicines to be produced. It must also invest in the future by creating platforms with the capacity to develop the processes desired by their customers.
2. Current situation in the French CDMO sector
Article L5121-1 of the French Public Health Code and the professional legislation of the medicines industry (European Union legal framework) define a biomedicine as “any medicine whose active substance is produced or extracted from a biological source and that needs a combination of physico-chemical-biological testing together with knowledge of its production process and its control for its characterization and the determination of its quality”. Biomedicines thus encompass a diverse range of substances, such as modified human proteins, monoclonal antibodies, growth factors, vaccines, enzymes, organelles, viruses and living cells or tissues. Given the intrinsic complexity of all biological sources whether cellular or acellular, the (bio)production of biomedicines requires a highly controlled environment, strict regulatory compliance and onerous quality control procedures, to guarantee the safety and efficacy of the final product.
The bioproduction of biomedicines can be divided into 3 major key steps: USP, DSP and F&F.
USP (or Upstream Processing)
The aim during USP is to optimize the growth of the biological source and production of the biomedicine. This step involves the preparation and culture of the biological material necessary to produce the biomedicine, such as mammalian cells or microorganisms. It includes steps such as cell culture, fermentation, and development of an inoculum. Additional genetic engineering stages involving genome modification are also part of USP. Cell or microbial culture is carried out in increasing volumes (scale-up) in single-use or multi-use bioreactors. Several culture methods are now used in bioproduction with fixed volume culture without perfusion (Batch Culture), culture with the addition of medium (Fed-Batch Culture) and fixed volume culture with continuous perfusion (Continuous Culture). Regardless of the culture method, control and regulation of the different critical parameters of the medium are essential. At the end of the step, the medium will be saturated with the product of interest, but also with debris and culture waste.
DSP (or Downstream Processing)
The aim during DSP is firstly to remove the impurities derived from culture in the bioreactor and secondly to concentrate the biomedicine product of interest. Post-USP treatment consists in separating and purifying the product of the fermentation “broth” or of the cell culture. Harvesting separates the cells or microorganisms from the culture medium, to obtain solely the supernatant or biomass. Subsequently, a sequence of filtration, centrifugation, chromatography procedures and other separation techniques will isolate the product and remove impurities. Two filtration techniques are used to purify and concentrate the products. Direct Flow Filtration which involves the direct passage of the liquid through a filter, retaining impurities while the desired product is collected. Tangential Flow Filtration circulates the liquid tangentially at the surface of a membrane, allowing the product to pass through while retaining impurities. Chromatography steps are specific to each biomedicine type.
Once DSP is completed, additional product modification stages can also take place such as bioconjugation of monoclonal antibodies to yield immunoconjugates.
F&F (or Fill & Finish)
In this step, the purified product is formulated in its final dosage form, which may include liquid formulations or lyophilized powders. The product may also be packaged in accordance with its mode of administration in vials, infusion bags or syringes. Further, all necessary final treatment steps, such as sterilization or packaging, are carried out to prepare the product for distribution and use.
3. CDMO selection criteria
CDMO companies play a crucial role in the pharmaceutical industry by supplying a wide range of services to biotechnology and pharmaceutical companies. They appeared to meet the growing needs of biomedicine developers for specialist expertise, operational flexibility, cost reduction, accelerated development and risk management.
The choice of CDMO partner is decisive in project development and can significantly impact its success or failure. The selection process is therefore complex, long and dependent on the strategy of the company that is developing the biomedicine (placing on the market, licensing, sales…). Given the scale of the CDMO selection process, we suggest summarizing the main criteria generally used for this choice.
The main selection criteria are therefore:
Expertise & Experience
CDMOs are unique with different strengths and specialisms, distinguished mainly by their technical expertise and their practical experience. The selection criteria include GxP experience to meet regulatory requirements, familiarity with the required cell types, access to appropriate cellular materials, cell, molecular, biochemical biology tools, to carry out development and production.
Quality & Compliance
Quality is fundamental in pharmaceutical manufacturing. A CDMO must comply with strict quality control standards, such as GMP, and have certifications such as ISO, FDA, EMA. It is important to evaluate their quality systems, their regulatory inspections history, and their analytical and technology transfer capabilities. Stability studies and GMP compliance are also determining factors in guaranteeing project success. Your manufacturing partner must have experience in the preparation of IND dossiers or have legal support. The CDMO must offer support for navigating complex regulatory landscapes, with extensive expertise in regulatory compliance.
Customer relations
Effective communication is necessary to establish a relationship of trust and promote collaboration and transparency throughout the development process of a medicine. It is important to evaluate the CDMO’s project management approach, particularly the appointment of dedicated project managers, the definition of deadlines and milestones. Additionally, it is essential to understand their communication protocols, the frequency of reports and access to updates in real time. A check should also be made regarding whether their communication style matches your expectations and whether they are able to provide transparent, timely and proactive updates on the progress of the project.
Production capacity
When choosing a CDMO, it is crucial to consider their capacity to increase production as your project progresses in the different development stages and potentially in the marketing stages. Evaluate the capacity of their facilities, their available resources, and their flexibility to meet these growing needs to avoid bottlenecks.
Flexibility & Adaptability
To support customer programs effectively in the long term without compromising on quality, flexibility must be incorporated into the CDMO‘s operational process and culture. It is essential to choose a responsive, agile partner, capable of managing complex clinical programs while having the necessary expansion capacities.
Profitability
Choosing the cheapest CDMO may seem attractive, but a detailed analysis is necessary to avoid future problems. Outsourcing allows the reduction of general costs and more effective resource allocation, promoting more predictable financial planning. However, thorough due diligence is crucial before selecting a CDMO partner to avoid delays and additional costs. Prioritizing cost savings at task level can sometimes compromise the CDMO’s quality and technical support, leading to delays and additional costs in the long term. It is therefore essential to consider all factors when selecting a CDMO to avoid delays and risks.
4. Specific bioproduction characteristics according to biomedicine type
The heterogeneity, complexity and variable maturity of biomedicines mean that the challenges and strengths of their respective bioproduction value chains differ according to the type of therapeutic protein, viral vector, cell type or cell populations to be produced.
Therapeutic antibodies have the advantage of having now proved their worth… Since the first antibody was marketed in 1985 (muromonab), no fewer than 170 of them have arrived on the market to provide astonishing solutions for a great number of diseases then in treatment failure. Often targeting broad populations in oncology or inflammation (for example pembrolizumab which is being tested in 1407 parallel clinical trials), the production process is now known and controlled in its totality. While of course there is still room for improvement in terms of cheaper, higher yield production, the cost of a pouch of antibodies is several thousand euros… Having demonstrated their efficacy, some antibodies that have lost protection have been “copied” and biosimilars have arrived on the market with prices that can fall to several hundred or even tens of euros. The price of these biosimilars alone demonstrates that the cost of production, with a certain volume effect, can be controlled and maintained at an acceptable level for health care systems.
Gene therapy offers major advantages, in particular direct treatment of genetic diseases and lasting correction of defective genes. It also opens the way to new therapeutic approaches and to treatments for a wide range of diseases. Cell therapy enables precise, targeted treatment, providing tissue regeneration capacity, lower toxicity and treatment prospects for hitherto incurable diseases. It also makes it possible to personalize treatments, provides lasting effects, and reduces the treatment burden. However, the large-scale manufacture of these therapies must take into account the heterogeneity of the vector types and cell types to be produced.
In the absence of established standards, of a gold standard, in the bioproduction of this type of therapy, it has become customary to say that the process (production) is the product (therapy), as the two are so inseparable and specific.
In addition, the production capacities for some therapeutic cells remain limited, complicating scaling up and impairing process reproducibility. The production yield of viral vectors still needs to be improved. To these technological challenges, must also be added onerous regulations with strict quality controls. The use of autologous products, whose source material is taken from the patient and then administered to the same patient after bioproduction, adds additional logistical complexity to the value chain. All of these elements significantly impact the production cost of cell and gene therapies and of other Advanced Therapy Medicinal Products (ATMP). And it is this high production cost that will, in large part, and in most cases, impact the price of the therapeutic product.
In the United States, the price of autologous CAR-T treatment, a therapy based on genetically modified cells and used exclusively in oncology costs in the region of $400,000 while the only gene therapy treatment for haemophilia B currently stands at $3.5 million. Because the United States and Europe have different market access policies, some cell and gene therapy products are not always available in France or have been removed from the market. The emergence of allogeneic therapies whose source material comes from healthy donors, automation solutions and innovative new DSP and USP technologies should make it possible to improve the bioproduction of these therapies.
5.Recent deals in the bioproduction field
The dynamism of the bioproduction field is reflected particularly in recent financial mergers and acquisitions costed at several million euros, even several billion euros. At the beginning of 2023, Sartorius, through its French subsidiary Sartorius Stedim Biotech, reached an agreement to acquire the Strasbourg company Polyplus, which among other things offers transfection solutions, for around €2.4 billion. Polyplus had itself acquired the French CDMO Bio-Elpida and the Belgian CRO Xpress Biologics the previous year. The other notable acquisition in the French landscape in the same period is that of ABL Europe, a French CDMO and an Institut Mérieux subsidiary, by the UK’s Oxford Biomedica for €15 million which should allow the latter to expand its viral vector production capacity. More recently, the Danish investment giant Novo Holdings, which also controls Novo Nordisk, announced in early 2024 the acquisition of Catalent, one of the largest American CDMOs, for $16.5 billion. Novo Holdings anticipates finalizing the acquisition by the end of 2024 and will then surrender at least 3 production sites to Novo Nordisk for $11 billion with the aim of boosting production of its new blockbuster, Wegovy. And at the start of this year, two other CDMOs announced their alignment. Finland’s Biovian joined forces with the Spanish 3P Biopharmaceuticals, to form 3PBIOVIAN. This strategic merger aims to offer ‘End-to-End’ development and manufacturing services for protein expression systems and viral vectors, covering the preclinical to the commercial phases.
6. Conclusion
Taking into account the diversity of biomedicine types that can be produced in France, the number of production sites and the growing number of financial deals, we are witnessing a real revolution within the national bioproduction sector. This expansion promises not only a positive impact on the national economy, but also on public health and health sovereignty.
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Nicolas GROUX
Geoffrey RICHARD
Gavin VUDDAMALAY
