L3 - Bio-production and Biotechnology for Health (BIO²S)

In the field of healthcare biotechnology, recombinant proteins can be produced in various cell types—known as expression systems—which may be prokaryotic or eukaryotic. This is a mature and attractive technological field with strong employment prospects. Indeed, the bioproduction of biopharmaceuticals (proteins, monoclonal antibodies) represents a major challenge in human therapeutics. Before designing any biologic drug that involves a bioproduction step, it is essential to understand the various eukaryotic and prokaryotic expression systems used in biotechnology. 

This course unit includes interactive lectures, presentations by professionals, and hands-on exercises during which students will apply the knowledge gained in class: cell culture, monitoring of the production clone, recombinant protein production in a eukaryotic system, and production monitoring. 

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English tutorial for students in the “L3 Bioproduction and Biotechnology for Health” program, designed to help them achieve professional proficiency in English.

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The main objective of this course unit is to enable students to acquire theoretical and practical knowledge in molecular engineering. Specifically, students will learn how to integrate a gene encoding a molecule of interest and express that molecule in a suitable organism. This corresponds to the preparation stage of bioproduction.   

In order to produce a molecule of interest, it is necessary to first understand the molecular mechanisms and tools underlying a modified organism (prokaryote and/or eukaryote). The course will cover knowledge of the enzymes involved in genetic modification and the verification and validation of this modification through vectorization. Extraction, purification, and expression methods will be covered in laboratory sessions. In addition, a comprehensive overview of the significance of molecular engineering in the field of health will be presented.

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This course unit incorporates instruction that spans several disciplinary fields and addresses the various methodological approaches used in the industrial bioproduction of a biopharmaceutical. 

Biopharmaceuticals are health products that must meet strictly regulated health control standards for production facilities and final product quality control. To optimize production time and costs, statistical and mathematical methods are used to model bioprocesses.  

The objectives of this learning unit are therefore to present:  

- The development cycle of a biopharmaceutical and the good manufacturing practices required by regulations  

- Good laboratory practices necessary to ensure sanitary and safe control of production areas, as well as to ensure the traceability and integrity of experimental data 

- Quality control of biopharmaceuticals  

- Biostatistical methods and statistical analysis tools (software) for data from experiments 

- Bioinformatics (databases, OMICS, big data processing, etc.) for the characterization of a biopharmaceutical 

- Modeling bioprocesses using the design of experiments method to optimize the production of biopharmaceuticals 

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Immunotechnology is a field of biotechnology that applies knowledge of basic immunology to develop technological methods for therapeutic, diagnostic, or analytical purposes. This course unit will help students understand that immunotechnology can be used at various stages of the biomanufacturing process for a biopharmaceutical, from the research and development stage through to quality control. 

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This course unit (UE) is part of Skill Block 2 of the Bio²S Bachelor’s program (L3), titled “Preparing, Designing, and Conducting a Bioproduction Process.”

USP (Upstream Processing) refers to the “upstream” processes in the production chain of a biopharmaceutical. These processes involve the production of cells (cell therapy) and products (proteins, vaccines, monoclonal antibodies, etc.) in bioreactors.

The program focuses on:

1/ Knowledge of equipment: bioreactors ranging from laboratory scale to pilot or industrial scale, both traditional and single-use systems, and their immediate environment (sensors, etc.)

2/ Management of bioproduction processes.

Students will gain theoretical and practical knowledge of the structure and function of a bioreactor and how to prepare it for a culture.

Following a presentation on a standard bioreactor (a mechanically agitated and aerated tank), the various scales and the concept of scale-up will be discussed, along with other types of bioreactors (bubble column, airlift, etc.).

Next, all the preparatory steps prior to culture setup will be described and carried out both in the form of tTDs and during hands-on lab sessions on the Bioproduction educational platform. This section will cover: the preparation of culture media and the adjustment of their composition; the assembly, verification, and calibration of the probes and the bioreactor; sterilization; the setup of an aseptic sampling system; and the preparation of the inoculum (cell banks will be covered in UE 1.3—Recombinant Protein Expression Systems).

Next, the focus will be on "How to cultivate and implement a culture in a bioreactor."

In this section, the following topics will be covered:

- Indicators for monitoring biological reactions, as well as monitoring (offline, near-line, and online techniques) and culture control. The program includes: control loops, an introduction to Process Analytical Technology (PAT), and its integration with quality management (e.g., implementation of monitoring indicators, control charts, etc.).

- Management of industrial production constraints (particularly limitations caused by transport phenomena such as heat and gas (_O2))

- The different operating modes (batch, fed-batch, continuous): Following a general overview of the different modes, the course provides an in-depth look at each one. The goal is for students to engage in an engineering approach to developing viable technical solutions so that they will be able to:

o Analyze experimental results

o Use a production planning (simulation) tool at the industrial scale (or conduct experiments at the lab-pilot scale)

o To anticipate the various possible scenarios for feed management in fed-batch and continuous-flow processes

o To perform cultures during lab sessions on the Bioproduction educational platform

This learning unit is based on three cross-cutting projects spanning competency blocks 1 (Applying Key Theories and Concepts to Bioproduction), 2 (Preparing, Designing, and Implementing a Bioproduction Process), and 3 (Communicating About One’s Work), namely:

Project A: Production and purification of a monoclonal antibody using hybridoma cells (laboratory scale—screening). Cell culture (preparation of media, cell counting, and cell culture) will be performed after the producer clone has been verified (Work Package 1.3).

Project B: Production of a fluorescent recombinant fusion protein in a prokaryotic host using batch-mode bioreactors (laboratory scale). Culture setup and monitoring will be performed after the construction of the producer strains and their small-scale characterization (Module 1.2). In addition to conducting the culture and analyzing the results obtained, the objective of this lab is to master the preparation of a bioreactor (assembly, calibration, sterilization, etc.). This lab is also linked to Unit 2.1 for the design of the experimental plan and to Unit 3.1 for the preparation of reporting documents.

Project C: Production and purification of a fusion protein used as a veterinary vaccine in a prokaryotic host using fed-batch bioreactors (pilot scale). Preparation of the fermenter and initiation of fed-batch culture using anE. coli strain from a cell bank. Monitoring of the culture (online and offline parameters) and recovery of the biomass, calculation of yields. The complete DSP will be carried out in Unit 2.3. Batch records and production reports will be prepared in conjunction with Units 2.1 and 3.1.

The educational module on bioproduction:

USP:

- Eukaryotic and prokaryotic cell culture (Type II PSM, incubators)

- 4 instrumented benchtop bioreactors (2 to 5 L usable volume)

- 1 instrumented pilot-scale bioreactor (20 L usable volume)

DSP:

- Juicer

- High-pressure homogenizer (Emulsiflex, Avestin)

- AKTAPure + GSTPrep preparative affinity column

- Instrumented pilot-scale freeze-dryer

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This course unit (UE) is part of Skill Block 2 of the Bio²S Bachelor’s program (L3), titled “Preparing, Designing, and Conducting a Bioproduction Process.”

DSP (Downstream Processing) processes are the so-called downstream processes in the production chain of a biopharmaceutical. They involve the extraction and purification of the target molecule (recombinant protein or monoclonal antibody derived from a hybridoma). In this course unit, the aspects of distribution and packaging, as well as the related controls, will also be covered.

The program focuses on:

1) Knowledge of equipment (cell lysis, chromatography, filtration, freeze-drying, etc.)

2) Process management and quality control for the production of recombinant proteins

Students will gain theoretical and practical knowledge of how cell lysis, chromatography, and fractionation/packaging equipment works. They will be able to select the appropriate equipment and processes based on the characteristics of the target protein.

First, students will study the physicochemical properties of the target protein using simple sequence analysis tools. Based on this data and the protein’s intended use, the students will propose a purification strategy (lab).

These elements will be applied in the practical portion of the course, during which students will purify the target protein while performing a series of in-process sampling and quality control checks to ensure traceability and the final quality of the product.

Next, students will need to evaluate the performance of the process and the quality of both the active ingredient and the finished product by proposing an analytical approach appropriate for therapeutic proteins. They will thus need to determine production yields, purity levels, and the nature of impurities, and confirm the identity of the target protein (TD).

This learning unit is based on two cross-cutting projects covering skill sets 1 (Applying Key Theories and Concepts to Bioproduction), 2 (Preparing, Designing, and Conducting a Bioproduction Process), and 3 (Communicating About One’s Work), namely:

Project A: Production and purification of a monoclonal antibody using hybridoma cells (laboratory scale—screening). Purification, titration, and testing of the antibody will be performed following cell culture (UE2.2) and testing of the producing clone (UE 1.3).

Project C: Production and purification of a fusion protein used as a veterinary vaccine in a prokaryotic host in fed-batch bioreactors (pilot scale). Following the USP practical session (UE.2.2), the resulting biomass is weighed and then lysed (HHP). Emphasis is placed on monitoring critical parameters (viscosity, pressure, concentration, etc.), the efficiency of the chosen process (yield, purity), and the storage conditions for the produced protein (stability, sterility, etc.). All results, analyzed critically, may be presented in the form of a batch production report.

The educational module on bioproduction:

USP:

- Eukaryotic and prokaryotic cell culture (Type II PSM, incubators)

- 4 instrumented benchtop bioreactors (2 to 5 L usable volume)

- 1 instrumented pilot-scale bioreactor (20 L usable volume)

DSP:

- Juicer

- High-pressure homogenizer (Emulsiflex, Avestin)

- AKTAPure + GSTPrep preparative affinity column

- Instrumented pilot-scale freeze-dryer

- SDS-PAGE and Western blot, UV spectroscopy, nanoDSF

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In biotechnology laboratories and companies, scientific, technical, and regulatory documentation is essential for project management, ensuring the reproducibility of experimental results, and complying with production standards for biological products. Knowing how to record, analyze, and communicate information related to the production of a biomolecule makes it possible to document every step of a bioproduction process and thereby ensure the quality, safety, and efficacy of biopharmaceutical products. 

Through lectures and tutorials, this course unit will cover: 

-Tools for conducting scientific and technological monitoring 

-Writing techniques for drafting standard operating procedures (SOPs) and experimental protocols.  

-Writing methods for preparing a detailed report on experimental results and data analysis (reporting/data communication). 

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