Engineering and Production of Biopharmaceuticals

The plastid genome of modern higher plants remains well conserved, with little interspecific variation in genomic organization and coding capacity. Identical copies of the plastid genome are present in a diverse array of plastid transformation types proplastids (precursor plastids found in most plant cells and present predominantly in meristematic tissues). 

Biopharmaceuticals in Plants Toward the Next Century of Medicine 

Proplastids Small, undifferentiated plastids found in most plant cells, 

Chloroplasts Center for photosynthesis, present in leaves, immatnre frnit, and 

Chromoplasts Contain colored lipids, accnmnlate yellow or red carotenoids present in mature flowers and frnit 

---

The biopharmaceutical sector is largely based upon the application of techniques of molecular biology and genetic engineering for the manipulation and production of therapeutic macromolecules. The majority of approved biopharmaceuticals (described from Chapter 8 onwards) are proteins produced in engineered cell lines by recombinant means. Examples include the production of insulin in recombinant E. coli and recombinant S. cerevisiae, as well as the production of EPO in an engineered (Chinese hamster ovary) animal cell line. 

Validation of systems is obligatory in the production of biopharmaceuticals and, thus, the bioreactors must be validatable. In the case of stirred-tank bioreactors, apart from the functional validation, the cleaning and sterilization procedures have to be validated, since these are repeated use equipment. These requirements pose additional challenges to the process engineers. 

Before the advent of genetic engineering, hGH was purified from cadavers pituitary glands, with several drawbacks. It was Genentech, the first biotech company founded in 1976, to clone and express the hGH gene in Escherichia coli, opening the way for the production of biopharmaceuticals through recombinant... 

Mammalian cells allow the production of complex biopharmaceutical proteins. Advances in the generation of stable recombinant clones, media formulation, and process and fermentor design have significantly increased yields over the past two decades. Exciting networks across the pro-teome and transcriptome are elucidated that show the enormous potential still hidden in mammalian cells. The near future will definitely show further improvement with cell lines specifically designed and metabolically engineered for industrial-scale production of biopharmaceuticals. 

A number of examples from biochemical engineering are presented in this chapter. The mathematical models are either algebraic or differential and they cover a wide area of topics. These models are often employed in biochemical engineering for the development of bioreactor models for the production of biopharmaceuticals or in the environmental engineering field. In this chapter we have also included an example dealing with the determination of the average specific production rate from batch and continuous runs. 

In the following, the focus will be on some bioprocess engineering fundamental aspects of cultivation and characterization of mammalian cells for the production of biopharmaceuticals. 

Ludovic Mouhat is an engineer in bioinformatics. He is affiliated to the ERT 62 laboratory and holds a position as a researcher in a biopharmaceutical company. He is involved in the design and chemical production of candidate therapeutic peptide drugs. 

The process of fermentation is used in various industrial settings, including the production of protein biopharmaceuticals. This process involves growing cells and microbes for the production of the desired product in large quantities under well-specified conditions. Fermentation procedures are typically optimized in a systematic manner in a pilot plant with a fermentor with a capacity on the order of 30 liters, and engineers determine the best strategies to develop fermenters with a capacity on the order of 100,000 liters (Ho and Gibaldi, 2003). 

---