Upstream Production of the Biopharmaceutical Drug Substance

Upstream production of the biopharmaceutical drug substance involves living cells – whether it is living recombinant cells that express a recombinant protein or monoclonal antibody, or living cells that assemble and then propagate a viral vector, or living patient cells that are to be genetically modified. Tight control and cGMP adherence over the handling of these living cells determine the outcome of the upstream production – the yield of the intended biopharmaceutical, the type and amount of biomolecular structural variants formed, and the type and amount of process-related impurities that must be managed in purification. The focus of this chapter is on the upstream production process for both the protein-based biopharmaceuticals (recombinant proteins and monoclonal antibodies) and the gene therapy-based biopharmaceuticals (viral vectors and genetically modified patient cells, mRNA non-viral vector). Regulatory authorities have high expectations, as well as major requirements for the upstream production process, which will be examined in this chapter. Application, where appropriate, for the minimum CMC regulatory compliance continuum risk-based approach, will be discussed. In addition, the upstream production process for mRNA non-viral vector – using cell-free in vitro transcription production – will also be examined.