Process from Vector Development to In-house Manufacturing
Vector Design, Construction and Production
Host Strain Development
Process Development/Outsourcing
Product Development
Technology Transfer/Manufacturing
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The era of small molecule drugs, made in a glass retort using organic chemistry, is fast yielding to biologics, or biopharmaceuticals, which are ‘intelligent designs’, made in living cell factories. In addition to recombinant proteins, monoclonal antibodies and peptide hormones, next generation biotechnology products include: DNA vaccines, bacterial extract vaccines, gene therapeutics and viral vector therapeutics. Unlike their predecessors, biologics are designed from the ground up, incorporating the necessary components of: genes, viruses, vectors, receptors, enzymes, hormones, and immunological entities (such as cytokines, chemokines, antibodies, adjuvants and antigens). Biologics development starts with the design, usually at the genetic, or vector level.
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Vector Development: Frequently the most overlooked aspect of biologics is the initial and rate limiting one: vector design. The vector is usually a genetic entity, such as a plasmid or other gene construct that is inserted into the production host organism or cells. Often, there are specific regulatory guidelines, or Points to Consider, in vector design and development. Rather than simply ‘jockying genes’ into off-the-shelf vectors, NTC biologists and engineers carefully design gene constructs base-by-base, removing ‘junk’ and testing carefully ordered components for efficient expression at the DNA, RNA and protein levels. This orderly process of multi-component gene assembly is enabled by NTC’s Gene Self-Assembly (GENSA™) technology.The most effort goes into the design of the expressed biological entities, which may be optimized for codon preferences (of the host organism), RNA structure (folding, stability, accessibility), intron structure (processing, efficient expression), conjugation, or affinity purification. Often, an existing NTC backbone vector (such as pDNAVACCUltra™) can be used as the preferred starting point for RapidVec™ (vector development), including RapidVacc™ (DNA vaccines). The most effective vectors are usually designed at NTC and assembled in days.
Strain Development: The cells used in production of biologics are specially engineered or adapted for production of specific biological entities, such as proteins and nucleic acids. Strain engineering previously involved mostly mutagenesis and selection, for over- or under-expression of desired traits, knock-outs and knock-ins. Ideally, however, strains are designed from the ground up, using advanced genetic engineering technology that goes far beyond traditional plasmid engineering, to wholesale transfer and manipulation of genomic DNA, called Genome Mass Transfer (GMT™) technology, developed by NTC scientists. Often, NTC has already developed the host strains needed for production, as exemplified by NTC autolytic host strains for production of plasmid DNA and recombinant proteins. Strains are carefully designed for the fermentation process, and are always optimized for yield.
Process Development: Production of biologics in living cell factories involves optimizing conditions between: the production host cells, the entities that will be grown (including toxicity and metabolic burden on the host cell), the mode of expression (secreted, soluble cytoplasmic, periplasmic, insoluble) and the fermentation process itself. Usually, this involves incorporation of previous experience and knowledge together with several optimizations, or shake-down runs, in order to arrive quickly at an optimized process that can be scaled-up without disruption. Examples of NTC’s successes in process development include: record plasmid production (2.2g/L) and recombinant protein production (2-20g/L), using the HyperGRO™ and pVEX™ processes, respectively. These tried and proven methods can be quickly adapted to your biologics to give you record-breaking yields and purity. Efficient processes, such as HyperGRO™ and pVEX™ lead naturally to more highly purified products, because proportionately less biomass must be processed. Of course, decreased cost and waste streams, and increased ROI are logical outcomes.
Product Development: Ideally, the goal is a highly effective and safe product that can be scaled-up and produced at a most economical price in a GMP environment. These results are predicted outcomes, when early stage development tasks (vector design, strains, and process development) are carefully attended to.
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