Boosting Mammalian Cell-line Manufacturing Pilot Plant—A Case Report - - BioPharm International


Boosting Mammalian Cell-line Manufacturing Pilot Plant—A Case Report

Figure 2. Pilot Plant Realization Timelines at ProBioGen's Berlin Manufacturing Site for Investigational Medicinal Products (Drug Bulk Substances) Derived from Mammalian Cells
We completed the construction and validation of the facility within 18 months (Figure 2), thereby complying with the EU guideline 91/356/EWG (current 2003/94 EC) and the German drug law where applicable. 19,000 ft2 came into operation with a manufacturing core unit of less that 5,000 ft2 (25 percent of space). The remaining space was divided into functional units for cell line development (15 percent), up-and downstream development (20 percent), quality control and product characterization (20 percent), and offices and utilities (20 percent). Expansion space in excess of 6,000 ft2 within the building allows for flexibility to expand functional units according to market demands. The manufacturing core unit comprises a cleanroom for preculture and two upstream manufacturing suites. Up to five portable bioreactor units with fully disposable culture ware can be simultaneously operated in those process suites. Welding equipment for sterile connection and disconnection of flexible tubes and installations in cleanroom walls allow for feed media and waste allocation in unclassified areas. The downstream process suite, equipped with purification systems sized for dozens of grams per purification cycle, serves for protein purification from bulk supernatant. A separate cleanroom area is available for final sterile and nanofiltration of bulk drug substance. With an effective quality management system in place, simultaneous manufacturing of different proteins in upstream suites can be performed. In addition air-flow layout, airlock systems, pressure regimen, and cleanroom classifications within the manufacturing unit allow the processing of investigational medicinal viruses and cell-therapy products.

Advantages of the facility can be summarized as the following:

  • Lack of media preparation areas
  • Lack of centralized steam and WFI production
  • Segregation of media and waste from process areas
  • Portable, closed bioreactor systems operating in batch or perfusion modes
  • Segregation of process personnel and material flow
  • Simultaneous protein manufacturing in upstream suites
  • Significantly reduced validation requirements
  • Fast change over

DISPOSABLE BIOREACTORS SUPPORT TAILOR-MADE PROCESSES A growing number of disposable- based culture systems are commercially available worldwide. Conventional disposable based culture systems such as roller bottles2 and cell factories3 are in use for low-volume, high-potency proteins such as erythropoetin and INF beta. Having been developed and explored in research application, most of these disposable bioreactor systems have deficiencies in industrial hardware design, reliable process control standards, and human interface and software performance. Two types of disposable-based bioreactors in use for investigational medicinal protein manufacturing are the Wave and Biovest's Acusyst hollow-fiber bioreactor families.4,5

Flexibility of the pilot plant and portability of the systems allow ProBioGen to apply both to customer processes, thereby providing both perfusion and batch modes of operation. Cell-line poductivity, cell growth characteristics, complexity of proteins, sensitivity to proteases, product titers in crude bulk, process economics, and other parameters contribute to the choice of culture mode and system.

The scalability of Acusyst hollow-fiber bioreactors within the reactor family is based on increasing numbers of a standard hollow-fiber cartridge in each reactor system. A specific cycling pressure regimen, differentiating the system from conventional hollow-fiber bioreactors creates active media perfusion through the cell culture space of the cartridge. Cells and proteins are separated in such a cartridge from the media stream by hollow fibers with a membrane cut of lower than 10 kD. Through this process media perfusion and harvest are separated from each other.

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