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utilizing a continuous cell line of up to 25g/L in a fully disposable system. Titers in more common fed batch cultures are up to 8 g/L in disposable bioreactors up to 2m3
. This means that one batch derived
from fully disposable systems that can be installed and started up quickly and at reduced capital cost can deliver approximately 16 kg of product into purification in an extremely small footprint – who would have thought this possible 20 years ago?
Next to bacterial fermentation for “relatively simple” recombinant proteins or antibody fragments, the work horse of the industry is still Chinese Hamster Ovary (CHO) cells. Yeast strains producing high yields of recombinant proteins such as EPO, or specific cell lines like the aforementioned continuous human cell line producing recombinant antibodies have been reported. However, these new cell culturing systems appear unlikely to replace the current work horses of the industry, E. coli bacteria and CHO cells, based on their significant successes and regulatory experience and acceptance. Non-cell culturing systems, such as transgenic animals or plants , have yet to make a significant dent in the established preference for E. coli or CHO cells.
In the late 1990s, the elimination of animal-derived raw materials both upstream (serum, peptones removed to yield chemically-defined medium) and downstream (Veggie Protein A affinity resin) delivered meaningful reductions in the virus contamination risks to cell culture processing.
Additional risk mitigation was delivered through the
implementation of viral clearance barriers in manufacturing processes (High Temperature Short Time heat treatment, novel virus filters, UV inactivation, etc.).
To increase efficiencies and mitigate risks, most companies have developed and implemented platform bioprocess technologies, beginning with a host cell line and media platform translated into a manufacturing platform based on standardized bioreactor platforms (including their design) and standardized purification processes (2 or 3 chromatography steps followed by formulation and filtration). The partnership with major suppliers – as in other industries – has enabled significant gains in throughput and robustness of processes based on these platforms.
The processing options gained through these
collaborations help the industry accelerate development work, gain knowledge, use common validation principles, and mitigate risks for scale up and technology transfers.
Today’s biopharmaceutical value and supply chains have matured. Supply chain risk mitigation through applications of mature technologies has become more and more important, as can be seen via examples of recent process contaminations having significant impact on a company’s well-being. In this case, “old” technologies such as HTST (High Temperature Short Time) heat treatment and other technologies analogous to pasteurization go through revitalization. In general, pilot and large scale manufacturing facilities are equipped with high tech sensors, sophisticated data analysis systems, and are highly automated to support process monitoring and continuous improvement. Pursuit of the PAT and QbD initiatives require enhanced analytics and data management capabilities.
While the discussion to this point has been focused on the bioprocess, it is important to note that advances and trends in pharmaceutical R&D
50 | | September/October 2013 - 15TH ANNIVERSARY ISSUE
have driven improvements in the ability to formulate, manufacture, and deliver biological drug products.
Increasing desire for subcutaneous
delivery of protein products has driven development of stable high concentration (100-200 mg/mL) formulations. Such applications can trigger the need to address significantly increased product viscosities, which present challenges in delivering the product. These challenges have been met both by improved formulation components as well as through improved delivery devices. Significant growth has occurred in the use of pre-filled syringe devices that can better support targeted self-administered applications (such as for arthritis indications). Development of sophisticated auto-injectors have further improved dosing simplicity for self-administration. Combination products (more than one API) have also advanced, one interesting example being the use of hyaluronidase co-formulated to facilitate subcutaneous delivery for products previously administered only intravenously. Such innovation provided for improvement in patient convenience and reduction of infusion reactions while enabling self-administration. On the protein drug product manufacturing front, manufacturers have adopted greater use of vapor phase hydrogen peroxide as a means of providing greater sterility assurance for these products which cannot be terminally sterilized.
Finally, the role of manufacturing has grown increasingly important. Manufacturing in the 21st century has to be agile, efficient and resilient. Planned and predictable performances along the supply chain are of crucial importance to guarantee uninterrupted supply to patients with high quality and acceptable financial performance. The goal for this part of the organization is to adapt to a changing portfolio of existing and new products, meeting quality and supply expectations and freeing up resources to be invested back into R&D – manufacturing has to become “externally supportive” and a strategic enabler for the industry [26-32].
What to Expect in the Next Decade
New molecular formats will be developed in pursuit of better answers to unmet medical needs. Combination products will be pursued as one means of improving patient convenience while reducing healthcare costs.
Further increases in automation
capability and efficiency of paperless systems for manufacturing will also be key to reducing costs and improving efficiencies. Two types of biopharmaceutical manufacturing facilities will likely be common – platform-based large scale manufacturing facilities in large-market regions, and small regional disposable plants in emerging markets.
Given that large-scale (> 10 m3 ) plants have
the ability to produce great quantities of proteins for blockbuster markets, and that more targeted (and smaller) patient populations can be addressed through moderate-scale (up to 2 m3
) disposable
systems, cell culture titers will not necessarily need to increase from current productivities.
Resources will be spent more on
improving control of protein product quality attributes to address Quality by Design and Process Analytical Technologies objectives and increasing downstream processing efficiency to drive costs down further. With increased product titers to a large extent based
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