Ask the Expert: Key Considerations for Advanced Therapies Manufacturing

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On 12 September 2018, Thomas Page, PhD (vice president of engineering and asset development at Fujifilm Diosynth Biotechnologies, FDB) shared a brief overview of challenges encountered in manufacturing of advanced biotherapeutics.

Page’s Presentation
FDB is a contract and development manufacturing organization (CDMO) that uses microbial and mammalian cell lines to produce protein therapeutics as well as viral vaccines and gene therapies. The company’s Center of Excellence for Advance Therapies Manufacturing is located in Texas. FDB set out some years ago to make sure that it could cover the path from development through clinical manufacturing into process validation and commercial manufacturing.

Page discussed key points to consider when working with advanced therapies. He began with the product life cycle, focusing on early phase development, when sponsors should have an understanding of their own phasing. Many start with a proof-of-concept for their construct that might be at odds with long-term needs. For example, you might use an adherent cell line during the proof-of-concept phase that won’t work for commercial manufacturing because of low yield and high cost. FDB is working on suspension technology that can be used for manufacturing these products.

The advanced-therapy market is quite different from that of recombinant proteins, which have a different life cycle. FDB recommends outsourced manufacturing for these products given the nature of their life cycle. Your control strategy must be built in from the beginning.

Next Page discussed scale. “It seems strange that you might need a small-scale capability,” he said. “For many of these products, you don’t need much for commercial manufacturing. So you need to be set up to do commercial manufacturing across different scales.”

Considerations: Advanced-therapy products are different from recombinant proteins. The products themselves (viruses and cells) are alive. Viruses are designed to infect human targets, with genetic alterations that could be permanent. That brings a major issue with environmental health and safety (EHS) in manufacturing and handling these materials.

Also critical is the strategy for control of adventitious agents, for which many advanced bioprocesses lack dedicated unit operations. “You need to protect the whole process,” said Page, “and include the vendor qualification control strategy, your EHS/quality alignment, and quality risk controls.”

The final challenge concerns procuring drug products and accessing facilities and formatting. Given the nature of these products, they need isolated systems.

Sponsors need an integrated approach (e.g., stage-gated and closed processes) to managing their advanced-therapy programs. FDB uses risk-based approaches to operational procedures that achieve all requirements for good manufacturing practice (GMP) and containment needs. High containment allows for multiproduct, multiclass manufacturing. FDB discusses with its clients hazard pathways that can be documented and mitigated to allow for transparent communication and set the stage for successful manufacturing and regulatory approval.

Questions and Answers
Can you tell us about the work that FDB has been doing with the industry groups on these topics, what you’ve been working on, and who you’ve been working with? We’ve worked quite a lot with the BioPhorum Operations Group (BPOG) organization, which is forming a cell–gene therapy track. In fact, we’re hosting a face-to-face meeting in November that will include tours of our Texas facility layout.

It’s critical for us to work with other groups in this area, including reaching out to regulators. It’s going to need development, focus, and thought, and we don’t have a 20- or 30-year history in handling these materials. So we all need to work together to push these lifechanging materials forward into the market.

Do EHS considerations apply only in the presence of the bio risk? No. Some cell lines that are used may be derived from other mammals, which can bring other problems. We need to understand all the EHS issues that can arise, even from the cell line that we are handling. We’re certainly doing a great amount of characterization work on those before we bring them in because of the elevated requirements for adventitious-agent control and the need to be meticulous. You could apply some of the same constructs for handling microbial and other types of systems, as well.

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