Modular Bioprocessing Alleviates Drug Manufacturing Woes

Drug launches face intense competition, especially those involving biologics. Biologics are large molecule drugs isolated from living organisms that are used as targeted therapy to precisely regulate disease pathways. Pharma companies tend to focus on the same pathways, so a biologic that gets to market first, or one with more recognized value, can become the market leader for a specific indication. A blockbuster biologic can generate millions of dollars in profit, but it comes at a cost.

Biologics require much higher development and manufacturing costs than classic small molecule drugs.  Because of the large expense, and long development time, pharma companies developing biologics try to balance the timing of their investments in research and development  versus manufacturing. They usually delay capital expenditures until the drug shows positive results in clinical trials, indicating it has a high chance of success, before funding manufacturing efforts.

Once the drug is approved, manufacturing it quickly is of utmost importance because each day the drug is not supplied to the market is a day a patient could go without a potentially life-saving treatment, as well as a day of lost revenue and expired patent protection. Although a contract manufacturing facility (CMO) is often used to expedite manufacturing of a small molecule drug, many biopharma companies choose to build their own bioprocessing facilities for a biologic drug to retain full control over product quality and certainty of supply. Even if outside manufacturing were to be considered, CMOs in many parts of the world lack deep understanding of the mechanisms of drug action for manufacturing biologics.

When a pharmaceutical company decides to build a manufacturing facility, it is always a rush to complete. Building a facility is usually a complicated process and requires partnering with not only drug developers, but also many different experts in structural design and engineering, process flow, equipment, automation, and information technology networking. If it is the company’s first time manufacturing a biologic drug, staff will need to be hired and trained.

BeiGene, a commercial-stage biotechnology company with a largescale biological manufacturing facility currently under construction in Guangzhou, China, can attest to these challenges.

GLOBAL EXPANSION PLANS PROMPT NEED FOR NEW MANUFACTURING FACILITIES

BeiGene aspires to develop and commercialize innovative cancer drugs for the world-wide market. Focused on molecularly-targeted and immunooncology drugs, BeiGene’s global vision today is no different from when it was established in 2010: Build the first next-generation biopharmaceutical company – one that expands the highest quality therapies to billions more people – through courage, persistent innovation, and challenging the status quo.

One of BeiGene’s late-stage drug candidates is tislelizumab (BGB-A317), a humanized monoclonal antibody that belongs to a class of immunooncology agents called immune checkpoint inhibitors. Checkpoint inhibitors are an important advance, designed to boost the immune system against cancer cells, and those currently on the market  have dramatically altered the history of hard-to-treat cancers by producing substantial clinical benefits for certain tumor types and patients. Many pharma companies are trying to develop checkpoint inhibitors to be the most effective and beneficial drugs to patients.

Knowing the importance of getting tislelizumab to patients as quickly as possible after regulatory approval and the importance of the drug to the company’s future, BeiGene has taken great care planning for its production. In the past the company used a trusted CMO partner to produce tislelizumab for clinical investigations. But with the  anticipated demand, the company needed to explore other options.

According to Dr. Jonathan Liu, SVP of Biomanufacturing at BeiGene and General Manager of BeiGene Biologics Co., Ltd, “China has made many wonderful basic discoveries and is now moving to the stage of commercializing its discoveries. But we don’t have a mature manufacturing capacity to support this new post-discovery demand yet  and the regulators are establishing procedures for ensuring quality manufacturing. As a result, most Chinese biotech companies rely heavily on outsourcing to meet their clinical and commercial supply needs. But most of the CMOs in China are not really up to international standards, or their own capacity is in shortage. And this creates a gap.“

With all this in mind, BeiGene decided to manufacture tislelizumab inhouse, a daunting task to say the least. For  the first time in the company’s history, it needed to find experts to help it to design the entire facility that would take into consideration every aspect of its biologic drug production, from the external structure to the equipment and process flow inside. It also needed project managers and a scientific staff to operate the facility once built. Despite the many well-educated and well-trained chemists and biologists on staff, the expertise in biological  manufacturing and bioprocessing of sophisticated drugs like monoclonal antibodies is still in its infancy in China.

The essence of what BeiGene needed was threefold:

• Efficient production of their biologic drug for the global market
• Close control over the intellectual property and quality of the drug
• Support from experts to design a robust operational bioprocess

CONFIGURABLE SOLUTIONS SAVE TIME AND MONEY

BeiGene knew that lower up-front costs and a shorter time to market would result in faster revenue growth for their drug, ultimately leading to its increased value. Since they had minimized manufacturing costs thus far, at this point they needed a solution that would allow them to start drug production quickly and meet timeline expectations. To shortcut the usual time of building a manufacturing facility, BeiGene chose to use Cytiva's KUBio™ solution. The KUBio is a prefabricated biopharma facility designed for cGMP production which incorporates Cytiva's FlexFactory™ single-use technology for bioprocessing cells and drug intermediates.

According to Liu, “Cytiva is the only company that offers both the drug manufacturing structure, as well as the single-use manufacturing equipment.” The KUBio could be constructed, fully commissioned, and qualified in 18 months, about half of the time needed to build a legacy facility. By going modular, the facility is expected to start manufacturing upon regulatory approval.

Right from the start, BeiGene and Cytiva worked together to assess the manufacturing requirements, understand the regulatory environment, and evaluate the technology options. Cytiva provided expertise in both facility construction and bioprocessing technology and helped with centralized project management. Cytiva could draw from experience gained in building two other KUBio facilities in China: one in Wuhan and another in Hangzhou, both operating with FlexFactory single-use technology.

Since BeiGene’s manufacturing facility in Suzhou, China, already uses Cytiva's FlexFactory components, the advantages of the system were already known. In-process components are housed in the singleuse assemblies from the time cells are expanded in bioreactors to the time intermediates are purified using equipment such as chromatography columns. Integrated Figurate™ automation is incorporated in each individual processing step. Figurate is also used to move material to the next processing step, streamlining productivity and data analysis. A centralized monitoring and control system enables each step to be optimized in real time.

The FlexFactory platform eliminates the costs associated with cleaning and sterilizing stainless steel equipment, reduces the likelihood of crosscontamination, and allows for faster, less expensive production setup and assembly. Single-use systems add the flexibility to manufacture smaller batches as well as quickly change to different products in the same facility. Cytiva's standardized components in both the KUBio and FlexFactory are configurable and easily arranged to BeiGene’s production needs.

GEARING UP TO MARKET WITH THE ABILITY FOR FUTURE EXPANSION

After the assembly of more than 70 KUBio modules at BeiGene’s site, the Cytiva Fast Trak Team is working closely with staff at BeiGene to increase productivity, optimize protein quality, and simplify operations through the use of appropriate equipment and processes. All of these activities will be required to commission the facility and satisfy regulators while minimizing both financial and production risks. Equipment and processes are being validated at the site. Within the first quarter of this year, BeiGene will complete the first phase of the KUBio facility construction. Liu did not hesitate in stating, “We are not just meeting production deadlines; we are accelerating them. It is our goal to create a miracle in China Biotech by building a bioprocessing facility and producing high-quality drug product faster than it has ever been done before.”

BeiGene has doubled the number of employees working on the tislelizumab project in the last year. The Cytiva Fast Trak team is working closely with project leaders, managers, and staff to educate and train in every aspect of daily operations and troubleshooting. BeiGene is working toward being ready for inspection by the Chinese and the U.S. regulatory authorities in the near future.

Liu says, “The KUBio is a permanent solution with flexible possibilities. If BeiGene outgrows the capacity of its current KUBio for tislelizumab, it has options. It can add capacity to the current facility or move to a new facility, modular or not. If there is a need to manufacture another biological product, the current KUBio can easily be switched to it. Cytiva and its KUBio have provided BeiGene a clear path forward for manufacturing tislelizumab and any biological products we plan to produce. I am fully confident that Beigene is positioned to satisfy international standards and bring this potential treatment option to market for cancer patients around the world.”

This article was brought to you by Cytiva. You may be a startup launching a new molecule for the first time, an established player bringing biosimilars to emerging markets, or an international powerhouse moving toward distributed manufacturing. Whatever your goals, Cytiva Enterprise Solutions provides you with new options to achieve and maintain them at every level of biomanufacturing: process, capacity, equipment, automation, and human competencies— all managed from one point of contact.

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