To help drive sales, producers of biosimilar medicines seek to gain as much pricing advantage as possible over their products’ reference biological medicines while maintaining as much profit margin as they can. That’s why they are always looking to minimize production costs, especially in raw materials and labor, their largest cost components. While the costs of the former depend on market prices and a buyer’s negotiating skills, the latter can be best reduced through automation and continuous processing.
At the same time, adopting the latest production technologies are driven by two other interrelated reasons: manufacturing flexibility and time to market. The first enables rapid process optimization, which can be especially critical to scaling up multiple product lines with overlapping time frames. Proficiency in this area will accelerate time to market, helping biosimilar producers recapture their investments sooner, while generating faster ongoing returns.
After all, when the exclusivity periods expire on reference biological medicines, producers of biosimilars need to have their products ready to fill their distribution channels worldwide. Each passing day of lost sales could amount to millions in opportunity costs. In addition, first-mover market advantages can result in substantially higher revenues and profits over the life cycle of a biosimilar medicine, compared to products that come to market later.
Introducing AlphaMab, a fully equipped bio-developer and producer
AlphaMab Co. Ltd, a fast-growing biosimilar developer and producer, is one such company looking for those kinds of capabilities. Founded in 2009 and located in Suzhou, a city about 60 miles northwest of Shanghai, AlphaMab’s R&D center consists of more than 60,000 square feet of offices and labs, fully equipped for investigating, commercializing, and producing the latest in biologic products.
Its BDS and FFP suites are built to meet the rigorous cGMP requirements of the CFDA, FDA and EMA. After those facilities opened in 2013, the Jiangsu CFDA certified them for biologics manufacturing. Facilities also include a pilot plant, GMP production, and a fill-and-finish plant.
At AlphaMab, more than 100 scientists are engaged in a wide range of activities that include target validation, hit screening, H2L, PK/PD, pharmacology, cell line construction, process development, scale-up GMP manufacturing and IND filing. Currently, the staff is involved in almost 60 projects including treatments for autoimmune diseases, blood clotting issues, diabetes, infections, tumor immunology, cancer, ophthalmology, and osteoporosis. Of these, nearly 20 are technology transfer projects.
AlphaMab uses lab-scale bioreactors in 1 L, 3 L, and 15 L sizes, with antibody production projects in the 5 g/L to 10 g/L sizes, and sometimes more. While it still uses glass vessels in its R&D and PD labs, the company has adopted single-use bioreactors across all its cGMP manufacturing facilities, instead of the glass and stainless steel vessels it used before.
Many challenges of scale-up, especially across different projects
According to Dr. Ting Xu, CEO at AlphaMab, the company facilities have quickly matured: “We now have a number of development platforms, including ones for prescreening as well as yeast and phage displays, so we can screen humanized antibody sequences plus nano antibodies, too. Our protein engineering capabilities include a patented mixture platform and an EI-specific platform. And our process R&D and pilot production platforms include DHDP production, in addition to our fill-and-finish platform.”
Xu points out that scaling up production from lab to pilot to full commercial production raises many challenges — especially across so many different projects. “Mainly, the key difficulties are understanding the depth of process and the impact of parameters on process scale-up,” he says. “These must be known in order to guide how we set our parameters for consistency during scale-up, so we can ensure cell growth, viability and yield and, ultimately, product quality.”
AlphaMab has been an early adopter of single-use technology to help boost productivity in its cGMP manufacturing stage, while also reducing scale-up cycle times and costs. The company used to favor stainless steel equipment, but migrated to a single-use model for many reasons. The primary reasons were lower production costs, manufacturing flexibility, and faster time to market.
“For starters, stainless steel is expensive and time-consuming to deploy,” Xu explains. “Once deployed, it has a high risk of cross-contamination, thus requiring time and resources to clean, sterilize, and validate. Then there’s constant maintenance that commands even more time and money. The business case for single-use technology is compelling on many levels.”
Automation, a bio-development and production accelerator
One complement to single-use technology is having a consistent automation platform across AlphaMab’s different upstream and downstream phases, which the company defines using a Quality by Design (QbD) approach.
“Because each process is special,” Xu says, “it’s difficult to have one common platform for all projects. But starting from small lab project to a complete process scale-up using one platform, especially the controller, can help to increase our success rate. Of course, this depends on the accuracy of sensors and stability of the controller, which is what we were looking for.”
Specifically, for AlphaMab’s glass-vessel, bench-top bioreactors in its R&D and PD labs, the company deployed a Finesse G3Lab Universal modular control configuration. This consists of a utility tower and a TruFlow gas manifold, which are sized to minimize the footprint while providing company researchers with maximum process flexibility.
In its cGMP facility, AlphaMab installed single-use Thermo Fisher Scientific HyPerforma™ bioreactors, each using a Finesse SmartSystem with G3Lite SmartControllers. The system consists of a control tower featuring Finesse SmartPart transmitters and actuators, the latter controlling four mass flow controllers.
Finesse SmartParts are intelligent, modular, plug-and-play hardware building blocks for measuring and controlling bio-processes. They have built-in diagnostics and factory calibrations, can be auto-detected by AlphaMab’s network, and provide optimized local control of its various bio-process functions.
“Previously we were using bioreactors from Applikon and Sartorius, but chose the Thermo Fisher Scientific platform with Finesse G3 controllers because they offer proven performance, stability, and reliability, plus Finesse provides good service and support,” Xu says.
Finesse SmartSystem scalability and flexibility
What AlphaMab found unique about the Finesse G3 SmartControllers for bioreactors is their versatile ability to scale-up and scale-down. “The scalability of the Finesse G3 control platform helps us facilitate process transfers from 0.5L to 2000L,” says Xu. “This enhances the quality, productivity, consistency and reproducibility across our processes, whether we’re using batch, fed-batch or perfusion.”
Another distinction that sets the Finesse G3 SmartControllers apart is their adaptability to third-party systems and peripherals. For example, in addition to the Thermo Fisher Scientific bioreactors that AlphaMab deployed, the Finesse G3 SmartControllers are compatible with single-use, glass, and rocker systems from Applikon, Sartorius, Eppendorf, Millipore, Xcellerex, CerCell and GE. This enables customers to automate a wide range of both legacy and new-build infrastructure using what they determine to be best-of-breed solutions.
In combination with the Finesse G3 SmartControllers, AlphaMab has found the Finesse TruBio DV (DeltaV) software extremely useful in controlling the bioprocesses of its cell culture operations. Finesse developed the hardware-independent software system based on the Emerson Process Management DeltaV® control platform. “Having the DeltaV automation control engine in the TruBio DV software was an important factor in our selecting the Finesse automation platform,” says Xu. “It really gave us confidence we were making the right choice.”
What’s more, he notes, the Finesse automation controller platform is proven globally, with more than 1,500 lab-scale and nearly 500 large-scale bioreactors installed and operating across more than 60 customers. “This helped reduce any sense of risk in choosing Finesse G3 Series controllers for use in our R&D and PD labs as well as for use in the single-use bioreactors we use in our cGMP manufacturing,” he says.
Finesse TruBio DV (DeltaV) software, pre-configured and ready to use
The cGMP-compliant TruBio DV software comes pre-configured with algorithms for controlling bioprocess parameters such as pH, dissolved oxygen, temperature, and pressure. With tridundant sensor loops as well as unlimited gas and liquid addition capability, the software can be used with glass vessels, wave rockers and, like the Finesse G3 SmartControllers, most brands of single-use bioreactors.
Xu reports that his staff especially likes the flexibility, easy operation, and precision control of the AlphaMab’s Finesse automation control system. “In particular, they like the ease of configuring parameters for DO and pH control. This has helped them more easily and quickly define and then use the same scale-up standards for the same projects,” he says.
Executing scale-up standards for one project — or many projects simultaneously
“In the scale-up process, you have to find the key control parameters that affect your critical quality attributes, but each project has its own characteristics,” Xu explains. “For example, some may be more sensitive to speed, some to pH, some to the concentration of CO2. By finding your own control range of key parameters, you can conduct a successful scale-up process. The Finesse SmartSystem platform is a huge help in accelerating the technology transfer phases of our operations by enabling us to execute a scale-up standard across an entire project.”
By migrating from glass to single-use bioreactors while also automating with the same scale-up standards using the Finesse SmartSystem with G3 SmartControllers and TruBio DV (DeltaV) software, AlphaMab achieved two key goals: it reduced its scale-up cycle times to as little as 12 months, and it upheld its QbD standards, which ensure the quality of its process.
The Finesse SmartSystem is also helping AlphaMab to manage the scale-up and technology transfer of as many as 20 projects at a time. Xu believes that the manufacturing flexibility it has gained with Finesse G3 Series controllers has helped accelerate the time to market for its biosimilar medicines, sometimes saving weeks compared to the company’s previous infrastructure.
“Doing multiple scale-ups, each with their own technology-transfer standards, without an automation platform would be nearly impossible, not to mention error-prone,” says Xu. “But with the Finesse SmartSystem, we can cut out the errors along with a lot of time and cost to ensure faster time to market and, ultimately, greater profitability and competitiveness.”