Supplement: Next-Generation Processing: A Multidisciplinary Pursuit

September 1, 2018 (Vol. 38, No. 15)

MilliporeSigma Advocates Evolutionary Transformation through Collaboration

With the 2017 release of the Biomanufacturing Technology Roadmap published by BioPhorum Operations Group,¹ our industry projected a clear vision for the future of monoclonal antibody (mAb) production. Market forces have created a compelling need for agile and flexible facilities, greater speed to market for new products, increased process robustness and product quality, and dramatically reduced product costs for both operational and capital expenses (Figure 1). As a result, we have identified three key enablers to achieve the aspired-to transformation: intensified processing, single-use systems, and process analytical technologies.

A rough consensus on an ideal end-state has emerged: a single-use, fully closed continuous process with in-line and real-time analytics allowing for integrated and holistic process control. The magnitude of improvement required to achieve this end-state is far greater than that corresponding to the sum of the incremental improvements in the mAb process template seen in the past decade. Instead, a step change is required across a series of disciplines including analytics, process technologies, and controls and automation (Figure 2). Paradoxically, due to the complexity and interdependence of these disciplines, the transformation will be evolutionary, with each generation bringing quantifiable benefits to the process and manufacturer.

No single organization can deliver this transformation by itself. We will need to break the traditional silos within our industry (biomanufacturers, suppliers, academics, and regulators) and within our own organizations (upstream processing, downstream processing, quality control and assurance, R&D, and operations) to deliver real collaboration. Let’s explore two examples of evolutionary transformation through collaboration.

Figure 1. Market trends, business drivers, and key enablers for next-generation processing

Process Intensification for an Existing Facility

Recently, a biomanufacturer was preparing for the launch of a new mAb product. In preparation for transfer of the manufacturing process to an existing facility for commercial production, it was calculated that the projected market demand for the product would consume >90% of the facility capacity, leaving no upward elasticity in production capacity and no ability for production of other products in the facility.

Significant resources were placed in the intensification of the upstream process to produce more product mass. The intensification effort focused on two areas: increasing cell densities and optimizing the cell culture media.

A perfusion step was implemented at the N-1 seed-train bioreactor, allowing for the cell density to be increased significantly prior to inoculation of the production bioreactor. This had the dual effect of shortening the run time in the production bioreactor and increasing the expression levels of the mAb. The production cell culture media were then optimized for product expression. These two improvements led to a fourfold increase in productivity of the upstream process.

Understanding that this change in productivity would have a significant impact on the purification operations, the downstream process development team was engaged in collaboration with MilliporeSigma. The increased product mass from the bioreactor meant that the existing intermediate hold tanks in the downstream suite were undersized. A bottleneck had been created through the intensification of the upstream process.

The development and implementation of a continuous concentration step using single-pass tangential flow filtration (SPTFF) after the Protein A capture column significantly reduced the product volume that would be processed through the remaining downstream operations. This intensified operation rightsized the intermediate product pools to fit in the existing tanks, effectively debottlenecking the purification suite.

Through the introduction of three intensification steps—perfusion in the N-1 seed train, optimization of cell culture media, and protein concentration by SPTFF—the facility utilization rate for the mAb product was reduced to

Figure 2. Evolutionary journey across many disciplines to achieve next-generation processing

Continuous Viral Inactivation

An area of intense interest in next-generation processing is the conversion of the low-pH virus inactivation step from its current stepwise operation to a continuous process. During the typical virus inactivation process, the Protein A eluate pool is adjusted to pH 3.5–3.7 and transferred to a second tank for incubation for 30–60 minutes before neutralization in either the same tank or a third tank. The use of multiple tanks reduces the risk associated with reintroduction of product droplets on the tank walls that may not have been exposed to the low pH. The number of tanks, product transfers, and extended incubation time make process intensification critical for viral inactivation.

According to published works by biomanufacturers and suppliers, viral inactivation can be incorporated into the development of continuous processes that occupy reduced footprints. For example, MilliporeSigma has presented results for an in-line viral inactivation method and system that uses in-line acid and base additions with static mixers to control the product basis under constant flow conditions.²

Importantly, inactivation kinetics for large enveloped viruses demonstrate >5 logarithmic reduction value virus clearance in less than 10 minutes. Using similar methodologies, several biomanufacturers, in collaboration with academic partners, have published data on incubation chambers that create uniform flow distribution in the product feed, ensuring uniform product exposure to low-pH conditions.^3,4

Given the novelty of this application, it is critical that development work and publications come from multiple sources. Regulators have encouraged the move to continuous processing, but they expect a similar level of rigor and validation for these next-generation processes. In 2017, MilliporeSigma and two biomanufacturers met with the FDA to present the method, systems, and viral inactivation results mentioned above. This was an opportunity to share knowledge and gain feedback on future expectations for regulatory filings that include this method for viral safety validation. Feedback was positive for the method, and supporting data gave confidence that this new continuous, in-line method could be accepted given the proper validation strategy and results.

Summary

Market trends are forcing the biopharmaceutical industry to transform the way in which we develop processes and manufacturer mAbs. Next-generation processing offers significant opportunities to meet our goals for manufacturing agility and cost reduction through evolutionary changes across many interdependent disciplines and technologies. It requires courage to embrace this level of change in a conservative industry.

By destroying the silos that prevent innovation, both internally and across our industry, we foster collaboration between academics, suppliers, biomanufacturers, and regulators to increase speed to market and access to life-saving and life-changing medicines globally. We are at the dawn of a new revolution in biologics manufacturing. It is imperative that we achieve the promises of next-generation processing on behalf of our companies, our customers, and our patients.

Michael Felo is director, downstream process integration, and Michael Phillips, Ph.D. ([email protected]), is director, next-generation process, R&D, at MilliporeSigma.