The growing expectation from payers, governments and patients that new medicines provide significantly improved results compared to existing drug products is placing increasing pressure on biopharmaceutical manufacturers to be first to market. Accelerating drug development and commercialization while maintaining safety and quality has consequently become a necessity.

The use of contract development and manufacturing services can facilitate this process, but only if the contract development and manufacturing organization (CDMO) has the skills and expertise to achieve efficient and effective upstream and downstream process development and “right-first-time” technology transfer.

Introduction

Biologic drugs are large molecules with complex structures and product profiles produced via a series of upstream and downstream unit operations. A given drug is defined by its structurally derived product quality attributes. The product quality attributes — not limited to glycosylation, glycation, charge profile, aggregation etc. — are defined during the upstream and downstream processes. The process conditions used during manufacture influence the final product’s characteristics. The ability to predict and model the effects of process conditions on product quality in the laboratory prior to GMP manufacture is critical to the success of a technology transfer. Biopharmaceutical contract development and manufacturing organizations (CDMOs) must, therefore, have extensive knowledge about the impact of process conditions on product characteristics, in-depth experience with all of the operations at both the laboratory and commercial scale, and a deep understanding of how laboratory results translate to production performance.

Expertise in process modeling is crucial for the successful development of biopharmaceutical processes. De novo process development begins at bench scale. Effective bench-scale models are designed to accurately predict the performance of production-scale runs, and thus allow rapid development and optimization of processes in preparation for scale up and transfer to the manufacturing plant. Once a process is transferred to manufacturing, a scale-down model can be qualified for use in characterization and validation.

“Right-first-time” technology transfer, whether of an established process from a customer facility to the CDMO or from the process development lab to the production facility within the CDMO, is a crucial capability for competitive biopharmaceutical contract service providers. CDMOs that have a track record of consistently achieving smooth technology transfers assist their biopharma partners by delivering high-quality drug substances with shortened commercialization timelines and lower costs.

Benefits Of Scale-Down Modeling

Scale-down models are used in the development of both upstream and downstream biopharmaceutical manufacturing processes to identify the impacts of different process parameters on product quality attributes (PQAs). A scale-down model is qualified by a rigorous comparison with representative production runs and must pass a panel of pre-specified acceptance criteria. Qualified scale-down models are used not only to characterize and optimize processes. They are also necessary for conducting viral clearance, resin cleaning, lifetime validation studies, troubleshooting, including investigation of the root causes of deviations, and continuous process improvement.

The process conditions used during manufacture influence the final product’s characteristics.

Experience Matters

Developing effective upstream scale-down models that accurately predict performance at production scale requires a strong understanding of the relationship between shear, mixing and mass transfer at the different scales. All parameters cannot be scaled at once. Scale down of the recovery process is performed with a continuous centrifuge sized for 100 – 200 L scale with appropriate filtration. Downstream chromatography scale down models are developed by reducing column diameter and holding resin load, column heights, linear flow rates, relative buffer volumes and composition constant. Thus, equivalent product can be made in a 5 L or a 20,000 L bioreactor and purified in a 1.6 cm or 1.6 meter column. It is far easier and cheaper to study a process at small scale. Also, studies that require spiking-like viral clearance can only be performed at small scale. Viral safety assessment, study design and execution are important parts of most projects.

A real-world understanding of both the laboratory and plant equipment and operating conditions, and the differences between them, is therefore essential for the effective application of scale-down and scale-up modeling during biopharmaceutical process development. Problem solving skills and the ability to apply them are also invaluable, because process development teams must be able to develop processes within any constraints established by the customer that yield products with the desired characteristics at acceptable cost levels.

The scientists in the GSK Biopharmaceutical Technology Laboratory have an average of over 15 years experience. This experience in process development and technology transfer of an extensive array of processes and conditions is highly beneficial for the rapid development and successful transfer of new processes into manufacturing. Having worked through both straightforward and challenging scale ups and transfers gives the team the tools to handle the twists and turns a project may take.

The Advantages Of Integration

As a CDMO that operates as an independent group within a large pharmaceutical company, GlaxoSmithKline Biopharmaceuticals has found that integration of upstream and downstream process development has been tremendously helpful for accelerating development efforts and transferring manufacturing-ready, optimized processes into the plant more quickly. The process development laboratory has an open design containing both the upstream and downstream equipment. With shared laboratory space and open, continuous communication, everyone is part of the same team and gains a greater understanding/awareness of the needs and concerns of the others in the group. As a result, upstream and downstream scientists work together to dial in the correct product quality, titer and purity needed for each project. A well-coordinated effort leads to shorter development times and an increased success rate.

Process Modeling At Gsk Biopharmaceuticals

The Biopharmaceutical Technology (BPT) laboratory within GSK Biopharmaceuticals has developed a process development/process assessment system using scale-down models for common upstream and downstream unit operations, including various types of cell-culture processes (batch, fed-batch, high/low titer, etc.), continuous centrifugation/depth filtration for harvesting, chromatography, various downstream filtration steps including UF/DF and single-pass tangential flow filtration. Additionally, the lab can assess the effects of media pasteurization (preferred for any media/feeds used in the production facility to prevent virus contamination), and controlled rate freezing of final products in bags.

The laboratory has the ability to model processes coming in from different sources by having the flexibility in the bench scale bioreactor design to mimic different agitation strategies, gassing strategies and processes. The lab is equipped to allow processing of volumes up to 200 L (e.g., 5, 15 and 200 L bioreactors, 1 to 30 cm chromatography columns and ultrafiltration/diafiltration) for development, material generation or toxicology lot production. As a result, the company is uniquely positioned to model processes that will be transferred to its 1,600 and 20,000 L reactors and to customer or other contract manufacturing facilities.

The highly experienced process development team at GSK Biopharmaceuticals has a great understanding of bioprocess technology, and how lab-scale processes with certain characteristics translate to the manufacturing/commercial scale. Use of robust scale-down models and advanced on-site analytical capabilities, including process analytical technology (PAT), helps the team achieve “right-first-time” technology transfer. The starting point for a project could be anywhere from preclinical to late stage processes. Process fit to manufacturing is assessed by performing a series of consistency runs in the laboratory. If the process runs correctly in the laboratory, the probability of success in manufacturing is extremely high.

In all cases, the laboratory group retains a focus on manufacturing and remains aware of how processes will translate from the lab or pilot scale to the manufacturing facility, whether at GSK or somewhere else. As a result, commercial-scale production conditions are always under consideration to ensure that all processes are aligned with the needs of the manufacturing plant. It is common to ensure that processes will fit into multiple plants. After a process is manufacturing ready, the laboratory team interfaces with the tech-transfer team to create a process flow diagram, batch records and all documentation needed to transfer the process to the plant. The laboratory team also provides floor support during the first manufacturing runs to ensure the process performs as expected.

Expertise in the development and application of scale-down modeling is crucial for the successful accelerated development of biopharmaceutical processes.

Conclusions

Robust process modeling is effective for accelerating process development, validation and achieving smooth technology transfer. They also enable effective problem resolution. CDMOs with comprehensive scale-down modeling capabilities, such as GSK Biopharmaceuticals, are positioned to rapidly bring biopharma partner processes into their facilities (or other manufacturing sites), whether they require extensive process development or only slight modifications to provide similar product profiles in any plant.