How Scale-Up Benefits a Clinical Program to get Results
Progression of promising drug candidates from early pre-clinical evaluation through to clinical trials and eventual commercialization requires a scalable manufacturing process. Not only does scalable manufacture promise increased process understanding and manufacturing flexibility to deliver a robust, reliable commercial product, but it also helps with timely delivery to market, translating to a competitive advantage when it comes to gaining market share.
Transitioning the production of microbial and cell culture-derived biologics to a scale suitable for clinical or commercial supply can be challenging. In contrast to small molecules, biologics often demonstrate complex, scale-dependent behaviors. This makes switching from small-scale manufacturing to full-scale production more difficult, highlighting the importance of well-defined scale-up principles to support a predictable transition.
With a proven track record in manufacturing biologics at the varying scales required to support IND-enabling non-human pre-clinical studies, AbbVie’s scale-up laboratory (SUL) demonstrates process scalability in the non-GMP space to afford considerable financial benefit. Using equipment, materials and methods representative of commercial-scale production, highly skilled personnel rapidly optimize key process control parameters to assure delivery of reproducible product. This builds confidence in the process and its scalability prior to GMP manufacturing and can expedite the biologics development lifecycle by circumventing costly program delays.
Leveraging scale-up expertise to meet evolving needs
AbbVie’s scale-up laboratory was founded in 2003 to support the technology transfer from 3L bench-scale production of microbial and mammalian cell culture-derived biologics to 12,000L GMP manufacture. At that time, little historical data or process expertise existed to inform potential issues related to process design, raw materials, or regulatory requirements. However, by building a comprehensive data set over a period of many years, AbbVie has developed a substantial understanding of process scale-up and is now widely recognized as a leader in the field. This knowledge base has been especially pertinent to the production of IgG monoclonal antibodies (mAb IgG) which, unlike newer classes of biomolecule, no longer necessitate early process development and can be rapidly screened in scale-up to accelerate program timelines.
Currently, AbbVie’s scale-up laboratory averages 15+ bioreactor runs for 8+ programs per year. This generates material for non-human use for many purposes, including:
· GLP/non-GLP Tox Studies
· DMPK Studies
· Formulation Studies
· Developmental Stability
· Interim Reference Standard
· Drug Product Representative Batch
· Centrifugation Process Characterization
· Deviation Investigation Support
· Process Technology Evaluation
· Support of further process development
· Site transfer/tech-transfer for in-license/acquisition/operations contract manufacturing (OCM) for mid-late life cycle programs
In addition to extensive experience with mAb IgGs, AbbVie’s scale-up laboratory is practiced in handling dual variable domain IgGs (DVD-IgG)/bispecific antibodies, Fc fusion proteins, single-chain variable fragments (scFv), and diabodies, as well as in scaling up enzymes for third party manufacturing (TPM) projects. A key aspect of these newer modalities is an exceptionally high dependence on scale with, for example, many notable differences between runs of 3L and 300L.
Leveraging existing knowledge to understand those process parameters most important to control at scale, AbbVie researchers have successfully streamlined scale-up for a wide range of biologics. This accomplishment is underpinned by flexible SUL equipment that has historically proven to perform process fit and scale-up for every AbbVie facility within the global network, ranging from 1,000L GMP to 12,000L GMP production facilities.
AbbVie’s scale-up laboratory performs cell culture in bioreactors ranging from 10-500L capacity, using both single-use (SU) and stainless steel (SS) systems. These provide the flexibility to run many options for control strategies, allowing dynamic and automated control of key processes such as gassing and feeding. For instance, using process analytical technologies (PAT) such as in-line measurement of glucose and lactate concentrations, capacitance to monitor cell growth, and monitoring off-gas composition, it is possible to rapidly implement small changes that benefit the overall process.
Perfusion capabilities at the N-1 stage are supported by multiple cell retention formats. These include the Repligen XCell™ ATF System (a cell retention device that attaches to the bioreactor to deliver high cell density and process intensification), and the Carr Centritech Separation System (the first single-use centrifuge developed for perfusion cell culture processes and cell banking applications). Complementing these are centrifugation capacities as low as 50L, and depth filtration with multiple vendor SU formats including Millipore, 3M, and Sartorius. Moreover, optimization of SU bioreactors intended to achieve higher cell densities and improved product yields may be employed for intensified cell-culture processes.
AbbVie’s scale-up laboratory also provides aseptic downstream processing, column chromatography, membrane-based separations, viral filtration, ultrafiltration/diafiltration, and a portfolio of filtration studies to ensure product quality.
Development and implementation of new and novel manufacturing technologies
As well as supporting many different pre-clinical studies, AbbVie’s scale-up laboratory regularly tests new products and equipment to assess the utility of these to enhance existing and next generation processes. Recently, this has included evaluation of perfusion cell culture processes for N-1, N-stage, and continuous concentrated fed-batch operations; design and optimization of both SU and SS bioreactors to handle high density cell cultures with high O2 consumption; and process analytical technology development for automation and control of cell culture processes.
A further goal of the scale-up team is to speed up processes by reducing the number of unit operation steps. This has lately been addressed by investigating point-of-use buffer blending chromatography systems, straight-through processing, and multi-column chromatography. These approaches are an effective way to achieve scalable process intensification since they provide the capacity to run unit operations simultaneously rather than in batch mode.
AbbVie’s scale-up laboratory offers many benefits
Scalable manufacture is an essential consideration during biologics development since it is inevitable that the manufacturing process will require at least one round of scale-up during the product lifecycle. The first of these will most likely occur during technology transfer from bench-scale production to GMP manufacture. By demonstrating the scalability of this step within non-GMP space, AbbVie’s scale-up laboratory provides a cost-effective approach to generate the data required to progress to GMP manufacturing.
It is important to note that although any biologic produced in this manner will be suitable only for non-human studies, performing scale-up in a non-GMP environment permits dynamic changes while still delivering a biologic of representative product quality. Moreover, by using equipment, materials, and methods representative of commercial processes, this and any subsequent scale-ups can be streamlined.
A further advantage of operating in a non-GMP environment is that it provides capacity to generate a range of data with more flexible operations regarding procedures, split process streams, or various special requests. In all cases, supply material is generated under batch records, tested by QC, and reviewed by QA to perform important activities such as developmental stability, drug product development, method validation, and preclinical toxicology test article supply (e.g. bulk drug intermediate, bulk drug substance, placebo vehicle). This data is pivotal for transition to the next stage of the biologic’s lifecycle.
Another function of AbbVie’s scale-up laboratory is to support technology transfer for TPM clients prior to GMP campaigns. The team also contributes to process development for operations not possible at lab-scale or that pose scale-up challenges, for example disk-stack centrifugation for primary recovery, or evaluation of normal-flow filtration dynamics with respect to capacity. By providing confidence in manufacturing scalability whatever the nature of the biologic, AbbVie drives the development of drugs with significant potential to address unmet medical need and make a remarkable impact on patients’ lives.
AbbVie CMO leverages established expertise to support partners with scale-up at any stage of the drug product lifecycle. To learn more about how AbbVie CMO can deliver on your scale-up requirements, contact us at 1-847-938-8524 or visit www.abbviecontractmfg.com for more details.
By: M. Omon Herigstad, Principal Scientist / Group Leader, Scale-Up Lab
Evan Pasenello, Account Manager, Operations Contract Manufacturing
Mark A. Shannon, Scientist II
Paul M. Reynolds, Senior Scientist II
Andrew S. Bulger, Scientist II