Finding Efficiencies to Accelerate Biopharmaceutical Development

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Biologics success requires quality and speed to INDAn old engineering adage says that in any technical project, you can get speed and/or quality and/or cost-efficiency — but you never get to have all three. The idea is that emphasizing any one of those parameters necessarily deemphasizes one or both of the others. For most of the biopharmaceutical industry’s early years, companies operated on that assumption. Many organizations saw speed as the weakest link that could be more or less ignored; others had money to burn. The smartest companies always have considered quality simply to be the cost of doing business when customer lives are at stake. Only bad actors put money ahead of all else.

The 21st century has changed that old rule of thumb. Modern technology and business strategies consider all three criteria equally. Time is money, after all, and quality failures compromise both. Making high-quality products is a “given” because nothing else will pass regulatory approval. But now managers ask how to achieve that level of success in the shortest possible time by making the best use of what often can be limited resources. Efficiency is the byword that links these criteria together.

Biotechnology is by nature an expensive endeavor. The instruments and equipment are pricey, the raw materials are costly, and the expertise to work with them is hard to come by. Basic skills learned in college must be honed and merged with regulatory expectations through standard operating procedures. Product-specific knowledge grows over years of development — evidenced nowadays by vast quantities of data. Science forms the foundation of it all.

With an eye toward the early phase of drug development that culminates in preparation of an investigational new drug (IND) regulatory application, I spoke with three noted experts for this featured report. We discussed elements of efficiency for upstream production, downstream processing, and analytical development of biopharmaceutical products, from monoclonal antibodies (MAbs) and other proteins to vaccines and cell/gene therapies. It all boils down to a combination of technology and expertise that is vital to project success.

Much “speed to IND” discussion at bioprocess conferences over the past few years has focused on cell-line development, and for good reason. At the 2019 BPI West Conference, for example, Yves Durocher (mammalian cell expression section head in the Human Health Therapeutics Research Center at the National Research Council of Canada) described the significant investments in time and money required to generate good laboratory practice (GLP) toxicological materials and good manufacturing practice (GMP) cell banks as obstacles to bringing new biotherapeutics into clinical testing, especially for smaller companies.

Durocher highlighted three rapid alternatives that are less expensive than high-tech instruments and in-licensed cell lines: transient gene expression (TGE), stable pools, and targeted (site-specific) gene integration — the last of which he referred to as recombination-mediated cassette exchange (RMCE). With quality attributes that match those of stable clones, those alternatives can be used to generate material for toxicology (and even early clinical) studies. “The emphasis should be on product quality, safety, and process robustness,” he concluded, even when speed is the goal (1).

Implementing new ideas can be a challenge, pointed out industry consultant Thomas Ransohoff at a BPI Theater presentation back in 2015 (2). A regulated industry must be both risk averse and conservative in its approach to new technologies. Associated costs and time lags can be significant, so companies want as much assurance of success as possible. “The biopharmaceutical industry invests relatively little in new technology development,” Ransohoff explained, “and that may have to change.”

The conversations that fill out this report seem to suggest that, over the past five years, the paradigm has changed indeed. From laboratory robotics and process automation enabling high-throughput screening (3) to single-use technologies providing for manufacturing efficiency (4) and advanced data-management solutions keeping track of it all (5), the pace of innovation has picked up (6). It has allowed even the smallest companies to think in rapid-development terms (7, 8), and that’s good for their bottom lines. Until the first clinical results become available, many start-ups depend on angel investments and venture-capital money to get by. Stock-market investors and potential partners want to see real clinical data before they’ll be willing to pitch in, and that encourages a “speed to IND” mindset.

And that’s not always a good thing, as BPI’s editor in chief learned when she spoke with Susan Dana Jones (senior vice president of product development at Harpoon Therapeutics) for an eBook in December 2019 (9). With so many biopharmaceuticals obtaining breakthrough or fast-track designations, companies that depend too greatly on speed to IND to be first in human studies can be left with significant quality and manufacturing challenges that must be solved later on. Despite regulatory encouragement to create solid design spaces and define parameters according to quality by design (QbD), the pressures of speed can compromise a company’s ability or willingness to comply. If the reward is seen as the IND itself, then some companies could end up “locking in” subpar processes and assays that they’ll be stuck with later — or wind up making costly process changes and rework. “Speed at all stages can bring earlier achievement of development milestones (and ultimately return on investment sooner), but going too fast can leave gaps in process understanding and scalability that must be addressed” (9).

Teamwork and knowledge based on product and process understanding are key to preventing such problems. Upstream production and downstream processing groups must meet and discuss how their needs and strategies overlap and interact. Analytical specialists need to know what those groups want to know — and inform them in turn regarding what’s possible. Read on for detailed discussions with representatives of all three cohorts.

References
1 Scott C. Introduction: Reporting from the Frontiers of Cell Line Engineering at BPI Europe and BPI West. BioProcess Int. September 2019; https://bioprocessintl.com/analytical/cell-line-development/introduction-reporting-from-the-frontiers-of-cell-line-engineering-at-bpi-europe-and-bpi-west.

2 Scott C. Speeding Development and Lowering Costs While Enhancing Quality: A BPI Theater Roundtable at the 2015 BIO Convention. BioProcess Int. August 2015; https://bioprocessintl.com/manufacturing/manufacturing contract-services/speeding-development-and-lowering-costs-while-enhancing-quality-a-bpi-theater-roundtable-at-the-2015-bio-convention.

3 Ransohoff T, et al. Using New Technologies to Compress Timelines, Increase Capacity, and Reduce Costs: Speed — Why, When, and How. BioProcess Int. August 2018; https://bioprocessintl.com/bpi-theater/bpi-theater-bio-2018/using-new-technologies-to-compress-timelines-increase-capacity-and-reduce-costs-speed-why-when-and-how.

4 Rios M, Zhao Q. CMC Development Platforms and Outsourcing to Reduce Timelines. BioProcess Int. October 2019; https://bioprocessintl.com/october-2019-featured-report-technologies-to-accelerate-speed-to-market.

5 Rios M, Roesch M. Smart Sensors and Data Management Solutions for Modern Facilities. BioProcess Int. October 2019; https://bioprocessintl.com/october-2019-featured-report-technologies-to-accelerate-speed-to-market.

6 Rios M. Introduction: Technology Highlights from the 2019 BioProcess International Conference. BioProcess Int. October 2019; https://bioprocessintl.com/october-2019-featured-report-technologies-to-accelerate-speed-to-market.

7 Scott C. Aspects of Acceleration: Biomanufacturers Need Smart Strategies to Speed Products to Market. BioProcess Int. February 2019; https://bioprocessintl.com/business/economics/speed-to-clinic-accelerating-biopharmaceutical-products-to-market.

8 Kenyon D. It’s All About Speed: Getting to Early Development Clinical Trials Quickly. BioProcess Int. August 2018; https://bioprocessintl.com/sponsored-content/its-all-about-speed-patheon-quick-to-clinic-getting-to-early-development-clinical-trials-quickly.

9 Montgomery SA, Jones SD. Speed to IND: Balancing Risk and Reward. BioProcess Int. eBook December 2019; https://bioprocessintl.com/business/economics/ebook-speed-to-ind-balancing-risk-and-reward.

Further Reading on Speed to IND
Brooks B, et al. BioPhorum Operations Group Technology Roadmapping, Part 3: Enabling Technologies and Capabilities. BioProcess Int. April 2017; https://bioprocessintl.com/manufacturing/single-use/biophorum-operations-group-technology-roadmapping-part-3-enabling-technologies-capabilities.

Cooney B, Jones SD, Levine HL. Quality By Design for Monoclonal Antibodies, Part 1: Establishing the Foundations for Process Development. BioProcess Int. June 2016; https://bioprocessintl.com/analytical/upstream-development/quality-by-design-for-monoclonal-antibodies-part-1-establishing-the-foundations-for-process-development.

DePalma A. Special Report: Turning Discoveries into Products — Developability Assessments and Highly Efficient Process Design. BioProcess Int. October 2015; https://bioprocessintl.com/analytical/cell-line-development/special-report-turning-discoveries-into-products-developability-assessments-and-highly-efficient-process-design.

Dhanasekharan K, et al. Rapid Development and Scale-Up Through Strategic Partnership: Case Study of an Integrated Approach to Cell-Line and Process Development for Therapeutic Antibodies. BioProcess Int. June 2014; https://bioprocessintl.com/upstream-processing/upstream-contract-services/rapid-development-and-scale-up-through-strategic-partnership.

Ellert A, Vikström C. Design of Experiments with Small-Scale Bioreactor Systems: Efficient Bioprocess Development and Optimization. BioProcess Int. September 2014; https://bioprocessintl.com/analytical/upstream-development/design-experiments-small-scale-bioreactor-systems-efficient-bioprocess-development-optimization.

Jain S. Process Effectiveness Analysis Toward Enhanced Operational Efficiency, Faster Product Development, and Lower Operating Costs. BioProcess Int. November 2014; https://bioprocessintl.com/business/economics/process-effectiveness-analysis-toward-enhanced-operational-efficiency-faster-product-development-lower-operating-costs.

Jones S. BioPhorum Operations Group Technology Roadmapping, Part 2: Efficiency, Modularity, and Flexibility As Hallmarks for Future Key Technologies. BioProcess Int. February 2017; https://bioprocessintl.com/business/economics/biophorum-operations-group-technology-roadmapping-part-2-efficiency-modularity-flexibility-hallmarks-future-key-technologies.

Mire-Sluis A, et al. Accelerated Product Development: Leveraging Industry and Regulator Knowledge to Bring Products to Patients Quickly. BioProcess Int. December 2014; https://bioprocessintl.com/analytical/downstream-development/accelerated-product-development.

O’Kennedy RD. Multivariate Analysis of Biological Additives for Growth Media and Feeds. BioProcess Int. March 2016; https://bioprocessintl.com/upstream-processing/biochemicals-raw-materials/multivariate-analysis-of-biological-additives-for-growth-media-and-feeds.

Pathange LP, Huang L, Tsang J. Development and Application of a Simple and One-Point Multiparameter Technique: Monitoring Commercial-Scale Chromatography Process Performance. BioProcess Int. December 2018; https://bioprocessintl.com/manufacturing/process-monitoring-and-controls/development-and-application-of-a-simple-and-one-point-multiparameter-technique-monitoring-commercial-scale-chromatography-process-performance.

Rajamanickam V, Herwig C, Spadiut O. Data Science, Modeling, and Advanced PAT Tools Enable Continuous Culture. BioProcess Int. April 2018; https://bioprocessintl.com/manufacturing/continuous-bioprocessing/data-science-modeling-and-advanced-pat-tools-enable-continuous-culture.

Rekhi R, et al. Decision-Support Tools for Monoclonal Antibody and Cell Therapy Bioprocessing: Current Landscape and Development Opportunities. BioProcess Int. December 2015; https://bioprocessintl.com/manufacturing/monoclonal-antibodies/decision-support-tools-for-monoclonal-antibody-and-cell-therapy-bioprocessing-current-landscape-and-development-opportunities.

Rios M. Enhancing Manufacturing and Development Efficiency. BioProcess Int. September 2012; https://bioprocessintl.com/2012/enhancing-manufacturing-and-development-efficiency-334614.

Seely JE, Hart RA. Prior-Knowledge Assessments. BioProcess Int. October 2012; https://bioprocessintl.com/analytical/downstream-validation/prior-knowledge-assessments-335629.

Skibo AD. Managing Cost Without Sacrificing Quality. BioProcess Int. December 2012; https://bioprocessintl.com/analytical/downstream-development/managing-cost-without-sacrificing-quality-337780.

Taylor SC. Lean Six Sigma. BioProcess Int. December 2012; https://bioprocessintl.com/manufacturing/facility-design-engineering/lean-six-sigma-337825.

Tung G, et al. The Value of Plug-and-Play Automation in Single-Use Technology. BioProcess Int. December 2019; https://bioprocessintl.com/manufacturing/single-use/the-value-of-plug-and-play-automation-in-single-use-technology.

Wang X, et al. Antibody Higher Order Structure Stability: Polymorphism Revealed By Protein Conformational Array. BioProcess Int. November 2017; https://bioprocessintl.com/2017/antibody-higher-order-structure-stability-polymorphism-revealed-by-protein-conformational-array.

Watkinson A, et al. Antibody–Drug Conjugates: Fast-Track Development from Gene to Product. BioProcess Int. November 2017; https://bioprocessintl.com/manufacturing/emerging-therapeutics-manufacturing/antibody-drug-conjugates-fast-track-development-from-gene-to-product.

Cheryl Scott is cofounder and senior technical editor of BioProcess International, part of Informa Connect, PO Box 70, Dexter, OR 97431; 1-646-957-8879; cheryl.scott@informa.com.

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