Downstream Development

CMC Development Platforms and Outsourcing to Reduce Timelines

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Forty Seven is a company developing novel therapies based on anti-CD47 and other immuno-oncologies. CD47 is called the “don’t eat me” signal that cancer cells give out to escape elimination by the body’s immune system. Qinghai Zhao, vice president of technical development and manufacturing, is one of the scientists working on the company’s magrolimab (5F9) monoclonal antibody that is designed to block the binding of the CD47 signal to the cell receptor SIRP-α while boosting the “eat me” signal that…

October 21, 2019

Apparent Matrix Effects in an Iduronate 2-Sulfatase Specific Activity Assay

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The recombinant fusion protein SHP631 consists of a chimeric monoclonal antibody binding to human insulin receptor and iduronate-2-sulfatase (I2S). This product is being developed as an enzyme replacement therapy to treat cognitive symptoms of Hunter’s syndrome. Because the current therapy (idursulfase, brand name Elaprase from Shire) cannot cross the blood–brain barrier (BBB), SHP631 is being developed to do so, enabling the presence of I2S in the brain. The enzymatic activity of this molecule is measured using the substrate 4-methyl umbelliferyl-α-L-idopyranosiduronic…

March 14, 2019

Developing an End-to-End Scale-Down Model for a Commercial-Scale Downstream Process: Enhancing Technology Transfer Efficiency

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Large and complex protein molecules used as therapeutic agents are manufactured in a series of process steps that start with thawing of cell-bank vials and finish with filling and packaging (Figure 1). The cost and complexity of commercial-scale biomanufacturing processes make them prohibitive to troubleshoot or experiment at full commercial scale. Biopharmaceutical companies routinely use scale-down models (SDMs) of licensed commercial-scale processes to evaluate raw material changes, process improvements, and deviations (1) (Figure 2). Here, we outline some considerations in…

March 14, 2019

Continuous Chromatography: Experts Weigh in on the Possibilities and the Reality

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Discussions of continuous processing in the biopharmaceutical industry are an important part of current efforts toward intensifying bioproduction and bioprocessing. Biomanufacturers are looking at all components of their development and manufacturing processes for ways to reduce the size of their facilities, lower costs, and increase speed and flexibility of operations. Increasing options for and availability of single-use technologies have been major enablers of myriad attempts to improve efficiencies. Although the general consensus may still be that single-use components are more…

February 28, 2019

Aspects of Acceleration: Biomanufacturers Need Smart Strategies to Speed Products to Market

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No matter what the industry, it’s widely accepted that slow-moving companies give their nimbler competitors an advantage, allowing them room to dominate the market even if their products are not superior. “Me-too” products and their sponsors often are seen as followers rather than leaders — even if they offer improvements over what is already available. Fast movers are flexible and adaptive to a dynamic business environment. They capitalize on opportunities and navigate risks and challenges by responding quickly to changes…

February 14, 2019

Process Analytics and Intermediate Purification of Bispecific Antibodies with a Non-Affinity Platform

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The therapeutic benefits of monoclonal antibodies (MAbs) have been demonstrated in recent decades with uncontestable success as treatments for human disease. Despite MAbs’ key features such as specificity, selectivity, and safety, the format has limitations (1, 2). Bispecific antibodies may overcome number of difficulties (3). Multiple formats of bispecific antibodies have been developed, although only the κλ-body is fully human and devoid of linkers or mutations. It requires no genetic modifications of heavy and light chains and results in bispecific antibodies…

October 15, 2018

A UF–DF Screening System for Bioprocess Development: Efficient and Cost-Effective Process Fit and Scale-Up to Manufacturing

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Ultrafiltration and diafiltration (UF–DF) of therapeutic proteins are performed in either tangential or crossflow mode using membrane filters. UF–DF plays a critical role in both downstream and upstream processes for the biopharmaceutical industry (1). In upstream production processes, classical tangential-flow filtration (TFF) or alternating tangential-flow (ATF) systems are used in high–cell-density perfusion for protein expression by cell culture (2). TFF is used in downstream processing for UF–DF and concentration of therapeutic proteins. TFF unit operations are common in protein purification…

September 15, 2018

eBook: Quality By Design for Monoclonal Antibodies — Establishing the Foundations for Process Development, Design Space, and Process Control Strategies

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The quality by design (QbD) modernized approach to pharmaceutical development is intended to provide regulatory flexibility, increased development and manufacturing efficiency, and greater room to innovate as well as improve manufacturing processes within defined ranges without obtaining regulatory approval first. QbD is a systematic developmental approach that starts with a clear goal in mind and emphasizes understanding of how variability in both process and materials affects a final product (1). Historically, product quality has been assured either with end-product testing…

June 22, 2018

Host-Cell Protein Risk Management and Control During Bioprocess Development: A Consolidated Biotech Industry Review, Part 2

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Even with increased understanding of host cell proteins (HCPs) and their potential risks, no practical approach has been made available for HCP risk management during bioprocess development. A BioPhorum Development Group (BPDG) team has identified common HCP-related risk factors and built a template for semiquantitative risk assessment during process development based on publicly available information. To this end, the BPDG HCP working team’s assay and knowledge-sharing experts have established a common HCP risk assessment tool and mitigation strategy to guide…

June 20, 2018

Host-Cell Protein Risk Management and Control During Bioprocess Development: A Consolidated Biotech Industry Review, Part 1

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Host-cell proteins (HCPs) constitute a significant class of process-related impurities during biologics manufacturing. Due to their potential impact on product quality and efficacy as well as patient safety, the total amount of residual HCP in a biological drug substance generally is considered a critical quality attribute (CQA) that usually needs to be tested for during batch release (1, 2). It is both an “industrywide” common understanding and a regulatory requirement to remove HCPs from biologics to acceptably low levels that…

June 1, 2018