Manufacturing

Optimizing and Intensifying ADC Aggregate Removal: A DoE Approach to Membrane Chromatography and Rapid Cycling

Antibody–drug conjugates (ADCs) represent a growing therapeutic segment of the oncology field. Five such treatments received market approval from the US Food and Drug Administration (FDA) between 2008 and 2018, whereas three were approved in 2019 and two each were approved in 2020 and 2021 (1). This disruptive technology combines highly potent small-molecule payloads with monoclonal antibodies (MAbs) to improve their specificity as cancer treatment. The antibodies deliver those toxic compounds directly to cancer cells but not to healthy cells,…

Advanced Liquid Transfer with Single-Use Systems

Most biopharmaceuticals are manufactured in large-scale stainless-steel piping and vessels, with downstream processes taking place within rigid and inflexible facilities. Although process steps such as harvest, purification, fermentation, filtration, dispensing, and freezing require flexibility, stainless steel has not been replaced yet by single-use systems at a large scale. However, manufacturers wanting to optimize process efficiency and scalability to obtain a viable and valuable product for commercial use inevitably will need single-use technology. Aseptic fluid management with single-use systems offers numerous…

Applying Quality By Design Principles to AAV Manufacturing

The expectation to apply quality by design (QbD) principles to new manufacturing processes has been voiced by regulatory authorities for over a decade (1, 2). They recognize that because of the generally low patient populations for emerging therapies, such as adeno-associated virus (AAV)-based therapeutics, available chemistry, manufacturing, and controls (CMC) information might not be as exhaustive as for other biologicals such as monoclonal antibodies (3, 4). Other challenges include the need for rapid development to address currently unmet medical needs…

A Plug-and-Produce GMP Plant for Cell and Gene Therapies Part 2: Rapid Deployment of a Commercial-Scale Facility

Extending the use of approved advanced-therapy medicinal products (ATMPs) to the tens of thousands of patients who could benefit from such treatment requires a 10- to 100-fold production scale-up. Given that each autologous ATMP batch yields one dose for one patient, expanding production throughput is not a question of boosting volume, but rather of amplifying single manufacturing runs. That is, scale-up is actually scale-out, and the dimensions of the ensuing endeavor extend beyond what occurs in the cleanroom. Coupled with…

Two-Step Monoclonal Antibody Purification Using a Multicolumn Continuous Chromatography Platform

Biomanufacturers typically have relied on multistep processes for optimal removal of impurities such as host-cell proteins (HCPs), DNA, adventitious viruses, and aggregates. However, additional purification steps increase downstream expenses significantly, including costs of supplementary resin, hardware, and buffers. The substantial footprint required at a processing site and additional time needed to perform a complete multistep purification process also increase production costs and complicate process execution. Thus, it is imperative to design and test effective purification procedures for high-quality biotherapeutics, but…

Investigation of HCP Enrichment During CGMP Scale-Up

On paper, scaling a bioprocess from a 10-L to a 100-L to a 2,000-L bioreactor may seem like a straightforward math problem that could be solved by software. In practice, however, the exercise relies on a complex set of biological, chemical, and engineering assumptions; on maintenance of healthy cell cultures; and on management of equipment and analytics while adjusting to each increase in scale (1). Process development and quality control groups need to monitor how scale-up might affect critical quality…

Appropriate Estimation of Long-Term Variability: Using Biopharmaceutical Release and Stability Data

Numeric results from quality attributes testing of drug product and drug substance lots can be used for different statistical analyses. One study is the calculation of statistical tolerance intervals from lot-release data to assist in the determination of specification acceptance criteria (1). Data from manufactured batches placed on stability at the recommended storage condition (RSC) also can provide useful information to estimate long-term variation. Below, I address potential concerns associated with pooling disparate data sources and illustrate a technique to…

eBook: Drug-Delivery Systems — Measurement-System Analysis Using Gauge R&R Studies

When a biological product requires a specialized delivery device, the resulting combination product can introduce new types of quality evaluation. Product development brings together regulatory requirements for biologics and drug-delivery systems, and for many people on the biopharmaceutical side, that includes a number of unfamiliar terms, processes, and procedures. Among those are gauge repeatability and reproducibility studies for measuring variations that arise from measurement devices and the operators using them. This eBook introduces the concept of attribute-data gauge repeatability and…

Hardware, Software, and Wetware: 20 Years of Advancements in Biopharmaceutical Production, Part 2

The past couple of decades have witnessed significant advances in upstream bioprocess technologies and approaches. Since its establishment, BPI has been a facilitator of discussion both in print and at professional conferences, as well as in webcasts and news online. To mark the 20th anniversary of the publication, we surveyed articles published over the past two decades and found hundreds that highlight significant advances in both emerging and established themes in biopharmaceutical production: • “hardware” technology (e.g., analytical instrumentation, bioreactors,…

Future Supply-Chain Needs for Allogeneic Cell Therapies: Why Strategic Partnerships Are Critical

Allogeneic products are an attractive option for cell-therapy developers because multiple batches can be manufactured using apheresis material collected from one healthy donor — and because the resulting therapies could be made available as off-the-shelf products. The appeal of this approach is apparent from growth in allogeneic-therapy development. According to the Alliance for Regenerative Medicine, the number of clinical trials for allogeneic cell-based cancer treatments has increased by 30% over the past five years. Early in 2022, allogeneic candidates accounted…