Manufacturing

Reducing Clinical-Phase Manufacturing Costs: Collaborating for Savings without Compromising Quality or Performance

In downstream purification of monoclonal antibodies (MAbs), the single greatest contributor to manufacturing costs is the expensive capture step typically based on protein A affinity chromatography. Almost since its introduction to bioprocessing, efforts have been made to reduce the cost of this step. Several alternative ligands have been promulgated as potential replacements for protein A, but they have proven difficult to adopt and scale up. Supplier companies have pushed for increases in capacity and economics, but those are always accompanied…

The First Single-Use Diaphragm Valve: Automated and Controllable Systems Increase Process Reliability

Single-use components and systems now are firmly established in the pharmaceutical and biotechnology industries. The trend toward simplified and flexible upstream and downstream plant design means that these components are becoming increasingly important — especially in biopharmaceutical production. In the past, the only available disposables were primarily tubes, fittings, and possibly filters. But the number of single-use systems has been increasing for a number of years now. It is hardly surprising that plant designers and operators now can rely on…

Cell-Delivered Gene Therapy: This Viral Vector Manufacturing Method Could Widen Its Applicability

Cell-delivered gene therapy is making an impact on a range of diseases (1–17). To date, successful treatments have generally been in conditions involving genetic deficiencies/abnormalities, for which introduction of a normal gene allele has been corrective (1–12, 18). Such an approach requires a vector containing the normal allele to overcome the mutant or lacking gene. The vector of choice for cell-delivered gene therapy is often a lentivirus that integrates and expresses introduced therapeutic genes in host target cells and their…

Biosimilar Therapeutic Monoclonal Antibodies: Gaps in Science Limit Development of an Industry Standard for Their Regulatory Approval, Part 2

Last month, Part 1 of this discussion briefly described the regulatory landscape for developing biosimilar therapeutic monoclonal antibodies (TMAbs). We identified certain specific structural components of TMAb drug substances that warrant particular attention because alterations to them are likely to affect therapeutic safety and effectiveness. Now we conclude by considering whether studies of reference materials can further the development of analytical industry standards to ensure comparability of putative biosimilar TMAbs with innovator TMAbs. We suggest that the time is right…

Special Report on Antibody-Drug Conjugates: Technical Challenges and Opportunities

Among the emerging targeted therapies in biotechnology, antibody–drug conjugates (ADCs) hold a unique position. An ADC consists of a monoclonal antibody (MAb) with affinity to tumor cells, a cytotoxic small-molecule payload, and a linker connecting the two. Together the MAb, conjugation chemistry, and cytotoxin increase the complexity of ADCs several-fold relative to unmodified MAbs — and exponentially relative to chemotherapies. Viewing ADCs as hybrids of antibody- and chemotherapy-based cancer therapies is tempting. That description applies chemically and structurally, but ADCs’…

Engineering Tissues with Bioprinting

Commonly referred to as three-dimensional (3D) printing, additive manufacturing encompasses a set of technologies that fabricate objects in an additive way, layer by layer, rather than conventional means of fabrications that generally subtract unwanted material from a larger block. Precise control over material placement allows 3D printing to fabricate objects that otherwise would not be manufacturable. Although many of these technologies have been around for two or three decades, recently they have received a significant amount of attention from industry,…

Progress Toward Commercial Scale and Efficiency in Cell Therapy Bioprocessing

Regenerative medicine includes both cell and gene therapies. Currently 672 regenerative medicine companies operate around the world, and 20 products have been approved by the US Food and Drug Administration (FDA). Of 631 ongoing clinical trials by the end of 2015 (1), over 40% are in oncology, followed in prominence by cardiovascular and infectious diseases. Here I focus on gene and cell therapy bioprocessing in which the final products delivered to patients are cells. Cell therapies are either autologous (derived…

Manufacturing Plasmid DNA: Ensuring Adequate Supplies for Gene and Cell Therapies

The concept of gene therapy is far from new, with initial studies performed over 20 years ago (1). However, in the past few years an explosion of interest in this area has gone beyond initial regenerative approaches using viral vectors. Interest is now moving increasingly into potential use of T cells modified using recombinant viral vectors for immunotherapy applications. Such therapies are based on using either adenoassociated virus (AAV) or lentivirus (1), both vectors being frequently generated through transient expression…

Designing the Optimal Manufacturing Strategy for an Adherent Allogeneic Cell Therapy

Cell therapies (CTs) offer potential treatments for a wide range of medical conditions (1–6) by replacing cells, repairing tissues affected by either disease or damage (7), or delivering genetic or molecular agents that promote self-healing (8). CT research and development is continuously growing (9), with increasing numbers of CT candidates reaching phase 3 clinical trials (9–11). Developers aim to make products that can survive in a competitive landscape while complying with stringent regulatory requirements to control the quality and safety…

Biosimilar Therapeutic Monoclonal Antibodies: Gaps in Science Limit Development of an Industry Standard for Their Regulatory Approval, Part 1

Biosimilars are biologically derived pharmaceuticals intended to have clinical similarity to a legally marketed innovator product when that product’s patent or market exclusivity has expired. By contrast with generic small-molecule drugs, clinical performance of a biologic pharmaceutical is a function of its structural complexity and higher-order structure (HOS). Biomanufacturing controls of such complex products cannot fully ensure chemical similarity between an innovator product and putative biosimilar because minor differences in chemical modifications and HOS can significantly alter a product’s safety…