Antibody–drug conjugates (ADCs) are monoclonal antibodies coupled to cytotoxic agents with stable linkers. ADCs travel to target cells, where the antibody binds to its antigen expressed on the cell surface. Upon binding, the full ADC can be internalized by a process called receptor-mediated endocytosis. That process is followed by lysosomal degradation of ADC complexes, which ultimately leads to release of the cytotoxic agent and apoptosis of the target cell. Drugs used in ADCs can be up to a thousand times…
QA/QC
Fed-Batch Cell Culture Process Development: Implementing a Novel Nutrient Additive for a Robust, High-Titer, Scalable Process
The fed-batch culture of Chinese hamster ovary (CHO) cells has become well established as the primary method of manufacturing therapeutic recombinant protein products for various disease indications. Fed-batch process-development approaches focus on supporting high–cell-density cultures that are crucial to achieving high product titers but lead to proportionately high nutritional demands. Exhaustion of key nutrients negatively affects cell growth and ability to produce recombinant proteins. To counter that problem, concentrated feeds are added to the culture. Such feeds tend to be…
Higher-Order Structure Comparability: Case Studies of Biosimilar Monoclonal Antibodies
Great successes for monoclonal antibody (MAb)–based biologics over the past decade have provided many valuable options for patients combating some of the most serious diseases in the world, including cancer and autoimmune diseases. MAbs and antibody–drug conjugates (ADCs) are among the fastest growing biologic segments in development, with hundreds of candidates currently under clinical study. Meanwhile, society is facing the challenge of increasingly higher costs in healthcare including the cost of pharmaceuticals. With an aging population in many parts of…
Site-Specific Characterization of Glycosylation on Protein Drugs
A large proportion of biotherapeutic products are glycoproteins. These include erythropoietin and other cytokines, antibodies, glycosyltransferases, and glycosidases, which together generate billions of dollars in sales worldwide. Such drugs are inherently complex. As new treatments emerge and biosimilars are evaluated, the need to better understand their molecular structures is more acute than ever. Therapeutic glycoproteins are typically produced as recombinant products in cell culture systems. Glycosylation is of major importance during development of these drugs because their glycan chains markedly…
Qualification of Scale-Down Bioreactors: Validation of Process Changes in Commercial Production of Animal-Cell-Derived Products, Part 2 — Application
Here we apply our approach to validation of animal cell culture process changes using qualified, scale-down bioreactors. As described in Part 1 (including Table 1, Figures 1 and 2, and References 1–23), the goal is to facilitate implementation for the benefit of both the patients and industry. “Qualification of Scale-Down Bioreactors: Validation of Process Changes in Commercial Production of Animal-Cell–Derived Products, Part 1 — Concept” appears on pages 38–45 of BioProcess International’s May 2014 issue. Process changes often entail validation,…
Analytics for Modern Bioprocess Development
Twelve years ago, about the same time the US Food and Drug Administration was putting the finishing touches on its quality by design (QbD) and process analytical technology (PAT) guidelines, I wrote an article about breakthrough pharmaceutical educational programs. That article included the perspectives from a few members in academia of the future essential skills for pharmaceutical students. At the time, bioinformatics and computerized industrial process modeling were relatively new disciplines, but their importance in future manufacturing was clear. Several…
Essentials in Quality By Design
Quality by design (QbD) is a systematic approach to drug development. It begins with predefined objectives and emphasizes product and process understanding and process control, all based on sound science, data-based decision making, and quality risk management (QRM). As introduced by the US Food and Drug Administration (FDA), QbD brings modern drug development methodologies to chemistry, manufacturing, and control (CMC) teams working on biologics, pharmaceuticals, and vaccines. The innovations associated with QbD are not so much the development concepts (which…
Reference Standards for Therapeutic Proteins: Current Regulatory and Scientific Best Practices
Sponsors developing and manufacturing protein therapeutic products use a variety of analytical tests (e.g., cell-based potency and chromatographic assays) to assess quality attributes of their active ingredients and drug products. Those tests are used to assess product quality in a number of activities, including characterization, comparability, lot release, and confirmation product quality and stability. Reference standards play a critical role in calibrating and confirming the suitability of such tests and in helping analysts to draw scientifically sound conclusions from data…
Cell Therapy Manufacturing
Fueled by a recent resurgence in public financing and compelling clinical data for indications as diverse as acute macular degeneration and pancreatic cancer, a growing number of cell therapies are driving toward pivotal clinical studies and commercialization. Although regulatory precedents have been set for various autologous and allogeneic products in the United States, Asia, and the European Union, regulatory guidance continues to evolve for a widening array of cell products. Adult stem cells (e.g., mesenchymal stem cells), embryonic stem cells,…
Assessing Flange Strength and Dimensional Variability
Plastic syringes are viable alternatives to glass syringes in the biopharmaceutical market. They have two main advantages over glass syringes: their break resistance (specifically on the finger flange) and their ability to maintain tighter dimensional tolerances and less variability (because of the flexible molding process). Both attributes are critical when a 1-mL long prefilled syringe is used with an autoinjector device. The high break resistance of plastic syringes can reduce the number of rejected units during a fill–finish process. And…