Analytical

Regulating Quality in Continuous Processing

Regardless of the industry and product being manufactured, continuous processing has demonstrated numerous benefits. In addition to smaller manufacturing footprints, reduced material consumption and waste generation, increased efficiencies, and lower capital and operating costs continuous manufacturing typically leads to more consistent processes and product quality. In the pharmaceutical industry, the latter two attributes align perfectly with FDA’s Quality by Design (QbD) and process analytical technology (PAT) initiatives. The challenge is determining how to apply these concepts in practice. Applying the…

Using Technology to Overcome Bioprocessing Complexity: Advanced Concentration and Analytical Technologies Accelerate Development and Manufacture of mAbs, Vaccines, and Biosimilars

Unlike chemically synthesized drugs, whose structure is known and reproducible, biological drugs are derived from living cells and are sensitive, complex mixtures requiring cutting-edge biological technologies for their production. The growing importance of biosimilars in recent years is reflected in a corresponding rise in market value. The value of the global biologic therapeutic drug market reached approximately US$230 billion in 2014 and, according to BCC Research, will increase to nearly $390 billion by the end of 2019. This corresponds to…

Quality By Design for Monoclonal Antibodies, Part 1: Establishing the Foundations for Process Development

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…

Osmolality Measurements for High-Concentration Protein–Polymer Solutions: Variation Based on Working Principles of Osmometers

Osmolality is a critical attribute for injectable formulations. It is desirable to have products match physiological osmotic conditions. Furthermore, osmolality provides confirmation of soluble content in solution. Preventing injection of hypo- or hyperosmotic solutions is a key element of parenteral formulation development. Additionally, some investigators have explored correlations between injection pain and formulation osmolality, although no significant correlation has yet been observed (1–4). Osmolality is a valuable in-process test also because it provides a reliable and repeatable value that reflects…

Enhanced Biosimilar Product Characterization: A Case Study Using Raman Spectroscopy Combined with Dynamic Light Scattering

Biophysical characterization has drawn great attention from the biopharmaceutical industry and regulatory agencies across the globe, especially for use in biosimilar drug product development. Currently available biophysical characterization tools can help in screening and optimizing better (more stable) formulations for such products. However, most tools cannot be used for head-to-head comparison of the biophysical properties of an optimized biosimilar formulation with those of an innovator product at higher concentrations. We developed and optimized a formulation for monoclonal antibody MAb B…

Ask the Expert Liposome and Viral Vector Characterization: Use of Electron Microscopy and Image Analysis

with Dr. Josefina Nilsson For this webcast, Josefina Nilsson (EM Services business unit head) discussed Vironova’s work, including case studies. She focused on characterization of drug and gene delivery platforms with electron microscopy and image analysis, specifically for systems that use viral vectors or liposomes. Along with two colleagues — Gustaf Kylberg (image analysis expert) and Mathieu Colomb-Delsuc (electron microscopist) — she then answered questions from the audience. Nilsson’s Presentation Structural characterization provides important insights into the quality of development and…

Fucosylation of a Therapeutic Antibody: Effects on Antibody-Dependent, Cell-Mediated Cytotoxicity (ADCC) Potency and Efficacy

Product quality attributes are critical for the functionality and manufacturability of therapeutic antibodies. They can be significantly influenced by a number of production process parameters, such as cell culture media. The composition of growth and feed media can influence antibody glycosylation, including the concentration of ammonia, glutamine, glucose, and metal ions (1, 2). Thus, it is critical during media development and optimization to monitor and consider a culture medium’s impact on glycosylation. For therapeutic antibodies whose mechanism of action includes…

Benefits of Using Tetradetector SEC to Characterize Membrane Proteins

About 60% of all drug targets are membrane proteins. So understanding their structure and function as well as their interactions with drug candidates is critical to discovery and development of new therapeutic agents. Solubilization of these proteins is an essential precursor to in vitro studies of receptor function, structure, and activity. Purification and crystallization are important aspects. However, solubilization is complicated by the hydrophobic nature of a protein’s membrane-spanning part. Surfactant micelles and other stabilizing systems thus are used to…

Detecting the Broad Spectrum of Pyrogens with the Human Whole-Blood Monocyte Activation Test

In the early 20th century, some patients injected with the drug Salvarsan experienced febrile reactions due to contamination of the drug’s distilled water. That incident (involving the first effective treatment for syphilis) prompted not only the widespread use of injectable drugs, but also the need for pyrogen control. Pyrogens constitute a heterogeneous group of microbial and nonmicrobial substances that include those derived from Gram-negative and Gram-positive bacteria such as lipopolysaccharide (LPS) and lipoteichoic acid (LTA), respectively, as well as particles…

Defining Your Product Profile and Maintaining Control Over It | A Look Back with Emily Shacter

This is a transcript from a Q&A interview with Emily Shacter, PhD, Consultant, ThinkFDA LLC (former FDA Scientist and Regulator). We will be talking today about the CMC Forum that was published back in 2005. We are revisiting it in the magazine to specifically update our understanding of how to maintain process control; understanding your process. In general, how do you feel the discussions in the four-part paper from 2005 has held up after 10 years? Emily: I think they…