QA/QC

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…

Bridging Analytical Methods for Release and Stability Testing: Technical, Quality and Regulatory Considerations

To monitor the control and consistency of products derived from biological systems, a broad array of analytical methods are used for biopharmaceutical release and stability testing. These methods include both classical and state-of-the-art technologies as well as new technologies as they emerge over time.During the life cycle of a product, several reasons can arise for making changes in existing analytical methods: e.g., improved sensitivity, specificity, or accuracy; increased operational robustness; streamlined workflows; shortened testing times; and lowered cost of testing.…

Process- and Product-Relate Impurities: Part 1 – Process-Related Impurities An Overview

Introduction by Cheryl Scott The CMC Strategy Forums focus on relevant chemistry, manufacturing, and controls (CMC) issues throughout the life cycle of a therapeutic and thereby foster collaborative technical and regulatory interaction. Forum chairs share information with regulatory agencies to help them merge good scientific and regulatory practices. Outcomes of forum meetings are published in BioProcess International and on the CASSS website (www.casss.org). This process is meant to help ensure that biopharmaceutical products manufactured with advancing technologies in a regulated…

High-Throughput Methods Evaluation: Impurities Determination During Upstream and Downstream In-Process Development

Getting biologic drugs through development and into clinical proof-of-concept studies quickly and efficiently is critical for success in the biopharmaceutical industry. Implementing high-throughput approaches to both upstream and downstream process development is increasingly helping companies stay competitive. Innovative and highthroughput analytical technologies are needed to support rapid process development. The study reported herein focuses on innovative immunoassay platforms for impurity-removal monitoring of both host-cell proteins (HCPs) and leached protein A. HCPs come from host cells during cell culture production. Their…

Using Glycosidases to Remove, Trim, or Modify Glycans on Therapeutic Proteins

One of the most common posttranslational modifications of eukaryotic proteins is glycosylation. Glycosylation of proteins can affect many biological activities. For therapeutic glycoproteins, it can modify biological activity, targeting, trafficking, serum half life, clearance, and recognition by receptors (1, 2). For such reasons, biomanufacturers must monitor and characterize the glycosylation patterns of their recombinant therapeutic proteins (3, 4). Therapeutic proteins have two main types of glycosylation: N-linked glycans and O-linked glycans (5). Attachment of an N-glycan starts in the endoplasmic…

Development of a Novel Host-Cell Protein Assay: Supporting the Physcomitrella patens Expression System

Host-cell proteins (HCPs) constitute an inevitable impurity of biopharmaceutical products originating from recombinant-cell culture. HCPs are a heterogeneous mix of different proteins, their specific characteristics depending on the kind of organism used as an expression platform, on the “destination” of the expressed recombinant product (extra- or intracellular), and on the corresponding purification approach (1–3). Contamination of a final drug substance with residual HCPs could lead to immunogenic reactions in some patients who receive the drug product (DP). So a reliable…

The Case for a Standardized Assay to Test Suitability of Single-Use Systems in Cell Culture Applications

Increased commercial use of single-use systems (SUS) for large-scale biopharmaceutical production creates the need for consensus on industry best practices and standards for materials in SUS components. End users and suppliers are beginning to develop a shared vision of industry needs in such areas (1, 2). For example, highly visible efforts to harmonize extractables testing include contributions from groups such as the BioPhorum Operations Group (BPOG), Bio-Process Systems Alliance (BPSA), Parenteral Drug Association (PDA), ASTM, and ISPE. In addition to…

Accelerating Biologic and Biosimilar Drug Development: Ready-to-Use, Cell-Based Assays for Potency and Lot-Release Testing

With the drug industry’s expanding emphasis on biologics, the need for robust cell-based assays has grown at all stages of development. Requirements for efficacy, quality, and potency testing often demand a complex set of bioassays and/or cell-based assays for new therapeutics or biosimilars. Developers of the latter have found this need for cell-based assays to be particularly challenging. Commercially available, ready-to-use cell-based assays provide a robust functional response from specific therapeutic targets. They can significantly shorten assay development time while…

Primary and Higher-Order Structural Characterization Strategy for Biosimilarity Assessment

The development pathway of a biosimilar is unlike that of a novel biotherapeutic. Many regulatory authorities reference a stepwise approach to establishing biosimilarity. Analytical requirements are greatly increased before a product enters clinical testing. Enhanced analytical efforts entail physical, chemical, and biological characterization of a biosimilar product compared with an originator reference product. Strategies at this early stage must include intensive characterization of multiple batches to determine variability of quality attributes. Here I address some issues involved in meeting regulatory…