QA/QC

eBook: Quality By Design for Monoclonal Antibodies — Establishing the Foundations for Process Development, Design Space, and Process Control Strategies

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…

Methods on the Move: Addressing Method Transfer Challenges for the Biopharmaceutical Industry

Analytical method transfers are essential components of the current global biotechnology environment. Analytical method transfer can be defined as “a documented process that qualifies a laboratory (the receiving laboratory) to use a validated analytical test procedure that originated in another laboratory (sending laboratory), thus ensuring that the receiving laboratory has the procedural knowledge and ability to perform the transferred analytical procedure as intended” (1). The goal is to ensure that a method continues to perform in the validated state regardless…

Statistical Assessments of Bioassay Validation Acceptance Criteria

Analytical linearity as well as assessments of precision and accuracy determine the range for a bioassay (1). USP <1033> recommends comparing confidence intervals (CIs) against target validation acceptance criteria in a bioassay validation exercise, but there are no clear guidelines for determining the criteria (2). Here I address several aspects of a bioassay validation, namely • Linearity (coefficient of determination (R2), slope, and intercept parameters) • Accuracy (%relative bias, %RB) • Precision (percent coefficient of variation, %CV) CIs for the…

Ensuring the Integrity of Single-Use Containers: Providing Robustness, Science, and Helium-Based Technology with a Detection Limit of 2 μm

Identifying the greatest defect size, both for liquid leaks and microbial ingress, is a fundamental step toward protecting the integrity of single-use systems (SUS) under real process conditions. Integrity testing of such systems may become a prerequisite in the future because they are used in the most critical process steps, with detection limits correlating to liquid leaks and microbial ingress. Such testing guarantees the sterility of drug substances and drug products packaged in single-use systems and, therefore, enhance patient safety.…

Antibody Higher Order Structure Stability: Polymorphism Revealed By Protein Conformational Array

For protein therapeutics and other biologics, the importance of the molecule’s structure to its efficacy and safety is well established (1–5). In particular, their tertiary and quaternary structures play very important roles in product quality and have been monitored extensively in comparability studies (6–12). However, because of both the large molecular size and rotational property of amino acid α carbons, a protein can assume an enormous number of different conformations (13). For antibody-based biologics such as monoclonal antibodies (MAbs), fusion…

Viral Vector Particle Integrity and Purity Analyses in Early Process Development

Gene therapy is the transfer of genetic material to a patient’s cells to achieve a therapeutic effect. Therapeutic DNA typically is delivered using a viral vector system, and adenoviruses have been used for this purpose for over 20 years (1–3). Within the past 10 years or so, lentiviruses have shown promise in clinical trials (1–3), and adenoassociated viruses (AAVs) have been used in the first approved gene therapies in the Western world (4). The number of gene therapy applications based…

Development of a Host-Cell Protein Platform Assay for a Chinese Hamster Ovary Cell Line

The Chinese hamster ovary (CHO) cell line is the most prevalent biopharmaceutical expression system and has been proven safe for commercial production of protein therapeutics (1). However, even after multiple purification steps, biopharmaceuticals contain residual host-cell protein (HCP) impurities that pose a potential safety risk to patients (2). Health authorities demand close monitoring of HCP impurities and require sensitive analytical methods with high coverage: the ability to detect a broad range of HCP impurities (3, 4). Polyclonal sandwich immunoassays are…

Regulation, Analytical, and Process Issues with Leachables: Toward Harmonization for Latin America with Europe and North America

The pharmaceutical industry follows strict regulations regarding impurities, including process-related leachates. Plastic manufacturers use hydrophobic, nontoxic additives for manufacturing containers for use in the pharmaceutical and food industries. However, some issues about dealing with such impurities are not yet resolved. In developing countries, regulators are working on guidelines to help local companies ensure characterization of impurities. In this exclusive editorial eBook, authors from Mexico describe some issues related to plastic leachables in the context of ongoing efforts to harmonize regulations…

Aggregation from Shear Stress and Surface Interaction: Molecule-Specific or Universal Phenomenon?

Exposure to solid–liquid and air–water interfaces during production, freezing and thawing, shipment and storage of protein therapeutics may be a contributing factor in their degradation (e.g., aggregation, fragmentation) (1, 2). Surface exposure, particularly during manufacturing processes, often is accompanied by various degrees and durations of shear stresses originating from fluid flow and acting on proteins at interfaces. The magnitude and duration of shear rates depends on velocity gradients within each solution and varies significantly among manufacturing steps. On the low…

Strategies for Successful Sample Transfer

Nadine Ritter is president and senior analytical advisor of Global Biotech Experts, LLC and a long-time member of BioProcess International’s editorial advisory board. At a recent CASSS North American CMC Strategy Forum called “Methods on the Move: Addressing Method Transfer Challenges,” she discussed the biopharmaceutical industry’s logistical challenges of analytical test samples for drug substances and products. At the conference, BPI’s editor in chief Anne Montgomery met with her to discuss some key points of this topic. Logistics Challenges Montgomery:…