QA/QC

Development of a High-Throughput Formulation Screening Platform for Monoclonal Antibodies

The goal of formulation development for therapeutic proteins is to find conditions under which a protein remains stable during storage, transport, and delivery to patients. Both chemical and physical stability must be considered. Chemical stability is related to the rates of chemical modification to a protein molecule such as deamidation of aspargine residues and oxidation of methionine residues (1, 2). Particularly important to control if they affect biological function, those modifications could also lead to changes in conformation or half-life…

Compatibility Assessment of a Model Monoclonal Antibody Formulation in Glass and Blow–Fill–Seal Plastic Vials

PREPRINT October 2015 issue Blow–fill–seal (BFS) technology has been recognized by the industry as an advanced aseptic solution (1–3). Catalent Pharma Solutions has been commercially supplying sterile BFS products to the pharmaceutical industry for decades, primarily in the respiratory and topical ophthalmic markets. Such product formulations range from simple solutions to emulsions with drug substances from classical small molecules to large complex proteins such as biologics. The company also has optimized BFS processes and its Advasept plastic container system for…

Assessing Similarity with Parallel-Line and Parallel-Curve Models: Implementing the USP Development/Validation Approach to a Relative Potency Assay

Potency is a critical quality attribute to support development and release of biopharmaceutical products. Researchers assess most protein-drug potencies using biological assays (such as cell-based assays), which mimic a product’s known mechanism of action or binding assays (if the only known mechanism of action is a drug binding to its target or if a drug is in early phases development). Potency denotes an important feature of complex biologics: their biological activity produced as a direct result of the molecule’s tertiary/quaternary…

Fundamental Strategies for Viral Clearance Part 2: Technical Approaches

Viral safety is required for biologics manufactured to treat human diseases. Although significant improvements in ensuring viral safety have been made over the past few decades, “zero risk” of viral contamination is a myth. Viral contamination risk can be carefully managed by screening raw materials, testing process intermediates, and evaluating how effectively manufacturing processes remove and inactivate viruses. Viral clearance studies verify virus removal or inactivation by a manufacturing process. Although regulatory agencies have expectations for the designs of those…

Special Report on Product Stability Testing: Developing Methods for New Biologics and Emerging Markets

Stability testing is a vital part of product development and is conducted throughout a product’s life cycle (Figure 1). Stability is part of a biotherapeutic’s quality target product profile, and results help analysts understand how critical quality attributes (CQAs) of both drug substances and products are influenced under specific conditions of temperature, relative humidity (RH), light, storage, pH, and other factors. Manufacturers conduct stability tests to determine degradation pathways and establish shelf lives and storage conditions of their products, for…

Reagent Clearance Capability of Protein A Chromatography: A Platform Strategy for Elimination of Process Reagent Clearance Testing

During the manufacturing of monoclonal antibody (MAb) products, many process reagents are used for cell culture and MAb purification to facilitate and control process performance. Process reagents are considered to be process-related impurities, so demonstration of their clearance is required for the chemistry, manufacturing, and controls (CMC) information submission of an investigational new drug (IND) application (1, 2). These reagents may be classified into two categories: generally recognized as safe (GRAS) reagents and potential safety concern (PSC) reagents (3). GRAS…

Hamster Phospholipase B-Like 2 (PLBL2): A Host-Cell Protein Impurity in Therapeutic Monoclonal Antibodies Derived from Chinese Hamster Ovary Cells

All recombinant protein biotherapeutics must be tested for the presence of residual host-cell protein (HCP) impurities (1–3). The most common analytical method for doing so is a polyclonal sandwich immunoassay. Polyclonal anti-HCP antibodies are selected to recognize the broadest population of HCPs possible. The immunogen and analytical standard are produced from a blank-run fermentation that mimics the production run but lacks the specific biotherapeutic protein. Because of the large number of impurities present in harvested cell-culture fluid (HCCF) that might…

Building a Robust Biological Assay for Potency Measurement

Potency is a critical quality attribute of a biological product and is often determined by a biological assay (also called bioassay or biopotency assay). Specifically, potency is the biological activity or capacity of a product directly linked to its clinical efficacy. Potency tests are performed as part of product release, comparability studies, and stability testing. Nonbiological methods — which measure a product’s molecular or biochemical characteristics (e.g., ligand-binding assay) — have gained interest as replacements for often troublesome bioassays. Even…

Evaluating Freeze–Thaw Processes in Biopharmaceutical Development – Small-Scale Study Designs

Regulations mandate that biopharmaceutical product quality be controlled throughout manufacturing, storage, transportation, and delivery to patients (1). Operations often include freezing and thawing of a bulk drug substance, dilution of that purified substance to a target concentration, filtration, filling into a selected container–closure system, additional processing (e.g., lyophilization), inspection, packaging, storage, transport, and delivery (2). Freezing is a common processing step used to maintain stability and quality of a drug substance during development and production of biopharmaceutical products. It is…

Unwanted Immunogenicity: From Risk Assessment to Risk Management

Although vaccines and immunotherapies are designed to engage the human immune system in fighting disease, unwanted immunogenicity can be a major problem for protein-based therapeutics. Some patients produce antidrug antibodies (ADAs), which might lead to drug inactivation or adverse effects. Even human and humanized proteins have proven to be surprisingly immunogenic in some cases, suggesting that immune tolerance requires careful consideration in biologic product design. In rushing to deliver new drugs to market, some biotherapeutics developers have overlooked factors that…