Pre-Formulation

Investigation of Foreign-Particle Contamination: Practical Application of FT-IR, Raman, and SEM-EDS Technologies

The presence of visible foreign particulate matter is considered a critical defect in parenteral products and one of the main reasons they can be recalled (1). Foreign particles present during any stage of manufacturing are considered to be contaminants and can impose a risk to the control of the manufacturing processes (2). For those reasons, particle contamination arising in any manufacturing step initiates a nonconformance or out-of-specification observation. That requires an investigation to identify root cause so as to mitigate…

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…

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…

Critical Factors for Fill–Finish Manufacturing of Biologics

Over recent decades, protein-based therapeutics have emerged as key drivers of growth in the pharmaceutical industry. Drug development pipelines have filled with biologics, and a handful of monoclonal antibody (MAb) products have become some of the best-selling drugs around the world. Production of biotherapeutics is often challenging because of the inherent instability of these large, complex molecules. Their fragile nature has forced manufacturers to change how bulk drug substances (BDSs) are handled and final drug product is formulated, sterile filtered,…

Validation of Controlled Freezing and Thawing Rates: A 16-L–Bag Study

It is well understood that freeze– thaw processes affect the product quality of biopharmaceuticals (1–3). It has been reported that there is no consistent method of controlled freezing and thawing rates for biological formulations (4). Traditionally, ultralow temperature storage chambers that were not designed for freezing have been used to provide an energy state for the environment surrounding the product with very little excess capacity to change the state of the product. This study details a consistent method for controlled-rate…

Rapid Formulation Development for Monoclonal Antibodies

Monoclonal antibodies (MAbs) are at the focal point of biologics development. Many of the best-selling drugs are therapeutic MAbs or related proteins (1–2). The combined world-wide sales from MAbs will be nearly US$125 billion by 2020 (3). About 50 MAb products treating a range of diseases have been approved in the United States or Europe. With the large number of MAbs progressing through discovery, biomanufacturers need to accelerate process development and move projects rapidly into clinical manufacturing (4–5). Formulation development,…

Outsourcing Stability Testing: Discussions with Contract Laboratories

Stability testing is required for all biopharmaceutical drug products to detect all changes in identity, purity, and potency as a result of a number of environmental and processing factors. Whether testing is conducted in-house or through contact laboratories, it involves the development and performance of comprehensive and specific stability protocols for all stages of a product’s life cycle (1). Testing product stability in-house requires signficant time and resources, and carries challenges associated with commercialization market, time, and capacity. Market: The…

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

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 the manufacture of sterile…

Biophysical Analysis: A Paradigm Shift in the Characterization of Protein-Based Biological Products

Generating a stable environment for a biopharmaceutical drug substance is a critical step for ensuring a long drug-product shelf life (1–6). This process begins early in development with preformulation screening. Some of the most critical parameters to maintaining potency and activity are protein conformation (tertiary or three-dimensional (3-D) structure), folding (secondary structure), and proper subunit association (quaternary structure). Collectively, those are known as higher-order structure (HOS) and can be highly influenced by the formulation environment of a protein drug product.…

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…