Formulation

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…

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…

The Importance of the Concentration-Temperature-Viscosity Relationship for the Development of Biologics

JIM DELILLO (WWW.FREEIMAGES.COM) Patient preference and a competitive landscape in the parenteral market have fueled the need for convenient delivery systems and a desire for less‑frequent dosing injections. Monoclonal antibodies (MAbs) often have high dose requirements, so they must be formulated at very high concentrations (1). At low concentrations, an antibody solution’s viscosity increases moderately as a function of protein concentration. But at high concentrations (>100 mg/ mL, depending on the molecule), viscosity increases exponentially (2, 3). Thus, a specification…

Sterilization Effects on Elastomer Characteristics and Functionality in Parenteral Delivery Systems

To drive efficiencies in producing parenteral drug products, manufacturers are using containers and closure components that are received sterile and ready to be introduced into filling lines. The effects of sterilization on the properties of ready-to-use (RU) components must be assessed to ensure proper processing techniques and suitability over the components’ intended shelf lives. Sterile-drug manufacturers must determine the best sterilization method for components based on their respective drug products and processes. Critical areas of risk include potential changes related…

Replacing Reverse-Phase Chromatography for Mass Spectrometry: Is Salt-Free Size-Exclusion Chromatography Ready?

Protein mass is often determined using ultraperformance liquid chromatography (UPLC) coupled with electrospray-ionization mass spectrometry (UPLC/ ESI MS or simply LC-MS). A UPLC system equipped with an ultraviolet (UV) detector serves as an assisting vehicle to deliver purified and separated protein molecules to the mass analyzer. Reserved-phase chromatography (RPC) is the most common chemistry chosen to serve this purpose. For sample purification, not only does RP-UPLC use salt-free mobile phases that are amenable to MS, but it also can efficiently…

Highly Concentrated Protein Formulations: Finding Solutions for the Next Generation of Parenteral Biologics

Therapeutic protein formulation is no easy task. Biological drugs may be destined for prefilled syringes or glass vials, or they may be made into lyophilized powders that will be reconstituted in a clinical setting. No matter what their final state will be, recombinant proteins must remain potent and efficacious during storage. In recent years, pharmaceutical companies have turned increasingly to high-concentration protein formulations. Such drug formulations can offer patients the convenience of self-injection — instead of a trip to the…

Innovation in Biopharmaceutical Manufacture

The following is a report from a workshop on innovation in biopharmaceutical manufacturing held at the Annual bioProcessUK Conference in Bristol on 29 November 2012. The aim of the workshop was to access the experience of practitioners in the United Kingdom so as to understand better the challenges and opportunities for innovation in this sector. The workshop addressed the drivers that influence the implementation of process improvements and novel technologies in biopharmaceutical manufacture from the perspective of both manufacturers and…

Accounting for the Donnan Effect in Diafiltration Optimization for High-Concentration UFDF Applications

The biopharmaceutical industry is targeting high-concentration protein formulations to enable subcutaneous administrations. Such administration can provide better patient convenience than intravenous administration. One challenge associated with high-concentration formulations is increased electrostatic interaction between proteins and excipients. That is a result of increased protein-charge density at high protein concentrations. Such interactions can create an offset between excipient levels in final products and diafiltration buffers in ultrafiltration processes. The effect of such electrostatic interactions in a membrane process is known as the…

How to Hit a Moving Target

Although multiple factors can compromise the drug-like properties of biological molecules, we are still at a very early stage in learning how to assess them. This is despite — or perhaps more correctly, because of — the pharmaceutical industry’s accelerating drive to develop biological molecules as therapeutic agents. And I say “we” because this applies not only to the biopharmaceutical industry itself and the analytical instrument companies that serve it, but also those charged with regulating it. We are all…