Downstream Validation

Preuse, Poststerilization Filter Integrity Testing for Single-Use and Stainless-Steel Installations

According to current European Union good manufacturing practice (EU GMP), integrity testing of sterilizing-grade product filters should be performed preuse poststerilization (PUPSIT) and immediately after use. In addition, PDA’s Technical Report 26 states that preuse integrity tests are preferably performed after filter sterilization. Performing an integrity test of an already sterilized product filter in-line requires wetting the filter while maintaining the downstream side sterile. The test gas must also be evacuted on the downstream side throughout testing maintaining sterility. The…

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UV-Vis Based Determination of Protein Concentration: Validating and Implementing Slope Measurements Using Variable Pathlength Technology

No longer are scientists bound to the time-consuming, error-prone use of dilution factors and fixed-pathlength measurements in determining the concentration of an analyte in solution. Using the slope spectroscopy technique, the Solo VPE system (from C Technologies) offers a new method of determining analyte concentration based on the Beer–Lambert law and slope derived from absorbance measurements made at multiple pathlengths (1). Mathematics: The Beer–Lambert law is expressed as A = αlc, where A is the measured absorbance, α is the…

Ready-to-Use Cryopreserved Primary Cells

Abiological measurement of drug activity is perhaps the most critical step in the series of tests required for product release both for clinical trials and the market. This evaluation plays an important role in the stability assessment of drug candidates. According to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q6B document, measurements of biological activity can be performed in defined animal models that demonstrate a measurable physiological change in response to…

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…

Effects of Pressure Sensor Calibration Offset on Filter Integrity Test Values

Food and Drug Administration (FDA) and European good manufacturing practices (GMPs) require integrity testing of sterilizing-grade filters for producing injectables and other biologics. The diffusion test (also called the forward-flow test) and bubble-point test (also called the disk test) of a sterilizing-grade filter are both filter-integrity tests. The accuracy of both relies on calibration of a pressure sensor in the respective integrity test unit. Calibration of the pressure sensor of a filter-integrity testing device is an essential part of quality…

New Paradigms for Process Validation

    Both the United States and the European Union have recently evolved guidance on how to execute process validation (1, 2) with the prospect of a more appropriate life-cycle approach. It goes beyond the traditional three to five lots run at the center point of proposed ranges for operating parameters. New approaches leverage product design and process development information. They facilitate adapting the quality by design (QbD) paradigm to allow for a science- and risk-based selection of critical process…

A CMO Perspective on Quality Challenges for Biopharmaceuticals

    The global annual revenue for biopharmaceuticals has been growing consistently since 2001, accounting for 15.6% of the total pharmaceutical market in 2011. The global biopharmaceutical market was valued at US$138 billion in 2011 and is expected to surpass $320 billion by 2020 (1). The market for recombinant proteins now exceeds $100 billion, a milestone attained in 2011. Figure 1:  ()   Much of the growth in biopharmaceutical revenue is due to an increasing number and sales of recombinant…

Polysorbates, Immunogenicity, and the Totality of the Evidence

    Protein aggregation underlies many deleterious effects for biotherapeutics. Principal among those are loss of efficacy, induction of unwanted immunogenicity, altered pharmacokinetics, and reduced shelf life. Consequently, aggregation-preventing surfactants are essential components of many protein formulations. They facilitate the development, manufacture, and stability of dosage forms by helping formulators manage protein aggregation and reduce interactions with container and delivery device surfaces. Monoclonal antibodies (MAbs) present difficulties with respect to aggregation because they usually require relatively high doses for therapeutic…

Prior-Knowledge Assessments

    Process characterization (PC) studies are experiments performed primarily at laboratory scale to demonstrate process robustness and provide data necessary for planning, risk mitigation, and successful execution of process validation (1, 2). These typically involve extensive, multifactorial testing designed to determine the effects of operational parameter perturbations and raw materials on process performance and product quality (1, 2). Product-specific information from development studies may be used to help guide PC study design; however, such information may be limited or…

Integrity Testing of Ultrafiltration Systems for Biopharmaceutical Applications

    Ultrafiltration (UF) is a membrane-based separation technology commonly used in the biopharmaceutical industry for concentration or diafiltration of protein solutions to remove low–molecular-weight (LMW) impurities or exchange buffers. The nominal MW limit of UF membranes ranges from 1,000 Da (1 kDa) to 1,000,000 Da (1,000 kDa). A target product is retained by the membrane while lower-MW solutes or impurities pass through (1). For a target product with a smaller MW than the impurities, separation is accomplished by allowing…