Downstream Validation

Localized Surface Plasmon Resonance for Bioprocess Development, Monitoring, and Validation

    Academic laboratories have embraced localized surface plasmon resonance (LSPR) as the “new wave” of label-free technology (1). This technique is based on the ability of colloidal metal nanoparticles or nanostructured metallic films to absorb light in a narrow wavelength range. Metal nanostructures “sense” changes occurring at their surfaces by shifting the frequency of the light they absorb or reflect. As a consequence, a basic LSPR system requires only optical fibers, a source of white light, and a detector…

Top 10 Changes in FDA’s Process Validation Guidance

Two years after drafting a comprehensive revision of the 1987 process validation guidance, the FDA finalized the document this year. The revision elaborates on modern quality by design (QbD) techniques for developing a process, analyzing risks, and monitoring for control. The initial draft update remains largely intact, with some important adjustments focused on clarifying the FDA’s intent for how the industry is expected to validate its processes. 1 — Minor Changes: The guidance includes more references to the Code of…

Distinctions Between Analytical and Bioanalytical Test Methods

Analytical methods used for characterization, release, and stability testing of biotechnological/biological products are often automatically referred to as “bioanalytical” methods by some in the field. Many times the term is used to distinguish between test methods applied to small-molecule chemical products and those for macromolecular, biologically based products. It seems sensible enough: We use analytical methods to test chemical pharmaceutical products, so aren’t test methods used for biopharmaceutical products therefore bioanalytical methods? Any way, who cares whether the term is…

Understanding Virus Preparations Using Nanoscale Particle Characterization

As regulators become increasingly stringent in demanding a fuller understanding of whole virus preparations, researchers and manufacturers are looking beyond well-known characterization methodologies. Existing technologies for quantifying and characterizing viral preparations such as infectivity assays, quantitative polymerase chain reaction (qPCR), and protein assays provide crucial information but tell only half the story. We evaluated a unique technology developed by NanoSight Ltd. (www.nanosight.com) for visualizing viruses in liquid suspensions, measuring their approximate concentration, and characterizing their state of aggregation. Information generated…

Microanalytical Techniques for Identifying Nonprotein Contaminants in Biologics

Proteins can aggregate at any point during pharmaceutical manufacturing. Regulatory agencies pay special attention to aggregates that can enhance immune responses and cause adverse clinical effects and those that can compromise the safety and efficacy of a drug product. Biopharmaceutical companies have stringent quality control (QC) procedures in place to ensure that their final products are free of contaminants and defects, including protein aggregates. Trained QC inspectors, however, can typically see product defects or particulate material only as small as…

A Modular Approach to Facility Validation

Biopharmaceutical manufacturers are striving to maintain productivity and profits while controlling increasing costs. Historically, validation has been seen as an expensive, non–value-added necessity to gaining regulatory approval to manufacture. Less often is it seen as a key element of an overall quality management system (QMS) that supports the safety, quality, and efficacy of end products for patients while also providing invaluable knowledge and experience for enhanced process control and management. When fully integrated with a QMS, a modular validation platform…

New Validation Guidance Causes a Stir

In November 2008 the US FDA finally issued a new draft guidance on process validation (1). The original guidance on this topic was published in May 1987, and the FDA explained that “since then, we have obtained additional experience through our regulatory oversight that allows us to update our recommendations to industry on this topic.” The new guidance is intended to reflect some goals of the FDA’s Pharmaceutical GMPs for the 21st Century, an initiative that was finalized in 2004.…

The Reoccurrence of Mycoplasma Contamination: Prevention Strategies

    The contamination of microbiological media by mycoplasmas such as Acholeplasma laidlawii is not a recent phenomenon. It has been a major problem with animal-derived sera since the 1980s and has been a concern in the management of cell cultures for decades. The main culprit of serum contamination was the inadequate blood collection methodology and was eliminated with the introduction of hollow collection needles. In addition to the introduction of an improved collection method, serum was filtered with 0.1…

Robustness of Parvovirus–Retentive Membranes and Implications for Virus Clearance Validation Requirements

    Generic validation is conceivable only through a thorough understanding of the parameters affecting the performance of a process step. In this paper, we provide a detailed example demonstrating the robustness of a virus filtration step. As a first step towards the establishment of a generic validation package for a monoclonal antibody, the robustness of clearance of PP7 across the ViroSart CPV filter was evaluated by changing several critical operational parameters using a simple one-off experimental design. Two different…

Managing the Analytical Life-Cycle for Biotechnology Products

The analytical program for a given biotherapeutic has a life-cycle analogous to that of a manufacturing process used to prepare material for clinical and commercial use. This two-part article discusses analytical activities associated with the progression of biotherapeutic candidates from the early stages of clinical development through their appearance as licensed drugs on the market. In Part One, we examined the stages of the analytical life-cycle. Here we conclude by going into more detail on challenges associated with method qualification,…