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In this anniversary year, I find myself thinking back on things I once was told would never happen in — or never apply to — biopharmaceutical manufacturing. Initially peripheral (seemingly) topics ease into relevance and, by surprising us, emphasize the importance of keeping our eyes on the big picture(s). When I was an editorial assistant in the late 1980s, I was told simply to toss press releases related to, for example, anything having to do with centrifuges — on the theory that biomolecules were just too fragile for that sort of action. We now have, use, and value centrifuges after knowledge and instrument designs evolved to address specific needs of large molecules. I was also advised that benchtop bioreactors and laboratory analytical methods were “too small-scale” for commercially minded readers, and anything dealing with the properties of flexible plastic tubing was supposedly too broad in applicability. “Focus on stainless steel,” was the mantra. In the 1990s, I argued with my first assoc...
A common reaction to some patents directed to manufacturing processes (especially of biotherapeutics) is “How did they get a patent for that when we’ve been doing the same thing for years?” But the number of patents covering biotherapeutic production processes is steadily increasing along with the realization that upstream and downstream processing events provide a potentially abundant source of so-called “second-generation” patent protection for biologics, especially those facing biosimilar competition. Although some groups are prolific patent filers claiming a wide range of processes — from methods of culturing cells with a particular chemically defined media to methods for regenerating chromatography matrices — others choose to keep their manufacturing products and processes secret. Until recent US patent reforms introduced by the Leahy–Smith America Invents Act (AIA) became law, many organizations keeping their processes secret ran the risk of being sued for patent infringement, even if they’d been us...
Imagine a diagnostic test that sifts through millions of molecules in one drop of a patient’s blood to detect the tell-tale protein signature of a cancer subtype. Envision a drug “ferry” that doesn’t release its cytotoxic contents until it slips inside cancer cells — or a molecule or small panel of proteins that can reveal within days whether a cancer treatment is working. Bioprocess Applications of Nanoparticles () Researchers have created nanosized particles and devices that are as small as enzymes — about 100–10,000 times smaller than a human cell. Because of their tiny size, nanotherapeutics can travel far and wide in a patient’s body as well as slip inside cells, delivering treatment or detecting disease in ways unimagined before now. The small size of nanodevices — such as mechanical, chemical, or electronic sensors — coupled with sophisticated microscopic plumbing networks allows researchers to analyze a host of molecular and physical traits from individual cells. A complex network of nanosized wir...
Two major challenges associated with optimizing biomanufacturing operations remain unresolved. The first is variability: how to understand and improve manufacturing with significant variation in process times throughout all unit operations. The second is complexity: modern biomanufacturing facilities are complex and interconnected, with piping segments, transfer panels, and valve arrays, as well as water for injection (WFI) and other shared resource constraints. That complexity is becoming even greater with the need for process standardization and processing of higher (and more variable) titers and additional products. In such an environment, “debottlenecking” is becoming increasingly important as a means of quantitative process optimization. This technique allows biomanufacturing facilities to run new products with minimal retrofits and also increase the run rate of existing legacy products without significant regulatory impact. Debottlenecking therefore allows a biomanufacturing facility to significantl...
Clarifying cell culture broth is the first downstream unit operation in an elaborate sequence of steps required to purify a biological therapeutic. A combination of centrifugation, depth filtration, or tangential-flow filtration (TFF) is used for that operation. The availability of largescale, single-use, depth filtration technology in the recent years, however, has given process developers the capability to improve and simplify downstream processes. Clarification of Cell Culture Streams The main purpose of clarification is to efficiently separate cells, cell debris, and other colloidal matter and deliver a particle-free feed to downstream processes such as protein A capture chromatography. Various commercial technologies are available for this purpose. Figure 1 presents schematics of centrifugation, flocculation, TFF, and depth filtration combinations that are used in bioprocessing. Figure 1: () When only depth filtration (also referred to as depth microfiltration or prefiltration ) is used at this ...
Integrity testing of sterilizing-grade filters is necessary to reliably prevent damage to these sterile barriers from compromising the production of biopharmaceuticals. Documented integrity test results are essential to a manufacturing audit trail for releasing pharmaceutical products ( 1 , 2 ). Accordingly, problems encountered during this testing can lead to considerable financial damages and substantial delays or even entirely prevent a production lot from being released to the market. Therefore, filter integrity testing is a critical step with high economic importance for biopharmaceutical companies. Daily operations show time and again, however, that unnecessary problems can occur during and after integrity testing due to use errors and failure to comply with necessary basic conditions of the process. Essentially avoidable errors in data recording also can occur. Here I describe some measures that can significantly increase the reliability of filter integrity testing. PRODUCT FOCUS: ALL BIOLOGICS P...
Mycoplasma are infamous for contaminating cell culture lines at rates as high as 80% ( 1 , 2 , 3 , 4 , 5 ). For biopharmaceutical processes, the inadvertent use of contaminated culture medium or medium components can lead to contamination of an aseptic process-validation media fill or cell culture medium for a bioreactor ( 6 , 7 , 8 , 9 , 10 , 11 ). Thoroughly testing medium components before use is generally impractical because of the large volume of material in use. Frequently, culture media cannot be autoclaved (because of the presence of heat-sensitive components or large volumes), so sterilization by filtration is a practical alternative. Removal of mycoplasma with high assurance requires 0.1-µm rated filters. Currently, there is no standard method (no standard testing conditions) for rating such filters at 0.1 µm, and routine manufacturing tests are not always performed at elevated pressures. That has led to concerns regarding filter performance at elevated pressures. PRODUCT FOCUS: ALL BIOLOGICALS
Affinity Chromatography Product: CaptureSelect affinity ligands Applications: Antibody-based separations Features: BAC BV has teamed up with both Life Technologies and GE Healthcare to supply them with CaptureSelect antibodies for use as chromatography ligands. Life Technologies has launched a 0.1- to 7.9-mL range of POROS columns for analytical chromatography for IgG, IgM, human serum albumin fusion proteins, and antibody fragments containing κ or λ light chains. GE Healthcare has added LambdaFabSelect for GMP purification of antibodies and fragments that contain λ light chains. Contac t BAC BV www.bacbv.com , GE Healthcare www.gehealthcare.com , and Life Technologies www.lifetechnologies.com/poros/captureselect Electronic Meters Product: SevenCompact meters Applications: Benchtop monitoring of charge-based parameters Features: Mettler-Toledo’s SevenCompact line of benchtop meters for measuring pH, ion concentration, oxidation reduction potential (ORP), or conductivity includes two new univers...
This conference offers solutions toward better industry cooperation in standards harmonization and downstream processing. New applications for disposables in fill–finish and bulk storage will be covered through a series of case studies, panel discussions, point–counterpoint debates, and breakout-discussion roundtables. Program Highlights Keynotes Attend the colocated summit below at no extra charge. Find out more online at www.IBCLifeSciences.com/singleuse .
With increasing large-scale “-omic” and clinical studies, the value and need for large and small biobanks or biorepositories has grown exponentially. Many organizations are processing and storing hundreds, thousands, even millions of biosamples. Those samples are collected from a number of sources, however, and put to end uses that are not always anticipated at collection. Consistent standards thus must be established to collect and store samples. Everyone involved must work toward a common goal of high-quality, consistent, reliable, and traceable sample storage. Standardization in biobanking best practices has produced minimum guidelines for ensuring biospecimen reliability. Biobanks must be versatile and consistent. For example, samples need to be processed and stored appropriately for use in later assays. Each specific biomaterial (and sample use) requires a defined storage environment (from room temperature down to –150 °C) and processing techniques. Thus, biobanking can be divided into three main are...