Development of cell and tissue therapies presents bottlenecks in manufacturing process development and scale-up as commercial and academic groups move from small-scale research and development (R&D) to more complex logistics. Often, the simplicity of maintaining cell yield, viability, and function in a laboratory setting cannot be replicated when source tissue and final therapeutic products are subjected to the extended distances and times of actual clinical delivery. These bottleneck issues have a number of causes. One specific and common…
Analytical
Improving IEX Throughput and Performance with Differentiated Chromatography Sorbents
Optimized upstream processing and high-productivity cell culture increase not only target protein titers, but also impurity and contaminant concentrations to be removed from large volumes of feedstock. Simultaneously, biopharmaceutical drug production is increasingly driven by manufacturing cost reduction. These facts together increase the pressure on downstream processing and create an urgent need for more productive and streamlined chromatography operations. Key parameters to consider for enhanced process economics in chromatography are higher protein binding capacities at high flow rates…
Are Generic HCP Assays Outdated?
Biomanufacturers face a conflict between low-cost generic host cell protein (HCP) assays and highly sensitive but more costly process-specific HCP assays that are usually not initiated until the proof-of-concept stage. But drug developers cannot expect sufficient sensitivity from most commercially available generic assays. For some companies, multiproduct HCP assays could offer a solution to the dilemma. Biopharmaceutical manufacture using genetically modified microorganisms and cell lines is typically associated with contamination by process-related impurities. One of the most important…
Polymers and Additives Used in Fabrication of Disposable Bioprocess Equipment
The materials used to fabricate single-use processing equipment for biopharmaceutical manufacturing are usually polymers, such as plastic or elastomers (rubber), rather than the traditional metal or glass. Polymers offer more versatility because they are light-weight, flexible, and much more durable than their traditional counterparts. Plastic and rubber are also disposable, so issues associated with cleaning and its validation can be avoided. Additives can also be incorporated into polymers to give them clarity rivaling that of glass or to add color…
Isolation of Novel High-Osmolarity Resistant CHO DG44 Cells After Suspension of DNA Mismatch Repair
Recent technological advances in cell line and bioprocess development have driven significant improvements in product titers and enabled scientists to accelerate product development timelines (1). Despite those successes, many limitations in developing cell lines for biotherapeutics remain. One example in fed-batch cultures is an apparent paradox: when cell growth is inhibited by high osmolarity after multiple additions of concentrated nutrients intended to enhance cell growth and protein production. Generation of novel host cells to overcome specific bottlenecks found…
Are “Land Mines†Hiding in Your Supplier Records?
A growing trend in US Food and Drug Administration (FDA) warning letters has been citations for “no justified rationale.†Since 2004, warning letters taking companies to task for poorly documented decision-making and risk-assessment practices has more than doubled — from two in 2004 to four in 2008 and five in 2009. These citations are always in relationship to risk-based decisions: sampling (what, how often, and how much), nonconformances and corrective/preventative actions (when is “root cause†actual root cause,…
How Pore and Fibrous Interstice Structure Influence Filter Performance
A common objective in pharmaceutical processing is the removal of solids from fluid suspensions through filtration. The usual purpose is the removal of the solid particles to a specified extent, within a given time interval, at the largest possible throughput. Attainment of those goals is managed by proper selection of filtration conditions: principally an adequate effective filtration area (EFA) as defined by filter porosity and a proper rate of flow as regulated by applied differential pressure (ΔP) over…
Understanding the Basics of Peptide and Protein Production
With strong growth in biologics, large molecules, and biopharmaceutical therapeutics in recent years, the pharmaceutical and biotech industries are increasingly turning toward peptides and proteins in their search for drug discovery targets. While both offer significant therapeutic potential, there are fundamental differences between the two types of molecule. Definitions: Peptides are short polymers formed from the linking of (usually ≤100) amino acids. They comprise some of the most basic components of human biological processes, including enzymes and hormones. The link…
Is Bovine Albumin Too Complex to Be Just a Commodity?
Albumin is the most abundant serum protein. It serves several functions in vivo: e.g., binding and transport of fatty acids, hormones, and metal ions; maintenance of osmotic pressure and pH; and binding of exogenous toxins and products of lipid oxidation (1). Over time, development of large–scale purification methods have translated those functions into diagnostic, cell culture, and microbiological applications. It is important to note, however, that purification procedures can promote molecular changes and thereby add to the already…
Process Development’s Impact on Cost of Goods Manufactured (COGM)
Manufacturing throughput (the amount of material a plant can produce per year) is affected by process yield and plant run rate. The higher they are, the more a plant can produce per year, requiring fewer lots to meet annual demand. Although a process development team obviously determines the process yield, the team also determines the impact on the run rate of duration and potential implementation complexity of the entire train of unit operations. Thus, an optimized process maximizes…