Selected aromatic amides were used to model the chemical reactivity of aromatic polyamides found in thin-film composite reverse osmosis (RO) membranes. Chlorination and possible amide bond cleavage of aromatic amides upon exposure to aqueous chlorine, which can lead to membrane failure, were investigated. Correlations are made of the available chlorine concentration, pH, and exposure time with chemical changes in the model compounds. From the observed reactivity trends, insights are obtained into the mechanism of RO membrane performance loss upon chlorine exposure. Two chemical pathways for degradation are shown, one at constant pH and another that is pH-history dependent. An alternative strategy is presented for the design of chlorine-resistant RO membranes, and an initial performance study of RO membranes incorporating this strategy is reported.
Increasingly high cell density, high product titer cell cultures containing mammalian cells are being used for the production of recombinant proteins. These high productivity cultures are placing a larger burden on traditional downstream clarification and purification operations due to higher product and impurity levels. Controlled flocculation and precipitation of mammalian cell culture suspensions by acidification or using polymeric flocculants have been employed to enhance clarification throughput and downstream filtration operations. While flocculation is quite effective in agglomerating cell debris and process related impurities such as (host cell) proteins and DNA, the resulting suspension is generally not easily separable solely using conventional depth filtration techniques. As a result, centrifugation is often used for clarification of cells and cell debris before filtration, which can limit process configurations and flexibility due to the investment and fixed nature of a centrifuge. To address this challenge, novel depth filter designs were designed which results in improved primary and secondary direct depth filtration of flocculated high cell density mammalian cell cultures systems feeds, thereby providing single-use clarification solution. A framework is presented here for optimizing the particle size distribution of the mammalian cell culture systems with the pore size distribution of the gradient depth filter using various pre-treatment conditions resulting in increased depth filter media utilization and improved clarification capacity. Feed conditions were optimized either by acidification or by polymer flocculation which resulted in the increased average feed particle-size and improvements in throughput with improved depth filters for several mammalian systems.
Cell cloning and subsequent process development activities are on the critical path directly impacting the timeline for advancement of next generation therapies to patients with unmet medical needs. The use of stable cell pools for early stage material generation and process development activities is an enabling technology to reduce timelines. To successfully use stable pools during development, it is important that bioprocess performance and requisite product quality attributes be comparable to those observed from clonally derived cell lines. To better understand the relationship between pool and clone derived cell lines, we compared data across recent first in human (FIH) programs at Amgen including both mAb and Fc-fusion modalities. We compared expression and phenotypic stability, bioprocess performance, and product quality attributes between material derived from stable pools and clonally derived cells. Overall, our results indicated the feasibility of matching bioprocess performance and product quality attributes between stable pools and subsequently derived clones. These findings support the use of stable pools to accelerate the advancement of novel biologics to the clinic.
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