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51.
E.K. Read R.B. Shah B.S. Riley J.T. Park K.A. Brorson A.S. Rathore 《Biotechnology and bioengineering》2010,105(2):285-295
Implementing real‐time product quality control meets one or both of the key goals outlined in FDA's PAT guidance: “variability is managed by the process” and “product quality attributes can be accurately and reliably predicted over the design space established for materials used, process parameters, manufacturing, environmental, and other conditions.” The first part of the paper presented an overview of PAT concepts and applications in the areas of upstream and downstream processing. In this second part, we present principles and case studies to illustrate implementation of PAT for drug product manufacturing, rapid microbiology, and chemometrics. We further present our thoughts on how PAT will be applied to biotech processes going forward. The role of PAT as an enabling component of the Quality by Design framework is highlighted. Integration of PAT with the principles stated in the ICH Q8, Q9, and Q10 guidance documents is also discussed. Biotechnol. Bioeng. 2010; 105: 285–295. Published 2009 Wiley Periodicals, Inc. 相似文献
52.
Recovery of therapeutic protein from high cell density yeast fermentations at commercial scale is a challenging task. In this study, we investigate and compare three different harvest approaches, namely centrifugation followed by depth filtration, centrifugation followed by filter-aid enhanced depth filtration, and microfiltration. This is achieved by presenting a case study involving recovery of a therapeutic protein from Pichia pastoris fermentation broth. The focus of this study is on performance of the depth filtration and the microfiltration steps. The experimental data has been fitted to the conventional models for cake filtration to evaluate specific cake resistance and cake compressibility. In the case of microfiltration, the experimental data agrees well with flux predicted by shear induced diffusion model. It is shown that, under optimal conditions, all three options can deliver the desired product recovery ( >80%), harvest time ( <15 h including sequential concentration/diafiltration step), and clarification ( <6 NTU). However, the three options differ in terms of process development time required, capital cost, consumable cost, ease of scale-ability and process robustness. It is recommended that these be kept under consideration when making a final decision on a harvesting approach. 相似文献
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Michael A. Carpenter Ming Li Anurag Rathore Lela Lackey Emily K. Law Allison M. Land Brandon Leonard Shivender M. D. Shandilya Markus-Frederik Bohn Celia A. Schiffer William L. Brown Reuben S. Harris 《The Journal of biological chemistry》2012,287(41):34801-34808
Multiple studies have indicated that the TET oxidases and, more controversially, the activation-induced cytidine deaminase/APOBEC deaminases have the capacity to convert genomic DNA 5-methylcytosine (MeC) into altered nucleobases that provoke excision repair and culminate in the replacement of the original MeC with a normal cytosine (C). We show that human APOBEC3A (A3A) efficiently deaminates both MeC to thymine (T) and normal C to uracil (U) in single-stranded DNA substrates. In comparison, the related enzyme APOBEC3G (A3G) has undetectable MeC to T activity and 10-fold less C to U activity. Upon 100-fold induction of endogenous A3A by interferon, the MeC status of bulk chromosomal DNA is unaltered, whereas both MeC and C nucleobases in transfected plasmid DNA substrates are highly susceptible to editing. Knockdown experiments show that endogenous A3A is the source of both of these cellular DNA deaminase activities. This is the first evidence for nonchromosomal DNA MeC to T editing in human cells. These biochemical and cellular data combine to suggest a model in which the expanded substrate versatility of A3A may be an evolutionary adaptation that occurred to fortify its innate immune function in foreign DNA clearance by myeloid lineage cell types. 相似文献
55.
Shenoy GN Chatterjee P Kaw S Mukherjee S Rathore DK Bal V Rath S George A 《Journal of immunology (Baltimore, Md. : 1950)》2012,189(2):521-528
Successful recall Ab responses require recruitment of quiescent memory B cells to secondary lymphoid organs. However, the cellular dynamics of memory cells responding to local antigenic challenge at lymphoid sites distal from the initial Ag encounter are not well understood. We show in this study that memory B cells generated following s.c. immunization in one footpad generate secondary responses to soluble Ag given i.p. but not to Ag given s.c. in the contralateral footpad unless LPS is coadministered. Memory B cells do not express CD62L, and CD62L(-ve) cells cannot enter lymph nodes unless LPS-mediated inflammation is induced there. Functional TLR4 is required on the B cells, as well as on non-B cells, in the lymph node to achieve full recruitment. Furthermore, splenectomized mice fail to respond to such inflammatory s.c. challenge in contralateral footpads, unlike lymphadenectomized mice lacking the original draining lymph nodes. Splenectomized mice also fail to respond to i.p. challenge with soluble Ag. Together, these data indicate that, unlike the central memory pool of T cells, which circulates through resting lymph nodes, the majority of long-lived memory B cells are spleen resident and require inflammatory signals for mounting recall responses at distal challenge sites. 相似文献
56.
Watanabe S Tan KH Rathore AP Rozen-Gagnon K Shuai W Ruedl C Vasudevan SG 《Journal of virology》2012,86(10):5508-5514
There are conflicting data on the relationship between the level of secreted NS1 (sNS1), viremia, and disease severity upon dengue virus (DENV) infection in the clinical setting, and therefore, we examined this relationship in the widely accepted AG129 mouse model. Because of the failure of a routinely used NS1 detection kit to detect sNS1 of the mouse-adapted DENV2 strain, we screened 15 previously undescribed NS1 monoclonal antibodies and developed a robust capture enzyme-linked immunosorbent assay (ELISA) with detection sensitivity at the low nanogram level (0.2 ng/ml) using recombinant baculovirus-expressed sNS1 as well as sNS1 that was immunoaffinity purified from the various DENV2 strains employed in this study. Using this test, we demonstrated that increased viremia paralleled severe pathologies; however, sNS1 level did not correlate with viremia or severity. Furthermore, among the DENV2 strains that were tested, the level of NS1 secretion did not correspond to virus replication rate in vitro, at the cellular level. Together, our data indicate that the magnitude of NS1 secretion appears to be strain dependent and does not correlate with viral virulence in the AG129 mouse model. 相似文献
57.
A Bohra RK Saxena BN Gnanesh K Saxena M Byregowda A Rathore PB Kavikishor DR Cook RK Varshney 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2012,125(6):1325-1338
Pigeonpea (Cajanus cajan L.) is an important food legume crop of rainfed agriculture. Owing to exposure of the crop to a number of biotic and abiotic stresses, the crop productivity has remained stagnant for almost last five decades at ca. 750?kg/ha. The availability of a cytoplasmic male sterility (CMS) system has facilitated the development and release of hybrids which are expected to enhance the productivity of pigeonpea. Recent advances in genomics and molecular breeding such as marker-assisted selection (MAS) offer the possibility to accelerate hybrid breeding. Molecular markers and genetic maps are pre-requisites for deploying MAS in breeding. However, in the case of pigeonpea, only one inter- and two intra-specific genetic maps are available so far. Here, four new intra-specific genetic maps comprising 59-140 simple sequence repeat (SSR) loci with map lengths ranging from 586.9 to 881.6?cM have been constructed. Using these four genetic maps together with two recently published intra-specific genetic maps, a consensus map was constructed, comprising of 339 SSR loci spanning a distance of 1,059?cM. Furthermore, quantitative trait loci (QTL) analysis for fertility restoration (Rf) conducted in three mapping populations identified four major QTLs explaining phenotypic variances up to 24?%. To the best of our knowledge, this is the first report on construction of a consensus genetic map in pigeonpea and on the identification of QTLs for fertility restoration. The developed consensus genetic map should serve as a reference for developing new genetic maps as well as correlating with the physical map in pigeonpea to be developed in near future. The availability of more informative markers in the bins harbouring QTLs for sterility mosaic disease (SMD) and Rf will facilitate the selection of the most suitable markers for genetic analysis and molecular breeding applications in pigeonpea. 相似文献
58.
A typical biotech process starts with the vial of the cell bank, ends with the final product and has anywhere from 15 to 30 unit operations in series. The total number of process variables (input and output parameters) and other variables (raw materials) can add up to several hundred variables. As the manufacturing process is widely accepted to have significant impact on the quality of the product, the regulatory agencies require an assessment of process comparability across different phases of manufacturing (Phase I vs. Phase II vs. Phase III vs. Commercial) as well as other key activities during product commercialization (process scale-up, technology transfer, and process improvement). However, assessing comparability for a process with such a large number of variables is nontrivial and often companies resort to qualitative comparisons. In this article, we present a quantitative approach for assessing process comparability via use of chemometrics. To our knowledge this is the first time that such an approach has been published for biotech processing. The approach has been applied to an industrial case study involving evaluation of two processes that are being used for commercial manufacturing of a major biosimilar product. It has been demonstrated that the proposed approach is able to successfully identify the unit operations in the two processes that are operating differently. We expect this approach, which can also be applied toward assessing product comparability, to be of great use to both the regulators and the industry which otherwise struggle to assess comparability. 相似文献
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60.
Jitendra Singh Rathore Manoj K. Rai N. S. Shekhawat 《Physiology and Molecular Biology of Plants》2012,18(4):387-392
Factors affecting somatic embryogenesis from immature cotyledon of gum arabic tree [Acacia senegal (L.) Willd.] were investigated. Induction of somatic embryogenesis was influenced by plant growth regulator concentrations and addition of amino acids in medium. Best induction of somatic embryogenesis was obtained on MS medium supplemented with 0.45 μM 2, 4-D, 2.32 μM Kin and 15 mM L-glutamine. L-glutamine plays a significant role in the maturation of somatic embryos and most of embryos attained maturity only on L-glutamine (15 mM) containing medium. Maximum percent (75.0 ± 2.5) germination of somatic embryos was recorded on medium containing 0.22 μM BAP. 相似文献