Pub Date : 2021-02-03DOI: 10.12665/J20OA.STOLTZFUS
Stephen Stoltzfus, K. Bergmann
T issue-derived products are a class of biological materials harvested directly from animal or human tissue, in contrast to recombinant DNA materials grown in cell culture bioreactors. Tissue-derived products are often used for structural purposes and are typically regulated as medical devices. However, when used to treat human patients, tissuederived products are subject to many of the same concerns as recombinant DNA biotherapeutics, with viral safety being one of them. To address this, the tissue source material must undergo a risk analysis and testing regimen for the presence of viral contaminants. In addition, viral clearance studies must be performed to evaluate whether the purification process is robust enough to remove and/or inactivate viruses that may be present in the starting material. The goals of viral clearance studies are the same for tissuederived products and biotherapeutics, but the design and performance of these studies can be quite different because of the diverse nature of the materials. In this article, we will present an overview of viral clearance studies for tissue-derived products based on our experience in performing a large number of such studies. Rather than discussing the issues related to viral clearance in general, our focus will be on the unique challenges that tissue-derived products pose.
{"title":"Design and performance of viral clearance studies with tissue-derived products","authors":"Stephen Stoltzfus, K. Bergmann","doi":"10.12665/J20OA.STOLTZFUS","DOIUrl":"https://doi.org/10.12665/J20OA.STOLTZFUS","url":null,"abstract":"T issue-derived products are a class of biological materials harvested directly from animal or human tissue, in contrast to recombinant DNA materials grown in cell culture bioreactors. Tissue-derived products are often used for structural purposes and are typically regulated as medical devices. However, when used to treat human patients, tissuederived products are subject to many of the same concerns as recombinant DNA biotherapeutics, with viral safety being one of them. To address this, the tissue source material must undergo a risk analysis and testing regimen for the presence of viral contaminants. In addition, viral clearance studies must be performed to evaluate whether the purification process is robust enough to remove and/or inactivate viruses that may be present in the starting material. The goals of viral clearance studies are the same for tissuederived products and biotherapeutics, but the design and performance of these studies can be quite different because of the diverse nature of the materials. In this article, we will present an overview of viral clearance studies for tissue-derived products based on our experience in performing a large number of such studies. Rather than discussing the issues related to viral clearance in general, our focus will be on the unique challenges that tissue-derived products pose.","PeriodicalId":88836,"journal":{"name":"Bioprocessing","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45701205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Due to its antioxidant properties and favorable safety profile, glutathione (GSH) finds use in protein formulations by improving overall protein stability. Once degraded, primarily by oxidation into glutathione disulfide (GSSG), the protecting effect of GSH is lost. A simple, direct method using reversed-phase separation and charged-aerosol detection (RP-CAD) to quantitate GSH is described in this paper. The analytical methodology is also capable of monitoring several by-product degradants of GSH, both oxidative and non-oxidative. For high-concentration protein formulations, the method provides direct analysis of GSH and its degradants in the presence of protein at up to 225 mg/mL simply through a dilution of the sample. Quantitation of many amino acids typically included in pharmaceutical protein formulations is also possible. Use of an online diverting valve in the method prevents interference in the detector from the high protein concentration in formulation. Accuracy and effectiveness of this method is demonstrated through monitoring the stability of GSH in high-concentration protein formulations through confirmation of GSH concentration and mass-balance of its loss over time. Monitoring GSH stability in protein formulations is necessary, as GSH concentration is indicative of protein stability.
{"title":"A Direct Method to Monitor Glutathione Stability in High Concentration Protein Formulations","authors":"Seth Keever, B. Nakhle, B. Yeung","doi":"10.12665/J20OA.KEEVER","DOIUrl":"https://doi.org/10.12665/J20OA.KEEVER","url":null,"abstract":"Due to its antioxidant properties and favorable safety profile, glutathione (GSH) finds use in protein formulations by improving overall protein stability. Once degraded, primarily by oxidation into glutathione disulfide (GSSG), the protecting effect of GSH is lost. A simple, direct method using reversed-phase separation and charged-aerosol detection (RP-CAD) to quantitate GSH is described in this paper. The analytical methodology is also capable of monitoring several by-product degradants of GSH, both oxidative and non-oxidative. For high-concentration protein formulations, the method provides direct analysis of GSH and its degradants in the presence of protein at up to 225 mg/mL simply through a dilution of the sample. Quantitation of many amino acids typically included in pharmaceutical protein formulations is also possible. Use of an online diverting valve in the method prevents interference in the detector from the high protein concentration in formulation. Accuracy and effectiveness of this method is demonstrated through monitoring the stability of GSH in high-concentration protein formulations through confirmation of GSH concentration and mass-balance of its loss over time. Monitoring GSH stability in protein formulations is necessary, as GSH concentration is indicative of protein stability.","PeriodicalId":88836,"journal":{"name":"Bioprocessing","volume":"20 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47740417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rajib Malla, D. Shah, Chinmay N Gajendragadkar, Vijayalakshmi Vamanan, Deepak Singh, Suraj Gupta, Deepak Vengovan, Ravi Trivedi, H. Weichert, Melisa Carpio, K. Chandran
A perfusion approach at N-1, where cells stay in the exponential growth phase throughout the entire culture duration, is becoming more common as a strategy for process intensification. This is because the higher cell densities it generates allows manufacturers to skip seed stages and reduce process transfer time through multiple bioreactor sizes, thus providing more cost-effective biologics production in smaller facilities. However, this N-1 perfusion approach requires optimization. In this article, we describe the development and proof-of-concept studies with single-use rocking motion perfusion bioreactors in which we have achieved a ten-fold increase in viable cell count in N-1 seed stage, compared to the fed-batch control process, in just 6–8 days. We also mention in detail how we inoculated a 50 L bioreactor production run using this intensified seed train and show comparable growth kinetics and yield with a control process, also at 50 L scale. Using this intensification approach in the future will help our manufacturing facility, the Biopharma Division of Intas Pharmaceuticals Ltd., reach 4000 L production-scale volumes with fewer process transfer steps, and without changing the feeding strategy or production bioreactors of our biologics’ portfolio.
{"title":"Seed train process intensification strategy offers potential for rapid, cost-effective scale-up of biosimilars manufacturing","authors":"Rajib Malla, D. Shah, Chinmay N Gajendragadkar, Vijayalakshmi Vamanan, Deepak Singh, Suraj Gupta, Deepak Vengovan, Ravi Trivedi, H. Weichert, Melisa Carpio, K. Chandran","doi":"10.12665/j20oa.malla","DOIUrl":"https://doi.org/10.12665/j20oa.malla","url":null,"abstract":"A perfusion approach at N-1, where cells stay in the exponential growth phase throughout the entire culture duration, is becoming more common as a strategy for process intensification. This is because the higher cell densities it generates allows manufacturers to skip seed stages and reduce process transfer time through multiple bioreactor sizes, thus providing more cost-effective biologics production in smaller facilities. However, this N-1 perfusion approach requires optimization. In this article, we describe the development and proof-of-concept studies with single-use rocking motion perfusion bioreactors in which we have achieved a ten-fold increase in viable cell count in N-1 seed stage, compared to the fed-batch control process, in just 6–8 days. We also mention in detail how we inoculated a 50 L bioreactor production run using this intensified seed train and show comparable growth kinetics and yield with a control process, also at 50 L scale. Using this intensification approach in the future will help our manufacturing facility, the Biopharma Division of Intas Pharmaceuticals Ltd., reach 4000 L production-scale volumes with fewer process transfer steps, and without changing the feeding strategy or production bioreactors of our biologics’ portfolio.","PeriodicalId":88836,"journal":{"name":"Bioprocessing","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"66229877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Defining Therapeutic Window for Viral Vectors: A Statistical Framework to Improve Consistency in Assigning Product Dose Values","authors":"N. Sajjadi, J. Callahan","doi":"10.12665/j19oa.sajjadi","DOIUrl":"https://doi.org/10.12665/j19oa.sajjadi","url":null,"abstract":"","PeriodicalId":88836,"journal":{"name":"Bioprocessing","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47993152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Alvin G Thomas, Jessica M Ruck, Nadia M Chu, Dayawa Agoons, Ashton A Shaffer, Christine E Haugen, Bonnielin Swenor, Silas P Norman, Jacqueline Garonzik-Wang, Dorry L Segev, Mara McAdams-DeMarco
Background: Disability in general has been associated with poor outcomes in kidney transplant (KT) recipients. However, disability can be derived from various components, specifically visual, hearing, physical and walking impairments. Different impairments may compromise the patient through different mechanisms and might impact different aspects of KT outcomes.
Methods: In our prospective cohort study (June 2013-June 2017), 465 recipients reported hearing, visual, physical and walking impairments before KT. We used hybrid registry-augmented Cox regression, adjusting for confounders using the US KT population (Scientific Registry of Transplant Recipients, N = 66 891), to assess the independent association between impairments and post-KT outcomes [death-censored graft failure (DCGF) and mortality].
Results: In our cohort of 465 recipients, 31.6% reported one or more impairments (hearing 9.3%, visual 16.6%, physical 9.1%, walking 12.1%). Visual impairment was associated with a 3.36-fold [95% confidence interval (CI) 1.17-9.65] higher DCGF risk, however, hearing [2.77 (95% CI 0.78-9.82)], physical [0.67 (95% CI 0.08-3.35)] and walking [0.50 (95% CI 0.06-3.89)] impairments were not. Walking impairment was associated with a 3.13-fold (95% CI 1.32-7.48) higher mortality risk, however, visual [1.20 (95% CI 0.48-2.98)], hearing [1.01 (95% CI 0.29-3.47)] and physical [1.16 (95% CI 0.34-3.94)] impairments were not.
Conclusions: Impairments are common among KT recipients, yet only visual impairment and walking impairment are associated with adverse post-KT outcomes. Referring nephrologists and KT centers should identify recipients with visual and walking impairments who might benefit from targeted interventions pre-KT, additional supportive care and close post-KT monitoring.
背景：一般来说，残疾与肾移植（KT）受者的不良预后有关。然而，残疾可由多种因素造成，特别是视力、听力、肢体和行走障碍。不同的损伤可能通过不同的机制对患者造成损害，并可能对肾移植预后的不同方面产生影响：在我们的前瞻性队列研究（2013 年 6 月至 2017 年 6 月）中，465 名受助者在接受 KT 前报告了听力、视力、肢体和行走障碍。我们使用混合登记增强型 Cox 回归，利用美国 KT 群体（移植受者科学登记处，N = 66 891）调整混杂因素，以评估损伤与 KT 后结果[死亡剪除移植物失败（DCGF）和死亡率]之间的独立关联：在我们的 465 名受者队列中，31.6% 的人报告有一种或多种障碍（听力 9.3%、视力 16.6%、肢体 9.1%、行走 12.1%）。视力障碍与 DCGF 风险增加 3.36 倍[95% 置信区间（CI）1.17-9.65]有关，但听力[2.77（95% CI 0.78-9.82）]、肢体[0.67（95% CI 0.08-3.35）]和行走[0.50（95% CI 0.06-3.89）]障碍与 DCGF 风险无关。行走障碍与死亡率风险增加 3.13 倍（95% CI 1.32-7.48）有关，但视觉[1.20（95% CI 0.48-2.98）]、听觉[1.01（95% CI 0.29-3.47）]和肢体[1.16（95% CI 0.34-3.94）]障碍与死亡率风险无关：障碍在 KT 受者中很常见，但只有视力障碍和行走障碍与 KT 后的不良预后有关。转诊的肾科医生和 KT 中心应识别有视力和行走障碍的受者，他们可能会受益于 KT 前的针对性干预、额外的支持性护理和 KT 后的密切监测。
{"title":"Kidney transplant outcomes in recipients with visual, hearing, physical and walking impairments: a prospective cohort study.","authors":"Alvin G Thomas, Jessica M Ruck, Nadia M Chu, Dayawa Agoons, Ashton A Shaffer, Christine E Haugen, Bonnielin Swenor, Silas P Norman, Jacqueline Garonzik-Wang, Dorry L Segev, Mara McAdams-DeMarco","doi":"10.1093/ndt/gfz164","DOIUrl":"10.1093/ndt/gfz164","url":null,"abstract":"<p><strong>Background: </strong>Disability in general has been associated with poor outcomes in kidney transplant (KT) recipients. However, disability can be derived from various components, specifically visual, hearing, physical and walking impairments. Different impairments may compromise the patient through different mechanisms and might impact different aspects of KT outcomes.</p><p><strong>Methods: </strong>In our prospective cohort study (June 2013-June 2017), 465 recipients reported hearing, visual, physical and walking impairments before KT. We used hybrid registry-augmented Cox regression, adjusting for confounders using the US KT population (Scientific Registry of Transplant Recipients, N = 66 891), to assess the independent association between impairments and post-KT outcomes [death-censored graft failure (DCGF) and mortality].</p><p><strong>Results: </strong>In our cohort of 465 recipients, 31.6% reported one or more impairments (hearing 9.3%, visual 16.6%, physical 9.1%, walking 12.1%). Visual impairment was associated with a 3.36-fold [95% confidence interval (CI) 1.17-9.65] higher DCGF risk, however, hearing [2.77 (95% CI 0.78-9.82)], physical [0.67 (95% CI 0.08-3.35)] and walking [0.50 (95% CI 0.06-3.89)] impairments were not. Walking impairment was associated with a 3.13-fold (95% CI 1.32-7.48) higher mortality risk, however, visual [1.20 (95% CI 0.48-2.98)], hearing [1.01 (95% CI 0.29-3.47)] and physical [1.16 (95% CI 0.34-3.94)] impairments were not.</p><p><strong>Conclusions: </strong>Impairments are common among KT recipients, yet only visual impairment and walking impairment are associated with adverse post-KT outcomes. Referring nephrologists and KT centers should identify recipients with visual and walking impairments who might benefit from targeted interventions pre-KT, additional supportive care and close post-KT monitoring.</p>","PeriodicalId":88836,"journal":{"name":"Bioprocessing","volume":"2 1","pages":"1262-1270"},"PeriodicalIF":6.1,"publicationDate":"2020-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/ndt/gfz164","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88320515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
H. Anderle, A. Weber, Lucia Gnauer, Theresa Friederike Bauer, D. Horn, Matthias Spork
{"title":"Alcohol Determination in Protein Fractionation Intermediates by Steam Distillation and Digital Refractometry","authors":"H. Anderle, A. Weber, Lucia Gnauer, Theresa Friederike Bauer, D. Horn, Matthias Spork","doi":"10.12665/j19oa.anderle","DOIUrl":"https://doi.org/10.12665/j19oa.anderle","url":null,"abstract":"","PeriodicalId":88836,"journal":{"name":"Bioprocessing","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45543656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Porcine Serum, Trypsin, and Other Porcine-Derived Products: Swine Viruses of Importation and Adventitious Concern","authors":"P. Hawkes, Hawkes Consulting Llc","doi":"10.12665/j19oa.hawkes","DOIUrl":"https://doi.org/10.12665/j19oa.hawkes","url":null,"abstract":"","PeriodicalId":88836,"journal":{"name":"Bioprocessing","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"42072197","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kathryn Elliott, Glenn A Harris, S. Harcum, Kenion H. Blakeman, Colin Gavin, Ji Young Anderson
W hen working on biotherapeutic process development, the analysis of spent cell culture media is often a daily practice during the optimization of bioreactor conditions and media composition. The introduction of parallel microbioreactor systems has decreased the complexity and costs of process development by allowing for concurrent studies of multiple bioreactor and media variables. However, the bioreactors’ small volumes (typically less than 250 mL) limit the volume of media one can extract for daily sampling. We describe a means to analyze spent media with an integrated microchip capillary electrophoresis mass spectrometer (CE-MS) analyzer with minimal sample volume requirements and rapid analysis time. The platform was evaluated with a parallel microbioreactor system (ambr® 250) culturing a Chinese hamster ovary (CHO) cell line stressed by varying levels of ammonia (NH3). The spent media analysis identified net increases in the levels of the amino acids (AA) Ala, Arg, Asp, Glu, Gly, His, Ile, Leu, Lys, Phe, Thr, Trp, Tyr, and Val in all bioreactors, with Gly levels showing increases in excess of 8-fold initial levels in all bioreactors. Other media components either steadily decreased in concentration or were completely depleted by the end of culture. For example, Asn was depleted in all of the unstressed and 10 mM NH3-stressed bioreactors, but was approximately twice as high as the initial levels in the 30 mM NH3-stressed bioreactors at the end of the culture periods. Also, the 30 mM NH3-stressed condition may have caused either complete degradation or rapid consumption of choline, since it was no longer present starting at the t = 36 h sampling. Overall, the monitored media components were observed to have independent trajectories based on feeding and consumption by the cells, and depending on the stressed condition. The capability to have more frequent spent media analyses would allow for real-time observation of these process changes and associated control strategies. Spent Media Analysis with an Integrated CE-MS Analyzer of Chinese Hamster Ovary Cells Grown in an Ammonia-Stressed Parallel Microbioreactor Platform
{"title":"Spent Media Analysis with an Integrated CE-MS Analyzer of Chinese Hamster Ovary Cells Grown in an Ammonia-Stressed Parallel Microbioreactor Platform","authors":"Kathryn Elliott, Glenn A Harris, S. Harcum, Kenion H. Blakeman, Colin Gavin, Ji Young Anderson","doi":"10.12665/j19oa.elliott","DOIUrl":"https://doi.org/10.12665/j19oa.elliott","url":null,"abstract":"W hen working on biotherapeutic process development, the analysis of spent cell culture media is often a daily practice during the optimization of bioreactor conditions and media composition. The introduction of parallel microbioreactor systems has decreased the complexity and costs of process development by allowing for concurrent studies of multiple bioreactor and media variables. However, the bioreactors’ small volumes (typically less than 250 mL) limit the volume of media one can extract for daily sampling. We describe a means to analyze spent media with an integrated microchip capillary electrophoresis mass spectrometer (CE-MS) analyzer with minimal sample volume requirements and rapid analysis time. The platform was evaluated with a parallel microbioreactor system (ambr® 250) culturing a Chinese hamster ovary (CHO) cell line stressed by varying levels of ammonia (NH3). The spent media analysis identified net increases in the levels of the amino acids (AA) Ala, Arg, Asp, Glu, Gly, His, Ile, Leu, Lys, Phe, Thr, Trp, Tyr, and Val in all bioreactors, with Gly levels showing increases in excess of 8-fold initial levels in all bioreactors. Other media components either steadily decreased in concentration or were completely depleted by the end of culture. For example, Asn was depleted in all of the unstressed and 10 mM NH3-stressed bioreactors, but was approximately twice as high as the initial levels in the 30 mM NH3-stressed bioreactors at the end of the culture periods. Also, the 30 mM NH3-stressed condition may have caused either complete degradation or rapid consumption of choline, since it was no longer present starting at the t = 36 h sampling. Overall, the monitored media components were observed to have independent trajectories based on feeding and consumption by the cells, and depending on the stressed condition. The capability to have more frequent spent media analyses would allow for real-time observation of these process changes and associated control strategies. Spent Media Analysis with an Integrated CE-MS Analyzer of Chinese Hamster Ovary Cells Grown in an Ammonia-Stressed Parallel Microbioreactor Platform","PeriodicalId":88836,"journal":{"name":"Bioprocessing","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45908029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
B. Zoro, Sartorius Stedim Biotech, Kevin J. McHugh
{"title":"Scale-Down Models to Support Process Characterization","authors":"B. Zoro, Sartorius Stedim Biotech, Kevin J. McHugh","doi":"10.12665/j19oa.zoro","DOIUrl":"https://doi.org/10.12665/j19oa.zoro","url":null,"abstract":"","PeriodicalId":88836,"journal":{"name":"Bioprocessing","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45928304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Estimating the Uncertainty of Structured Pharmaceutical Development and Manufacturing Process Execution Risks Using a Prospective Causal Risk Model (PCRM)","authors":"Mark Witcher","doi":"10.12665/j18oa.witcher","DOIUrl":"https://doi.org/10.12665/j18oa.witcher","url":null,"abstract":"","PeriodicalId":88836,"journal":{"name":"Bioprocessing","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43174196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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