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Developing a Batch Isolation Procedure and Running It in an Automated Semicontinuous Unit: AWL CFD25 Case Study.

ABSTRACT: A key challenge during the transition from laboratory/small batch to continuous manufacturing is the development of a process strategy that can easily be adopted for a larger batch/continuous process. Industrial practice is to develop the isolation strategy for a new drug/process in batch using the design of experiment (DoE) approach to determine the best isolation conditions and then transfer the isolation parameters selected to a large batch equipment/continuous isolation process. This stage requires a series of extra investigations to evaluate the effect of different equipment geometry or even the adaptation of the parameters selected to a different isolation mechanism (e.g., from dead end to cross flow filtration) with a consequent increase of R&D cost and time along with an increase in material consumption. The CFD25 is an isolation device used in the first instance to develop an isolation strategy in batch (optimization mode) using a screening DoE approach and to then verify the transferability of the strategy to a semicontinuous process (production mode). A d-optimal screening DoE was used to determine the effect of varying the input slurry. Properties such as solid loading, particle size distribution, and crystallization solvent were investigated to determine their impact on the filtration and washing performance and the characteristics of the dry isolated product. A series of crystallization (ethanol, isopropanol, and 3-methylbutan-1-ol) and wash solvents (n-heptane, isopropyl acetate and n-dodcane) were used for the process. To mimic a real isolation process, paracetamol-related impurities, acetanilide and metacetamol, were dissolved in the mother liquor. The selected batch isolation strategy was used for the semicontinuous isolation run. Throughput and filtration parameters, such as cake resistance and flow rate, cake residual liquid content and composition, cake purity, particle-particle aggregation, and extent and strength of agglomerates, were measured to evaluate the consistency of the isolated product produced during a continuous experiment and compared with the isolated product properties obtained during the batch process development. Overall, the CFD25 is a versatile tool which allows both new chemical entity process development in batch and the production of the active pharmaceutical ingredient in semicontinuous mode using the same process parameters without changing equipment. The isolated product properties gained during the semicontinuous run are overall comparable between samples. The residual solvent content and composition differs between some samples due to filter plate blockage. In general, the mean properties obtained during semicontinuous running are comparable with the product properties simulated using the DoE.

SUBMITTER: Ottoboni S

PROVIDER: S-EPMC7171873 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Developing a Batch Isolation Procedure and Running It in an Automated Semicontinuous Unit: AWL CFD25 Case Study.

Ottoboni Sara S Shahid Muhid M Steven Christopher C Coleman Simon S Meehan Elisabeth E Barton Alastair A Firth Paul P Sutherland Richard R Price Chris J CJ

Organic process research & development 20200326 4

A key challenge during the transition from laboratory/small batch to continuous manufacturing is the development of a process strategy that can easily be adopted for a larger batch/continuous process. Industrial practice is to develop the isolation strategy for a new drug/process in batch using the design of experiment (DoE) approach to determine the best isolation conditions and then transfer the isolation parameters selected to a large batch equipment/continuous isolation process. This stage r ...[more]

PMID: 32336906

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Project description:BackgroundRadical antegrade modular pancreatosplenectomy (RAMPS) is an isolation procedure in pancreatosplenectomy for pancreatic body/tail cancer. Connective tissues around the bifurcation of the celiac axis are dissected, followed by median-to-left retroperitoneal dissection. This procedure has the potential to isolate blood and lymphatic flow to the area of the pancreatic body/tail and the spleen to be excised. This is achieved by division of the inflow artery, transection of the pancreas, and then division of the outflow vein in the early phases of surgery. In cases of pancreatic ductal adenocarcinoma (PDAC), the procedure has been shown to decrease intraoperative blood loss and increase R0 resection rate by complete clearance of the lymph nodes. This trial investigates whether the isolation procedure can prolong the survival of patients with pancreatic ductal adenocarcinoma who undergo distal pancreatosplenectomy (DPS) compared with those that undergo the conventional approach.Methods/designPatients with PDAC scheduled to undergo DPS are randomized before surgery to undergo either a conventional procedure (arm A) or to undergo the isolation procedure (arm B). In arm A, the pancreatic body, tail, and spleen are mobilized, followed by removal of the regional lymph nodes. The splenic vein is transected at the end of the procedure. The timing of division of the splenic artery (SA) is not restricted. In arm B, regional lymph nodes are dissected, then we transect the root of the SA, the pancreas, then the splenic vein. At the end of the procedure, the pancreatic body/tail and spleen are mobilized and removed. In total, 100 patients from multiple Japanese high-volume centers will be randomized. The primary endpoint is 2-year recurrence-free survival by intention-to-treat analysis. Secondary endpoints include intraoperative blood loss, R0 resection rate, and overall survival.DiscussionIf this trial shows that the isolation procedures can improve survival with a similar R0 rate and with a similar number of lymph node dissections to the conventional procedure, the isolation procedure is expected to become a standard procedure during DPS for PDAC. Conversely, if there were no significant differences in endpoints between the groups, it would demonstrate justification of either procedure from surgical and oncological points of view.Trial registrationUMIN Clinical Trials Registry UMIN000041381 . Registered on 10 August 2020. ClinicalTrials.gov NCT04600063 . Registered on 22 October 2020.

Project description:ObjectiveTo estimate the cost-effectiveness of running a paediatric oncology unit in Ethiopia to inform the revision of the Ethiopia Essential Health Service Package (EEHSP), which ranks the treatment of childhood cancers at a low and medium priority.MethodsWe built a decision analytical model-a decision tree-to estimate the cost-effectiveness of running a paediatric oncology unit compared with a do-nothing scenario (no paediatric oncology care) from a healthcare provider perspective. We used the recently (2018-2019) conducted costing estimate for running the paediatric oncology unit at Tikur Anbessa Specialized Hospital (TASH) and employed a mixed costing approach (top-down and bottom-up). We used data on health outcomes from other studies in similar settings to estimate the disability-adjusted life years (DALYs) averted of running a paediatric oncology unit compared with a do-nothing scenario over a lifetime horizon. Both costs and effects were discounted (3%) to the present value. The primary outcome was incremental cost in US dollars (USDs) per DALY averted, and we used a willingness-to-pay (WTP) threshold of 50% of the Ethiopian gross domestic product per capita (USD 477 in 2019). Uncertainty was tested using one-way and probabilistic sensitivity analyses.ResultsThe incremental cost and DALYs averted per child treated in the paediatric oncology unit at TASH were USD 876 and 2.4, respectively, compared with no paediatric oncology care. The incremental cost-effectiveness ratio of running a paediatric oncology unit was USD 361 per DALY averted, and it was cost-effective in 90% of 100 000 Monte Carlo iterations at a USD 477 WTP threshold.ConclusionsThe provision of paediatric cancer services using a specialised oncology unit is most likely cost-effective in Ethiopia, at least for easily treatable cancer types in centres with minimal to moderate capability. We recommend reassessing the priority-level decision of childhood cancer treatment in the current EEHSP.

Dataset Information

Developing a Batch Isolation Procedure and Running It in an Automated Semicontinuous Unit: AWL CFD25 Case Study.

Publications

Developing a Batch Isolation Procedure and Running It in an Automated Semicontinuous Unit: AWL CFD25 Case Study.

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