Upstream Unit Research Articles

Multi-objective robust optimization for multi-stage-multi-product agile closed-loop supply chain under uncertainty in the context of circular economy

Purpose A circular economy (CE) is an economic system that tries to eliminate waste and continually use resources. Due to growing environmental concerns, supply chain (SC) design should be based on the CE considerations. In addition, responding and satisfying customers are the challenges managers constantly encounter. This study aims to improve the design of an agile closed-loop supply chain (CLSC) from the CE point of view. Design/methodology/approach In this research, a new multi-stage, multi-product and multi-period design of a CLSC network under uncertainty is proposed that aligns with the goals of CE and SC participants. Recycling of goods is an important part of the CLSC. Therefore, a multi-objective mixed-integer linear programming model (MILP) is proposed to formulate the problem. Besides, a robust counterpart of multi-objective MILP is offered based on robust optimization to cope with the uncertainty of parameters. Finally, the proposed model is solved using the e-constraint method. Findings The proposed model aims to provide the strategic choice of economic order to the suppliers and third-party logistic companies. The present study, which is carried out using a numerical example and sensitivity analysis, provides a robust model and solution methodology that are effective and applicable in CE-related problems. Practical implications This study shows how all upstream and downstream units of the SC network must work integrated to meet customer needs considering the CE context. Originality/value The main goal of the CE is to optimize resources, reduce the use of raw materials, and revitalize waste by recycling. In this study, a comprehensive model that can consider both SC design and CE necessities is developed that considers all SC participants.

Zinc cyanide removal by precipitation with quaternary ammonium salts

In gold-processing plants, the final tailing containing metal cyanide species is typically treated using various oxidation methods to produce the main source of process water, which is subsequently recycled to the upstream units, such as flotation units. In some gold-processing plants, a considerable amount of metal cyanide species such as zinc cyanide remains in process water, despite the cyanide destruction process. Because residual zinc cyanide complexes can depress gold flotation, the amount of process water must be decreased such that it can be recycled to a flotation circuit. Previous studies report that the critical concentration of zinc cyanide, measured based on the total cyanide concentration during flotation depression, is 0.4 mmol/L. In the present study, the feasibility of using quaternary ammonium salts to precipitate zinc cyanide complexes to less than the critical concentration was studied. The results showed that 92.17% of 60 mg/L of cyanide and 88.86% of 50 mg/L of zinc (molar ratio Zn/CN = 1:3) can be removed using 0.4 g/L of octadecyl trimethyl ammonium bromide at a pH of 10. The concentration of the residual CN cyanide was less than the critical concentration. This indicates that the abovementioned process is effective when nonpolar organic contaminants and moderate amounts of salt (<50 mmol/L) are present. This work revealed that the precipitation process can be used as an advanced treatment method for process water subjected to oxidation treatment.

“Is your SIF trying to do too much?”

AbstractThe number of inputs and outputs to a SIF (safety instrumented function)—including voting—affects the probability of failure on demand (PFD) and the SIL (safety integrity level), assuming the test interval remains the same. The larger the number of inputs and outputs that perform separate functions, the higher the PFD and potentially the lower the SIL. What if the SIF includes all the sensors and final elements that are involved in any trip of a large processing unit like a heater, a reformer, or a distillation column? What if the SIF includes actions to shut down upstream and downstream units? When SIL verification is done for such a SIF, the target PFD and SIL may not be possible to achieve. The temptation may be to add redundancy in sensors and final elements or to reduce the proof test interval in an attempt to reduce the calculated PFD. Frustration may abound as capital and operating costs rise steeply. This paper shows how to use the principles of layer of protection analysis and the information in the process hazard analysis to split up the massive SIF into smaller SIFs that are more manageable. An example is included.

Design Optimization of Centrifugal Microfluidic “Lab-on-a-Disc” Systems towards Fluidic Larger-Scale Integration

Enhancing the degree of functional multiplexing while assuring operational reliability and manufacturability at competitive costs are crucial ingredients for enabling comprehensive sample-to-answer automation, e.g., for use in common, decentralized “Point-of-Care” or “Point-of-Use” scenarios. This paper demonstrates a model-based “digital twin” approach, which efficiently supports the algorithmic design optimization of exemplary centrifugo-pneumatic (CP) dissolvable-film (DF) siphon valves toward larger-scale integration (LSI) of well-established “Lab-on-a-Disc” (LoaD) systems. Obviously, the spatial footprint of the valves and their upstream laboratory unit operations (LUOs) have to fit, at a given radial position prescribed by its occurrence in the assay protocol, into the locally accessible disc space. At the same time, the retention rate of a rotationally actuated CP-DF siphon valve and, most challengingly, its band width related to unavoidable tolerances of experimental input parameters need to slot into a defined interval of the practically allowed frequency envelope. To accomplish particular design goals, a set of parametrized metrics is defined, which are to be met within their practical boundaries while (numerically) minimizing the band width in the frequency domain. While each LSI scenario needs to be addressed individually on the basis of the digital twin, a suite of qualitative design rules and instructive showcases structures are presented.

Development of an unmixed combustion (UMC) based water heating system – Modeling and CFD simulation study for the oxidation cycle

Conventional combustion of fuel is used in steam boilers that operate at high temperatures, are big, and produce environmentally harmful NOx and CO2 mixed flue gases. These limitations can be addressed using an unmixed combustion (UMC) process (a variant of chemical looping combustion (CLC)), an alternative to conventional combustion. In UMC, air and fuel are alternately passed over specific metal/metal oxides that undergo oxidation/reduction reactions and energy released can be used for relevant applications. Recent work has demonstrated that 85–95% of the energy generated in the UMC bed can be radially transferred to air while having sustained combustion (maintaining bed temperatures within 723 K–1173 K). However, when this system was used for heating water, achieving sustained combustion was a challenge. The design was then modified and the operational feasibility of the proposed system to heat water flowing in the laminar range was investigated for the oxidation cycle of UMC by carrying out modeling and simulation studies. A pseudo-homogeneous packed bed reactor model integrated with a non-isothermal pipe water-flow model was developed. It was implemented and simulated using CFD software COMSOL Multiphysics 5.5™. The results showed that for the considered operating conditions, the water (10 bar(g)) gets heated to saturated water temperature continuously with sustained combustion in most sections of the bed (>92%). The effects of four different parameters are also investigated and analyzed. This system thus has the potential to increase the boiler efficiency, if used as an upstream unit to transform water to saturated water.

Manufacturing Challenges and Rational Formulation Development for AAV Viral Vectors.

Adeno-associated virus (AAV) has emerged as a leading platform for gene delivery for treating various diseases due to its excellent safety profile and efficient transduction to various target tissues. However, the large-scale production and long-term storage of viral vectors is not efficient resulting in lower yields, moderate purity, and shorter shelf-life compared to recombinant protein therapeutics. This review provides a comprehensive analysis of upstream, downstream and formulation unit operation challenges encountered during AAV vector manufacturing, and discusses how desired product quality attributes can be maintained throughout product shelf-life by understanding the degradation mechanisms and formulation strategies. The mechanisms of various physical and chemical instabilities that the viral vector may encounter during its production and shelf-life because of various stressed conditions such as thermal, shear, freeze-thaw, and light exposure are highlighted. The role of buffer, pH, excipients, and impurities on the stability of viral vectors is also discussed. As such, the aim of this review is to outline the tools and a potential roadmap for improving the quality of AAV-based drug products by stressing the need for a mechanistic understanding of the involved processes.

Exergy Assessment and Thermo-Economic Analysis of Hybrid Solar Systems with Seasonal Storage and Heat Pump Coupling in the Social Housing Sector in Zaragoza

A real case study of an energy system based on a Solar Assisted Heat Pump (SAHP) fed by hybrid photovoltaic-thermal solar panels (PVT) and seasonal storage (SS) is presented in this paper. Exergy and exergy cost analyses are proposed as complementary methods for the assessment and better understanding of the efficiency of this cogeneration solar configuration. The system performance takes advantage of storage heat in summer, when the solar resource is high in Spain, and is then later consumed during the cold winter (heating season). The building is devoted to social housing, and it is currently under construction. The assessment is based on simulations developed using TRNSYS, a dynamic simulation software for energy systems. Results show that the unit exergy cost of the solar field is around 6. The cost of the seasonal storage is higher, about 13, and its formation is affected both by its own irreversibility and by the irreversibility of the PVT solar field. The cost of the heat delivered by the heat pump is around 15, being affected by all the upstream units and even by the grid. Besides, the analysis points out strategies for improving the system efficiency, such as increasing the size of the storage tank or improving the control strategy of the boiler.

The Potential of Single-Cell Oils Derived From Filamentous Fungi as Alternative Feedstock Sources for Biodiesel Production.

Microbial lipids, also known as single-cell oils (SCOs), are highly attractive feedstocks for biodiesel production due to their fast production rates, minimal labor requirements, independence from seasonal and climatic changes, and ease of scale-up for industrial processing. Among the SCO producers, the less explored filamentous fungi (molds) exhibit desirable features such as a repertoire of hydrolyzing enzymes and a unique pellet morphology that facilitates downstream harvesting. Although several oleaginous filamentous fungi have been identified and explored for SCO production, high production costs and technical difficulties still make the process less attractive compared to conventional lipid sources for biodiesel production. This review aims to highlight the ability of filamentous fungi to hydrolyze various organic wastes for SCO production and explore current strategies to enhance the efficiency and cost-effectiveness of the SCO production and recovery process. The review also highlights the mechanisms and components governing lipogenic pathways, which can inform the rational designs of processing conditions and metabolic engineering efforts for increasing the quality and accumulation of lipids in filamentous fungi. Furthermore, we describe other process integration strategies such as the co-production with hydrogen using advanced fermentation processes as a step toward a biorefinery process. These innovative approaches allow for integrating upstream and downstream processing units, thus resulting in an efficient and cost-effective method of simultaneous SCO production and utilization for biodiesel production.

Using flow simulation to inform the design and placement of remediation units in rivers

ABSTRACT Nitrogen pollution of surface water systems is becoming a global problem, especially within river networks that receive run-off from agricultural land. Methods such as riparian buffering and the construction of artificial wetlands have proven effective when the conversion of land is achievable. An alternate approach is to consider in-stream remediation methods that capture and process incoming river flow. Their design must consider a number of factors, such as effective remediation capacity within the system, and the delivery of water to the treatment region. Computational modelling can be an efficient means for exploring these large design spaces. The results from our models show that unit performance is influenced by flow penetration into the unit, which typically improves with increasing void fraction until through-flow is achieved, after which removal performance decreases, due to decreasing functional surface area. Splitting units into smaller sub-units placed in tandem parallel to the stream-wise flow also results in a performance increase, although only if sufficient spacing is given between the upstream and downstream units to prevent wake interactions, and allow freestream flow to mix into the wake of the upstream unit. Unit efficiency is also observed to improve with increased occlusion of the channel cross section.

Investigating efficiency improvement in sulfur recovery unit using process simulation and numerical modeling

Hydrogen sulfide exists mostly as a detrimental byproduct in the gas processing units as well as refineries, and it must be eliminated from natural gas streams. In a Sulfur Recovery Unit (SRU), hydrogen sulfide is converted into the elemental sulfur during the modified Claus process. Efficiency of sulfur recovery units significantly depends on the reaction furnace temperature. In this work, the effect of oxygen and acid gas enrichment on the reaction furnace temperature and accordingly on sulfur recovery is studied, using both numerical modeling and process simulation. Then, simulation and numerical model are benchmarked against the experimental data of an SRU unit. The validated model provides spotlight on optimizing the upstream sulfur removal unit as well as the oxygen purification process. Two cases of acid gas streams with low and high H2S content, 30% and 50%, are studied to investigate the effect of operating parameters on the overall recovery. Finally, average errors of the models are presented. According to the absolute difference with experimental values, the developed numerical model shows great potential for accurately estimating overall efficiency of the recovery unit.

Real-Time Identification of Irrigation Water Pollution Sources and Pathways with a Wireless Sensor Network and Blockchain Framework.

Real-time identification of irrigation water pollution sources and pathways (PSP) is crucial to ensure both environmental and food safety. This study uses an integrated framework based on the Internet of Things (IoT) and the blockchain technology that incorporates a directed acyclic graph (DAG)-configured wireless sensor network (WSN), and GIS tools for real-time water pollution source tracing. Water quality sensors were installed at monitoring stations in irrigation channel systems within the study area. Irrigation water quality data were delivered to databases via the WSN and IoT technologies. Blockchain and GIS tools were used to trace pollution at mapped irrigation units and to spatially identify upstream polluted units at irrigation intakes. A Water Quality Analysis Simulation Program (WASP) model was then used to simulate water quality by using backward propagation and identify potential pollution sources. We applied a “backward pollution source tracing” (BPST) process to successfully and rapidly identify electrical conductivity (EC) and copper (Cu2+) polluted sources and pathways in upstream irrigation water. With the BPST process, the WASP model effectively simulated EC and Cu2+ concentration data to identify likely EC and Cu2+ pollution sources. The study framework is the first application of blockchain technology for effective real-time water quality monitoring and rapid multiple PSPs identification. The pollution event data associated with the PSP are immutable.

Robust operating room planning considering upstream and downstream units: A new two-stage heuristic algorithm

This paper studies the operating room planning problem at the tactical and operational decision levels considering upstream and downstream units. For this purpose, a multi-objective mathematical programming model is proposed for the construction of master surgical scheduling and the allocation of elective and emergency surgeries. This model encompasses the profits of all stakeholders in the operating theater. A new policy, named complete opening policy, is introduced for the management of operating rooms that has some particular benefits compared to the conventional policy. Then, a scenario-based robust formulation is proposed to consider the uncertainties of surgery duration, length of stay and emergency demands. Because the simpler variants of this problem are known to be NP-complete, a new two-stage heuristic algorithm is developed for solving its large-scale instances. During the first stage, this algorithm generates an initial solution using a greedy constructive algorithm. To improve the initial solution, the algorithm applies eight actions and searches the neighborhoods. In the second stage, the algorithm evaluates whether or not closing an operating room could improve the incumbent solution. A heuristic algorithm, named partial-mixed integer programming, is also adapted as a benchmark algorithm. This algorithm incorporates the CPLEX solver and a very large-scale neighborhood search. Eventually, a hospital in Iran is introduced and evaluated. The computational results demonstrate that the application of the proposed methodology could potentially decrease the waiting cost, the overtime and idleness of operating rooms, and the total deviation from the average beds used in upstream and downstream. The computational results also show that an increase of two beds in the intensive care unit might potentially reduce the waiting cost by 3.6% and the total average of overtime and idleness of operating rooms each day by 20.3%.

Study of a diagnosis method of watershed water problems based on control units-- Taking Ashihe river basin as an example

The water quality often showed obvious spatial and temporal changes characteristics of a river system in the basin. However, the conventional water quality diagnosis method which based on the standard of cross-section, easily overlook the spatial-temporal characteristics of pollution load in the basin. Under the concept of ecological environment spatial management and control, the method for diagnosing water environmental problems which had been named the Equivalent pollution Load Duration Curve method was proposed. Combining the hydrological process of the main stream with the water quality concentration of the section, it could been used to effectively identify the main over standard pollutants and their sources in different control units of the river basin. From the results of the application evaluation of a certain basin, it showed that the excessive period was concentrated in the flood season. The main excessive factor was total phosphorus (TP) in the upstream area of the basin, which indicates that for the upstream control unit of the Basin, agricultural and other non-point sources were the main pollution sources. Meanwhile the main over standard pollutant was NH3-N, which was over standard in the whole period in the river estuary area. The pollution reduction control scheme of this control unit should focus on the industrial and living sources.

Research on the Reliability Allocation Method for a Production System Based on Availability

This paper involves a production system, which is composed of units (workstations) and buffers. The buffer is used to store semifinished and finished products in the production process, to reduce the impacts of bad equipment in the production system on the entire system performance. Considering the characteristics of the large number of components and the state of the buffers in the production system, this paper considers the influences of buffer states on upstream and downstream units. When using the availability as the allocation index and combining it with Markov theory, the production unit (workstation) and upstream and downstream buffers are regarded as an equivalent unit (workstation) with multiple output states. We establish the relationship between the availability of each equivalent unit (workstation) and the production system availability and determine a scaling factor for the availability of the equivalent unit to account for the system availability. The expected availability goal of the production system is allocated to each equivalent unit (workstation) by the scaling factor; then, the availability of each equivalent unit (workstation) is assigned to each unit. Finally, the Plant Simulation software is used to simulate and analyze the production system to verify the correctness of the allocation method and realize the reliability allocation from a complex production system to a unit.

基于选择容量价值的生态补偿标准与自然资源资产价值核算——以珠江水资源供应为例

PDF HTML阅读 XML下载 导出引用 引用提醒 基于选择容量价值的生态补偿标准与自然资源资产价值核算——以珠江水资源供应为例 DOI: 10.5846/stxb201903230549 作者: 作者单位: 作者简介: 通讯作者: 中图分类号: 基金项目: Quantifying the payments for ecosystem services and the value of natural resources based on the indicator of optional capacity value: a case study on water resources supply in Zhujiang River Basin, China Author: Affiliation: Fund Project: 摘要 | 图/表 | 访问统计 | 参考文献 | 相似文献 | 引证文献 | 资源附件 | 文章评论 摘要:选择容量价值是指，一项人类生存生产所必需的生态系统服务，其总量为消费该生态系统服务的消费活动所提供的选择自由度（即选择容量，optional capacity）与该消费活动所产生的经济社会价值的乘积。选择容量价值将经济发展状况和资源环境状况融合了起来，实现了经济社会发展与生态环境保护的价值统一，这对于推进保护与发展相辅相成的生态文明建设具有积极意义。为了探索以选择容量价值为指标的生态补偿标准与自然资源资产价值核算框架和核算方法，以珠江流域水资源供应为例，对跨水文单元的水资源供应流动进行了生态补偿核算，对各水文单元的水资源供应的自然资源资产价值进行了量化评估研究。研究结果显示，珠江三角洲地区的水资源供应的选择容量价值大部分（约74%）来自上游水文单元的跨区输入，而上游水文单元所提供的水资源供应的选择容量价值也在相当程度上依赖于下游水文单元的经济社会发展。基于跨区流动的水资源供应的选择容量价值，可以按照"共享共担"和"同工同酬"原则进行跨区生态补偿核算；基于各水文单元所提供的水资源供应的选择容量价值，可以对各单元内自然资源资产价值进行核定，这对于协调区域发展推进西江-珠江经济带流域生态文明建设具有重要意义。 Abstract:The ecosystem services (ES) optional capacity value (OCV) indicates the optional capacity of supporting the total value produced by human being's economic and social activities (TVPH) provided by the total volume of an ES which is indispensable to human survival. The OCV is described by the product of multiplying the TVPH by the optional capacity. The optional capacity is defined by the freedom of choosing the ES consumption from total ES volume, which is indicated by the average uncertainty of choosing the ES consumption from its total volume. The average uncertainty is described by log base 2, which indicates the uncertainty in a binary decision and is measured in bits. As combining the socio-economic index (i.e. TVPH) and the ES indexes (i.e. total ES volume and ES consumption), the OCV indicates the socio-economic conditions and the ES conditions at the same time. As the OCV describes the complementarity of development and protection, the usage of OCV in ES management will promote the endeavor for ecological civilization. However, how to introduce the OCV into management practice is still unclear. Especially, the method of how to introduce OCV into the frameworks and methods of quantifying the payments for ecosystem services (PES) and the value of natural resources (VNR) is needed to study urgently. To explore the frameworks and methods of quantifying the PES and the VNR based on the indicator of OCV, we analyzed the OCV of water resources supply in Zhujiang River Basin, China. Then, the PES between hydrologic units was discussed based on the OCV of ES spatial subsidies. The value of water resources in each hydrologic unit was quantified using the OCV of water resources supply. The results showed that the OCV of water resources supply of the hydrologic unit was supplied mostly (nearly 74%) by the subsidies from upstream hydrologic units. The value of water resources in each hydrologic unit (except the Zhujiang Delta) was more or less affected by the socio-economic conditions in downstream hydrologic units. We discussed the framework of the PES along with the principles of (1) interests sharing and responsibilities bearing, and (2) equal pay for equal work and based on the OCV of water resources supply of passing-by water. We also discussed the framework of water resources value quantification based on the OCV of water resources supply in our case study. It is obvious that these two frameworks based on the OCV will coordinate the development between hydrologic units and promote the watershed ecological civilization of Zhujiang River Basin. 参考文献 相似文献 引证文献

A robust nonlinear model predictive controller for a post-combustion CO2 capture absorber unit

This study presents the design of a robust nonlinear model predictive controller (NMPC) for the absorber unit of a post-combustion CO2 capture process operating downstream from a coal-fired power plant. The controller employs a dynamic mechanistic model for this process, which allows for a precise treatment of the sources of uncertainty. In the case of the absorber, the model enables explicit consideration of uncertainty in the process operating conditions dictated by upstream units and in physical property parameters associated with phenomenological descriptions of the process. Using the multi-scenario approach, discrete realizations of the uncertain parameters inside a given uncertainty region can be incorporated into the controller to produce control actions that result in a robust operation in closed-loop. The multi-scenario controller was tested under several disturbance rejection scenarios of varying complexity and their performance was assessed against that of single-scenario NMPCs. The benefits of the robust NMPC approach were most evident for longer simulations and, considering the continuous nature of a power plant and its emissions, make the robust NMPC approach suitable for the operation of this process in the presence of uncertainty and disturbances.

Seasonal chemical sucrose losses in upstream and downstream products at a cane sugar factory

Measurement of sucrose losses across a cane sugar factory are notoriously difficult to measure directly or indirectly. Six loss trials were conducted at one factory across a Louisiana processing season; per trial, 40 samples were collected across four upstream and downstream unit processes. Sucrose losses were directly measured with gas chromatography using two equations based on (1) an increase in glucose/sucrose ratios on a RDS basis across a process, or a (2) a decrease in sucrose/RDS. When actual losses were &lt;0.5%, eq. (2) did not detect losses due to the experimental error of the method being greater than the loss. Conversely, when high sucrose losses occurred, i.e., &gt;0.5%, sucrose losses based on eq. (1) were lower than those based on eq. (2), because concomitant acid degradation of glucose occurred. Mean season losses were 2.56% equivalent to 4.89 lbs sucrose lost per short ton of cane and USD1,404,000, with values being much higher than previously reported. Mean losses were 2%, 24.8%, 58.6%, and 14.8% across the MJ tank, clarifier, two pre-evaporators (in series), and from the pre-evaporators to the final evaporator, respectively. 53% of total season losses occurred in early season when the cane quality was worst.

A study of planar toroidal–poloidal beveling of monoblocks on the ITER divertor outer vertical target

The design of the monoblocks constituting the ITER divertor vertical targets comprises a simple toroidal (i.e. toroidally-facing) bevel of 0.5 mm in order to magnetically shadow poloidal (i.e. poloidally-running) leading edges, arising from radial misalignments between toroidally neighbouring blocks, from parallel heat loads between and during edge-localised modes (ELMs). Previous studies suggest that excessive heating of long toroidal edges could also occur, possibly leading to melting during ELMs. Furthermore, despite the toroidal bevel, tiny regions of the poloidal leading edges known as ‘optical hot spots’, accessible along magnetic field lines through toroidal gaps, remain exposed to parallel heat flux from ELMs. The intense heat flux onto those optical hot spots could be large enough to trigger tungsten boiling. A possible solution at the outer vertical target is to implement a planar toroidal–poloidal bevel that would hide all poloidal and toroidal edges and eliminate the optical hot spot. It will be demonstrated that a reasonable ‘shallow’ toroidal–poloidal bevel solution solves all these problems with minimal trade-offs, under the condition that monoblocks on neighbouring plasma-facing units be well aligned poloidally in order to prevent the appearance of exposed leading edges, meaning, in the worst case, a stepwise downward shift of each toroidally upstream plasma-facing unit by −2 ± 2 mm with respect to their downstream neighbours. A more deeply beveled solution has also been studied that is immune to poloidal misalignments, but which comprises important trade-offs in terms of higher heat load to the main wetted surface, and excessive ELM heat loads onto the magnetically shadowed side of the toroidal gaps. Unfortunately, due the inclination of magnetic flux surfaces, the planar toroidal–poloidal beveling solution does not work at the inner vertical target, meaning that its application at the outer target alone leaves the inner toroidal gaps unprotected. This, together with the technologically challenging requirement for a high degree of poloidal alignment of toroidally neighbouring plasma-facing units, has led to a decision not to apply the poloidal–toroidal bevel solution on the ITER vertical targets.

A machine‐learning approach to calibrate generic Raman models for real‐time monitoring of cell culture processes

The manufacture of biotherapeutic proteins consists of complex upstream unit operations requiring multiple raw materials, analytical techniques, and control strategies to produce safe and consistent products for patients. Raman spectroscopy is a ubiquitous multipurpose analytical technique in biopharmaceutical manufacturing for real-time predictions of critical parameters in cell culture processes. The accuracy of Raman spectroscopy relies on chemometric models that need to be carefully calibrated. The existing calibration procedure is nontrivial to implement as it necessitates executing multiple carefully designed experiments for generating relevant calibration sets. Further, existing procedure yields calibration models that are reliable only in operating conditions they were calibrated in. This creates a unique challenge in clinical manufacturing where products have limited production history. In this paper, a novel machine-learning procedure based on just-in-time learning (JITL) is proposed to calibrate Raman models. Unlike traditional techniques, JITL-based generic Raman models can be reliably used for different modalities, cell lines, culture media, and operating conditions. The accuracy of JITL-based generic models is demonstrated on several validation studies involving real-time predictions of critical cell culture performance parameters, such as glucose, glutamate, glutamine, ammonium, lactate, sodium, calcium, viability, and viable cell density. The proposed JITL framework introduces a paradigm shift in the way industrial Raman models are calibrated, which to the best of authors' knowledge have not been done before.

Managing API raw material variability in a continuous manufacturing line - Prediction of process robustness.

Many studies on continuous twin-screw granulation only focus on the granulator without linking this process step to the upstream and downstream unit operations. Product critical quality attributes (CQAs) are however not only determined by the granulation step. In this study, the possibility to manage the batch-to-batch variability of an active pharmaceutical ingredient (API) in a high drug loaded formulation on a continuous line was investigated to obtain consistent tablet CQAs. As the ultimate goal of continuous manufacturing is to produce 24/7, current study also aimed at guaranteeing long term stability of the process. To do so, previously identified API critical material attributes (CMAs) were varied together with granulation, drying and milling critical process parameters (CPPs) in a screening design of experiments to understand the influence of these factors upon product CQAs and process stability. To evaluate the factors affecting the process stability with a reduced amount of materials, process deviations recorded by process sensors were used. While product CQAs only depended on process CPPs, process stability was strongly affected by API CMAs. The effect of API batch-to-batch variability on process stability could nonetheless be managed by applying suitable granulation conditions. Therefore, appropriate ranges of CPPs were defined to ensure both product CQAs and process stability. By studying the fully integrated continuous manufacturing line, it was possible to highlight the interactions between the different unit operations and the API CMAs and to design a robust process.