Risk-Adjusted Control Charts: Theory,Methods, and Applications in Health

Control charts, the most popular tool of statistical process control, appeared in the literature to ensure that an industrial process is operating only with natural variability, i.e., under statistical control. In the last decades, control charts have been also widely used to assess the quality of non-industrial processes, such as medicine and public health. Mainly in the last two decades, a modification of standard and advanced control charts appeared in the bibliography to improve the monitoring mainly of medical processes. This is the risk-adjusted control charts which take into consideration the varying health conditions of the patients. These charts are used to monitor certain medical processes such as surgeries, mortality, and doctors’ experience. In this paper, we have tried to present all the risk-adjusted control charts presented in the literature appropriately categorized. The risk-adjusted charts have been grouped into three categories: control charts for continuous variables, control charts for attributes (non-continuous variables), time-weighted control charts. The application of risk-adjusted control charts in practical medical processes is also discussed. This review paper highlights the value of the risk-adjusted control charts.

     

ANOVA Method for Variance Component Decomposition and Diagnosis in Batch Manufacturing Processes

In batch manufacturing processes, the total process variation is generally decomposed into batch-by-batch variation and within-batch variation. Since different variation components may be caused by different sources, separation, testing, and estimation of each variance component are essential to the process improvement. Most of the previous SPC research emphasized reducing variations due to assignable causes by implementing control charts for process monitoring. Different from this focus, this article aims to analyze and reduce inherent natural process variations by applying the ANOVA method. The key issue of using the ANOVA method is how to develop appropriate statistical models for all variation components of interest. The article provides a generic framework for decomposition of three typical variation components in batch manufacturing processes. For the purpose of variation root causes diagnosis, the corresponding linear contrasts are defined to represent the possible site variation patterns and the statistical nested effect models are developed accordingly. The article shows that the use of a full factor decomposition model can expedite the determination of the number of nested effect models and the model structure. Finally, an example is given for the variation reduction in the screening conductive gridline printing process for solar battery fabrication.     

Design-to-Manufacturing Information Management for Electronics Assembly

This paper addresses design to manufacturing (DTM) for electronics assembly from several different perspectives. First, a working definition for DTM is proposed, and the distinction is made between DTM and the more commonly known design for manufacturability. Following an overview of surface mount technology assembly processes, DTM information management is introduced in terms of its data requirements and underlying decision and planning problems. Evaluation criteria are discussed, and specific requirements for a state-of-the-art DTM system are highlighted. The experiences of one Motorola factory are presented in a brief case study, which covers process mapping, system design and benchmarking, and installation and configuration activities. Benefits of an efficient DTM sytem are discussed in terms of the improvements in production time, engineering time, and product or process quality. Finally, a summary of future trends for DTM is given.     

Control charts for improved decisions in environmental management: a case study of catchment water supply in south‐west Western Australia

Environmental monitoring is becoming increasingly sophisticated with the widespread adoption of data loggers, sensor arrays and remote sensing, leading to larger scale, higher resolution and superior quality data. However, interpreting monitoring data and deciding when and how to apply environmental management remains a subjective and underdeveloped area of research. Control charts, developed in industrial settings to identify when manufacturing processes were beyond the acceptable bounds of production quality, represent one solution. Despite their potential utility, control charts have rarely been adopted in environmental monitoring. In theory, they are able to identify undesirable trends early and provide transparent and broadly consensual criteria for defining when management action should take place, that is action is triggered when parameter values are observed beyond the agreed control limits of the process. Once triggered, a predetermined management action is implemented. Possible actions are many and varied, and range from investigation and increased monitoring to intervention in the system. Here, the utility of control charts in monitoring water supply in south‐western Australia from 1911 to 2010 is examined, and their ability to provide an early, transparent and easily understandable means of triggering management action is assessed. Two control chart types are applied: the X‐bar chart and the CUSUM chart. X‐bar charts varied widely in their ability to trigger action and were insensitive to many traditional threshold criteria (of which there are many to choose from). In contrast, standard CUSUM charts are specifically designed to detect subtler shifts away from a mean trend and hence provided a more consistent warning of the decline in water supply. While managers were aware of the decline in water supply from an early stage, we believe that control charts could have clearly communicated this earlier, enabling consensus among decision makers to be reached more rapidly.     

Advances in Lentivirus Purification

Lentiviral vectors (LVs) have been increasingly used as a tool for gene and cell therapies since they can stably integrate the genome in dividing and nondividing cells. LV production and purification processes have evolved substantially over the last decades. However, the increasing demands for higher quantities with more restrictive purity requirements are stimulating the development of novel materials and strategies to supply the market with LV in a cost-effective manner. A detailed review of each downstream process unit operation is performed, limitations, strengths, and potential outcomes being covered. Currently, the majority of large-scale LV manufacturing processes are still based on adherent cell culture, although it is known that the industry is migrating fast to suspension cultures. Regarding the purification strategy, it consists of batch chromatography and membrane technology. Nevertheless, new solutions are being created to improve the current production schemes and expand its clinical use.     

Advances in bioreactor control for production of biotherapeutic products

Advanced control strategies are well established in chemical, pharmaceutical, and food processing industries. Over the past decade, the application of these strategies is being explored for control of bioreactors for manufacturing of biotherapeutics. Most of the industrial bioreactor control strategies apply classical control techniques, with the control system designed for the facility at hand. However, with the recent progress in sensors, machinery, and industrial internet of things, and advancements in deeper understanding of the biological processes, coupled with the requirement of flexible production, the need to develop a robust and advanced process control system that can ease process intensification has emerged. This has further fuelled the development of advanced monitoring approaches, modeling techniques, process analytical technologies, and soft sensors. It is seen that proper application of these concepts can significantly improve bioreactor process performance, productivity, and reproducibility. This review is on the recent advancements in bioreactor control and its related aspects along with the associated challenges. This study also offers an insight into the future prospects for development of control strategies that can be designed for industrial-scale production of biotherapeutic products.     

药品生产质量保证体系的建立

以《药品生产质量管理规范》(GMP)为依据,运用“过程方法”、“管理的系统方法”和“层次分析”理论,以药品生产体系的增值链系统为线索,对药品生产质量管理中的工序控制、信息传递、各子系统间的关联和衔接进行分析,以流程图的形式表示,并将系统要素人、物、信息和程序控制标明,建立起质量保证体系。涵盖了系统的全部关键质量控制点,职责清晰、不易遗漏、便于控制和发现问题。解决了药品生产质量控制及GMP实施中的难点,是药品生产企业行之有效的质量管理的手段。     

Enhanced Cumulative Sum Charts for Monitoring Process Dispersion

The cumulative sum (CUSUM) control chart is widely used in industry for the detection of small and moderate shifts in process location and dispersion. For efficient monitoring of process variability, we present several CUSUM control charts for monitoring changes in standard deviation of a normal process. The newly developed control charts based on well-structured sampling techniques - extreme ranked set sampling, extreme double ranked set sampling and double extreme ranked set sampling, have significantly enhanced CUSUM chart ability to detect a wide range of shifts in process variability. The relative performances of the proposed CUSUM scale charts are evaluated in terms of the average run length (ARL) and standard deviation of run length, for point shift in variability. Moreover, for overall performance, we implore the use of the average ratio ARL and average extra quadratic loss. A comparison of the proposed CUSUM control charts with the classical CUSUM R chart, the classical CUSUM S chart, the fast initial response (FIR) CUSUM R chart, the FIR CUSUM S chart, the ranked set sampling (RSS) based CUSUM R chart and the RSS based CUSUM S chart, among others, are presented. An illustrative example using real dataset is given to demonstrate the practicability of the application of the proposed schemes.     

Surface properties of calcium phosphate particles for self setting bone cements

Calcium phosphate cements (CPC), consist of multicomponent powder mixtures of calcium orthophosphates with grain sizes in the region of 1-20 microm. Due to the small particle sizes surface properties as the zeta potential and adsorption processes play a significant role during manufacturing and application. In the context of this work zeta potentials of different calcium phosphates, like dicalcium phosphate anhydride (DPCA) tetracalcium phosphate (TTCP) and hydroxyapatite were measured in various organic/aqueous media with different pH values. The results show a strong dependency of the zeta potential on the kind of suspension medium used associated with different milling properties. The addition of sodium phosphate leads to a pH value dependent stabilization of the particles in the liquid phase; the zeta potential of the surface increases from about -15 to -18 mV in water and from -35 to -45 mV in 0.05 mol/l sodium phosphate solution. Besides the interaction of particles with various antibiotics was determined on the basis of the zeta potential of the surface. The substances partly cause a tremendous change of the surface load. This is accompanied by a change of the rheological properties of the cement paste, the morphology of the hardened cement matrix and a significant deterioration of the application-relevant properties as setting time or mechanical strength.     

Online control of cell culture redox potential prevents antibody interchain disulfide bond reduction

The phenomenon of monoclonal antibody (mAb) interchain disulfide bond reduction during manufacturing processes continues to be a focus of the biotechnology industry due to the potential for loss of product, increased complexity of purification processes, and reduced stability of the drug product. We hypothesized that antibody reduction can be mitigated by controlling the cell culture redox potential and subsequently established a threshold redox potential above which the mAb remained intact and below which there were significant and highly variable amounts of reduced mAb. Using this knowledge, we developed three control schemes to prevent mAb reduction in the bioreactor by controlling the cell culture redox potential via an online redox probe. These control methodologies functioned by increasing the concentration of dissolved oxygen (DO), copper (II) (Cu), or both DO and Cu to maintain the redox potential above the threshold value. Using these methods, we were able to demonstrate successful control of antibody reduction. Importantly, the redox control strategies did not significantly impact the cell growth, viability, mAb production, or product quality attributes including aggregates, C-terminal lysine, high mannose, deamidation, and glycation. Our results demonstrate that controlling the cell culture redox potential is a simple and effective method to prevent mAb reduction.     

Approaches to Quality Risk Management When Using Single-Use Systems in the Manufacture of Biologics

Biologics manufacturing technology has made great progress in the last decade. One of the most promising new technologies is the single-use system, which has improved the efficiency of biologics manufacturing processes. To ensure safety of biologics when employing such single-use systems in the manufacturing process, various issues need to be considered including possible extractables/leachables and particles arising from the components used in single-use systems. Japanese pharmaceutical manufacturers, together with single-use suppliers, members of the academia and regulatory authorities have discussed the risks of using single-use systems and established control strategies for the quality assurance of biologics. In this study, we describe approaches for quality risk management when employing single-use systems in the manufacturing of biologics. We consider the potential impact of impurities related to single-use components on drug safety and the potential impact of the single-use system on other critical quality attributes as well as the stable supply of biologics. We also suggest a risk-mitigating strategy combining multiple control methods which includes the selection of appropriate single-use components, their inspections upon receipt and before releasing for use and qualification of single-use systems. Communication between suppliers of single-use systems and the users, as well as change controls in the facilities both of suppliers and users, are also important in risk-mitigating strategies. Implementing these control strategies can mitigate the risks attributed to the use of single-use systems. This study will be useful in promoting the development of biologics as well as in ensuring their safety, quality and stable supply.KEY WORDS: biologics, manufacturing technology, quality risk management, regulatory science, single-use system     

Functional integrity of intravenous immunoglobulin following irradiation with a virucidal dose of gamma radiation.

Although intravenous immunoglobulins (IVIG) and other plasma therapeutics have had a relatively good safety record, improved methods for viral clearance are constantly being evaluated and incorporated into new manufacturing processes. Gamma irradiation has been used routinely to assure sterility of healthcare products and medical devices, but it has not been applied successfully as a viral inactivation method for biologics. We examine whether virucidal doses of gamma irradiation (50 kGy) can be delivered to a manufacturing intermediate form of IVIG, a fractionated plasma paste, with negligible effect on structural and functional integrity of purified IgG product. Immunoglobulins from paste were examined for radiation-induced damage by SDS-PAGE and ELISAs utilizing viral antigens specific for rubella, CMV and mumps. Fc domain integrity was assessed by immunoblotting, quantitatively comparing the binding of irradiated and non-irradiated materials to cell surface Fcgamma receptors, and by employing quantitative RT-PCR to study the kinetics of accumulation of mRNA for the immune modulatory cytokines IL-1alpha, IL-1beta, IL-4, IL-8, IFNgamma, and TNFalpha. The results demonstrate that Fab and Fc domains of IVIG remain essentially intact and functional after gamma irradiation to virucidal doses, suggesting that this method could be used to enhance the safety of IVIG products.     

Avoiding catastrophic forgetting by coupling two reverberating neural networks

Gradient descent learning procedures are most often used in neural network modeling. When these algorithms (e.g., backpropagation) are applied to sequential learning tasks a major drawback, termed catastrophic forgetting (or catastrophic interference), generally arises: when a network having already learned a first set of items is next trained on a second set of items, the newly learned information may completely destroy the information previously learned. To avoid this implausible failure, we propose a two-network architecture in which new items are learned by a first network concurrently with internal pseudo-items originating from a second network. As it is demonstrated that these pseudo-items reflect the structure of items previously learned by the first network, the model thus implements a refreshing mechanism using the old information. The crucial point is that this refreshing mechanism is based on reverberating neural networks which need only random stimulations to operate. The model thus provides a means to dramatically reduce retroactive interference while conserving the essentially distributed nature of information and proposes an original but plausible means to ‘copy and paste’ a distributed memory from one place in the brain to another.     

Large-scale manufacturing of all four 2'-deoxynucleosides via novel strategies including a chemo-enzymatic process

A chemical synthesis of 2-deoxyribose-1-phosphate 2 and its enzymatic conversion into purine 2'-deoxynucleosides (dNus) are shown. Besides the chemo-enzymatic process for purine dNus, a modified process for practical dC preparation is also established. Consequently, a series of practical manufacturing processes of all four dNus have been realized via novel strategies.     

Performance Analysis of Auction-Based Distributed Shop-Floor Control Schemes from the Perspective of the Communication System

A growing level of interest in academia and industry centers on the paradigm of distributed shop-floor control in which task and resource allocation in the manufacturing system is accomplished in a distributed manner through message passing and auction-based decision making among autonomous entities. Due to the prominent role played by the communication system in this paradigm, it is important to consider the requirements and performance characteristics of the communication system during the design and evaluation of distributed shop-floor control schemes. In this paper, we propose a two-phase methodology for analyzing auction-based shop-floor control schemes from the perspective of the communication system. In the first phase, the control scheme is modeled as a closed queueing network and performance measures related to the auctioning process and the communication system are obtained rapidly using asymptotic bounding analysis and mean value analysis. Control schemes identified as attractive in the first phase are then evaluated in greater detail during the second phase, using a discrete event simulation model. We illustrate this methodology using two-class and four-class control schemes and discuss insights learned about the impact of various control-scheme-related factors on the performance of the auctioning process and the communication system.     

Emulating concurrency in a circuit card assembly system

Typical component-placement systems for populating surface mount technology printed circuit boards now exhibit a high degree of concurrency in their functional operations. This concurrency ideally yields high “burst-rate” estimates of throughput. However, if the concurrency is not properly understood and exploited, the burst rate is severely degraded, as exhibited by process rates observed in the actual production environment. This discernment requires an experimental characterization of the system's functional operation, which must also reflect the peculiarities of the controller. Such an experimental analysis is an essential precursor to performance-optimization procedures of numerically controlled flexible manufacturing systems. This article describes our analysis of an extremely complex workcell with a high degree of concurrency. Due to its enveloping complexity, the methodological framework for the analysis should be applicable to a broad class of concurrent systems. Empirically verifying the characterization required the development of an emulator that quantitatively defines the system to be modeled. As such, it is a numerical, off-line design and analysis tool. It has been utilized to obtain the process rate for particular products, preevaluate proposed engineering changes, interactively construct setups and sequences, and obtain parameters required for line-balancing procedures.     

The effect of silica fume on biodegradation of cement paste and its capacity to immobilize strontium during exposure to microbial sulfur oxidation

The disposal of low-level radioactive waste containing isotopes such as strontium by immobilization in cement paste has become common practice. However, the stability of cement paste in the environment may be impaired by sulfuric acid produced by sulfur-oxidizing bacteria. Since biodegradation rates in the environment of most radioactive waste burial sites are too low to be measured, determination of the degradation kinetics of cement paste is a difficult task. This study reports on the development of an accelerated biodegradation system for cement pastes in which the cement paste is exposed to a continuous culture of the sulfur-oxidizing bacterium Halothiobacillus neapolitanus. This system facilitated detection of the biodegradation processes in cement paste after as short a time as 15 days. A comparison of the durability of a cement paste blended with silica fume with that of unblended cement paste showed that the silica fume induced an increase in the leaching of Ca⁺² and Si and enhanced weight loss, indicating rapid deterioration in the structural integrity of the cement paste. The leaching of Sr⁺² from the silica fume amended cement paste was slightly reduced as compared with the non amended cement paste, indicating an increase in immobilization of strontium. Nevertheless, our findings do not support the use of silica fume as a suitable additive for immobilization of low-level radioactive waste.     

Application of Raman spectroscopy in monoclonal antibody producing continuous systems for downstream process intensification

Monoclonal antibodies (mAbs) are biopharmaceuticals produced by mammalian cell lines in bioreactors at a variety of scales. Cell engineering, media optimization, process monitoring, and control strategies for in vitro production have become crucial subjects to meet increasing demand for these high value pharmaceuticals. Raman Spectroscopy has gained great attention in the pharmaceutical industry for process monitoring and control to maintain quality assurance. For the first time, this article demonstrated the possibility of subclass independent quantitative mAb prediction by Raman spectroscopy in real time. The developed model estimated the concentrations of different mAb isotypes with average prediction errors of 0.2 (g/L) over the course of cell culture. In situ Raman spectroscopy combined with chemometric methods showed to be a useful predictive tool for monitoring of real time mAb concentrations in a permeate stream without sample removal. Raman spectroscopy can, therefore, be considered as a reliable process analytical technology tool for process monitor, control, and intensification of downstream continuous manufacturing. The presented results provide useful information for pharmaceutical industries to choose the most appropriate spectroscopic technology for their continuous processes.     

LARGE-SCALE MANUFACTURING OF ALL FOUR 2′-DEOXYNUCLEOSIDES VIA NOVEL STRATEGIES INCLUDING A CHEMO-ENZYMATIC PROCESS

A chemical synthesis of 2-deoxyribose-1-phosphate 2 and its enzymatic conversion into purine 2′-deoxynucleosides (dNus) are shown. Besides the chemo-enzymatic process for purine dNus, a modified process for practical dC preparation is also established. Consequently, a series of practical manufacturing processes of all four dNus have been realized via novel strategies.     

Application of multivariate analysis toward biotech processes: case study of a cell-culture unit operation

This paper examines the feasibility of using multivariate data analysis (MVDA) for supporting some of the key activities that are required for successful manufacturing of biopharmaceutical products. These activities include scale-up, process comparability, process characterization, and fault diagnosis. Multivariate data analysis and modeling were performed using representative data from small-scale (2 L) and large-scale (2000 L) batches of a cell-culture process. Several input parameters (pCO2, pO2, glucose, pH, lactate, ammonium ions) and output parameters (purity, viable cell density, viability, osmolality) were evaluated in this analysis. Score plots, loadings plots, and VIP plots were utilized for assessing scale-up and comparability of the cell-culture process. Batch control charts were found to be useful for fault diagnosis during routine manufacturing. Finally, observations made from reviewing VIP plots were found to be in agreement with conclusions from process characterization studies demonstrating the effectiveness of MVDA as a tool for extracting process knowledge.