Process Control Testing Research Articles

Generative data augmentation and automated optimization of convolutional neural networks for process monitoring.

Chemometric modeling for spectral data is considered a key technology in biopharmaceutical processing to realize real-time process control and release testing. Machine learning (ML) models have been shown to increase the accuracy of various spectral regression and classification tasks, remove challenging preprocessing steps for spectral data, and promise to improve the transferability of models when compared to commonly applied, linear methods. The training and optimization of ML models require large data sets which are not available in the context of biopharmaceutical processing. Generative methods to extend data sets with realistic in silico samples, so-called data augmentation, may provide the means to alleviate this challenge. In this study, we develop and implement a novel data augmentation method for generating in silico spectral data based on local estimation of pure component profiles for training convolutional neural network (CNN) models using four data sets. We simultaneously tune hyperparameters associated with data augmentation and the neural network architecture using Bayesian optimization. Finally, we compare the optimized CNN models with partial least-squares regression models (PLS) in terms of accuracy, robustness, and interpretability. The proposed data augmentation method is shown to produce highly realistic spectral data by adapting the estimates of the pure component profiles to the sampled concentration regimes. Augmenting CNNs with the in silico spectral data is shown to improve the prediction accuracy for the quantification of monoclonal antibody (mAb) size variants by up to 50% in comparison to single-response PLS models. Bayesian structure optimization suggests that multiple convolutional blocks are beneficial for model accuracy and enable transfer across different data sets. Model-agnostic feature importance methods and synthetic noise perturbation are used to directly compare the optimized CNNs with PLS models. This enables the identification of wavelength regions critical for model performance and suggests increased robustness against Gaussian white noise and wavelength shifts of the CNNs compared to the PLS models.

Laboratory Safety Program Fundamentals

Key TakeawaysAn effective laboratory safety program focuses on preventing harm by reducing risks to staff and the laboratory itself.All laboratory safety programs should include documentation and training, safety data sheets, personal protective equipment, emergency shower/eyewash, fire safety, and first aid.Safety programs should address the specific analysis, such as microbiology or hazardous chemicals present.Operations laboratories should also have safety programs, even if they only perform process control testing.

Study of Protection Mechanism of On Time Delivery with Smart Production Control System in Industry 4.0

In order to achieve on time delivery and win in competition, the Protection Mechanism of On Time Delivery with Smart Production Control System in Industry 4.0 is proposed in this paper from the perspective of process control. The Smart Production Control System is set up for Protection Mechanism with the shortest transmission path and the endogenous security strategy by minimum device cost in Internet of things. The statistical techniques of the Measurement System Analysis, Statistical Process Control and Hypothesis Testing are utilized to analyze the real-time data and monitor business order workflow in the Smart Production Control System. The performance evaluation shows the Protection Mechanism has sufficient capability of Cp>1.33 and Cpk>1 with output increased 51% and days saved 33% for on time delivery, which demonstrates that the Protection Mechanism with Smart Production Control System can ensure on time delivery and achieve business goal in supply chain management in Industry 4.0.

In the mind of an insider attacker on cyber‐physical systems and how not being fooled

Insider attacks are one of the most serious threats for cyber-physical systems, they have potentials to inflict destructive damages on physical processes while remaining stealthy. This study dissects several insider attacks by examining their modes of data tampering. To set the scene, a general framework of a cyber-physical system is constructed, a pattern characterising insider attacks is introduced in the form of attack goals, resources, constraints, modes, and attack paths. The conditions under which the attackers can maintain stealthy are examined in both temporal and spatial domains. With the inside knowledge, an attacker can use an attack graph to exploit system vulnerabilities and determine the high impact targets. To demonstrate the effectiveness of this analysis, a cyber-physical system is constructed by using networks and a nuclear process control test facility with ports deliberately left open for attackers. Two attack scenarios are staged, and their characteristics and impacts are examined. This case study demonstrates how an insider attacker might mount an attack by using data tampering and how they can maintain stealthy before major damages are done to the physical system. The significance of this study is to uncover the techniques of insider attackers so that vulnerabilities can be mended.

Automated E-mail Reminders Linked to Electronic Health Records to Improve Medication Reconciliation on Admission.

Introduction:Medication reconciliation can reduce medication discrepancies, errors, and patient harm. After a large academic hospital introduced a medication reconciliation software program, there was low compliance with electronic health record documentation of home medication reconciliation. This quality improvement project aimed to improve medication reconciliation on admission in 4 pediatric inpatient units by 50% over 3 months.Methods:We used Lean Sigma methodology to observe medication reconciliation processes; interview residents, nurses, pharmacists, and families; and perform swim lane process mapping and Ishikawa Cause and Effect analysis. The improvement plan included education and automated e-mails sent to admitting residents who had not completed medication reconciliation within 24 hours of admission. The daily percentage of patients without medication reconciliation within 24 hours of admission, indicated by the presence of old prescriptions in Sunrise Prescription Writer (RxWriter) (Allscripts Healthcare Solutions, Chicago, Ill.) from prior admissions, was assessed from March 2015-June 2016. We constructed statistical process control charts and identified special causes.Results:Key barriers included lack of knowledge about RxWriter and lack of accountability for completing medication reconciliation. The percentage of patients without medication reconciliation decreased from 32% at baseline to 22% with education (P < 0.001), to 15% with the use of automated e-mail reminders (P < 0.001). We sustained improvement over the following year. Statistical process control testing indicated shifts aligning with each stage of the study.Conclusion:Provider-tailored, automated e-mail reminders linked to electronic health record with educational training significantly improved resident compliance with use of an electronic tool for documentation of home medication reconciliation on hospital admission.

Research on the full life cycle management system of smart electric energy meter

At present, China’s smart electric energy meter life management is started from the procurement and acceptance. The related monitoring and management of the manufacturing sector has not yet been carried out. This article applies RFID technology and network cloud platform to full life cycle management system of smart electric energy meters, builds this full life cycle management system including design and manufacturing, process control, measurement and calibration testing, storage management, user acceptance, site operation, maintenance scrap and other aspects. Exploring smart electric energy meters on-line and off-line communication by the application of active RFID communication functions, and the actual functional application such as local data exchange and instrument calibration. This system provides technical supports on power demand side management and the improvement of smart electric energy meter reliability evaluation system.

Surface Treatment Method and Its Metrology for Preventing Pattern Collapse

As semiconductor industry continues to make patterns smaller and more sophisticated, stable patterns with high AR (aspect ratio) is required. Pattern collapse is often affected by the AR, rigidity of pattern material, and surface chemistry of the sidewalls. Historically, hot IPA treatment was used but it does not support latest generation devices. One of the novel effective pattern collapse prevention approaches is the surface treatment with an organic layer [1, 2]. The modified structure surface has lower surface tension and the capillary force is reduced. This treatment process is normally performed by a silane-coupling reaction using organic solvent, so that the hydrophilic surface (-Si-OH) is modified to hydrophobic (-Si-O-SiR3) after silylation reaction. Silyning agent has limited stability and decompose upon exposure to air, moisture or reactive surfaces. Thus, there is a need the tight process control. A variety of spectroscopic methods were studied in order to measure selectively the active silyning agent and breakdown byproducts. Presentation will summarize advantages and disadvantages of different approached, preferred process control strategy and test results for non-reagent, real time analyzer of STM chemistry. TOKYO OHKA KOGYO CO., LTD. (TOK) is highly acknowledged for providing test samples and technical discussions. [1] D. Mori et al. Surface treatment agent and surface treatment method United States Patent Application 15/268,904 [2] E. Kesters et al. Wet clean challenges in 22nm ½ pitch and 16nm ½ pitch Proceedings of SPCC conference 2017 Figure 1

Surface Treatment Method and Its Metrology for Preventing Pattern Collapse

This paper demonstrates a variety of spectroscopic methods to measure selectively the active silylating agent and breakdown byproducts in an organic solvent used for effective pattern collapse prevention. Advantages and disadvantages of different approached, preferred process control strategy and test results for non-reagent, real time analyzer of STM chemistry are discussed.

Process control testing for fused filament fabrication

PurposeThe purpose of this research is to determine what tests can be most useful in quality assurance and control when using fused filament fabrication (FFF) 3D printing machines. The quality of the bond between layers is critical for the structural integrity of the fused filament fabricated parts.Design/methodology/approachTherefore, to determine the influence of process parameters on the quality of parts’ tensile, flexural, notched and un-notched impact, test specimens were fabricated in polylactic acid (PLA) using FFF with different layer thicknesses, fill densities, orientation and print speeds. The mechanical properties were then assessed along with the accuracy and mass of the samples.FindingsIt is concluded that a notched impact test gives a measure of interlayer bond strength which can be used across build styles to track machine performance, and that this, together with the mass and dimensions of the impact-test specimens, offers an appropriate set of tests capable of tracking the mechanical properties of parts produced using the FFF technique.Originality/valueTherefore, this research finding will be of value in benchmarking FFF machines for quality parts fabrications.

Control Strategies for Drug Product Continuous Direct Compression—State of Control, Product Collection Strategies, and Startup/Shutdown Operations for the Production of Clinical Trial Materials and Commercial Products

Continuous manufacturing (CM) has emerged in the pharmaceutical industry as a paradigm shift with significant advantages related to cost, efficiency, flexibility, and higher assurance of quality. The inherent differences from batch processes justify examining the CM control strategy more holistically. This article describes the current thinking for the control and implementation of CM, using the example of a direct compression process and taking into consideration the ICH Q10 definition of “state of control” and process validation requirements. Statistical process control using control charts, sources of variation, process capability, and process performance is explained as a useful concept that can help assess the impact of variation within a batch and indicates if a process is in state of control. The potential for time-variant nature of startup and shutdown with CM is discussed to assure product quality while minimizing waste as well as different options for detection and isolation of non-conforming materials due to process upsets. While different levels of control are possible with CM, an appropriate balance between process control and end product testing is needed depending on the level of process understanding at the different stages of development from the production of clinical supplies through commercialization.

Development of an engineering simulator for a physical component based nuclear process control test facility

To support research in instrumentation and control (I&C) of a nuclear power plant (NPP), a physical simulator based on scaled version of real plant processes using physical components has been developed, known as a NPP process control test facility (NPCTF). Even though this facility has proved to be a must-have system for any nuclear I&C system research activities, it is not without limitations of its own. Because this facility is made up with physical components, many variables are bounded by their safe operating ranges. This fundamentally limits the applicability of the facility in studying NPP under accident conditions, where excursions of the physical variables, such as pressure, temperature, may suppress the safe limits of the physical components. Furthermore, the facility can only be used for one experiment at a time. Henceforth, an engineering simulator (ES) based on software model, which extends functionalities of the NPCTF to examine accident scenarios and to allow multiple users to run different experiments, ought to be developed. This paper details the development of such a simulator by describing the models for thermal-hydraulic systems in the NPCTF as well as the corresponding NPP processes. The simulator is then implemented in Matlab Simulink environment with the help of Simscape toolbox. The performance of the ES has been validated by comparing the simulation results against those from the experiments on the NPCTF. Some operational scenarios that are not permitted to conduct safely on the NPCTF can now be conveniently carried out in the ES. The paper has demonstrated that the ES indeed plays a complementary role to the NPCTF in the support of I&C research and development for nuclear power plants.

Development of a non-linear process control test bench and empirical investigation of control performance

Development of a non-linear process control test bench and empirical investigation of control performance

Building automation system of payment platform weight component for large spacecraft reflector

Considered Design and the logic of opening large convertible antenna. The necessity of compensation weight component in the assembly and testing of the design. Given the logic of the movement elements of power spokes, concluded that the use of the tracking system to compensate for the weight component.The analysis of the existing equipment and control systems. Produced selection of the manufacturer of automated equipment that meets the stated objectives of management and control. It is concluded that the design component of the weight compensation system based on servo controllers and sensors combined platform automation, controlled by special software.The structure of the platform automation, consistent workflow testing. It defines the principles of interaction between subsystems of the weight compensation component for receiving, processing and monitoring of process parameters testing. It is concluded that the proposed system can be integrated into the automation system and the perspective of process control testing of disclosure of large spacecraft.

HCP-12IMPROVING THE EFFICIENCY OF MOLECULAR TESTING FOR EXPEDITED BRAIN TUMOR PATIENT MANAGEMENT AND CLINICAL TRIAL ENROLLMENT

BACKGROUND: O6-methylguanine methyltransferase (MGMT) methylation status is prognostic in glioblastoma. It is a critical datum in optimizing care in elderly glioblastoma patients. Further, MGMT methylation status is increasingly required for clinical trial enrollment (e.g. NCT02336165, NCT02287428). As such, maximizing efficiency of molecular tumor testing is critical in order to provide the best care for glioblastoma patients. METHODS: Using the longitudinal electronic medical record and pathology sample tracking systems, we determined the turn around time (TAT) from tumor resection to MGMT methylation status reporting, along with various intermediate steps along the way. We performed interdepartmental process mapping to identify opportunities for process change, followed by 2 process interventions with follow-up tracking of TAT with statistical process control testing. RESULTS: The baseline average interval from craniotomy to MGMT methylation result was 25.1 days for the 30 weeks prior to intervention, which included ∼5 days from craniotomy to pathological diagnosis, and ∼18 days from pathological diagnosis to MGMT result. Two tests of change were implemented, including a switch from batched to daily DNA extraction and MGMT methylation testing, and implementation of a new procedure for pathology sample inventory within the molecular pathology laboratory. The median time from craniotomy to MGMT methylation status reporting was reduced to from 25.1 days to 17 days after the first intervention, and to 15 days after the second intervention, with significant TAT reduction. CONCLUSIONS: Through clinical process improvement strategies and interdepartmental collaboration, we significantly reduced the TAT from craniotomy to MGMT methylation status reporting by an average of 10 days (40%). This allows for improved patient care by accelerating the delivery of potentially treatment-altering information as well as supplying earlier eligibility information for clinical trial enrollment. We continue to study additional opportunities for intervention, as this work highlights the possibility for neuro-oncology care improvement through process improvement strategies.

Development of a multivariate light-induced fluorescence (LIF) PAT tool for in-line quantitative analysis of pharmaceutical granules in a V-blender

Process analytical technologies (PAT) enable process insight, process control and real-time testing. Light-induced fluorescence (LIF) spectroscopy is especially well suited for low-concentration ingredients as, in many cases, it is the most sensitive probe of the in-line PAT toolbox. This study is aimed at verifying the applicability of a multivariate LIF analyzer to monitor granulated powder blends in industrial settings. Its targets are to: (1) evaluate the critical parameters of powders to obtain robust, precise and accurate concentration predictions and (2) assess technology performance for in-line monitoring of blending operations. Varying dye properties, moisture levels and particle sizes have been shown to have the most significant impact on fluorescence emission. Reliable quantitative models can be obtained by controlling and/or mitigating these factors.

Analysis of Nonhuman N-Glycans as the Minor Constituents in Recombinant Monoclonal Antibody Pharmaceuticals

Minor N-linked glycans containing N-glycolylneuraminic acid residues and/or α-Gal epitopes (i.e., galactose-α1,3-galactose residues) have been reported to be present in recombinant monoclonal antibody (mAb) therapeutics. These contaminations are due to their production processes using nonhuman mammalian cell lines in culture media containing animal-derived materials. In case of the treatment of tumors, we inevitably use such mAbs by careful risk-benefit considerations to prolong patients' lives. However, expanding their clinical applications such as for rheumatism, asthma, and analgesia demands more careful evaluation of the product characteristics. The present work for detailed evaluations of N-glycans demonstrates the methods using capillary electrophoresis with laser-induced fluorescence detection (CE-LIF) and a combination of high-performance liquid chromatography and electrospray ionization time-of-flight mass spectrometry. The CE-LIF method provides excellent separation of both major and minor N-glycans from six commercial mAb pharmaceuticals within 30 min and clearly indicates that a possible trigger of immunogenicity in humans due to the presence of nonhuman N-glycans is present. We strongly believe that the proposed method will be a powerful tool for the analysis of N-glycans of recombinant mAb products in various development stages, such as clone selection, process control, and routine release testing to ensure safety and efficacy of the products.

A Formulation Case Study Comparing the Dynamic Gastric Model with Conventional Dissolution Methods

Even in the 21st century, conventional compendial dissolution testing remains a key cornerstone of the drug development process and quality control testing. However, opportunities exist with respect to in vitro technology developments that provide the potential for formulation and analytical scientists to exceed the capabilities of the conventional dissolution test toward a more biorelevant testing regime. This work presents a product development case study in which bioequivalence was observed between an immediate-release (IR) innovator product and a comparative singlelayer reference product. Despite this, when the constituent granule of the comparative single-layer reference product was formulated in a bilayer formulation with a nondisintegrating second layer, bioequivalence versus the innovator was not achieved. The use of USP Apparatus 2 dissolution testing failed to predict the bioequivalence failure, and hence an investigation was undertaken to develop a mechanistic understanding of in vivo behavior. Using both USP Apparatus 4 dissolution in the open-loop configuration and the dynamic gastric model (a novel in vitro model designed to mimic the human stomach), an understanding of the dissolution and disintegration properties of the reference product was established. The insights gained using novel technology facilitated the redesign and subsequent improvement in pharmacokinetic parameters of a complex pharmaceutical dosage form. INTRODUCTION The correlation of in vitro performance to in vivo behavior is a critically important and cost-effective objective for the drug development process within the pharmaceutical industry (1). It is imperative to work toward the development of a mechanistic understanding of the conditions of the gastrointestinal environment and its influence on drug liberation phenomena from the various oral pharmaceutical dosage forms (2). While fully characterizing the complexity of the gastrointestinal tract may remain an elusive goal (3), understanding the key parameters that can facilitate the prediction of dosage form behavior in vivo may be achieved. A key contributor to developing an understanding is the development of dissolution technologies that are designed to mimic the in vivo environment more closely. The noncompendial dissolution methods have been detailed in an excellent recent review (4). These include multicompartmental models such as the artificial stomach duodenal model (ASD), which has been used to evaluate the effect of gastric emptying on drug dissolution, solubilization, and precipitation in separate duodenal compartment in several studies (5–8). In addition, models exist that are designed to simulate GI physical stress forces such as the novel stress dissolution tester (9, 10) or the modified Apparatus 2 by Burke et al. (11). Systems that mimic absorption have been described, from the simple partitioning approach using USP apparatus with organic solvents (12–14) to the more complex models like the FloVitro Dissolution Testing system provided by Rohm and Haas (15). In addition, the human gastric simulator (HGS) is a recent technological advance that has been used to study the gastric digestion of foods (16), although this has yet to be applied in the pharmaceutical development space. The next evolutionary stage of dissolution technology comprises complex systems that are multicompartmental, not only mimicking the hydrodynamics and composition of media but also incorporating mechanical processing, digestion of real food, and gastric emptying. Examples of these systems are the TNO TIM–1 system (17) and the dynamic gastric model (DGM). The DGM, developed by the Institute of Food Research in Norwich, UK, is designed to simulate the human gastric compartment of the fundus and antrum (18, 19). It is the first “dynamic” in vitro model that replicates both the complex biochemical conditions and the array of gastric hydrodynamics, critical for the prediction of digestive processes and the bioperformance of pharmaceutical agents and dosage forms. The DGM is gaining increasing utility not only as a general biopharmaceutics tool for the evaluation of dosage form disposition and drug release characteristics, but also for the evaluation of (1) food effect potential, (2) dosage form integrity (especially the propensity for dose dumping), and (3) bespoke drug–alcohol interactions. This work reports a formulation development case study that utilized noncompendial in combination with traditional in vitro tools. The study has proved useful in gaining insight into the in vivo mechanisms of success and failure of the pharmaceutical product development of a complex multilayer pharmaceutical dosage form. *Corresponding author. e-mail: james_mann@merck.com dx.doi.org/10.14227/DT190412P14

Treatment Techniques Target Wildfire‐Affected Water Supplies

This article discusses maintaining raw water quality in areas that are difficult to treat and optimizing procedures for ensuring effective use of each unit process employed by their treatment facilities. Particular interest is focused on small water systems for being the most at risk for noncompliance and public health issues in raw water quality. The article discusses treatment considerations such as disinfectant demand, ongoing process control testing, monitoring coagulation chemistry through observation and jar‐testing procedures, and assessing filters.

Quantification of emission potential from asphalt binders using mass loss and opacity measurements

A total of 23 asphalt binders were obtained from around the country. Contractors that reported emission complaints from neighbors were asked to supply samples from problem binders as well as a sample of asphalt binders, when used, generated either fewer or no complaints. The percent mass loss and opacity measurements were used to determine if a simple means of identifying asphalt binders with emission potential could be identified for use as a screening or process control test for the contractors. Results indicate that a maximum mass loss of 0.5% as measured with the rolling thin film oven test or 0.7% as measured with a prototype emissions oven will minimize emission potential. The prototype oven was fitted with an opacity meter; a percent mass loss of 0.7% or lower corresponds with visible emissions of 1.2% or less. Most of the asphalt binders rated with high emissions problems by the contractor are identified by using these limits.

Sensitivity of penetrant and magnetic particle testing

Abstract The sensitivity of penetrant and magnetic particle testing (PT and MT) depends, among other things, on the quality and performance of the “detection media” (for PT designated as “product family”). The determination of the sensitivity is carried out on “reference pieces” with natural or artificial gap-like flaws by determining the visibility of the indications as a measure of the performance. European standardisation specifies the requirements of detection media, in accordance with prEN ISO 3452-2 for PT and EN ISO 9934-2 for MT for type and batch as well as for process control testing. This paper describes the evaluation and qualification of performance during the type testing procedure. The proposed methods are validated by experimental investigations using an image processing system for the determination of the visibility. The reliability of the proposed methods is discussed with reference to the qualification of the detection media.