Retrospective study on performance of constancy check device in Linac beam monitoring using Statistical Process Control

AimTo examine the application of Statistical Process Control (SPC) and Ishikawa diagrams for retrospective evaluation of machine Quality Assurance (QA) performance in radiotherapyBackgroundSPC is a popular method for supplementing the performance of QA techniques in healthcare. This work investigates the applicability of SPC techniques and Ishikawa charts in machine QA.Materials and MethodsSPC has been applied to recommend QA limits on the particular beam parameters using the QUICKCHECK^webline QA portable constancy check device for 6 MV and 10 MV flattened photon beams from the Elekta Versa HD linear accelerator (Linac). Four machine QA parameters – beam flatness, beam symmetry along gun target direction and left-right direction, and beam quality factor (BQF) – were selected for retrospective analysis. Shewhart charts, Exponentially Weighted Moving Average (EWMA) charts and Cumulative Sum (CUSUM) charts were obtained for each parameter. The root causes for a failure in machine QA were broken down into an Ishikawa diagram enabling the user to identify the root cause of error and rectify the problem subsequently.ResultsShewhart charts and EWMA charts applied could detect loss in control in one variable in the 6 MV beams and in all four variables in 10 MV beams. CUSUM charts detected offsets in the readings. The Ishikawa chart exhaustively included the possible errors that lead to loss of control.ConclusionSPC is proven to be effective for detection of loss in control in machine QA. The Ishikawa chart provides the set of probable root causes of machine error useful while troubleshooting.     

Parametric and non-parametric prediction intervals based phase II control charts for repeated bioassay data

Quality control for repeated bioassay runs can be performed by phase II control charts, well-known from industrial quality control. The value of interest is the potency, of which a single value per run is available. Parametric and non-parametric prediction intervals are described to estimate quality control intervals for future re-test runs. Violations against the normal distribution occur in real data frequently, particularly outliers. The non-parametric prediction intervals are limited to not too small sample sizes in both the historical and future sampling phases. Therefore, robust prediction intervals based on winsorization are proposed. R-functions for all prediction intervals are provided.     

Biosensors for process monitoring

Summary A short review about the biosensor research activities for bioprocess monitoring in the F.R.G. after its reunification is given. The principles of biosensor applications are presented. In situ sensors and sensors based on the principles of flow injection analysis are studied. Some applications of a four-channel enzyme thermistor, bio-field effect transistors, and immunoanalysis systems for real process monitoring are presented.     

Characterization of irregular electron beam for boost dose after whole breast irradiation

Irradiating a tumor bed with boost dose after whole breast irradiation helps reducing the probability of local recurrence. However, the success of electron beam treatment with a small area aiming to cover a superficial lesion is a dual challenge as it requires an adequate dosimetry beside a double check for dose coverage with an estimation of various combined uncertainty of tumor location and losing lateral electron equilibrium within small field dimensions.Aim of workthis work aims to measure the electron beam fluence within different field dimensions and the deviation from measurement performed in standard square electron applicator beam flatness and symmetry, then to calculate the average range of the correction factor required to overcome the loss of lateral electron equilibrium.Material and methodthe electron beam used in this work generated from the linear accelerator model ELEKTA Precise and dosimetry system used were a pair of PTW Pin Point ion chambers for electron beam dosimetry at standard conditions and assessment of beam quality at a reference depth of measurement, with an automatic water phantom, then a Roos ion chamber was used for absolute dose measurement, and PTW 2Darray to investigate the beam fluence of four applicators 6, 10, 14 and 20 cm² and 4 rectangular cutouts 6 × 14, 8 × 14, 6 × 17 and 8 × 17 cm², the second part was clinical application which was performed in a precise treatment planning system and examined boost dose after whole breast irradiation.Resultsrevealed that lower energy (6MeV and 8MeV) showed the loss of lateral electron equilibrium and deviation from measurements of a standard applicator more than the high energy (15 MeV) which indicated that the treatment of superficial dose with 6MeV required higher monitor unit to allow for the loss of lateral electron equilibrium and higher margin as well.     

Investigating output and energy variations and their relationship to delivery QA results using Statistical Process Control for helical tomotherapy

The aims of this study were to investigate machine beam parameters using the TomoTherapy quality assurance (TQA) tool, establish a correlation to patient delivery quality assurance results and to evaluate the relationship between energy variations detected using different TQA modules. TQA daily measurement results from two treatment machines for periods of up to 4 years were acquired. Analyses of beam quality, helical and static output variations were made. Variations from planned dose were also analysed using Statistical Process Control (SPC) technique and their relationship to output trends were studied. Energy variations appeared to be one of the contributing factors to delivery output dose seen in the analysis. Ion chamber measurements were reliable indicators of energy and output variations and were linear with patient dose verifications.     

Artifact-free CT images for electron beam therapy using a patient-specific non metallic shield

Patient’s CT images taken with metallic shields for radiotherapy suffer from artifacts. Furthermore, the treatment planning system (TPS) has a limitation on accurate dose calculations for high density materials. In this study, a Monte Carlo (MC)-based method was developed to accurately evaluate the dosimetric effect of the metallic shield. Two patients with a commercial tungsten shield of lens and two patients with a custom-made lead shield of lip were chosen to produce their non-metallic dummy shields using 3D scanner and printer. With these dummy shields, we generated artifact-free CT images. The maximum CT number allowed in TPS was assigned to metallic shields. MC simulations with real material information were carried out. In addition, clinically relevant dose-volumetric parameters were calculated for the comparison between MC and TPS. Relative dosimetry was performed using radiochromic films. The dose reductions below metallic structures were shown on MC dose distributions, but not evident on TPS dose distributions. The differences in dose-volumetric parameters of PTV between TPS and MC for eye shield cases were not clearly shown. However, the mean dose of lens from TPS and MC was different. The MC results were in superior agreement with measured data in relative dosimetry. The lens dose could be overestimated by TPS. The differences in dose-volumetric parameters of PTV between TPS and MC were generally larger in lip cases than in eye cases. The developed method is useful in predicting the realistic dose distributions around the organs blocked by the metallic shields.     

Biosensors for process control

Biosensors have been extensively studied during the last 20 years, and a myriad of laboratory biosensors have been developed. Improvements are required in biosensor design and performance before they become widely accepted in industrial process monitoring. However, as the biotechnology industry expands, biosensors may become more acceptable because, despite their limitations, they are the only devices capable of delivering the information required.     

A semi-analytical model for calculating the penetration depth of a high energy electron beam in a water phantom with a magnetic field

PurposeAs an electron beam is incident on a uniform water phantom in the presence of a lateral magnetic field, the depth-dose distribution of the electron beam changes significantly and forms the well-known ‘Bragg peak’, with a depth-dose distribution similar to that of heavy ions. This phenomenon has pioneered a new field in the clinical application of electron beams. For such clinical applications, evaluating the penetration depth of electron beams quickly and accurately is the critical problem.MethodsThis paper describes a model for calculating the penetration depth of an electron beam rapidly and correctly in a water phantom under the influence of a magnetic field. The model was used to calculate the penetration depths under different conditions: the energies of electron beams of 6, 8, 12 and 15 MeV and the magnetic induction intensities of 0.75, 1.0, 1.5, 2.0 and 3.0 T. In addition, the calculation results were compared with the results of a Monte Carlo simulation.ResultsThe comparison results indicate that the difference between the two calculation methods was less than 0.5 cm. Moreover, the computing time of the calculation model was less than a second.ConclusionsThe semi-analytical model proposed in the present study enables the penetration depth of the electron beam in the presence of a magnetic field to be obtained with a computational efficiency higher than that of the Monte Carlo approach; thus, the proposed model has high potential for application.     

An approach for vat color printing on cotton and polyester fabrics with electron beam irradiation curable formulations

Accelerated electrons delivered by electron beam accelerator were used to fix vat colors, incorporated in curable formulations containing diluting monomer and an oligomer, to cellulosic fabric, cotton and polyester fabric. Tetrahydrofurfuryl acrylate, hexane dioldiacrylate, monomers and trifunctional urethane methacrylate, oligomer were used as curable base beside ethylene glycol. The fabrics were printed with these formulations and exposed to various doses of electron beam irradiation generated from the 1.5 MeV (25 kW) electron beam accelerator machine. Critical factors included the irradiation dose, formulation composition, and vat color concentration were studied. The fabrics printed with the vat colors by electron beam irradiation displayed higher color yield than those fabrics printed by the conventional curing at equal vat color ratios. The durable properties of fabrics printed by electron beam irradiation except the roughness properties are extremely better than those printed by conventional fixation method.     

Using focus ion beam to prepare crystal lamella for electron diffraction

Electron diffraction provides a powerful tool to solve the structures of small protein crystals. However, strong interactions between the electrons and the materials limit the application of the electron crystallographic method on large protein crystals with micrometer or larger sizes. Here, we used the focused ion beam (FIB) equipped on the scanning electron microscope (SEM) to mill a large crystal to thin lamella. The influences of the milling on the crystal lamella were observed and investigated, including radiation damage on the crystal surface during the FIB imaging, deformation of the thin crystal lamella, and variation in the diffraction intensities under electron radiation. These observations provide important information to optimize the FIB milling, and hence is important to obtain high-quality crystal samples for routine structure determination of protein crystals using the electron cryo-microscope.     

Recent developments in the monitoring,modeling and control of biological production systems

Current trends in the development of methods for monitoring, modeling and controlling biological production systems are reviewed from a bioengineering perspective. The ability to measure intracellular conditions in bioprocesses using genomics and other bioinformatics tools is addressed. Devices provided via micromachining techniques and new real-time optical technology are other novel methods that may facilitate biosystem engineering. Mathematical modeling of data obtained from bioinformatics or real-time monitoring methods are necessary in order to handle the dense flows of data that are generated. Furthermore, control methods must be able to cope with these data flows in efficient ways that can be implemented in plant-wide computer communication systems.Mini-review for the proceedings of the M3C conference     

Multi-angle light scattering as a process analytical technology measuring real-time molecular weight for downstream process control

For many protein therapeutics including monoclonal antibodies, aggregate removal process can be complex and challenging. We evaluated two different process analytical technology (PAT) applications that couple a purification unit performing preparative hydrophobic interaction chromatography (HIC) to a multi-angle light scattering (MALS) system. Using first principle measurements, the MALS detector calculates weight-average molar mass, M_w and can control aggregate levels in purification. The first application uses an in-line MALS to send start/stop fractionation trigger signals directly to the purification unit when preset M_w criteria are met or unmet. This occurs in real-time and eliminates the need for analysis after purification. The second application uses on-line ultra-high performance size-exclusion liquid chromatography to sample from the purification stream, separating the mAb species and confirming their M_w using a µMALS detector. The percent dimer (1.5%) determined by the on-line method is in agreement with the data from the in-line application (M_w increase of approximately 2750 Da). The novel HIC-MALS systems demonstrated here can be used as a powerful tool for real-time aggregate monitoring and control during biologics purification enabling future real time release of biotherapeutics.     

Molecular templates for bio-specific recognition by low-energy electron beam lithography

Protein patterning has become an important topic as advances are made in biologically integrated devices and protein chip technology. Versatile and effective patterning requires substrates that can be quantified, with active presentation of proteins and control over protein density and orientation. Herein we describe a model system and the use of low-energy electron beam lithography to pattern molecular templates for immobilization of antibodies through ligand recognition. The templates were patterned over a background of poly(ethylene glycol) (PEG) modified silicon oxide (SiO _x ). These substrates were exposed to a low-voltage (2 keV) electron beam to remove PEG selectively from exposed regions. These regions were then functionalized with a dinitrophenyl (DNP) ligand and tested for specific binding of fluorescently labeled anti-DNP antibodies. The PEG modified regions in conjunction with ligand-presenting regions in the patterned arrays substantially reduces non-specific adsorption of proteins, yielding a specific/nonspecific ratio of approx 10. The surface coverage of the biologically active DNP groups on SiO _x and the amount of immobilized antibody on DNP were measured with a fluorescence-based, enzyme-linked immunosorbent assay. The specificity of the interaction between DNP ligand and fluorescently labeled anti-DNP antibodies was evaluated with fluorescence microscopy. This approach to patterning of molecular templates and assays for quantification are generally applicable to immobilization of any ligand-receptor pair on a wide range of substrates.     

A streamlined workflow for automated cryo focused ion beam milling

Cryo-electron tomography (cryo-ET) is an emerging technique to study the cellular architecture and the structure of proteins at high resolution in situ. Most biological specimens are too thick to be directly investigated and are therefore thinned by milling with a focused ion beam under cryogenic conditions (cryo-FIB). This procedure is prone to contaminations, which makes it a tedious process, often leading to suboptimal results. Here, we present new hardware that overcomes the current limitations. We developed a new glove box and a high vacuum cryo transfer system and installed a stage heater, a cryo-shield and a cryo-shutter in the FIB milling microscope. This reduces the ice contamination during the transfer and milling process and simplifies the handling of the sample. In addition, we tested a new software application that automates the key milling steps. Together, these improvements allow for high-quality, high-throughput cryo-FIB milling. This paves the way for new types of experiments, which have been previously considered infeasible.     

Performance assessment of surface-guided radiation therapy and patient setup in head-and-neck and breast cancer patients based on statistical process control

PurposeTo assess the effectiveness of SGRT in clinical applications through statistical process control (SPC).MethodsTaking the patients’ positioning through optical surface imaging (OSI) as a process, the average level of process execution was defined as the process mean. Setup errors detected by cone-beam computed tomography (CBCT) and OSI were extracted for head-and-neck cancer (HNC) and breast cancer patients. These data were used to construct individual and exponentially weighted moving average (EWMA) control charts to analyze outlier fractions and small process shifts from the process mean. Using the control charts and process capability indices derived from this process, the patient positioning-related OSI performance and setup error were analyzed for each patient.ResultsOutlier fractions and small shifts from the process mean that are indicative of setup errors were found to be widely prevalent, with the outliers randomly distributed between fractions. A systematic error of up to 1.6 mm between the OSI and CBCT results was observed in all directions, indicating a significantly degraded OSI performance. Adjusting this systematic error for each patient using setup errors of the first five fractions could effectively mitigate these effects. Process capability analysis following adjustment for systematic error indicated that OSI performance was acceptable (process capability index C_pk = 1.0) for HNC patients but unacceptable (C_pk < 0.75) for breast cancer patients.ConclusionSPC is a powerful tool for detecting the outlier fractions and process changes. Our application of SPC to patient-specific evaluations validated the suitability of OSI in clinical applications involving patient positioning.     

Digital twin of a continuous chromatography process for mAb purification: Design and model-based control

Model-based design of integrated continuous train coupled with online process analytical technology (PAT) tool can be a potent facilitator for monitoring and control of Critical Quality Attributes (CQAs) in real time. Charge variants are product related variants and are often regarded as CQAs as they may impact potency and efficacy of drug. Robust pooling decision is required for achieving uniform charge variant composition for mAbs as baseline separation between closely related variants is rarely achieved in process scale chromatography. In this study, we propose a digital twin of a continuous chromatography process, integrated with an online HPLC-PAT tool for delivering real time pooling decisions to achieve uniform charge variant composition. The integrated downstream process comprised continuous multicolumn capture protein A chromatography, viral inactivation in coiled flow inverter reactor (CFIR), and multicolumn CEX polishing step. An online HPLC was connected to the harvest tank before protein A chromatography. Both empirical and mechanistic modeling have been considered. The model states were updated in real time using online HPLC charge variant data for prediction of the initial and final cut point for CEX eluate, according to which the process chromatography was directed to switch from collection to waste to achieve the desired charge variant composition in the CEX pool. Two case studies were carried out to demonstrate this control strategy. In the first case study, the continuous train was run for initially 14 h for harvest of fixed charge variant composition as feed. In the second case study, charge variant composition was dynamically changed by introducing forced perturbation to mimic the deviations that may be encountered during perfusion cell culture. The control strategy was successfully implemented for more than ±5% variability in the acidic variants of the feed with its composition in the range of acidic (13%–17%), main (18%–23%), and basic (59%–68%) variants. Both the case studies yielded CEX pool of uniform distribution of acidic, main and basic profiles in the range of 15 ± 0.8, 31 ± 0.3, and 53 ± 0.5%, respectively, in the case of empirical modeling and 15 ± 0.5, 31 ± 0.3, and 53 ± 0.3%, respectively, in the case of mechanistic modeling. In both cases, process yield for main species was >85% and the use of online HPLC early in the purification train helped in making quicker decision for pooling of CEX eluate. The results thus successfully demonstrate the technical feasibility of creating digital twins of bioprocess operations and their utility for process control.     

Process for degradation of nitrobenzene: combining electron beam irradiation with biotransformation

Electron beam irradiations of aqueous solutions containing 15-30 mg/L of nitrobenzene at 60 kGy dose removed 78% of the contaminant. Three mononitrophenols were detected as by-products of electron beam treatment of nitrobenzene. A mixed culture enriched on a mixture of 2-, 3-, and 4-nitrophenol degraded both the residual nitrobenzene and the nitrophenol products. Percentage removal of nitrobenzene increased with increasing electron beam dose. This observation led to the conceptual design of a two-stage electron beam microbial process for degradation of nitrobenzene. Three groups of pure isolates were characterized from the mixed culture based on their abilities to grow on cor- responding nitrophenol substrates: Group A, 2NP(-)3NP(-)4NP(+); Group B, 2NP(+)3NP(+)4NP(-); and Group C, 2NP(-)3NP(+)4NP(-). Bacteria that grew on 3-NP transformed nitrobenzene into ammonia in the electron beam-treated nitrobenzene samples.