Batch Manufacturing Research Articles

Model-Free Adaptive Iterative Learning Control Method for the Czochralski Silicon Monocrystalline Batch Process

Model-based control methods do not produce satisfactory control results with the batch process control of Czochralski (CZ) silicon monocrystalline with complex nonlinearity, large delay, and time-varying dynamics. Therefore, this paper proposes a data-driven model-free adaptive iterative learning control method (MFAILC) to achieve precision control of the batch process. Firstly, to improve the accuracy of the data-driven model, a novel deep learning model for crystal growth process is established by combining a stacked autoencoder (SAE) and a long short-term memory network (LSTM) to extract the working condition information and the dynamic timing features in process data. Traditional model-based control methods are limited by the difficulties in modeling and by the unmodeled dynamics. So, to overcome this problem, the heater controller and the crystal puller controller are designed, based on the iterative dynamic linearization technology, to ensure that the silicon monocrystalline batch manufacturing process always maintains precision control. Also, the discrete-time extended state observer (ESO) is introduced to compensate for the influence of disturbances, to improve the robustness of the control system. Finally, the efficacy of the proposed method is verified by applying it for the predictive modeling and batch control of thermal field temperature and crystal diameter during crystal growth.

Compliance with the ISO 27020:2019 norm of a sample of currently available preadjusted Orthodontic bracket systems. Are the actual dimensions as expected?

BackgroundDetermine the exact slot dimension of a sample of a MBT prescription stainless steel conventional brackets from different manufacturers to compare the actual values with the nominal ones declared by the manufacturers and to verify the compliance with tolerance limits given by the ISO 27020:2019. Different batches from each manufacturer were evaluated to determine whether or not they are different in size. In addition, the geometry of the slot walls was assessed.Methods360 stainless steel preadjusted orthodontic brackets of 12 different manufacturers were assessed. All brackets had a nominal slot size of 0.022 by 0.028 inches, belonged to the right upper central incisor, and were fabricated with the metal injection molding technique (MIM). For each manufacturer, three different manufacturing batches were evaluated. Brackets were coded using a single-blind design.ResultsAll bracket systems in the study group except one displayed a statistically significant difference with the nominal declared value, although only four of the systems did not comply with the tolerance limits established by the ISO 27020:2019. In most of the systems, the slot height was oversized when compared to the nominal one. A significant interbatch variability was found in most of the evaluated systems. Most of the brackets walls were divergent.ConclusionsThe dimensional accuracy of commercially available metal brackets is not guaranteed. The respect for the norm should be enforced as well as the quality controls along the manufacturing process since orthodontic brackets are a precision medical device.

Fabrication and characterisation of piezoelectric thick-film microcantilever deposited on stainless steel using electrohydrodynamic jet deposition

This paper presents a lead zirconate titanate (PZT) thick-film microcantilever fabricated on a stainless-steel substrate using electrohydrodynamic jet (E-jet) deposition. PZT thick-film functional layer arrays were produced directly on stainless-steel substrates via E-jet deposition to form microcantilevers with a width of only 150 μm and thickness of 62 μm. The method can realise batch manufacturing of microscale cantilevers, improve the PZT active layer energy and microcantilever fracture toughness under vibrational deformation, and eliminate the need for complex photolithography and etching processes. The microcantilever accurately realised the correct mode shapes, consistent with simulation results. The vibrational amplitude of the microcantilever reached 5.14 μm, while Qm was up to 688.1, considerably larger than those of thick-film silicon-based microcantilevers and free-standing microcantilevers with similar sizes. An effective electromechanical coupling coefficient, Keff, of approximately 0.13 was obtained. The potential for efficient applications in microelectromechanical system piezoelectric devices was confirmed.

Continuous manufacture of hydroxychloroquine sulfate drug products via hot melt extrusion technology to meet increased demand during a global pandemic: From bench to pilot scale

During pandemics and global crises, drug shortages become critical as a result of increased demand, shortages in personnel and lockdown restrictions that disrupt the supply chain. The pharmaceutical industry is therefore moving towards continuous manufacturing instead of conventional batch manufacturing involving numerous steps, that normally occur at different sites. In order to validate the use of large-scale industrial processes, feasibility studies need to be performed using small-scale laboratory equipment. To that end, the scale-up of a continuous process and its effect on the critical quality attributes (CQAs) of the end product were investigated in this work. Hydroxychloroquine Sulphate (HCQS) was used as the model drug, Soluplus® as a model polymeric carrier and both horizontal and vertical twin screw extruders used to undertake this hot melt extrusion (HME) study. Seven formulations were processed using a small-scale horizontal extruder and a pilot-scale vertical extruder at various drug loadings, temperature profiles and screw speeds. When utilising a horizontal extruder, formulations with the highest drug load and processed at the lowest screw speed and temperature had the highest crystallinity with higher drug release rates. Upon scale-up to a vertical extruder, the crystallinity of the HCQS was significantly reduced, with less variation in both crystallinity and release profile across the different extrudates. This study demonstrates improved robustness with the pilot-scale vertical extruder compared to lab-scale horizontal extruder. The reduced variation with the vertical extruder will allow for short increases in production rate, with minimum impact on the CQAs of the final product enabling high-performance continuous manufacturing with minimum waste of raw materials. Finally, this research provides valuable information for the pharmaceutical industry in accessing continuous technologies for the manufacture of pharmaceutical products, allowing for efficient utilisation of resources upon scale-up and mass production during global pandemics and drug shortages.

Мелкозернистый бетон на основе техногенного сырья для дорожных покрытий .

On the basis of technogenic raw materials – ash and slag waste and burnt rocks of mine dumps – the compositions of fine-grained concrete were selected. The developed compositions have been tested in the manufacture of pilot batches of paving slabs. The introduction of fly ash and crushing screenings of burnt rocks into the composition of concrete improves the physical and mechanical properties of products with significant savings in cement. The applicability of the investigated technogenic raw materials in fine-grained concrete, intended for the manufacture of paving slabs and road paving elements, has been proved. Products have high indicators of physical and mechanical properties and quality.

Development of low-cost planar electrodes and microfluidic channels for applications in capacitively coupled contactless conductivity detection (C4 D).

Electrochemical techniques are commonly applied to micro total analysis system (μTAS) devices mainly due to its high sensitivity and miniaturization capacity. Among many electrochemical techniques, capacitively coupled contactless conductivity detection (C4 D) stands out for not requiring direct electrode-solution contact, avoiding several problems such as electrolysis, bubble formation, and metal degradation. Furthermore, the instrumentation required for C4 D measurements is compact, low cost, and easy to use, allowing in situ measurements to be performed even by nonspecialized personal. Contrarily, the production of metallic electrodes and microchannels adequate for C4 D measurements commonly requires specialized facilities and workers, increasing the costs of applying these methods. We propose alternatives to batch manufacture metallic electrodes and polymeric microchannels for C4 D analysis using more straightforward equipment and lower-cost materials. Three devices with different dielectric layer compositions and electrode sizes were tested and compared regarding their analytical performance. The constructed platforms have shown a reduction of more than 64% in cost when compared to traditional techniques and displayed good linearity (R2 ≥ 0.994), reproducibility (RSD ≤ 4.07%, n = 3), and limits of detection (≤0.26mmol/L) when measuring standard NaCl samples. Therefore, the proposed methods were successfully validated and are available for further C4 D applications such as diagnosis of dry-eye syndrome.

The Chronotopic™ System for Pulsatile and Colonic Delivery of Active Molecules in the Era of Precision Medicine: Feasibility by 3D Printing via Fused Deposition Modeling (FDM).

The pulsatile-release Chronotopic™ system was conceived of as a drug-containing core surrounded by a coat made of swellable/soluble hydrophilic polymers, the latter being able to provide a programmable lag phase prior to drug liberation. This system was also proposed in a colon-targeting configuration, entailing a gastroresistant film to prevent early interaction of the inner coat with gastric fluids and enabling the attainment of a lag phase matching the small intestinal transit time. Over the years, various multiple-step manufacturing processes have been tested for the fabrication of the Chronotopic™ system in both its configurations. This work focused on the evaluation of 3D printing by fused deposition modeling in view of its potential towards product personalization, on demand one-step manufacturing and efficient scale down of batches. The feasibility of each part of the Chronotopic™ system was independently investigated starting from in-house made filaments, characterizing the resulting specimens for physico-technological and performance characteristics. The printing parameters identified as suitable during the set-up phase were then used to fabricate prototypes either in a single step for the pulsatile configuration or following two different fabrication approaches for the colon-targeting one.

AMRI expands for rare disease services

Albany Molecular Research Inc. (AMRI) has made a series of investments in R&D services for therapies targeting orphan and rare diseases. The drug services firm has added batch manufacturing suites with capacity for 10–15 kg at its headquarters facility in Albany, New York. In Grafton, Wisconsin, AMRI has expanded its hydrogenation, analytical, filtering and drying, and spectrometry capabilities. The company added an unspecified number of researchers at these sites as well as at its formulation development and sterile drug manufacturing operation in Glasgow, Scotland.

Advances in Twin-Screw Granulation Processing.

Twin-screw granulation (TSG) is a pharmaceutical process that has gained increased interest from the pharmaceutical industry for its potential for the development of oral dosage forms. The technology has evolved rapidly due to the flexibility of the equipment design, the selection of the process variables and the wide range of processed materials. Most importantly, TSG offers the benefits of both batch and continuous manufacturing for pharmaceutical products, accompanied by excellent process control, high product quality which can be achieved through the implementation of Quality by Design (QbD) approaches and the integration of Process Analytical Tools (PAT). Here, we present basic concepts of the various twin-screw granulation techniques and present in detail their advantages and disadvantages. In addition, we discuss the detail of the instrumentation used for TSG and how the critical processing paraments (CPP) affect the critical quality attributes (CQA) of the produced granules. Finally, we present recent advances in TSG continuous manufacturing including the paradigms of modelling of continuous granulation process, QbD approaches coupled with PAT monitoring for granule optimization and process understanding.

PRACTICAL APPLICATION OF FUZZY LOGIC IN PRODUCTION CONTROL SYSTEMS OF ENGINEER TO ORDER SMES

In this paper the method of improving production control in engineer to order [ETO] small and medium sized enterprises is presented. Briefly, the strategy of Mass Customization [MC] and a concept of the hybrid MC-ETO production system are demonstrated. Thereafter, a method of choosing components for small batch manu-facturing in advance, under conditions of single unit ETO production system, with application of fuzzy logic is described. This approach can be used in ETO companies during their transition into the hybrid MC-ETO production systems. The research was done in a collaboration with experts from the real ETO pro-duction system, in Polish SME, which manufactures mechanical parts.

Enhancing protein A productivity and resin utilization within integrated or intensified processes.

Recent interest in continuous manufacturing of biologics has driven the development and evaluation of multicolumn chromatography systems to drive down resin costs by increasing productivity and maximizing resin utilization, especially for the expensive protein A capture step. Single-pass tangential flow filtration can be used to reduce the volume of perfusion harvest, enabling a further increase in the productivity of the capture step by up to fivefold. However, there are expected to be practical limits for the productivity of the capture step, which must be determined based on the manufacturing batch size, duration, and frequency, especially as it relates to efficient utilization of the column lifetime. For short fed-batch manufacturing campaigns, intensified capture processes may result in up to 82% lower resin consumption, while avoiding the long-term storage of used resin. For perfusion processes and longer fed-batch campaigns, it may be more efficient to operate at a lower productivity that enables the column lifetime to be routinely achieved and achieves the desired resin and buffer savings without introducing unnecessary process risk or complexity. An intensified batch capture process, "super-batch," will be compared as an alternative to multicolumn chromatography processes to achieve high productivity and resin utilization with a potentially simpler process.

Manufactured Flexible Electrodes for Dopamine Detection: Integration of Conducting Polymer in 3D‐Printed Polylactic Acid

Flexible electrochemical sensors based on electroactive materials have emerged as powerful analytical tools for biomedical applications requiring bioanalytes detection. Within this context, 3D printing is a remarkable technology for developing electrochemical devices, due to no design constraints, waste minimization, and batch manufacturing with high reproducibility. However, the fabrication of 3D printed electrodes is still limited by the in‐house fabrication of conductive filaments, which requires the mixture of the electroactive material with melted of thermoplastic polymer (e.g., polylactic acid, PLA). Herein, a simple approach is presented for preparing electrochemical dopamine (DA) biosensors. Specifically, the surface of 3D‐printed PLA specimens, which exhibit an elastic modulus and a tensile strength of 3.7 ± 0.3 GPa and 47 ± 1 MPa, respectively, is activated applying a 0.5 m NaOH solution for 30 min and, subsequently, poly(3,4‐ethylenedioxythiophene) is polymerized in situ using aqueous solvent. The detection of DA with the produced sensors has been demonstrated by cyclic voltammetry, differential pulse voltammetry, and chronoamperometry. In summary, the obtained results reflect that low‐cost electrochemical sensors, which are widely used in medicine and biotechnology, can be rapidly fabricated using the proposed approach that, although based on additive manufacturing, does not require the preparation of conductive filaments.

Continuous manufacturing versus batch manufacturing: benefits, opportunities and challenges for manufacturers and regulators

Continuous manufacturing (CM) is the integration of a series of unit operations, processing materials continually to produce the final pharmaceutical product. In recent years, CM of pharmaceuticals has transformed from buzzword to reality, with at least eight currently approved drugs produced by CM. Propelled by various driving forces, manufacturers and regulators have recognized the benefits of CM and are awaiting the completion of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q13, a harmonized guideline on CM that would be implemented by ICH members. Although significant progress is evident, the uptake of CM is still sluggish in the pharmaceutical industry due to many existing challenges that have hindered manufacturers from adopting this technology. The top two barriers that manufacturers currently face are regulatory uncertainties and high initial cost. These issues are crucial in unleashing the untapped potential of CM, which has significant implications on patients’ access to life-saving medicines, while mutually benefitting manufacturers and regulators. Despite numerous studies, there have been few existing publications that review current regulatory guidelines, highlight the latest challenges extensively and propose recommendations that are applicable for all pharmaceuticals and biopharmaceuticals. Therefore, this critical review aims to present the recent progress and existing challenges to provide greater clarity for manufacturers on CM. This review also proposes vital recommendations and future perspectives. These include regulatory harmonization, managing financial risks, hybrid processes, capacity building, a culture of quality and Pharma 4.0. While regulators and the industry work towards creating a harmonized guideline on CM, manufacturers should focus on overcoming existing cost, technical and cultural challenges to facilitate the implementation of CM.

Rapid Synthesis and Sintering of Metals from Powders.

Powder to bulk processes, such as additive manufacturing and metal injection molding (MIM), have enabled great potential for complex metal designing and manufacturing. However, additive manufacturing process normally introduces a high residue stress and textures due to the locally intense temperature. MIM is an excellent batch manufacturing process; nevertheless, it is not suitable for rapid screening and development of new metal compositions and structures due to the slow sintering process. Herein, an ultrafast high‐temperature sintering (UHS) process is reported that enables the rapid synthesis and sintering of bulk metals/alloys and intermetallic compounds. In this process, elemental powders are mixed and pressed into pellets, followed by UHS sintering in just seconds at a temperature between 1000 and 3000 °C. Three representative compositions, including pure metals, intermetallics, and multielement alloys, are demonstrated with a broad range of melting points. The UHS process for metal sintering is nonmaterials specific, in addition to being extremely rapid, which make it suitable for materials discovery. Furthermore, the sintering method does not apply pressure to the samples, making it compatible with 3D printing and other additive manufacturing processes of complex structures. This rapid sintering technique will greatly facilitate the development and manufacturing of metals and alloys.

In Vitro-In Vivo Correlation (IVIVC) Population Modeling for the In Silico Bioequivalence of a Long-Acting Release Formulation of Progesterone.

Health authorities carefully evaluate any change in the batch manufacturing process of a drug before and after regulatory approval. In the absence of an adequate in vitro–in vivo correlation (Level A IVIVC), an in vivo bioequivalence (BE) study is frequently required, increasing the cost and time of drug development. This study focused on developing a Level A IVIVC for progesterone vaginal rings (PVRs), a dosage form designed for the continuous delivery in vivo. The pharmacokinetics (PK) of four batches of rings charged with 125, 375, 750 and 1500 mg of progesterone and characterized by different in vitro release rates were evaluated in two clinical studies. In vivo serum concentrations and in vitro release profiles were used to develop a population IVIVC progesterone ring (P-ring) model through a direct differential-equation-based method and a nonlinear-mixed-effect approach. The in vivo release, , was predicted from the in vitro profile through a nonlinear relationship. was used as the input of a compartmental PK model describing the in vivo serum concentration dynamics of progesterone. The proposed IVIVC P-ring model was able to correctly predict the in vivo concentration–time profiles of progesterone starting from the in vitro PVR release profiles. Its internal and external predictability was carefully evaluated considering the FDA acceptance criteria for IVIVC assessment of extended-release oral drugs. Obtained results justified the use of the in vitro release testing in lieu of clinical studies for the BE assessment of any new PVRs batches. Finally, the possible use of the developed population IVIVC model as a simulator of virtual BE trials was explored through a case study.

A new approach in the economic design of acceptance sampling plans based on process yield index and Taguchi loss function

Acceptance sampling plan is used for decision making in the field of products quality control. These plans provide the producer and the consumer with decision rules for accepting or rejecting the lot. In this paper, a new approach for the economic design of resubmitted and multiple dependent state (MDS) sampling plans is proposed based on the process yield index considering Taguchi loss function and the average number of sample size n, which minimizes the costs related to the yield index Spk. In the proposed model the loss of a batch is considered rather than a single product. Also, the loss of both producer and consumer based on the yield index is minimized simultaneously through solving an optimization model and the parameters of the proposed sampling plans are obtained. The performance of both proposed sampling plans is analyzed and compared in terms of average sample number and total expected loss. The results indicate that both proposed sampling plans show satisfactory performance. Moreover, the advantages of the proposed model over the existing resubmitted and MDS sampling plans are presented. Finally, the application of the proposed model and sampling plans is illustrated through a real case in batch manufacturing processes.

Solvent-free temperature-facilitated direct extrusion 3D printing for pharmaceuticals

In an era moving towards digital health, 3D printing has successfully proven its applicability in providing personalised medicine through a technology-based approach. Among the different 3D printing techniques, direct extrusion 3D printing has been demonstrated as a promising approach for on demand manufacturing of solid dosage forms. However, it usually requires the use of elevated temperatures and/or the incorporation of an evaporable solvent (usually water). This can implicate the addition of a drying step, which may compromise the integrity of moisture- or temperature-sensitive drugs, and open the door for additional quality control challenges.Here, we demonstrate a new approach that simplifies direct extrusion 3D printing process with the elimination of the post-printing drying step, by merely adding a fatty glyceride, glyceryl monostearate (GMS), to a model drug (theophylline) and permeable water insoluble methacrylate polymers (Eudragit RL and RS). Indeed, rheological studies indicated that the addition of a combination of a plasticiser, (triethyl citrate), and GMS to theophylline: methacrylate polymer blends significantly reduced the extensional viscosity (to <2.5 kPa·Sec) at 90 °C. Interestingly, GMS demonstrated a dual temperature-dependant behaviour by acting both as a plasticiser and a lubricant at printing temperature (90–110 °C), while aiding solidification at room temperature. X-ray powder diffraction indicated incomplete miscibility of GMS within the polymeric matrix at room temperature with the presence of a subtle diffraction peak, at 2(Θ) = 20°. The 3D printed tablets showed acceptable compendial weight and content uniformity as well as sufficient mechanical resistance. In vitro theophylline release from 3D printed tablets was dependant on Eudragit RL:RS ratio.All in all, this work contributes to the efforts of developing a simplified, facile and low-cost 3D printing for small batch manufacturing of bespoke tablets that circumvents the use of high temperature and post-manufacturing drying step.

Current status, enablers and barriers of implementing cellular manufacturing system in sports industry through ISM

The sports goods manufacturing industry in India has gained phenomenal growth over the past five decades and now holds a prominent place in the Indian economy by providing massive employment and export revenue to the country. To enhance the quality and efficiency of production the industry is trying to implement new and efficient techniques in its manufacturing operations. Cellular manufacturing is a solution to the batch manufacturing process; hence reducing the lead-time with higher machine utilization, improved product quality, and enhanced customer satisfaction. In this work an attempt has been made to study the current status, enablers, and barriers in the implementation of cellular manufacturing principles in the sports industry-specific to Meerut and nearby regions. An ISM based structural modeling and MICMAC analysis of implementation enablers, and barriers of cellular manufacturing practices in sports industry in Meerut are also presented. Management vision and Government support are the major driving enablers while ‘Limited technological support, infrastructure and role model industry’, and ‘Lack of management support’ are among the major barriers. The implementation barriers are also arranged into five categories based on the factors related to their removal. The practical implications and future scope of the study are also proposed.

Impact of failure rates, lot definitions and scheduling of upstream processes on the productivity of continuous integrated bioprocesses

AbstractBACKGROUNDThe failure rates and the scheduling of bioprocesses have a substantial impact on process performance and economics but are often overlooked and neglected. Integrated continuous biomanufacturing is more flexible in respect to scheduling and the impact of failures can be reduced by appropriate scheduling and lot definitions.RESULTSIn this work, we used a Monte Carlo approach on an integrated continuous biomanufacturing process with varying daily failure rates in the upstream and scheduling scenarios for seed fermentation (N‐1 stage) to quantify the impact on the actual productive uptime of the integrated process. The optimum targeted production time in the continuous upstream ranges between 45 and 90 days depending on the daily failure rate and the lot definition used for the process. We showed that a minimal flexibility for planning of the seed fermentation is necessary to harvest the full potential of integrated continuous biomanufacturing. A comparison with batch manufacturing in the upstream processing showed a higher productive uptime for continuous biomanufacturing regardless of daily failure rates. Computation of productive uptime for different lot definitions showed that a daily lot definition only shows a loss of 3% to a maximum of 5% productivity, depending on the daily failure rate, compared to a real‐time release approach.CONCLUSIONSWith this study, we provide a decision‐making tool for the scheduling of upstream processes and implementation of integrated continuous biomanufacturing taking failure into account, showing the extent to which planning of flexibility and batch definitions influence the productivity of continuous integrated bioprocesses. © 2020 The Authors. Journal of Chemical Technology &amp; Biotechnology published by John Wiley &amp; Sons Ltd on behalf of Society of Chemical Industry.

An outbreak of Ralstonia pickettii bloodstream infection among pediatric leukemia patients.

Ralstonia pickettii is an opportunistic waterborne microbe which can survive in many kinds of solutions. Contamination of these solutions may result as outbreaks, which can be mortal for immuncompromised patients. Herein we report an outbreak of R. pickettii related to contaminated saline infusion in our center. This study was conducted in Ankara Pediatric City Hospital. An outbreak occured in Pediatric Hematology and Oncology Unit between August 28, 2019 and September 13, 2019. When the outbreak occured, infection control team began an investigation. Environmental samples were collected in order to find the source of the outbreak. A total of 11 patients with catheter related blood stream infection caused by R. pickettii who were diagnosed with leukemia were affected. None of the patients infected with R. pickettii died during the outbreak. A total of seventy environmental samples were cultured with the purpose of finding the source of outbreak. R. pickettii grew in normal saline solution culture and all isolates had the same clone of R. pickettii. The outbreak lasted two weeks and was controlled by stopping the usage and sending back the saline solutions belonging to the same manufacturing batch. We reported an outbreak of R. pickettii BSIs in highly immunocompromised patients due to contaminated intravascular solution, which was rapidly controlled by infection control measures. Vigilant surveillance by hospital infection control teams and prompt investigation to identify the source of nosocomial infections are crucial to stop an outbreak.