Comparison Of Pressure Measurements Research Articles

Emerging PAT for Freeze-Drying Processes for Advanced Process Control

Lyophilization is a widely used drying operation, but long processing times are a major drawback. Most lyophilization processes are conducted by a recipe that is not changed or optimized after implementation. With the regulatory demanded quality by design (QbD) approach, the process can be controlled inside an optimal range, ensuring safe process conditions. Process analytical technology (PAT) is crucial because it allows real-time monitoring and is part of a control strategy. In this work, emerging PAT (manometric temperature measurement (MTM), comparative pressure measurement, heat flux sensors, and ice ruler) are used for measurements during the freeze-drying process, and their potential for implementation inside a control strategy is outlined.

Advanced Process Analytical Technology in Combination with Process Modeling for Endpoint and Model Parameter Determination in Lyophilization Process Design and Optimization

Lyophilization is widely used in the preservation of thermolabile products. The main shortcoming is the long processing time. Lyophilization processes are mostly based on a recipe that is not changed, but, with the Quality by Design (QbD) approach and use of Process Analytical Technology (PAT), the process duration can be optimized for maximum productivity while ensuring product safety. In this work, an advanced PAT approach is used for the endpoint determination of primary drying. Manometric temperature measurement (MTM) and comparative pressure measurement are used to determine the endpoint of the batch while a modeling approach is outlined that is able to calculate the endpoint of every vial in the batch. This approach can be used for process development, control and optimization.

Automatic control of a freeze-drying process: Detection of the end point of primary drying

In freeze-drying, the detection of the end of primary drying is a crucial aspect for both the process economics and product quality. Furthermore, the extreme process conditions (low temperature, high vacuum, and sterility) require monitoring devices with a high degree of assurance. In this paper, the most promising methodologies for the detection of the end point of primary drying were investigated and compared. These devices include thermocouples, comparative pressure measurement, condenser pressure, controlled leakage, vacuum shut-off valve, microbalance, mass spectrometers, moisture sensors, and pressure rise test. Furthermore, a multi-scale model of the process was used to describe the process dynamics during the last part of drying, showing that the time difference between the onset and offset points depends on the batch heterogeneity, as well as process conditions and batch size. Ultimately, an automatic stop criterion, named EPD, has been designed and experimentally tested in a wide range of process conditions, batch size, vial size, and drug products. In particular, the experimental validation involved some of the most used excipients as model products, i.e., mannitol, dextran, lactose, and sucrose. In all the runs, the EPD drying times reasonably agreed with the comparative pressure measurement, which was the most reliable way to detect the end of primary drying. Thus, EPD can effectively be used to optimize primary drying without risking the product collapse because of a premature increase in shelf temperature for secondary drying.

Model-Based Optimisation and Control Strategy for the Primary Drying Phase of a Lyophilisation Process.

The standard operation of a batch freeze-dryer is protocol driven. All freeze-drying phases (i.e., freezing, primary and secondary drying) are programmed sequentially at fixed time points and within each phase critical process parameters (CPPs) are typically kept constant or linearly interpolated between two setpoints. This way of operating batch freeze-dryers is shown to be time consuming and inefficient. A model-based optimisation and real-time control strategy that includes model output uncertainty could help in accelerating the primary drying phase while controlling the risk of failure of the critical quality attributes (CQAs). In each iteration of the real-time control strategy, a design space is computed to select an optimal set of CPPs. The aim of the control strategy is to avoid product structure loss, which occurs when the sublimation interface temperature () exceeds the the collapse temperature () common during unexpected disturbances, while preventing the choked flow conditions leading to a loss of pressure control. The proposed methodology was experimentally verified when the chamber pressure and shelf fluid system were intentionally subjected to moderate process disturbances. Moreover, the end of the primary drying phase was predicted using both uncertainty analysis and a comparative pressure measurement technique. Both the prediction of and end of primary drying were in agreement with the experimental data. Hence, it was confirmed that the proposed real-time control strategy is capable of mitigating the effect of moderate disturbances during batch freeze-drying.

In-Situ Molecular Vapor Composition Measurements During Lyophilization.

Monitoring process conditions during lyophilization is essential to ensuring product quality for lyophilized pharmaceutical products. Residual gas analysis has been applied previously in lyophilization applications for leak detection, determination of endpoint in primary and secondary drying, monitoring sterilization processes, and measuring complex solvents. The purpose of this study is to investigate the temporal evolution of the process gas for various formulations during lyophilization to better understand the relative extraction rates of various molecular compounds over the course of primary drying. In this study, residual gas analysis is used to monitor molecular composition of gases in the product chamber during lyophilization of aqueous formulations typical for pharmaceuticals. Residual gas analysis is also used in the determination of the primary drying endpoint and compared to the results obtained using the comparative pressure measurement technique. The dynamics of solvent vapors, those species dissolved therein, and the ballast gas (the gas supplied to maintain a set-point pressure in the product chamber) are observed throughout the course of lyophilization. In addition to water vapor and nitrogen, the two most abundant gases for all considered aqueous formulations are oxygen and carbon dioxide. In particular, it is observed that the relative concentrations of carbon dioxide and oxygen vary depending on the formulation, an observation which stems from the varying solubility of these species. This result has implications on product shelf life and stability during the lyophilization process. Chamber process gas composition during lyophilization is quantified for several representative formulations using residual gas analysis. The advantages of the technique lie in its ability to measure the relative concentration of various species during the lyophilization process. This feature gives residual gas analysis utility in a host of applications from endpoint determination to quality assurance. In contrast to other methods, residual gas analysis is able to determine oxygen and water vapor content in the process gas. These compounds have been shown to directly influence product shelf life. With these results, residual gas analysis technique presents a potential new method for real-time lyophilization process control and improved understanding of formulation and processing effects for lyophilized pharmaceutical products.

The Influence of Mannitol Hemihydrate on the Secondary Drying Dynamics of a Protein Formulation: A Case Study

The objective of this research was to study the atypical secondary drying dynamics observed during the freeze-drying of a formulation consisting of mannitol, disaccharide, and sodium chloride, where “bursts” of water vapor release were observed during secondary drying as detected by comparative pressure measurement. “Thief” samples were removed at the end of primary drying and during secondary drying as the shelf temperature was increased in a stepwise fashion. These samples were examined by X-ray powder diffraction and thermal analysis. From the X-ray powder diffraction data, we determined that mannitol crystallized predominantly as its hemihydrate. The physical state of mannitol changed from the hemihydrate form to anhydrous forms during secondary drying. Investigation of the effect of excipients on mannitol crystallization demonstrated that sodium chloride (at 225 mM, 1.3% w/v) had the greatest influence on hemihydrate crystallization, followed by trehalose and sucrose. However, only negligible hemihydrate formation was observed when mannitol was freeze-dried either by itself or in the presence of 150 mM sodium chloride and no hemihydrate in the presence of 75 mM sodium chloride. In general, a combination of a disaccharide and sodium chloride promoted the hemihydrate formation to a greater extent than the individual components. Comparative pressure measurement was demonstrated to be an effective tool to monitor mannitol hemihydrate dehydration during secondary drying.

Application of Geocell Track Substructure Support System to Correct Surface Degradation Problems Under High-Speed Passenger Railroad Operations

Ballast fouling and associated degradation of track geometry is a serious problem for railway systems in general and high-speed passenger rail systems in particular. This paper presents the results of a field test on Amtrak’s Northeast Corridor where a long-term problem area existed near Oakington Road, Havre de Grace, Maryland, near MP 63.7 between Philadelphia and Washington DC. This test looked at the application of a new generation of three-dimensional cellular confinement systems (geocells) in reducing the rate of track geometry degradation, particularly in poor subgrade and ballast locations which require frequent, expensive, track surface maintenance. The field test compared two distinct sets of rebuilt track conditions, to include zones with and without a layer of geocell material. Both zones were rebuilt with improved drainage and a good, well-defined track structure and substructure (to include a well-defined depth of clean ballast). The test measurements included pre-maintenance and post-maintenance track geometry measurements together with comparative subgrade pressure measurements inside and outside the geocell cell zones. The pressure cell measurements, which looked at subgrade pressure under left and right rails in both the geocell zone and the control (non-geocell) zones, included measurements under both Acela high-speed trains and lower speed regional trains. In all cases, the subgrade pressures in the geocell zone were approximately half of those for the cells in the control zone (no geocell). Track geometry measurements were made using Amtrak’s track geometry vehicle which measures key track geometry parameters at 1-ft intervals along the track. There were several well-defined locations in the overall test zone that experienced significant track geometry degradation; these were all corrected during reconstruction. In the zones with no geocell material, these geometry variations reappeared within 6 to 7 months with the same if not greater amplitudes. By contract, in the geocell zone, the “after” geometry variations were significantly smaller than the pre-reconstruction geometry variations. Furthermore, the rate of geometry degradation was signficantly less for the geocell zones compared to the pre-geocell time periods for the exact same track. This indicated the effectiveness of the geocell material in reducing the rate of track geometry degradation and extending the surfacing maintenance cycles. Analysis of the rate of degradation showed that the effect of installing the geocell material was to significantly reduce the rate of degradation (and thus increase the surfacing cycle) by a factor of 6.7 times the pre-geocell installation surfacing cycle.

Explosion yield estimation from pressure wave template matching.

A method for estimating the yield of explosions from shock-wave and acoustic-wave measurements is presented. The method exploits full waveforms by comparing pressure measurements against an empirical stack of prior observations using scaling laws. The approach can be applied to measurements across a wide-range of source-to-receiver distances. The method is applied to data from two explosion experiments in different regions, leading to mean relative errors in yield estimates of 0.13 using prior data from the same region, and 0.2 when applied to a new region.

Does Objective Measurement of Tracheal Tube Cuff Pressures Minimise Adverse Effects and Maintain Accurate Cuff Pressures? A Systematic Review and Meta-analysis

Correct inflation pressures of the tracheal cuff are recommended to ensure adequate ventilation and prevent aspiration and adverse events. However there are conflicting views on which measurement to employ. The aim of this review was to examine whether adjustment of cuff pressure guided by objective measurement, compared with subjective measurement or observation of the pressure value alone, was able to prevent patient-related adverse effects and maintain accurate cuff pressures. A search of PubMed, Web of Science, Embase, CINAHL and ScienceDirect was conducted using keywords 'cuff pressure' and 'measure*' and related synonyms. Included studies were randomised or pseudo-randomised controlled trials investigating mechanically ventilated patients both in the intensive care unit and during surgery. Outcomes included adverse effects and the comparison of pressure measurements. Pooled analyses were performed to calculate risk ratios, effect sizes and 95% confidence intervals. Meta-analysis found preliminary evidence that adjustment of cuff pressure guided by objective measurement as compared with subjective measurement or observation of the pressure value alone, has benefit in preventing adverse effects. These included cough at two hours (odds ratio [OR] 0.42, confidence interval [CI] 0.23 to 0.79, P=0.007), hoarseness at 24 hours (OR 0.49, CI 0.31 to 0.76, P <0.002), sore throat (OR 0.73, CI 0.54 to 0.97, P <0.03), lesions of the trachea and incidences of silent aspiration (P=0.001), as well as maintaining accurate cuff pressures (Hedges' g 1.61, CI 2.69 to 0.53, P=0.003). Subjective measurement to guide adjustment or observation of the pressure value alone may lead to patient-related adverse effects and inaccuracies. It is recommended that an objective form of measurement be used.

Evaluation of Heat Flux Measurement as a New Process Analytical Technology Monitoring Tool in Freeze Drying

This study investigates the suitability of heat flux measurement as a new technique for monitoring product temperature and critical end points during freeze drying. The heat flux sensor is tightly mounted on the shelf and measures non-invasively (no contact with the product) the heat transferred from shelf to vial. Heat flux data were compared to comparative pressure measurement, thermocouple readings, and Karl Fischer titration as current state of the art monitoring techniques. The whole freeze drying process including freezing (both by ramp freezing and controlled nucleation) and primary and secondary drying was considered. We found that direct measurement of the transferred heat enables more insights into thermodynamics of the freezing process. Furthermore, a vial heat transfer coefficient can be calculated from heat flux data, which ultimately provides a non-invasive method to monitor product temperature throughout primary drying. The end point of primary drying determined by heat flux measurements was in accordance with the one defined by thermocouples. During secondary drying, heat flux measurements could not indicate the progress of drying as monitoring the residual moisture content. In conclusion, heat flux measurements are a promising new non-invasive tool for lyophilization process monitoring and development using energy transfer as a control parameter.

Does objective measurement of tracheal tube cuff pressures minimise adverse effects and maintain accurate cuff pressures? A systematic review and meta-analysis.

Correct inflation pressures of the tracheal cuff are recommended to ensure adequate ventilation and prevent aspiration and adverse events. However there are conflicting views on which measurement to employ. The aim of this review was to examine whether adjustment of cuff pressure guided by objective measurement, compared with subjective measurement or observation of the pressure value alone, was able to prevent patient-related adverse effects and maintain accurate cuff pressures. A search of PubMed, Web of Science, Embase, CINAHL and ScienceDirect was conducted using keywords 'cuff pressure' and 'measure*' and related synonyms. Included studies were randomised or pseudo-randomised controlled trials investigating mechanically ventilated patients both in the intensive care unit and during surgery. Outcomes included adverse effects and the comparison of pressure measurements. Pooled analyses were performed to calculate risk ratios, effect sizes and 95% confidence intervals. Meta-analysis found preliminary evidence that adjustment of cuff pressure guided by objective measurement as compared with subjective measurement or observation of the pressure value alone, has benefit in preventing adverse effects. These included cough at two hours (odds ratio [OR] 0.42, confidence interval [CI] 0.23 to 0.79, P=0.007), hoarseness at 24 hours (OR 0.49, CI 0.31 to 0.76, P <0.002), sore throat (OR 0.73, CI 0.54 to 0.97, P <0.03), lesions of the trachea and incidences of silent aspiration (P=0.001), as well as maintaining accurate cuff pressures (Hedges' g 1.61, CI 2.69 to 0.53, P=0.003). Subjective measurement to guide adjustment or observation of the pressure value alone may lead to patient-related adverse effects and inaccuracies. It is recommended that an objective form of measurement be used.

Leak localization in water distribution networks using a mixed model-based/data-driven approach

This paper proposes a new method for leak localization in water distribution networks (WDNs). In a first stage, residuals are obtained by comparing pressure measurements with the estimations provided by a WDN model. In a second stage, a classifier is applied to the residuals with the aim of determining the leak location. The classifier is trained with data generated by simulation of the WDN under different leak scenarios and uncertainty conditions. The proposed method is tested both by using synthetic and experimental data with real WDNs of different sizes. The comparison with the current existing approaches shows a performance improvement.

Innominate Artery Stenting: A Single Centre Experience

Objectives: To analyze retrospectively the procedures of PTA with stenting of the innominate artery lesions performed in our Centre. Background: Endovascular interventions have revolutionized the contemporary treatment of periferal vascular atherosclerotic disease. Innominate artery lesions have traditionally been treated with surgical extra-anatomic bypass via a cervical approach or median sternotomy. Percutaneous transluminal angioplasty (PTA) with stenting may be a viable alternative to traditional open by-pass. Methods: Between January 2002 and March 2009, 6 patients affected by innominate artery lesions (1 occlusion and 5 stenoses) were treated with PTA and stent using an humeral artery approach. All patients were symptomatic (previous transient ischemic attack, vertebrobasilar insufficiency, upper right limb claudicatio). Short and midterm follow-up included: physical examination, comparative blood pressure measurement on both arms and eco-Doppler examination of the supra-aortic truncks. Results: In all cases we obtained a successful immediate angiographyc result. No major complication (death, stroke) occurred during the immediate perioperative period and troughout all the follow up. Minor complications included puncture site hematoma (1 patients) and acute renal insufficiency (1 patient with known cronic renal insufficiency). Symptoms improved in all patients. Throughout follow up there have been no cases of restenosis detected by routine eco-Doppler examinations and all patients have remained symptoms free.

Sensitivity and specificity of hypopnoea detection using nasal pressure in the presence of a nasal expiratory resistive device (Provent®)

Nasal expiratory resistive valves (Provent®) have been proposed as novel therapy for obstructive sleep apnea. We compared pressure measurements from a standard nasal pressure catheter used to assess nasal airflow during sleep with those from nasal expiratory resistive device with attached proprietary nasal pressure cannula. Nasal pressure cannula or Provent® + proprietary nasal pressure cannula were attached to a bench model of human anterior nares and nasal passages, and pressure measured (P). Respiratory airflows generated by a subject breathing were applied to rear of model and airflow () measured via pneumotachograph. Airflow amplitude (Δ) was plotted against pressure amplitude (ΔP). Hypopnoea detection (<50% Δ) sensitivity and specificity was tested by expressing ΔP in terms of two reference breaths: reference breath 1, Δ 0.55 L s−1 = 100%; and reference breath 2, Δ 0.45 L s−1 = 100%. ΔP/Δ relationships were linear for Δ ≤ 0.55 L s−1; ΔP = 0.37ΔV + 0.16 (nasal pressure cannula), ΔP = 2.7ΔV + 0.12 (Provent® + proprietary nasal pressure cannula); both R2 > 0.65, p < 0.0001; p < 0.0001 for between slope difference). For nasal pressure cannula, specificity of hypopnoea detection differed between reference breaths one and two (80.2% and 40.0%, respectively), and Provent® + proprietary nasal pressure cannula (30.3% and 74.2%, respectively). Quantification of airflow obstruction in the presence of Provent® + proprietary nasal pressure cannula is greatly influenced by the reference breath chosen to determine a reduction in nasal airflow. Reported variability in therapeutic response to nasal expiratory resistive devices may relate to differences in measurement technique specificity used to quantify the severity of sleep disordered breathing.

Freeze drying of orally disintegrating tablets containing taste masked naproxen sodium granules in blisters

Orally disintegrating tablets (ODTs) were freeze dried in blisters using the Lyostar® II SMART™ Freeze Dryer Technology. ODT formulations either without non-water soluble particles (placebo) or containing large fractions (717 mg) of taste-masked naproxen sodium (NaS) granules were freeze dried. The process data revealed differences between ODTs with and without embedded granules in the pressure rise curves as well as in the shelf (inlet) temperature adjustments during freeze-drying. Pressure rise curves of the placebo ODTs from eight hours process time showed no distinct temperature-dominated part, and the last optimization step of the shelf temperature to achieve −24.4 °C might be prone to errors. The final shelf temperature of ODTs containing granules was −23.3 °C. The detection of primary drying endpoints using SMART™ Technology or comparative pressure measurements was reliable for both ODT formulations, whereas the application of thermocouples resulted in premature endpoint indication. Product resistance of ODTs containing granules was generally elevated in comparison to ODTs without granules, but increased only slightly over the course of the drying process. In summary, the developed freeze-drying cycle was found applicable for production of elegant ODTs with incorporated taste masked NaS granules.

High temperature fast response pressure probe for use in liquid metal droplet dispensers

A miniature fast response high temperature pressure probe, with demonstrated use in liquid metals up to 255 °C (528 K), has been developed. Innovative packaging technologies have been applied to integrate a conventional piezoresistive silicon pressure sensor into the probe, without the need of an auxiliary water-cooling system. In situ static calibrations are used to verify the linearity of the pressure signal and the stability of the pressure sensitivity (0.5% standard deviation over 70 min at 255 °C). Dynamic calibration, completed in an air shock tube facility, yields the probe's natural frequency. This frequency, when corrected for probe operation in liquid tin, is found to be 100 kHz. The reliability and accuracy of the probe is assessed by mounting it in a tin droplet dispenser for use in an extreme ultraviolet light source. Droplet dispensers typically include an excitation mechanism, which can be based on the generation of acoustic pressure waves to impose a desired droplet frequency. The probe accuracy is verified by the comparison of pressure measurements with laser Doppler vibrometry measurements of the pressure generating structure. A reference pressure measurement, conducted at representative conditions, shows a complex frequency response, with peaks distributed over three orders of magnitude and maximum amplitude of 440 mbar. Time variance of the excitation mechanism due to thermal transients is studied by monitoring the pressure response during operation. Finally, the linearity of the excitation system, with respect to the excitation amplitude, is verified by response measurements. In conclusion, the developed probe is capable of characterizing the excitation mechanism of a liquid metal droplet dispenser. Additionally, real-time monitoring of the performance of the excitation system during long-term operation is possible.

The Effect of Dryer Load on Freeze Drying Process Design

Freeze-drying using a partial load is a common occurrence during the early manufacturing stages when insufficient amounts of active pharmaceutical ingredient (API) are available. In such cases, the immediate production needs are met by performing lyophilization with less than a full freeze dryer load. However, it is not obvious at what fractional load significant deviations from full load behavior begin. The objective of this research was to systematically study the effects of variation in product load on freeze drying behavior in laboratory, pilot and clinical scale freeze-dryers. Experiments were conducted with 5% mannitol (high heat and mass flux) and 5% sucrose (low heat and mass flux) at different product loads (100%, 50%, 10%, and 2%). Product temperature was measured in edge as well as center vials with thermocouples. Specific surface area (SSA) was measured by BET gas adsorption analysis and residual moisture was measured by Karl Fischer. In the lab scale freeze-dryer, the molar flux of inert gas was determined by direct flow measurement using a flowmeter and the molar flux of water vapor was determined by manometric temperature measurement (MTM) and tunable diode laser absorption spectroscopy (TDLAS) techniques. Comparative pressure measurement (capacitance manometer vs. Pirani) was used to determine primary drying time. For both 5% mannitol and 5% sucrose, primary drying time decreases and product temperature increases as the load on the shelves decreases. No systematic variation was observed in residual moisture and vapor composition as load decreased. Further, SSA data suggests that there are no significant freezing differences under different load conditions. Independent of dryer scale, among all the effects, variation in radiation heat transfer from the chamber walls to the product seems to be the dominant effect resulting in shorter primary drying time as the load on the shelf decreases (i.e., the fraction of edge vials increases).

In vitro evaluation of mechanical characteristics of a novel Patent Ductus Arteriosus (PDA) occlusion device with a new lateral pressure measurement study

Persistence of the ductus arteriosus (DA), connecting the aorta to the pulmonary artery, after birth leads to a congenital heart disease known as Patent Ductus Arteriosus (PDA). The objective of this study was to propose a new intraductal design for PDA occlusion and determine the efficacy of the new device by means of an in vitro mechanical evaluation. A novel intraductal design device called the Novel design 36 (ND36) was proposed, fabricated and tested. Mechanical tests included tests to determine the mechanical characteristics, force–displacement characteristics, stiffness, device slenderization, minimum diameter attained, insertion force required to pull device at site and lateral pressure exerted on the PDA walls. Comparative analysis was carried out with the Amplatzer Duct Occluder (AGA Medical Corporation, Golden Valley, MN). The results showed that the ND36 when fully stretched was shorter than the ADO implying an easier in vivo movement. The minimum diameter attained by ND36 is 2.52 mm which is compatible with standard catheter bores of 6–8 Fr (2–2.7 mm) bore sizes. A new setup was devised in order to carry out comparative lateral pressure measurements between the ND36 and ADO. The results showed that the ND36 exerted a pressure of 10 KPa (=75 mm Hg) and the ADO exerted 80 KPa (=600 mm Hg) over the walls of the tubes which is a physiologically promising result for the ND36 as it shows that the ND36 would exert lesser stress on the walls of the duct. The results suggest that the novel intraductal design (ND36) would prove to be a safer, reliable and effective device for PDA occlusion.

Determination of end point of primary drying in freeze-drying process control.

Freeze-drying is a relatively expensive process requiring long processing time, and hence one of the key objectives during freeze-drying process development is to minimize the primary drying time, which is the longest of the three steps in freeze-drying. However, increasing the shelf temperature into secondary drying before all of the ice is removed from the product will likely cause collapse or eutectic melt. Thus, from product quality as well as process economics standpoint, it is very critical to detect the end of primary drying. Experiments were conducted with 5% mannitol and 5% sucrose as model systems. The apparent end point of primary drying was determined by comparative pressure measurement (i.e., Pirani vs. MKS Baratron), dew point, Lyotrack (gas plasma spectroscopy), water concentration from tunable diode laser absorption spectroscopy, condenser pressure, pressure rise test (manometric temperature measurement or variations of this method), and product thermocouples. Vials were pulled out from the drying chamber using a sample thief during late primary and early secondary drying to determine percent residual moisture either gravimetrically or by Karl Fischer, and the cake structure was determined visually for melt-back, collapse, and retention of cake structure at the apparent end point of primary drying (i.e., onset, midpoint, and offset). By far, the Pirani is the best choice of the methods tested for evaluation of the end point of primary drying. Also, it is a batch technique, which is cheap, steam sterilizable, and easy to install without requiring any modification to the existing dryer.

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries