Time Temperature Superposition Evaluation and Modeling for Container Closure System's Seal Performance at Low Temperatures.

There has been a growing interest in the assessment of container closure systems (CCS) for cold storage and shipment. Prior publications have lacked systematic considerations for the impact of dynamic time temperature transition on sealing performance associated with the viscoelastic characteristics of rubber stoppers used in container closure systems (CCSs). This paper demonstrates that sealing performance changes inherently and is fundamentally both time- and temperature-dependent. Our research results display this critical time temperature transition impact on CCS sealing performance by applying compression stress relaxation (CSR) on a rubber stopper for experimental data collection and modeling evaluation. The experimental results agree with modeling evaluation following Maxwell-Wiechert theory and the time temperature superposition based on the Arrhenius and Williams-Landel-Ferry methods. Both testing and modeling data show good consistency, demonstrating that the sealing force inevitably changes over time together with temperature transition because of the viscoelastic nature of the rubber stoppers. Our results show that compression seal force decreases quickly as temperature decreases. The significant loss of rubber stopper sealing force at lower temperature transitions could contribute significant risk to CCI at low storage and transport temperatures. Modeling evaluation, with a powerful capability to handle actual testing data, can be employed as a predictive tool to evaluate the time- and temperature-dependent sealing force throughout the entire sealed drug product life span. The present study is only applicable before reaching the rubber glass transition temperature Tg - a critical transition phase that can not be skipped/separated from real time temperature transition, and it will further determine the CCS sealing performance while approaching cryogenic temperature. The present work provides a new, integrated methodology framework and some fresh insights to the parenteral packaging industry for practically and proactively considering, designing, setting up, controlling, and managing stopper sealing performance throughout the entire sealed drug product life span.

Quantifying the Vial-Capping Process: Reexamination Using Micro-Computed Tomography.

A vial-capping process for lyophilization stopper configurations was previously quantified using residual seal force (RSF). A correlation between RSF and container closure integrity (CCI) was established, and component positional offsets were identified to be the primary source of variability in RSF measurements.To gain insight into the effects of stopper geometry on CCI, serum stoppers with the same rubber formulation were investigated in this study. Unlike lyophilization stoppers that passed CCI (per helium leak testing) even with RSF of 0 N owing to their excellent valve seal, serum stoppers consistently failed CCI when RSF was <15.8 N. When the plug was removed, both types of stoppers exhibited a comparable critical lower RSF limit (19-20 N), below which CCI could not be maintained. When CCI was retested at later time points (up to 6 mo), some previously failed vials passed CCI, suggesting that CCI improvement might be related to rubber relaxation (viscous flow), which can fill minor imperfections on the vial finish.To confirm component positional offsets are the primary sources of RSF variability, a novel quantification tool-micro-computed tomography (micro-CT)-was used in this study. Micro-CT provided images for quantification of positional offsets of the cap and stopper that directly correlated with RSF fluctuations. Serum stoppers and lyophilization stoppers are comparable in RSF variations, although lyophilization stoppers are more robust in CCI. The use of micro-CT provides a nondestructive and innovative tool in quantitatively analyzing component features of capped vials that would otherwise be difficult to investigate.

Long-Term Study of Container Closure Integrity of Rubber-Glass Vial Systems by Multiple Methods.

A one-year study to establish the container closure integrity (CCI) performance landscape of systems comprising rubber stoppers and glass vials was performed. Focus was on addressing the issues of CCI performance versus: (a) time, (b) compression levels and residual seal force (RSF) values, and (c) potential variation in results based upon the deterministic measurement method (tracer gas and frequency modulated spectroscopy). To reduce sample size to a manageable number, the study was based upon a design of experiments that considered a range of: (a) stopper formulations, sizes, and configurations; (b) vial sizes, types, and suppliers; and (c) compression levels. All systems showed good performance; there was no decrease in CCI with time, highlighting the general robustness of rubber-glass vial systems. Lower compression/RSF values tended to give slightly lower performance and wider scatter in data and thus should not be recommended for commercial applications. A small amount of oxygen exchange through the stoppers was observed for all systems-to be expected because rubber is known to be gas permeable. Consistent with models, RSF values decreased initially and then remained constant. Results are consistent with the literature.

[Rubber granules on synthetic turf pitches: safe or not safe for children?] / Rubbergranulaat op kunstgrasvelden.

Rubber granules from old car tyres used in synthetic turf pitches contain a significant number of carcinogenic and endocrine-disrupting chemicals. In 2017 the Dutch National Institute for Public Health and the Environment (RIVM) and the European Chemical Agency (ECHA) concluded that the risks for children are negligible. However, their reports contain some scientific inaccuracies and omissions which may have led them to underestimate the risks for children. It is therefore premature to conclude that it is safe for children to play on synthetic turf pitches with rubber granules. It is now primarily up to the parents to decide whether or not playing sports is acceptable in these circumstances. The Dutch government should, in accordance with ECHA recommendations, advise parents that their children ought to avoid hand-and-mouth contact with these granules as much as possible.

Quantifying the Vial Capping Process: Residual Seal Force and Container Closure Integrity.

Capping completes the closure of parenteral drug products in the final packaging container and is critical in maintaining an integral seal to ensure product quality. Residual seal force (RSF) is considered the sole quantifiable attribute for measuring seal "goodness" and potentially enables nonsubjective, consistent setting of cappers across manufacturing sites. However, the consistency and reliability of RSF measurement and data have been scarcely reported, and the relationship between RSF and container closure integrity (CCI) remains poorly understood.Here, we present a large data set generated from a commercial capper and the results from a laboratory capper of glass vials and rubber stoppers with aluminum caps. All RSF values exhibited significant variability. We evaluated four potential sources of variability: the capper, the RSF tester, the time-dependent nature of RSF, and the components. We determined that the capper, the tester, and the time-dependent nature are not main sources. Dimensional tolerances of the packaging components were the root cause for the container closure system (CCS) configurations tested in this study.This study correlated RSF with CCI (via helium leakage), although CCI is not sensitive to RSF; CCI was maintained even for loosely capped vials with no measurable RSF. This was attributed to the stopper's two sealing surfaces: the valve seal and the land seal. A methodology capable of differentiating the two seals' functions demonstrated that vials with only the valve seal always passed leakage testing for a selected CCS configuration in this study, while vials with only the land seal failed CCI at low RSF values. This observation allows proposal of a low RSF limit that is safe even when the valve seal is defective. Simplified statistical analysis of commercial capping data, with the input of sample size, allowed the relationship between RSF's low limit and an allowable failing rate to be established. Overall, despite the inherent variability of RSF, this study shows that it is a feasible parameter for capping process quantification and demonstrates the potential of RSF measurement in capper setup.LAY ABSTRACT: Pharmaceutical vials are typically closed off with an elastomeric stopper that is secured onto the vial with an aluminum crimp cap (or seal) such that the entire assembly is meant to protect the vial's contents from external contamination. Therefore, the capping process is critical for ensuring container closure integrity. Characterizing the effectiveness of a seal in a nonsubjective and quantifiable manner is challenging. In this communication, we report the evaluation of residual seal force measurements (the compression force that the crimp cap exerts on the stopper) to evaluate capping for a large set of samples generated on both an at-scale commercial capper and a benchtop laboratory capper. We propose a test methodology, based on a statistical approach, for establishing permissible lower residual force limits that would provide a high degree of confidence to the capping process. This is a useful tool for consistent capper setup and capping process quantification.

Artificial Leaks in Container Closure Integrity Testing: Nonlinear Finite Element Simulation of Aperture Size Originated by a Copper Wire Sandwiched between the Stopper and the Glass Vial.

Container closure integrity (CCI) testing is required by different regulatory authorities in order to provide assurance of tightness of the container closure system against possible contamination, for example, by microorganisms. Microbial ingress CCI testing is performed by incubation of the container closure system with microorganisms under specified testing conditions. Physical CCI uses surrogate endpoints, such as coloration by dye solution ingress or gas flow (helium leakage testing). In order to correlate microbial CCI and physical CCI test methods and to evaluate the methods' capability to detect a given leak, artificial leaks are being introduced into the container closure system in a variety of different ways. In our study, artificial leaks were generated using inserted copper wires between the glass vial opening and rubber stopper. However, the insertion of copper wires introduces leaks of unknown size and shape. With nonlinear finite element simulations, the aperture size between the rubber stopper and the glass vial was calculated, depending on wire diameter and capping force. The dependency of the aperture size on the copper wire diameter was quadratic. With the data obtained, we were able to calculate the leak size and model leak shape. Our results suggest that the size as well as the shape of the artificial leaks should be taken into account when evaluating critical leak sizes, as flow rate does not, independently, correlate to hole size. Capping force also affected leak size. An increase in the capping force from 30 to 70 N resulted in a reduction of the aperture (leak size) by approximately 50% for all wire diameters. From 30 to 50 N, the reduction was approximately 33%. LAY ABSTRACT: Container closure integrity (CCI) testing is required by different regulatory authorities in order to provide assurance of tightness of the container closure system against contamination, for example, by microorganisms. Microbial ingress CCI testing is performed by incubation of the container closure system with microorganisms under specified testing conditions. Physical CCI uses surrogate endpoints, such as coloration by dye solution ingress or gas flow. In order to correlate microbial ingress CCI and physical CCI test methods and to evaluate the methods' capability to detect a given leak, artificially created defects (artificial leaks) are being introduced into the container closure system in a variety of different ways. In our study, artificial leaks were generated using inserted copper wires between the glass vial opening and rubber stopper. Up to date, the insertion of copper wires introduced leaks of unknown size and shape. With nonlinear finite element simulations, the effective aperture size between the rubber stopper and the glass vial was calculated, depending on wire diameter and capping force, and the leak shape was modelled. Our results suggest that the size as well as the shape of the artificial leaks should be taken into account when evaluating critical leak sizes, as flow rate does not, independently, correlate to the hole size.

Impact of Vial Capping on Residual Seal Force and Container Closure Integrity.

UNLABELLED: The vial capping process is a critical unit operation during drug product manufacturing, as it could possibly generate cosmetic defects or even affect container closure integrity. Yet there is significant variability in capping equipment and processes, and their relation to potential defects or container closure integrity has not been thoroughly studied. In this study we applied several methods-residual seal force tester, a self-developed system of a piezo force sensor measurement, and computed tomography-to characterize different container closure system combinations that had been sealed using different capping process parameter settings. Additionally, container closure integrity of these samples was measured using helium leakage (physical container closure integrity) and compared to characterization data. The different capping equipment settings lead to residual seal force values from 7 to 115 N. High residual seal force values were achieved with high capping pre-compression force and a short distance between the capping plate and plunge. The choice of container closure system influenced the obtained residual seal force values. The residual seal force tester and piezoelectric measurements showed similar trends. All vials passed physical container closure integrity testing, and no stopper rupture was seen with any of the settings applied, suggesting that container closure integrity was warranted for the studied container closure system with the chosen capping setting ranges. LAY ABSTRACT: The vial capping process is a critical unit operation during drug product manufacturing, as it could possibly generate cosmetic defects or even affect container closure integrity. Yet there is significant variability in capping equipment and processes, and their relation to potential defects or container closure integrity has not been thoroughly studied. In this study we applied several methods-residual seal force tester, a self-developed system of a piezo force sensor measurement, and computed tomography-to characterize different container closure system combinations that had been sealed using different capping process parameter settings. The residual seal force tester can analyze a variety of different container closure systems independent of the capping equipment. An adequate and safe residual seal force range for each container closure system configuration can be established with the residual seal force tester and additional methods like computed tomography scans and leak testing. In the residual seal force range studied, the physical container closure integrity of the container closure system was warranted.

Influence of Different Container Closure Systems and Capping Process Parameters on Product Quality and Container Closure Integrity (CCI) in GMP Drug Product Manufacturing.

Capping equipment used in good manufacturing practice manufacturing features different designs and a variety of adjustable process parameters. The overall capping result is a complex interplay of the different capping process parameters and is insufficiently described in literature. It remains poorly studied how the different capping equipment designs and capping equipment process parameters (e.g., pre-compression force, capping plate height, turntable rotating speed) contribute to the final residual seal force of a sealed container closure system and its relation to container closure integrity and other drug product quality parameters. Stopper compression measured by computer tomography correlated to residual seal force measurements.In our studies, we used different container closure system configurations from different good manufacturing practice drug product fill & finish facilities to investigate the influence of differences in primary packaging, that is, vial size and rubber stopper design on the capping process and the capped drug product. In addition, we compared two large-scale good manufacturing practice manufacturing capping equipment and different capping equipment settings and their impact on product quality and integrity, as determined by residual seal force.The capping plate to plunger distance had a major influence on the obtained residual seal force values of a sealed vial, whereas the capping pre-compression force and the turntable rotation speed showed only a minor influence on the residual seal force of a sealed vial. Capping process parameters could not easily be transferred from capping equipment of different manufacturers. However, the residual seal force tester did provide a valuable tool to compare capping performance of different capping equipment. No vial showed any leakage greater than 10(-8)mbar L/s as measured by a helium mass spectrometry system, suggesting that container closure integrity was warranted in the residual seal force range tested for the tested container closure systems. LAY ABSTRACT: Capping equipment used in good manufacturing practice manufacturing features different designs and a variety of adjustable process parameters. The overall capping result is a complex interplay of the different capping process parameters and is insufficiently described in the literature. It remains poorly studied how the different capping equipment designs and capping equipment process parameters contribute to the final capping result.In this study, we used different container closure system configurations from different good manufacturing process drug product fill & finish facilities to investigate the influence of the vial size and the rubber stopper design on the capping process. In addition, we compared two examples of large-scale good manufacturing process capping equipment and different capping equipment settings and their impact on product quality and integrity, as determined by residual seal force.

The Pharmaceutical Capping Process-Correlation between Residual Seal Force, Torque Moment, and Flip-off Removal Force.

The majority of parenteral drug products are manufactured in glass vials with an elastomeric rubber stopper and a crimp cap. The vial sealing process is a critical process step during fill-and-finish operations, as it defines the seal quality of the final product. Different critical capping process parameters can affect rubber stopper defects, rubber stopper compression, container closure integrity, and also crimp cap quality. A sufficiently high force to remove the flip-off button prior to usage is required to ensure quality of the drug product unit by the flip-off button during storage, transportation, and until opening and use. Therefore, the final product is 100% visually inspected for lose or defective crimp caps, which is subjective as well as time- and labor-intensive. In this study, we sealed several container closure system configurations with different capping equipment settings (with corresponding residual seal force values) to investigate the torque moment required to turn the crimp cap. A correlation between torque moment and residual seal force has been established. The torque moment was found to be influenced by several parameters, including diameter of the vial head, type of rubber stopper (serum or lyophilized) and type of crimp cap (West(®) or Datwyler(®)). In addition, we measured the force required to remove the flip-off button of a sealed container closure system. The capping process had no influence on measured forces; however, it was possible to detect partially crimped vials. In conclusion, a controlled capping process with a defined target residual seal force range leads to a tight crimp cap on a sealed container closure system and can ensure product quality. LAY ABSTRACT: The majority of parenteral drug products are manufactured in a glass vials with an elastomeric rubber stopper and a crimp cap. The vial sealing process is a critical process step during fill-and-finish operations, as it defines the seal quality of the final product. An adequate force to remove the flip-off button prior to usage is required to ensure product quality during storage and transportation until use. In addition, the complete crimp cap needs to be fixed in a tight position on the vial. In this study, we investigated the torque moment required to turn the crimp cap and the force required to remove the flip-off button of container closure system sealed with different capping equipment process parameters (having different residual seal force values).

Shape optimization of rubber bushing using differential evolution algorithm.

The objective of this study is to design rubber bushing at desired level of stiffness characteristics in order to achieve the ride quality of the vehicle. A differential evolution algorithm based approach is developed to optimize the rubber bushing through integrating a finite element code running in batch mode to compute the objective function values for each generation. Two case studies were given to illustrate the application of proposed approach. Optimum shape parameters of 2D bushing model were determined by shape optimization using differential evolution algorithm.

[Species specificity of fungi isolated from the affected rubber tires and their components].

The mycobiota of the rubber technical wares, containing different plasticizers (natural and synthetic) have been investigated. Violation of production technology and storage conditions of the staggered rubber tires, caused their deterioration by the microfungi. Twenty seven (27) species of micromycetes, related to 16 genera were isolated from the surface and internal layers of such objects and their components. A number of species, which can exist theoretically on investigated rubber tires and their components, is calculated. The unfavorableness of the existence conditions for majority of fungi on such substrates is proved. The groups of species, which make the most contribution to deterioration of rubber tires and their components were revealed. These data were obtained using the methods of floristic analysis and computer processing of the data.

Avaliação da intensidade das forças liberadas por ligaduras elásticas de diferentes cores / Evaluation of intensity of forces liberated by different colour elastic ligatures

Foi avaliada a intensidade das forças liberadas por ligaduras elásticas de cinco cores quando imersas em solução de saliva artificial. As amostras foram testadas por meio de uma máquina de ensaios de tração, nos períodos de tempo inicial, 1 dia, 7, 14, 21 e 28 dias de imersão em saliva artificial. Encontrou-se uma diminuição acentuada e estatisticamente significante nas forças liberadas para as primeiras 24 horas (P<0,0001), sendo que entre os demais períodos (7, 14, 21, 28 dias) ocorreu uma queda gradativa não significante destes valores. Entretanto, não houve diferença significante para as magnitudes de forças liberadas pelas ligaduras elásticas modulares em relação às diferentes cores analisadas

Latex allergy diagnosis: in vivo and in vitro standardization of a natural rubber latex extract.

For the diagnosis of IgE-mediated (immediate) hypersensitivity to natural rubber latex (NRL), skin prick testing with extracts of latex gloves has been widely used, but such extracts are difficult to standardize. The present study aimed to produce on an industrial scale an NRL extract from freshly collected NRL and to evaluate, calibrate, and standardize the extract by both in vivo and in vitro testing. The source material, latex of the rubber tree, Hevea brasiliensis (clone RRIM 600), was frozen immediately after collection in Malaysia and shipped in dry ice to Stallergènes SA, France. Protein and allergen profiles were analyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), immunoblotting, isoelectric focusing (IEF), crossed immunoelectrophoresis (CIE), and crossed radioimmunoelectrophoresis (CRIE). Allergen quantification was effected by RAST inhibition. The capacity of the preparation to elicit immediate hypersensitivity reactions in vivo was measured by skin prick testing in 46 latex-allergic patients and 76 nonallergic control subjects. SDS-PAGE and immunoblot profiles of the extract and an NRL standard (E8) provided by the US Food and Drug Administration were almost identical, disclosing several distinct IgE-binding proteins with apparent molecular weights of 14, 20, 27, 30, and 45 kDa, conforming to reported molecular weights of several significant NRL allergens. An arbitrary index of reactivity (IR) of 100 was assigned to the extract at 1:200 dilution (w/v), having a protein content of 22 micrograms/ml. Skin prick testing of latex-allergic patients and controls using the extract at 100 IR revealed 93% sensitivity, 100% specificity, 100% negative predictive value, and 96% positive predictive value. In conclusion, a skin prick test reagent for diagnosis of type I NRL allergy was successfully standardized. The reagent was demonstrated to contain most, if not all, of the currently known clinically significant NRL allergens, and it showed high sensitivity and specificity.

Determination of lubricating film thickness for permeable hydrogel and non-permeable polyurethane layers bonded to a rigid substrate with particular reference to cushion form hip joint replacements.

The lubricating film thickness in a model of compliant layered bearings, using both permeable hydrogels and non-permeable polyurethane elastomers for total hip joint replacements, has been measured using optical interferometry, under both entraining and squeeze-film motion. The film thickness in the lubricated contact was measured for both water and a 40 per cent glycerol solution in water as a function of entraining velocity and squeeze-film time. The measured lubricating film thickness for the permeable hydrogel was compared to that of the non-permeable polyurethane elastomer and little difference was found when the lubricating film thickness was sufficiently large (greater than 150 nm). Comparison of the experimental results and the theoretical predictions based upon elastohydrodynamic lubrication analysis showed good agreement in the entraining experiments where the film thickness was greater than 150 nm. In the squeeze-film experiments the experimental measurements were greater than the theoretical predictions for all squeeze times due to the formation of a central pocket of fluid which was not predicted by the simple theory used. This also occurred for the hydrogels for films greater than 150 nm. For longer squeeze times the film thickness for the hydrogel fell below the theoretical prediction. This was considered to be due to the permeability of the hydrogel reducing the film thickness when the film thickness was less than 150 nm. The permeability of the hydrogel was not modelled in the theoretical lubrication analysis used in this study.

Estudo comparativo entre diferentes parâmetros utilizados no controle da qualidade de materiais elastoméricos para uso em equipamentos odonto-médico-hospitalares / Elastomeric materials dental-medical-hospital equipment use: quality control and metodology avaluation

Foram analisados 22 amostras de materiais elastoméricos para uso em equipamentos odonto-médicos-hospitalares por três regulamentos técnicos: legislaçäo brasileira - Portaria 23/64, que establece testes padronizados para avaliar a qualidade de embalagens e equipamentos para produtos farmacêuticos em geral; norma alemä - DIN 58367, de 1986 e Farmacopéia Americana - USP XXII ediçäo, que estabelecem testes específicos para materiais elastoméricos. Os resultados demonstraram que foram aprovados respectivamente: 18,2, 31,8 e 13,6(por cento) das amostras, quando analisadas por estas três metodologias. Em todos os casos, a porcentagem de aprovaçäo foi muito baixa, e portanto a qualidade das mesmas näo é satisfatória. Este estudo tem como objetivo, além de efetuar um levantamento sobre a qualidade destes produtos, sugerir que seja elaborada, pelos órgäos competentes do Ministério da Saúde, uma legislaçäo nacional específica para o controle destes materiais.

Influence of dimensional stability of impression materials on the probability of acceptance of a prosthetic restoration.

The accuracy of rubber impression materials was evaluated by taking impressions of a steel model, pouring it with stone and comparing certain measurements between steel and stone models. It is assumed that acceptance is achieved when the difference in measurements is within permissible limits, defined by clinical criteria. A mathematical formulation of these criteria will lead to the concept of probability of acceptance. The probability is affected when the limits are changed. The particular case of satisfying two acceptance criteria that contain variables which are not statistically independent is considered, leading to the application of the bivariate normal distribution in the evaluation of acceptance probability.

Biocompatibility evaluation of laser-induced AAm and HEMA grafted EPR. Part 1: In-vitro study.

Samples based on ethylene-propylene rubber (EPR) have been surface grafted with acrylamide (AAm) and 2-hydroxyethyl methacrylate (HEMA) using CO2-pulsed laser as a stimulation source. Scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDXA) and attenuated total reflectance infrared (ATR-IR) spectra were performed on the modified samples. These techniques revealed the formation of grafted poly(AAm) and poly(HEMA) on the surface of EPR. The surface grafted poly(AAm) and poly(HEMA) were found to have a fractal type of morphology. EDXA showed insignificant grafted AAm and HEMA in regions where fractals were absent. Fractal patterned surfaces provide hydrophilic and hydrophobic sites, making EPR suitable as a biomaterial. In-vitro adhesion and spreading of alveolar macrophages (AMs) cultured on the surface of modified samples have been evaluated by hemocytometry and SEM, respectively, and compared with unmodified controls. Relationships between AM adhesion and their spreading, with surface morphology, graft level and water compatibility are also discussed. Generally, more AMs attach onto unmodified surfaces with a greater degree of spreading, than on the modified EPR. Samples grafted between 0.7 mg/cm2 and 1 mg/cm2 showed fairly low AM density compared with both unmodified EPR and lightly modified samples (less than 0.2 mg/cm2). AMs cultured on the unmodified EPR were larger and displayed pronounced ruffling of the plasma membrane, an increased capacity for adherence and spreading on the surface, and an increased number of extensive filopodia. Moreover, AMs attached onto the surface of modified samples appeared rounded, with minimal cytoplasmic spreading and ruffling.