Lavagem, preparo e esterilização de materiais / Lavado, preparación y esterilización de materiales / Washing, preparation and sterilization of materials

Esta Norma Técnica tem por objetivo estabelecer os critérios para lavagem, preparo e esterilização de vidrarias e materiais utilizados nos processos de manipulação e controle da qualidade do leite humano ordenhado, visando a garantia da qualidade em Bancos de Leite Humano e Postos de Coleta de Leite Humano e sua certificação.

Esta Norma Técnica tiene por objetivo establecer los criterios de lavado, preparación y esterilización de la vidriería y materiales utilizados en los procesos de manipulación y control de calidad de la leche humana extraída, con el fin de asegurar la calidad en los Bancos de Leche Humana y Centros de Recolección de Leche Humana y su certificación.

Long-term stability of an infusion containing paracetamol, alizapride, ketorolac and tramadol in glass bottles at 5±3°C.

Background and objective: Infusion containing paracetamol, alizapride, ketorolac and tramadol is used after a general anaesthesia in order to limit pain, fever and nausea. Currently, these infusions are prepared according to demand in the anaesthesia unit, but the preparation in advance could improve quality of preparation and time management. The aim of this study was to investigate the long-term stability of this infusion in glass bottles at 5°C ± 3 °C. Method: Five bottles of infusion were stored at 5°C ± 3 °C for 60 days. A visual and microscope inspection were performed periodically to observe any particle appearance or colour change. pH and absorbance at three wavelengths were measured. The concentrations were measured by ultra-high performance liquid chromatography - diode array detection. Results: Multiple verifications were performed during the first 35 days and no crystal, impurity or colour change were observed. At the next time point (42nd day), crystals were visible to the naked eye. pH and absorbance at 350 nm and 550 nm were stable. A slight increase in the absorbance at 410 nm was observed during the study, suggesting that a degradation product could be formed and absorb at this wavelength. The infusion was considered chemically stable while the lower one-sided prediction limit at 95% remains superior to 90% of the initial concentration. Concentration measurements demonstrated that ketorolac and alizapride remained stable in the infusion for 35 days. The stability of tramadol was 28 days. However, degradation of paracetamol was much faster given that concentration has fallen below 90% of the initial concentration after 7 days. Conclusion: Infusion of paracetamol, alizapride, ketorolac and tramadol remains stable for 7 days in glass bottles at 5°C ± 3 °C and could be prepared in advance with these storage conditions.

Standardization of Sandwich-Structured Cu-Glass Substrates Embedded in a Flexible Diode Laser-Plasma Interface for the Detection of Cholesterol.

This study introduced sandwich-structured copper-glass substrates for standardization of laser desorption and plasma ionization. For standardized quantitative analysis, cavities were constructed which allow better reproducibility in droplet deposition and for laser application. Applying the diode laser, molten substrate material is incorporated into the glass, being trapped inside. Therefore, this method can be separated from laser ablation, achieving high ion signals without ablating material from the surface. Flexible microtube plasma (FµTP) was selected as the ionization source, this being the first time that laser desorption and FµTP ionization are coupled. This laser-plasma interface was applied to the detection of cholesterol, which showed a significantly improved limit of detection of 0.46 ng and linear dynamic range of 3 orders of magnitude in positive ion mode compared to other (ambient air mass spectrometry) methods. The main reason was the change of phase on the copper surface. The dehydrated molecule [M-H2O+H]+ was the base peak of the spectrum and no further dissociation or fragmentation was observed. Blood plasma was spiked with cholesterol. In a 1:100 chloroform dilution, the presence of the plasma was neglectable and led to the same detection limits and linear dynamic range as in the cholesterol standard. No sample preparation or internal standards were needed for calibration. The physical effects of the surface modification were investigated, including the calculation of the laser beam waist to simplify the comparison and reproducibility of results.

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.

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.

Use of a Predictive Regression Model for Estimating Hold-Up Volume for Biologic Drug Product Presentations.

A drug delivery system is designed to administer a therapeutic dose according to its label claim. Upon delivery of a parenteral drug product, the volume remaining inside the container that cannot be extracted at the end of drug administration is called the hold-up volume (HUV) and is primarily considered product wastage. To meet the label claim, every drug product container is filled with a slight excess volume. For early-stage products in clinical phase, for which material availability is often a limitation, excess volume in drug product containers has to be determined experimentally using several grams of product. In such scenarios, established models that can predict HUV in primary drug product containers would be valuable for product development. The objective of this study was to determine HUV with 95% confidence intervals across various container closures and drug delivery systems by using aqueous PEG 400 solution mimicking the viscosity of biologic drug products. ISO 2R, 6R, and 10R vials and single-use hypodermic syringes attached to a Luer lock needle (25 gauge, 1½ in.) were used to mimic parenteral drug product container and delivery systems for determination of HUV. Glass prefilled syringes in 1 mL and 2.25 mL configurations were also used to determine HUV with 95% confidence intervals. A linear regression model was developed for determination of HUV as a function of viscosity and as a function of container closure and a needle-based delivery system. This model predicting HUV was confirmed by using monoclonal antibodies of varying formulations and viscosities for container closure and delivery systems tested in this study. The model provided here can be used to determine HUV for a particular container closure for a drug solution with known viscosity that can subsequently be used to evaluate fill volume specifications and label claim for a dosage form.

Investigating the Effects of the Chemical Composition on Glass Corrosion: A Case Study for Type I Vials.

Glass is the favorite material for parenteral packaging because of its physico-chemical properties. Type I borosilicate glass is worldwide use at this scope, but it may have some issues related to breakage, corrosion and delamination that might compromise the drug quality, safety and efficacy. These issues can be mitigated and avoided starting from the appropriate selection of the most suitable raw material at the early stage of the glass container design. In this study, Type I borosilicate glass vials manufactured using two glass tubes having different chemical compositions, were studied and compared in terms of their resistance to corrosion. Testing design was applied with the aim to select the best practice approach comparing different storage simulation conditions: ageing treatment through autoclaving and stability testing (real-time and accelerated). Clear differences were found between the different glass types in terms of hydrolytic and corrosion resistance that highlighted the relation between chemical composition and glass chemical durability. Non-negligible differences were also observed using different storage conditions.

Commonly used adjuvants (liquid soap, foam sanitizer, or ultrasound gel) do not improve strength or curing time of fiberglass cast material.

BACKGROUND: Bone fractures are one of the most common injuries in the USA. Fiberglass tape is a commonly used casting material, and many medical professionals apply adjuvants including liquid hand soap, foam sanitizers, and ultrasound gel in the hopes of improving outcomes relating to ease of molding and eventual strength, lamination, and smoothness of cast material. However, the efficacy of these agents to improve fiberglass cast mechanics has not been scientifically evaluated. The purpose of this study was to assess the mechanical effects of commonly used adjuvants on fiberglass cast materials. METHODS: Studies compared regularly shaped samples of water-activated, untreated fiberglass tape (Ossur Techform Premium) to water-activated fiberglass tape treated with one of three commonly used adjuvants (liquid soap, foam hand sanitizer, or ultrasound gel) during lamination. Material stiffness, yield stress, and ultimate load were measured by 3-point bending. RESULTS: These studies demonstrated that that liquid soap and ultrasound gel did not affect fiberglass tape mechanical properties, but alcohol-based foam sanitizer significantly reduced stiffness (- 32.8%), yield stress (- 33.6%), and ultimate load (- 31.0%) of the cast material as compared to the control group. Regression slopes were not significantly different between groups, suggesting that no adjuvants improved material curing time. CONCLUSIONS: These data suggest that the application of adjuvants is not beneficial and potentially harmful to fiberglass cast behavior. Despite the widespread practice of adjuvant application by medical professionals during casting, results from the current study suggest that use of these agents for structural enhancement of fiberglass casts is not beneficial and should largely be discouraged.

Comparative Leachable Study of Glass Vials to Demonstrate the Impact of Low Fill Volume.

The pharmacopeia method for measuring the chemical durability of parenteral glass packaging is the hydrolytic resistance test in which the vial is filled to 90% of its brimful volume as described, for example, in USP <660>. However, an increasing number of innovative drugs are filled significantly below the nominal volume of the vial. As a consequence, the determined hydrolytic resistance is not representative of the concentrations of leached "glass" elements for low fill volumes. This is attributable to two main factors: Firstly, an increasing ratio of the wetted surface to volume and secondly an increased leaching tendency typically observed with borosilicate glass of the wall near bottom area, especially when standard manufacturing technology is applied.The extent of both contributing effects has been analyzed by determining the amounts of the representative leached "glass" elements, boron, sodium, and silicon, after vial storage for 24 weeks at 40°C with different fill volumes (0.5, 1.0, and 2.0 mL). The vials which have been investigated in this study have a nominal fill volume of 2 mL, were made from Type I class B borosilicate glass (Fiolax®) and from aluminosilicate glass and were filled with either purified water or a 15% KCl solution.The standard conversion process for tubing into vials was used for Fiolax vials (standard quality vials) and for aluminosilicate vials. In addition, an optimized conversion process (delamination controlled technology) was used to create low-fill quality Fiolax vials. The vial quality obtained from the two different converting technologies greatly influenced the concentrations of leached "glass" elements measured, especially when low fill volumes were used.LAY ABSTRACT: Borosilicate glass containers, because of their chemical inertness, excellent barrier properties, high transparency, and mechanical stability, have been successfully used for decades to package parenteral drug formulations. Nevertheless, Type I glass can be altered over a period of time when in contact with the drug formulation. The result of this interaction is even more pronounced for some new innovative drugs that are delivered to the patient in small dosages significantly below the nominal storage capacity of the glass vials. When the fill volume of the vials is reduced, the contribution of the bottom area to the wetted surface increases, resulting in a higher surface-to-volume ratio. Therefore, the concentrations of leached elements will be increased and this can cause problems for sensitive medical products. This effect is not usually observed with the standard test procedures described in the pharmacopeia because the vials are filled with a high volume to 90% brimful capacity (e.g., as described in USP <660>). In this study, the leachable behaviors of vials made of borosilicate and aluminosilicate glass were evaluated by using medium and low fill volumes with storage for 24 weeks at 40°C. The standard conversion process to manufacture a vial from glass tubing introduces volatile "glass" elements into the vial wall near the bottom area. This mechanism has been described and supported by time-of-flight secondary ion mass spectrometry (TOF-SIMS) measurements of the inner vial surface as reported by Rupertus et al. The diffusion mechanism of volatile components will increase the leaching propensity of the vial, especially for low fill volumes. However, innovative manufacturing techniques are able to avoid the diffusion of volatile elements into the wall near the bottom area. This is achieved by a specific process setup in combination with a suitable monitoring test during vial production, which gives a quantitative measure of the leaching tendency of the wall near the bottom area. Borosilicate glass vials manufactured with this setup (low-fill quality vials) showed a drastic reduction in leachables, especially with low fill volumes. Vials composed of a boron-free glass showed no advantages in terms of leaching behavior when compared with borosilicate glass vials in general.

Introducing the Alba® Primary Packaging Platform. Part 2: Inorganic Extractables Evaluation.

Sensitivity of drugs to one or more elements of the primary packaging is a serious concern for the pharmaceutical industry. Biologics in particular are highly sensitive, leading to a higher risk of incompatibility and stability test failure as worst-case scenario.This potential incompatibility-and the consequent formulation instability due to the interactions between the drug and the primary container surface-may have multiple causes: the intrinsic nature of the container surface, leachables coming from the materials used, substances coming from the production process, or silicone oil droplets or other particles.The Alba primary packaging platform was designed to have the same interface between the drug and the glass container surface on the different primary packaging containers in order to minimize the emergence of instabilities at later stages of formulation development. Alba containers are internally treated with an innovative cross-linked coating based on silicone oil lubricant, and the additional rubber components have been selected to minimize the possible differences between the container typologies.This paper shows in great detail the reduction of the inorganic extractables released and the comparability of the performances of the different containers obtained using Alba technology.The improvement has been demonstrated by stressing the containers with different extract solutions; Alba-coated containers show a strong reduction of inorganic extractables and of corrosion degree compared to spray-on siliconized and bulk products. The containers included in the Alba platform present comparable results, and this represents a strong advantage during the drug formulation development by facilitating the transition from one container to another.LAY ABSTRACT: The sensitivity of drugs to one or more elements of the primary packaging is a serious concern for the pharmaceutical industry. Biologics in particular are highly sensitive, leading to a higher risk of incompatibility and stability test failure worst-case scenario.This potential incompatibility-and the consequent formulation instability due to the interactions between the drug and the primary container surface-may have multiple causes: the intrinsic nature of the container surface, leachables coming from the materials used, substances coming from the production process, or silicone oil droplets or other particles.The Alba primary packaging platform was designed to minimize these problems associated with the interaction between the drug and its primary packaging. This paper shows in great detail and with robust data the inorganic extractables release reduction and the delamination risk mitigation obtained using the Alba technology.

Comparing Physical Container Closure Integrity Test Methods and Artificial Leak Methodologies.

The sterility of drug products intended for parenteral administration is a critical quality attribute (CQA) because it serves to ensure patient safety and is thus a key requirement by health authorities. While sterility testing is a probabilistic test, the assurance of sterility is a holistic concept including adequate design of manufacturing facilities, process performance, and product design. Container closure integrity testing (CCIT) is necessary to confirm the integrity of a container closure system (CCS), until the end of a product's shelf life. The new and revised United States Pharmacopeia (USP) General Chapter <1207> is a comprehensive guidance on CCI. Nevertheless, practical considerations including the choice of CCIT methods, the acceptance criteria, or the positive control samples (artificial leaks) must be addressed by the pharmaceutical manufacturer.This study is the first to provide a systematic comparison of four commonly used physical CCIT (pCCIT) methods [Helium (He) leak, vacuum decay, laser-based headspace analysis (HSA), and dye ingress] and four commonly used modes of creating artificial leaks (laser-drilled micro holes, copper wire introduced leaks, and two types of capillary leaks).The results from these experiments provide comprehensive data to allow a direct comparison of the capabilities of the individual methods. The results confirmed that the He leak detection method, which is considered the "gold-standard" for pCCIT regarding method sensitivity, indeed demonstrates the highest detection sensitivity (lowest detection limit). In comparison to the dye ingress method, HSA and vacuum decay also demonstrated better detection sensitivity in our study.Capillary leaks with orifice diameter (capillary leak with flow according to an ideal orifice) and micro holes yielded similar leak rates, whereas capillaries with nominal diameters yielded significantly lower leak rates. In conclusion, method sensitivity cannot be compared by means of a leak diameter, but requires the consideration of multiple impacting factors (e.g., path length, uniformity).LAY ABSTRACT: Sterility of drug products intended for parenteral administration is a critical quality attribute to ensure patient's safety and is thus a key requirement by health authorities. The absence of microbial contamination must be demonstrated by container closure integrity (CCI) of the container closure system (CCS). Currently, the revised United States Pharmacopeia (USP) General Chapter <1207> provides the most extensive guidance on how CCI should be assessed. Nevertheless, practical considerations on the choice of an appropriate CCIT method, artificial leaks or the choice of an acceptance criteria are lacking and must be addressed by the pharmaceutical manufacturer.This study provides a systematic comparison of four commonly used physical CCIT (pCCIT) methods [Helium (He) leak, vacuum decay, laser-based headspace analysis (HSA) and dye ingress] and four commonly used modes of creating artificial leaks (laser-drilled micro holes, copper wire introduced leaks, and two types of capillary leaks).

An Evaluation of the Glass Vial Hydrolytic Resistance Method.

The European Pharmacopoeia (Ph. Eur.) hydrolytic resistance method for glass vials is routinely used to screen pharmaceutical glass vial supply. In an effort to better understand and control the factors affecting method precision and robustness, several potential sources of variability in the Ph. Eur. alkalinity method have been studied for 3 cc glass vials. Method parameters including vial rinsing, vial covering, autoclave cycle execution, sample hold times, and titration procedure were evaluated in this study. The results of this study indicate the method parameters which require stringent control in order to achieve acceptable method precision and robustness.LAY ABSTRACT: The European Pharmacopoeia (Ph. Eur.) hydrolytic resistance method for glass vials is routinely used to screen biopharmaceutical glass vial supply. The method was studied to assess contributions to its variability and to potentially improve its reliability. The results of this study indicate which method parameters require stringent control in order to generate reliable data using the Ph. Eur. hydrolytic resistance method.

Impact of Natural Variations in Freeze-Drying Parameters on Product Temperature History: Application of Quasi Steady-State Heat and Mass Transfer and Simple Statistics.

Inter- and intra-batch variability in heat and mass transfer during the drying phase of lyophilization is well recognized. Heat transfer variability between individual vials in the same batch arise from both different positions in the vial array and from variations in the bottom contour of the vials, both effects contributing roughly equally to variations in the effective heat transfer coefficient of the vials, Kv. Both effects can be measured in the laboratory, and variations in average Kv values as a function of vial position in the array for lab and production can be calculated by use of the simple steady-state heat and mass transfer theory. Typically, in the laboratory dryer, vials on the edge of the array, "edge vials," run 2-4°C warmer than "center vials," but differences between laboratory and manufacturing temperatures are modest. The variability in mass transfer can be assigned to major variations in ice nucleation temperature (both intra-batch and inter-batch), including major differences between laboratory and manufacturing. The net effect of all random variations, for each class of vial, can be evaluated by a simple statistical model-propagation of error, which then allows prediction of the distribution in product temperatures and drying times, and therefore prediction of percent of vials dry and percent of vials collapsed and proximity to the edge of failure for a given process. Good agreement between theoretical and experimentally determined maximum temperatures in primary drying and percent collapsed product demonstrates the calculations have useful accuracy.

Tackling bioactive glass excessive in vitro bioreactivity: Preconditioning approaches for cell culture tests.

Bioactive glasses (BGs) are being increasingly considered for biomedical applications in bone and soft tissue replacement approaches thanks to their ability to form strong bonding with tissues. However, due to their high reactivity once in contact with water-based solutions BGs rapidly exchange ions with the surrounding environment leading in most cases to an undesired increase of the pH under static in vitro conditions (due to alkaline ion "burst release"), making difficult or even impossible to perform cell culture studies. Several pre-conditioning treatments have been therefore proposed in laboratories worldwide to limit this problem. This paper presents an overview of the different strategies that have been put forward to pre-treat BG samples to tackle the pH raise issue in order to enable cell biology studies. The paper also discusses the relevant criteria that determine the selection of the optimal pre-treatment depending on the BG composition and morphology (e.g. particles, scaffolds). STATEMENT OF SIGNIFICANCE: Bioactive glasses (BGs), since their discovery in 1971 by L.L Hench, have been widely used for bone replacement and repair, and, more recently, they are becoming highly attractive for bone and soft tissue engineering applications. BGs have in fact the ability to form a strong bond with both hard and soft tissues once in contact with biological fluid. The enhanced interaction of BGs with the biological environment is based on their significant surface bioreactivity. This surface effect of BGs is, on the other hand, problematic for cell biology studies by standard (static) cell culture methods: an excessive bioreactivity leads in most cases to a rapid and dramatic increase of the pH of the surrounding medium, which results in cell death and makes cell culture tests on BG samples impossible. The BG research community has been aware of this for many years and numerous pre-treatments have been proposed by different groups worldwide to limit this problem. For the first time, we have reviewed in this paper the variety of surface preconditioning treatments that have been put forward over the years, we provide a summary of such pre-treatments used in laboratory practice, discussing and offering criteria that can be used for the determination of the optimal pre-treatment depending on BG composition and morphology of the sample tested (bulk, particulate, scaffolds). The information and discussion provided in this review should support best research practice when testing bioactive glasses in cell culture.

Characterization of surface properties of glass vials used as primary packaging material for parenterals.

The appropriate selection of adequate primary packaging, such as the glass vial, rubber stopper, and crimp cap for parenteral products is of high importance to ensure product stability, microbiological quality (integrity) during storage as well as patient safety. A number of issues can arise when inadequate vial material is chosen, and sole compliance to hydrolytic class I is sometimes not sufficient when choosing a glass vial. Using an appropriate pre-treatment, such as surface modification or coating of the inner vial surface after the vial forming process the glass container quality is often improved and interactions of the formulation with the surface of glass may be minimized. This study aimed to characterize the inner surface of different type I glass vials (Exp33, Exp51, Siliconized, TopLyo™ and Type I plus®) at the nanoscale level. All vials were investigated topographically by colorimetric staining and Scanning Electron Microscopy (SEM). Glass composition of the surface was studied by Time-of-Flight - Secondary Ion Mass Spectrometry (ToF-SIMS) and X-ray Photoelectron Spectroscopy (XPS), and hydrophobicity/hydrophilicity of the inner surface was assessed by dye tests and surface energy measurements. All containers were studied unprocessed, as received from the vendor, i.e. in unwashed and non-depyrogenized condition. Clear differences were found between the different vial types studied. Especially glass vials without further surface modifications, like Exp33 and Exp51 vials, showed significant (I) vial-to-vial variations within one vial lot as well as (II) variations along the vertical axis of a single vial when studying topography and chemical composition. In addition, differences and heterogeneity in surface energy were found within a given tranche (circumferential direction) of Exp51 as well as Type I plus® vials. Most consistent quality was achieved with TopLyo™ vials. The present comprehensive characterization of surface properties of the different vial types may serve as basis to further guide the selection of adequate primary packaging based on the desired quality target product profile and to support studies of glass surface interactions with formulations. The proposed analytical method panel can be used for characterization of future glass vials either before delivery to the manufacturer or drug product manufacturing.

Enhancing Patient Safety through the Use of a Pharmaceutical Glass Designed To Prevent Cracked Containers.

An essential role of packaging material for the storage and delivery of drug products is to provide adequate protection against contamination and loss of sterility. This is especially important for parenteral containers, as lack of sterility or contamination can result in serious adverse events including death. Nonetheless, cracked parenteral containers are an important source of container integrity failures for injectable drugs and pose a serious risk for patients. Despite significant investments in inspection technology, each year many injectable drugs are investigated and recalled for sterility risks associated with cracked borosilicate containers. Multiple studies and the many difficulties in detection of cracked containers suggest that the magnitude of the public health risk is even larger than the recall rate would suggest. Here we show that the root cause of cracked parenteral containers (low internal energy following annealing) is inherent to the glasses currently used for primary packaging of the majority of injectable drugs. We also describe a strengthened aluminosilicate glass that has been designed to prevent cracks in parenteral containers through the use of an engineered stress profile in the glass. Laboratory tests that simulate common filling line damage events show that the strengthened aluminosilicate glass is highly effective at preventing cracks. Significant safety benefits have been demonstrated in other industries from the use of special stress profiles in glass components to mitigate failure modes that may result in harm to humans. Those examples combined with the results described here suggest that a significant improvement in patient safety can be achieved through the use of strengthened aluminosilicate glass for parenteral containers.LAY ABSTRACT: Cracks are small cuts or gaps in a container which provide a pathway for liquid, gas, or microbes through a glass container. When these defects are introduced to conventional glass containers holding injectable medicines, the affected drug can pose serious risks to the patient receiving that medication. Specifically, the drug product may become less effective or even non-sterile, which could lead to bloodstream infections and, in some cases, death. This article presents a review of some previously documented cases of cracked glass containers that led to patient infections and deaths. Following a survey of common crack locations in glass vials, lab-based methods for replicating these cracks are presented. These methods are then used to compare the fracture response of vials made from conventional borosilicate glass and strengthened aluminosilicate glass. The results show that stable cracks are essentially prevented (at least 31 times less likely to occur) in the strengthened aluminosilicate glass containers (relative to conventional borosilicate glass). This improvement in safety is similar to improvements already engineered into other glass product designs by utilizing stored strain energy to mitigate certain failure modes.

A Comparison of Protein Stability in Prefillable Syringes Made of Glass and Plastic.

The development of protein therapeutics requires stabilization of these labile molecules during shipment and storage. Biologics, particularly monoclonal antibodies, are frequently packaged at high concentration in prefillable syringes traditionally made of glass. However, some biologics are unstable in glass due to sensitivity to silicone oil, tungsten, glue, or metal ions. Syringes made from the plastic cyclic olefin polymer, Daikyo Crystal Zenith® (CZ), with a Flurotec-laminated piston, have none of these issues. This study compared the stability of several proteins including biotherapeutics when stored up to 14 months at 5 °C and 25 °C in prefillable siliconized syringes made of glass or silicone oil-free CZ syringes, and when subjected to mild agitation by end-over-end rotation at room temperature. At each time point, proteins were analyzed by several techniques including turbidity, size exclusion high-performance liquid chromatography, reversed phase high-performance liquid chromatography, ion-exchange chromatography, electrophoresis, and light scattering to monitor changes in aggregation and degradation. The results show that proteins have comparable stability when stored in glass syringes or in syringes made of CZ sterilized by E-beam or autoclave. In addition, proteins stressed by agitation were generally more stable and aggregated less in syringes made of CZ than in ones made of glass.LAY ABSTRACT: Biotherapeutic protein drugs such as monoclonal antibodies are frequently packaged at high concentration in prefillable syringes, which allows the drug to be directly administered by the patient or caregiver. Protein drugs, or biologics, can be unstable, and may aggregate, particularly when shaken. These aggregates can be immunogenic, stimulating the body's immune system to produce antibodies that can reduce the drug's efficacy. Although prefillable syringes are traditionally made of glass, some biologics are unstable in glass syringes due to the presence of substances used in their manufacture, including silicone oil, which is necessary for lubricity. Syringes made from the plastic cyclic olefin polymer, Daikyo Crystal Zenith® (CZ), have none of these issues. This study compared the stability of several biotherapeutic proteins when stored up to 14 months at 5 °C and 25 °C in prefillable siliconized syringes made of glass or silicone oil-free CZ syringes, and when mildly agitated at room temperature. Proteins were analyzed by several techniques to detect changes in aggregation and degradation. The results show that biotherapeutic proteins have similar stability whether stored in syringes made of glass or CZ. In addition, proteins subjected to agitation were generally more stable and aggregated less in CZ syringes than in glass syringes.

Method Development for Container Closure Integrity Evaluation via Headspace Gas Ingress by Using Frequency Modulation Spectroscopy.

USP <1207.1> Section 3.5 states that "A deterministic leak test method having the ability to detect leaks at the product's maximum allowable leakage limit is preferred when establishing the inherent integrity of a container-closure system." Ideally, container closure integrity of parenteral packaging would be evaluated by measuring a physical property that is sensitive to the presence of any package defect that breaches package integrity by increasing its leakage above its maximum allowable leakage limit. The primary goals of the work presented herein were to demonstrate the viability of the nondestructive, deterministic method known as laser-based gas headspace analysis for evaluating container closure integrity and to provide a physical model for predicting leak rates for a variety of container volumes, headspace conditions, and defect sizes. The results demonstrate that laser-based headspace analysis provides sensitive, accurate, and reproducible measurements of the gas ingress into glass vial-stopper package assemblies that are under either diffusive or effusive leak conditions. Two different types of positive controls were examined. First, laser-drilled micro-holes in thin metal disks that were crimped on top of 15R glass vials served as positive controls with a well-characterized defect geometry. For these, a strong correlation was observed between the measured ingress parameter and the size of the defect for both diffusive and effusive conditions. Second, laser-drilled holes in the wall of glass vials served as controls that more closely simulate real-world defects. Due to their complex defect geometries, their diffusive and effusive ingress parameters did not necessarily correlate; this is an important observation that has significant implications for standardizing the characterization of container defects. Regardless, laser-based headspace analysis could readily differentiate positive and negative controls for all leak conditions, and the results provide a guide for method development of container closure integrity tests.LAY ABSTRACT: The new USP 39 <1207>, "Package Integrity Evaluation-Sterile Products", states in section 3.4.1: "tracer gas tests performed using … laser-based gas headspace analysis [have] been shown to be sensitive enough to quantitatively analyze leakage through the smallest leak paths found to pose the smallest chance of liquid leakage or microbial ingress in rigid packaging." In addition, USP <1207> also states that "for such methods, the limit of detection can be mathematically predicted on the basis of gas flow kinetics." Using the above statements as a foundation, this paper presents a theoretical basis for predicting the gas ingress through well-defined defects in product vials sealed under a variety of headspace conditions. These calculated predictions were experimentally validated by comparing them to measurements of changes in the headspace oxygen content or total pressure for several different positive controls using laser-based headspace analysis. The results demonstrated that laser-based headspace analysis can, by readily differentiating between negative controls and positive controls with a range of defect sizes on the micron scale, be used to assess container closure integrity. The work also demontrated that caution must be used when attempting to correlate a leak rate to an idealized defect-size parameter.

Historical Review of Glasses Used for Parenteral Packaging.

Glass has long been used for packaging precious liquids, in particular pharmaceuticals. Its unique combination of hermeticity, transparency, strength, and chemical durability make it the optimal material for such an important role. Today's life-saving drugs are stored in borosilicate glasses, which evolved from applications in microscope optics and thermometers. As the glass compositions improved, so did the methods used to shape them and the tests used to characterize them. While all of these advances improved the quality of the glass container and its ability to protect the contents, problems still exist such as delamination, cracks, and glass particulates. In addition to these issues, we review new developments in glass composition development, performance, and testing in the 21st century.