Vial “Fogging” is a phenomenon observed after lyophilization due to drug product creeping upwards along the inner vial surface. After the freeze-drying process, a haze of dried powder is visible ...inside the drug product vial, making it barely acceptable for commercial distribution from a cosmetic point of view. Development studies were performed to identify the root cause for fogging during manufacturing of a lyophilized monoclonal antibody drug product. The results of the studies indicate that drug product creeping occurs during the filling process, leading to vial fogging after lyophilization. Glass quality/inner surface, glass conversion/vial processing (vial “history”) and formulation excipients, e.g., surfactants (three different surfactants were tested), all affect glass fogging to a certain degree. Results showed that the main factor to control fogging is primarily the inner vial surface hydrophilicity/hydrophobicity. While Duran vials were not capable of reliably improving the level of fogging, hydrophobic containers provided reliable means to improve the cosmetic appearance due to reduction in fogging. Varying vial depyrogenation treatment conditions did not lead to satisfying results in removal of the fogging effect. Processing conditions of the vial after filling with drug product had a strong impact on reducing but not eliminating fogging.
In a phase 1 dose escalation study, 13 subjects with hemophilia A received by peripheral intravenous infusion a retroviral vector carrying a B-domain–deleted human factor VIII (hFVIII) gene. ...Infusions were well tolerated. Tests for replication competent retrovirus have been negative. Polymerase chain reaction (PCR) analyses demonstrate the persistence of vector gene sequences in peripheral blood mononuclear cells in 3 of 3 subjects tested. Factor VIII was measured in serial samples using both a one-stage clotting assay and a chromogenic assay. While no subject had sustained FVIII increases, 9 subjects had FVIII higher than 1% on at least 2 occasions 5 or more days after infusion of exogenous FVIII, with isolated levels that ranged from 2.3% to 19%. Pharmacokinetic parameters of exogenous FVIII infused into subjects 13 weeks after vector infusion showed an increased half-life (T1/2; P < .02) and area under the curve (AUC, P < .04) compared with prestudy values. Bleeding frequency decreased in 5 subjects compared with historical rates. These results demonstrate that this retroviral vector (hFVIII(V)) is safe and, in some subjects, persists more than a year in peripheral blood mononuclear cells, with measurable factor VIII levels and with increased available FVIII activity (increased T1/2 and AUC) after infusion of exogenous FVIII concentrate.
There has been a growing interest in recent years in the assessment of suitable vial/stopper combinations for storage and shipment of frozen drug products. Considering that the glass transition ...temperature (T
) of butyl rubber stoppers used in container closure systems (CCSs) is between -55 °C to -65 °C, a storage or shipment temperature of a frozen product below the T
of the rubber stopper may require special attention because below the T
the rubber becomes more plastic like and loses its elastic (sealing) characteristics. Thus, they risk not maintaining container closure integrity (CCI). Given that the rubber regains its elastic properties and reseals after rewarming to ambient temperature, leaks during frozen temperature storage and transportation are transient and the CCI methods used at room temperature conditions are unable to confirm CCI in the frozen state. Hence, several experimental methods have been developed in recent years in order to evaluate CCI at low temperatures. Finite element (FE) simulations were applied in order to investigate the sealing behaviour of rubber stoppers for the drug product CCS under frozen storage conditions. FE analysis can help in reducing the experimental design space and thus the number of measurements needed, as they can be used as an add-on to experimental testing. Several scenarios have been simulated including the effect of thermal history, rubber type, storage time, worst-case CCS geometric tolerances, and capping pressure. The results of these calculations have been validated with experimental data derived from laboratory experiments (CCI at low temperatures), and a concept for tightness has been developed. It has been concluded that FE simulations have the potential to become a powerful predictive tool toward a better understanding of the influence of cold storage on the rubber sealing properties (and hence on CCI) when dealing with frozen drug products.
The growing interest in the assessment of suitable vial/stopper combinations for storage and shipment of frozen drug products has led to the development of a number of experimental methods to evaluate container closure integrity at low temperatures. The application of finite element simulations could aid in the investigation of the sealing behaviour of rubber stoppers for drug product container closure systems under frozen storage conditions by simplifying the experimental design space and the number of experimental measurements needed. In this work several scenarios have been simulated including the effect of thermal history, rubber type, storage time, worst-case container closure system geometric tolerances, and capping pressure. The results have been further validated with experimental data derived from laboratory experiments and a concept for tightness was developed. In conclusion, finite element simulations have shown the potential to become a powerful predictive tool toward a better understanding of the influence of cold storage on the rubber sealing properties (and hence on container closure integrity) when dealing with frozen drug products.
Display omitted
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.
Purpose
The proper understanding of glass delamination is important to glass manufacturers, pharmaceutical companies, and health authorities to mitigate the occurrence of glass flakes from the vial ...when in contact with specific drug product solutions. The surface of glass vials is altered during glass cane- and vial forming processes and is exposed to different stress conditions during drug product processing before coming in contact with the drug product solution. In this study, the impact of vial washing and depyrogenation including an evaluation of various residual water volumes on surface properties of glass vials was investigated for a defined set of vials.
Methods
3D laser scanning microscopy was established as a new method for topographic analysis of curved surfaces of glass vials operating in high-throughput mode. A subset of vials was subsequently exposed to delamination stress testing and both the stressed solution and inner vial surface were analyzed by a panel of conventional and advanced analytical techniques including 3D laser scanning microscopy.
Results
The data showed that vial washing and depyrogenation strongly influenced surface properties, in particular those of uncoated vials. Surface characteristics such as pits increased depending on the process conditions, which especially applies to Expansion 33 vials. Even low residual water volumes of 50 μL after vial washing were sufficient to change the surface properties of the glass and weaken the surface in those positions prone to glass delamination. An increase in pits was related to a greater risk for glass delamination.
Conclusions
Vial processing conditions need to be assessed when aiming at minimizing the glass delamination risk during parenteral product storage.
This paper is the result of two round robin activities run by the Technical Committee TC12, Pharma Packaging, of the International Commission on Glass (ICG). It deals with the phenomenon of ...delamination, that is, the formation of lamellae or flakes in drug products due to specific and localized corrosion of glass vials, and it follows a first paper PDA J Pharm Sci Technol. 2018, 72, 553–565where a testing protocol for the evaluation of the delamination propensity was proposed. The results showed that the protocol gives information on the quality of vials with respect to the propensity to corrosion, but no direct correlation with delamination could be demonstrated, as no lamellae formation was observed.
In response, further testing was carried out on five sets of vials with expected low delamination propensity, compared to a set of vials with high expected delamination propensity using both the proposed protocol and a more aggressive protocol. The objective was to observe lamellae at least in the high propensity vials to show a correlation to initial test protocols.
The results show that there is a very good consistency between the results of the two testing protocols and therefore, with a good level of reliability, the degree of glass surface corrosion can be estimated by the testing protocol proposed by the Technical Committee. In some cases, the glass surface corrosion results may indicate an increased risk of delamination (depending on the individual interaction between the pharmaceutical solution and the inner vial surface).
Display omitted
Parenteral drug products are protected by appropriate primary packaging to protect against environmental factors, including potential microbial contamination during shelf life ...duration. The most commonly used CCS configuration for parenteral drug products is the glass vial, sealed with a rubber stopper and an aluminum crimp cap. In combination with an adequately designed and controlled aseptic fill/finish processes, a well-designed and characterized capping process is indispensable to ensure product quality and integrity and to minimize rejections during the manufacturing process.
In this review, the health authority requirements and expectations related to container closure system quality and container closure integrity are summarized. The pharmaceutical vial, the rubber stopper, and the crimp cap are described. Different capping techniques are critically compared: The most common capping equipment with a rotating capping plate produces the lowest amount of particle. The strength and challenges of methods to control the capping process are discussed. The residual seal force method can characterize the capping process independent of the used capping equipment or CCS. We analyze the root causes of several cosmetic defects associated with the vial capping process.
In a phase 1 clinical trial, we are evaluating a murine leukemia virus (MuLV)-based retroviral vector encoding the human factor VIII gene hFVIII(V), administered intravenously, as a therapy for ...hemophilia A. Preclinical biolocalization studies in adult rabbits revealed vector-specific PCR signals in testis tissue at low levels. In follow-up animal studies we used PCR to (1) estimate the frequency with which a given cell in testis tissue is transduced, and (2) determine whether a positive PCR signal could be detected in semen samples from animals treated with hFVIII(V). Using the 99% confidence bound, results indicate that the probability that a given cell within the testis was transduced is less than 1/709,000 (97 days after treatment). This probability decreased with time after hFVIII(V) administration. Moreover, the rate of provector sequence detection in semen samples collected weekly throughout two cycles of spermatogenesis was 3/4281 reactions (0.07%), which is lower than the rate of false positives (1/800, 0.125%) observed for control animals. Using PCR assays with single-copy sensitivity, we have shown that the small number of transduced cells present in testis tissue does not give rise to detectable transduced cells in semen.
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%.
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.
PDF
