Stopper Movement and Headspace (Air Bubble Size) Limitations for 2.25 mL Prefilled Syringe.

The sterile barrier is one of the most important aspects of the container closure integrity (CCI) for a prefilled syringe (PFS or syringe). This crucial barrier enables the protection of the syringe contents from contamination. The plunger stopper (stopper) is naturally in a stationary position that is controlled by the static friction between the plunger stopper and the syringe barrel wall. When an applied force is greater than the static friction, which is commonly known as the break-loose force, the plunger stopper will move. In such conditions, the stopper movement can further be increased if an air bubble (AB) is introduced between the liquid fill in the syringe and the stopper during the stoppering process. This additional movement can occur when the pressure differential between the gaseous headspace inside the syringe and the external atmosphere is large enough that the force exerted on the stopper exceeds the break-loose force of the syringe. This can occur during altitude or temperature changes incurred during aerial or mountainous transport. This article, therefore, discusses the relationship between stopper movement and initial headspace (air bubble size/ABS) in a 2.25 mL Type I glass syringe using theoretical and empirical approaches. The results showed the maximum initial headspace needed to enable CCI at specified altitudes and plunger stopper movements for the syringe-plunger stopper combination used in the study. Empirical data also indicated that CCI can be maintained for this syringe-plunger stopper combination with up to 9.0 mm initial headspace at altitudes up to 17,000 feet.

Determination of ICH-Q3D Elemental Impurity Leachables in Glass Vials by Inductively Coupled Plasma Mass Spectrometry.

Container closure systems that are used for packaging pharmaceutical products are required to satisfy numerous safety requirements. Maximum permitted limits on the concentrations of numerous toxic elemental impurities that potentially leach from the packaging are one such requirement. The implementation of ICH-Q3D Guideline for Elemental Impurities, in conjunction with the 2018 publication of USP <232> Elemental Impurities-Limits and USP <233> Elemental Impurities-Procedures, requires a critical risk assessment of all container closure systems to evaluate their contribution of certain elemental impurities to the enclosed drug product. ICH-Q3D has established limits for each specific elemental impurity that considers relevant toxicological data and administration route (oral, parenteral, or inhalation) and presents them as permitted daily exposures based on the maximum daily dosage of the final drug product. A study was undertaken to assess the degree of elemental impurity leaching from one type of pharmaceutical glass vial under specific, fixed environmental controls. Multiple buffer systems representing a broad spectrum of possible parenteral drug product formulations were used in the study. Resulting buffer solutions that had been in contact with a single type of glass vial under specific conditions were subsequently analyzed using an inductively coupled plasma mass spectrometry (ICP-MS) method developed and validated specifically for the purpose of quantifying elemental impurity leachables in a variety of parenteral formulations. Results indicated that the degree of elemental impurity leachables imparted by the specific type of glass vial evaluated during this study posed no risk to patient safety, regardless of the drug product buffer formulation. Following this evaluation, the ICP-MS method developed for the determination of elemental impurities leachables has been successfully applied to the assessment of elemental impurities in a number of different biological parenteral drug product formulations currently under development. These data can be leveraged for inclusion in elemental impurities component ICH-Q3D risk assessments to satisfy the container closure system contribution.

Container Closure Integrity of Vial Primary Packaging Systems under Frozen Storage Conditions: A Case Study.

As the complexities of the pharmaceuticals needed to prevail over serious diseases continue to grow, the need for technologies to enable their efficient storage and delivery are as essential as ever. Lately, drugs such as vaccines, proteins, and stem cells are increasingly requiring frozen storage to maintain their efficacies before use. Notably, the advent of cellular therapy products has invariably elevated the need for cryopreservation and frozen storage of cellular starting materials, intermediates, and/or final product. The container closure integrity (CCI)-which is a major requirement for aseptic or sterile packaging systems-at these extremely low temperatures has not been fully understood. For vial-based systems particularly, the commonly used rubber stoppers are expected to lose their elastic properties below their glass transition temperatures, suggesting a potential temporary loss of sealability under frozen storage conditions and posing a risk to CCI. The measurement of the CCI at these conditions such as -80°C is therefore critical; a process that can be very challenging. Previous works had explored the use of Oxygen Headspace Analysis to measure CCI at low temperatures. Here, we present the evaluation of the CCI of rubber-stoppered aluminosilicate glass vials (Valor®) and plastic vials (Crystal Zenith®) using the helium leak CCI test method at -80°C, with correlation to residual seal force (RSF). The results and their implications are then discussed with regard to the suitability of certain packaging components as frozen storage container closure systems.

Balancing Container Closure Integrity and Aesthetics for a Robust Aseptic or Sterile Vial Packaging System.

Container closure integrity (CCI) is one of the requirements for a sterile packaging system. For vial-based systems, the capping process is a critical step in creating and ensuring an adequate seal with acceptable CCI. Container closure integrity tests (CCITs) such as the dye ingress and the helium leak rate are two methods among many that, in the appropriate scenario, help to challenge this required attribute. The use of locked-in stopper compression (compression under the crimp seal post capping) enables correlation of these methods to CCI and seal quality. In fact, the overall acceptability of a seal can be evaluated using quantitative and qualitative methods. Usually lost in these assessments is the existence of seal cosmetics as an essential additional seal quality attribute. Unacceptable cosmetic quality can have a major impact on manufacturing (reduced batch output, high yield cost, etc.) and user (perceived low quality, brand image, potential injury, etc.) experiences. Interestingly, the aesthetics of a seal is also impacted by the capping process which is quite complicated because the acceptance criteria for aesthetics of a seal is subjective. Ultimately, this affects commercial manufacturing efficiency and CCI. Here, we present a simple methodology for package selection and evaluated multiple package configurations using locked-in stopper compression (through residual seal force, RSF) measurements and seal aesthetics analyses (using a semi-quantitative aesthetics scale). The integrity of the seals was analyzed using multiple CCIT methods. We determined that component dimensions such as the seal length play a major role in obtaining proper seal aesthetics and integrity. This can ultimately enable the selection of robust packaging components that provide an adequate range of manufacturing conditions without cosmetic defects. A failure to do this could result in high rejects during drug product visual inspection culminating in low batch yield, high costs or could pose harm to patients if suitable CCI is not achieved.LAY ABSTRACT: One common container closure system for parenteral drug products includes a glass vial, rubber stopper, and aluminum crimp seal. The capping process, in which the elastomeric closure is compressed against the vial by means of an aluminum crimp seal, is key to ensuring an optimal seal from both an aesthetic and CCI perspective. Ensuring a robust capping process must include a deep and necessary understanding of the interconnection between the selected components, desired aesthetics of the seal, stopper compression, residual seal force, and CCI; the way in which the capper is configured (sealing parameters) will play a part in addition to the "style" used in manufacturing. Previous published studies have focused on capping process controls to only ensure CCI. Here, we present a useful methodology for selecting appropriate components and capping process parameters using a scaled-down approach to achieve elegant seal quality and CCI simultaneously. Dimensional analysis and capping design of experiments (DOEs) were conducted on lab-scale equipment that was representative of commercial configurations. The seals made from these studies were analyzed using residual seal force, helium leak, and dye ingress methods. The results and their implications were discussed with regard to the operating principle of the rail-type capping machine.

Axial strength test for round flat faced versus capsule shaped bilayer tablets.

There has been increasing interest in fixed dose combination (FDC) therapy. Multi-layer tablets are a popular choice among various technologies to deliver FDCs. In most cases, round flat faced tooling is used in testing tablets as they have the simplest geometry. However, shaped tooling is more common for commercial products and may have an effect on bilayer tablet strength. Capsule shaped bilayer tablets, similar to a commercial image, and holders conforming to the tablet topology, were compared with similar round flat faced bilayer tablets and their corresponding holders. Bilayer tablets were subjected to an axial test device, until fracture and the quantitative breaking force value was recorded. As the second layer compression force increases, regardless of holder design, an increase in breaking force occurs as expected. This consistent trend provides insight regarding the breaking force of capsule shaped bilayer tablets. The results of this study show that at lower second layer compression forces, tablet geometry does not significantly impact the results. However, at higher compression forces, a significant difference in breaking force between tablet geometries exists. Therefore, using a test geometry close to the final commercial tablet image is recommended to have the most accurate prediction for tablet breakage.