Effect of light source and UVA quotient on monoclonal antibody stability during ambient light exposure studies.

Therapeutic proteins such as monoclonal antibodies (mAbs) are exposed to ambient light conditions during manufacturing and handling processes, and the exposure time limits are generally determined by conducting relevant room temperature and room light (RT/RL) stability studies. In the case study presented here, a mAb drug product showed an unexpectedly higher level of protein aggregation during a formal RT/RL study conducted at a contract facility as compared to what had previously been seen during development studies. An investigation led to the finding that the RT/RL stability chamber was set up differently as compared to the one used for the internal studies. The UVA component of the light conditions used in the study was not representative of the conditions experienced by the drug product during normal manufacturing. During the investigation, three different light sources were evaluated for their UVA quotients along with the UV filtering effect of a plastic encasement. The mAb formulation showed a greater increase in aggregation when exposed to halophosphate and triphosphor-based cool white fluorescent (CWF) lights compared to a light emitting diode (LED) light. The plastic encasement on CWF lights significantly reduced the aggregation levels. Upon further assessment of additional mAb formulations, a similar trend was observed with sensitivity to the low level of UVA background emitted by the CWF lights. This study demonstrated that it is critical to understand UV levels at the sample handling level while setting up ambient light studies using CWF lights for biologic drug products. The use of non-representative light conditions (UV irradiance) can lead to unnecessary restrictions on the RL exposure allowance set for these products.

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.

Investigating the Degradation Behaviors of a Therapeutic Monoclonal Antibody Associated with pH and Buffer Species.

This study aimed in understanding the degradation behaviors of an IgG 1 subtype therapeutic monoclonal antibody A (mAb-A) associated with pH and buffer species. The information obtained in this study can augment conventional, stability-based screening paradigms by providing the direction necessary for efficient experimental design. Differential scanning calorimetry (DSC) was used for studying conformational stability. Dynamic light scattering (DLS) was utilized to generate B 22*, a modified second virial coefficient for the character of protein-protein interaction. Size-exclusion chromatography (SEC) and hydrophobic interaction chromatography (HIC) were employed to separate degradation products. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) was used for determining the molecular size and liquid chromatography mass spectrometry (LC-MS) were used for identifying the sequence of the separated fragments. The results showed that both pH and buffer species played the roles in controlling the degradation behaviors of mAb-A, but the pH was more significant. In particular, pH 4.5 induced additional thermal transition peaks occurring at a low temperature compared with pH 6.5. A continual temperature-stress study illustrated that the additional thermal transition peaks related to the least stable structure and a greater fragmentation. Although mAb-A showed the comparable conformational structures and an identical amount of aggregates at time zero between the different types of buffer species at pH 6.5, the aggregation formation rate showed a buffer species-dependent discrepancy over a temperature-stress period. It was found that the levels of aggregations associated with the magnitudes of protein-protein interaction forces.

Correlation of Phosphorus Cross-Linking to Hydration Rates in Sodium Starch Glycolate Tablet Disintegrants Using MRI.

Understanding the behavior of tablet disintegrants is valuable in the development of pharmaceutical solid dosage formulations. In this study, high-resolution magnetic resonance imaging has been used to understand the hydration behavior of a series of commercial sodium starch glycolate (SSG) samples, providing robust estimates of tablet disintegration rate that could be correlated with physicochemical properties of the SSGs, such as the extent of phosphorus (P) cross-linking as obtained from infra-red spectroscopy. Furthermore, elemental analysis together with powder X-ray diffraction has been used to quantify the presence of carboxymethyl groups and salt impurities, which also contribute to the disintegration behavior. The utility of Fast Low Angle SHot magnetic resonance imaging has been demonstrated as an approach to rapidly acquire approximations of the volume of a disintegrating tablet and, together with a robust voxel analysis routine, extract tablet disintegration rates. In this manner, a complete characterization of a series of SSG grades from different sources has been performed, showing the variability in their physicochemical properties and demonstrating a correlation between their disintegration rates and intrinsic characteristics. The insights obtained will be a valuable aid in the choice of disintegrant source as well as in managing SSG variability to ensure robustness of drug products containing SSG.

An Approach to Mitigate Particle Formation on the Dilution of a Monoclonal Antibody Drug Product in an IV Administration Fluid.

To support dose reduction, low dose of a monoclonal antibody (mAb) was required to be administered via IV infusion at a concentration of 0.1 mg/mL. To achieve the target protein concentration, the infusion solution was prepared by diluting the drug product containing 10-mg/mL mAb with normal saline, a 0.9% sodium chloride injection solution. However, particles were observed in the diluted solution. Particle formation must be avoided to administer the low dose using the existing drug product. To mitigate the particle formation, an unconventional compounding approach was used. With this approach, a stabilizing vehicle containing polysorbate-80 was added to saline before drug-product dilution to maintain suitable surfactant level to prevent precipitation of the mAb. In this way, use of the stabilizing vehicle to support low doses ensured suitable quality across a wider range of mAb concentrations, thereby allowing additional flexibility to the clinical trial. Such an approach may be useful for broader application in early-stage clinical trials where there is an uncertainty regarding doses or the need to revise to lower doses based on clinical observations or other drivers.

Finite Element Method (FEM) Modeling of Freeze-drying: Monitoring Pharmaceutical Product Robustness During Lyophilization.

Lyophilization is an approach commonly undertaken to formulate drugs that are unstable to be commercialized as ready to use (RTU) solutions. One of the important aspects of commercializing a lyophilized product is to transfer the process parameters that are developed in lab scale lyophilizer to commercial scale without a loss in product quality. This process is often accomplished by costly engineering runs or through an iterative process at the commercial scale. Here, we are highlighting a combination of computational and experimental approach to predict commercial process parameters for the primary drying phase of lyophilization. Heat and mass transfer coefficients are determined experimentally either by manometric temperature measurement (MTM) or sublimation tests and used as inputs for the finite element model (FEM)-based software called PASSAGE, which computes various primary drying parameters such as primary drying time and product temperature. The heat and mass transfer coefficients will vary at different lyophilization scales; hence, we present an approach to use appropriate factors while scaling-up from lab scale to commercial scale. As a result, one can predict commercial scale primary drying time based on these parameters. Additionally, the model-based approach presented in this study provides a process to monitor pharmaceutical product robustness and accidental process deviations during Lyophilization to support commercial supply chain continuity. The approach presented here provides a robust lyophilization scale-up strategy; and because of the simple and minimalistic approach, it will also be less capital intensive path with minimal use of expensive drug substance/active material.