Stress Factors in Primary Packaging, Transportation and Handling of Protein Drug Products and Their Impact on Product Quality.

Protein-based biologic drugs encounter a variety of stress factors during drug substance (DS) and drug product (DP) manufacturing, and the subsequent steps that result in clinical administration by the end user. This article is the third in a series of commentaries on these stress factors and their effects on biotherapeutics. It focuses on assessing the potential negative impact from primary packaging, transportation, and handling on the quality of the DP. The risk factors include ingress of hazardous materials such as oxidizing residuals from the sterilization process, delamination- or rubber stopper-derived particles, silicone oil droplets, and leachables into the formulation, as well as surface interactions between the protein and packaging materials, all of which may cause protein degradation. The type of primary packaging container used (such as vials and prefilled syringes) may substantially influence the impact of transportation and handling stresses on DP Critical Quality Attributes (CQAs). Mitigations via process development and robustness studies as well as control strategies for DP CQAs are discussed, along with current industry best practices for scale-down and in-use stability studies. We conclude that more research is needed on postproduction transportation and handling practices and their implications for protein DP quality.

[Investigation of Foreign Particles in Moderna COVID-19 Vaccine].

Particular batches of Moderna mRNA Coronavirus Disease 2019 (COVID-19) vaccine were recalled after foreign particles were found in some vaccine vials at the vaccination site in Japan in August 2021. We investigated the foreign particles at the request of the Ministry of Health, Labour and Welfare. Energy dispersive X-ray spectroscopy analysis suggested that the foreign particles found in the vials recalled from the vaccination sites were from stainless steel SUS 316L, which was in line with the findings of the root cause investigation by the manufacturer. The sizes of the observed particles ranged from <50 µm to 548 µm in the major axis. Similar foreign particles were also detected in 2 of the 5 vaccine vials of the same lot stored by the manufacturer, indicating that the foreign particles have already been administered to some people via vaccine. Observation of the vials of the same lot by digital microscope found smaller particles those were not detected by visual inspection, suggesting that more vials were affected. Contrarily, visual inspection and subvisible particulate matter test indicated no foreign particles in the vials of normal lots. Possible root cause and strategies to prevent such a deviation were discussed from technical and regulatory aspects.

Stress Factors in Protein Drug Product Manufacturing and Their Impact on Product Quality.

Injectable protein-based medicinal products (drug products, or DPs) must be produced by using sterile manufacturing processes to ensure product safety. In DP manufacturing the protein drug substance, in a suitable final formulation, is combined with the desired primary packaging (e.g., syringe, cartridge, or vial) that guarantees product integrity and enables transportation, storage, handling and clinical administration. The protein DP is exposed to several stress conditions during each of the unit operations in DP manufacturing, some of which can be detrimental to product quality. For example, particles, aggregates and chemically-modified proteins can form during manufacturing, and excessive amounts of these undesired variants might cause an impact on potency or immunogenicity. Therefore, DP manufacturing process development should include identification of critical quality attributes (CQAs) and comprehensive risk assessment of potential protein modifications in process steps, and the relevant steps must be characterized and controlled. In this commentary article we focus on the major unit operations in protein DP manufacturing, and critically evaluate each process step for stress factors involved and their potential effects on DP CQAs. Moreover, we discuss the current industry trends for risk mitigation, process control including analytical monitoring, and recommendations for formulation and process development studies, including scaled-down runs.

Intelligent foreign particle inspection machine for injection liquid examination based on modified pulse-coupled neural networks.

A biologically inspired spiking neural network model, called pulse-coupled neural networks (PCNN), has been applied in an automatic inspection machine to detect visible foreign particles intermingled in glucose or sodium chloride injection liquids. Proper mechanisms and improved spin/stop techniques are proposed to avoid the appearance of air bubbles, which increases the algorithms' complexity. Modified PCNN is adopted to segment the difference images, judging the existence of foreign particles according to the continuity and smoothness properties of their moving traces. Preliminarily experimental results indicate that the inspection machine can detect the visible foreign particles effectively and the detection speed, accuracy and correct detection rate also satisfying the needs of medicine preparation.

V-shaped pits in HVPE-grown GaN associated with columnar inversion domains originating from foreign particles of α-Si3N4 and graphitic carbon.

The v-shaped pits (so-called V-pits) observed in hydride-vapor-phase-epitaxy-grown GaN and associated with the columnar inversion domains originating from foreign particles were investigated. The inversion domains on the front and back surfaces of the test sample were recognized after chemical mechanical polishing. It was found that the V-pits originate from the columnar inversion domains. The inversion domains, in turn, arise from the particles that exist on a low-temperature GaN buffer layer on sapphire substrate. Using transmission electron microscopy, these particles were found to be of α-Si3N4 and graphitic carbon. Such particles are attributable to the components of the reactor and adhere to the low-temperature GaN buffer layer, which has a surface roughness of the order of several nanometers. Thus, an effective way of obtaining HVPE-grown thick GaN layers without the V-pits associated with columnar IDs is to maintain the parts of the HVPE chamber properly to prevent foreign particles from being generated.

Development of an Innovative 3D Printed Rigid Bronchoscopy Training Model.

OBJECTIVES: The objective of this study was to create a 3D printed airway model simulating the size and mechanical properties of various age groups for foreign body removal training. METHODS: Three-dimensional printing technology was used to print the anatomically correct airway from rubber-like translucent material, simulating the mechanical properties of human airway tissue. The model's effectiveness in trainee education was evaluated by otolaryngology residents with varying levels of experience. As part of an Airway Emergencies course, a rigid bronchoscopy procedure was performed on the 3D printed model as well as a porcine model. The participants completed surveys comparing the validity of the 2 models and the effectiveness of the overall training experience. RESULTS: The 3D printed model, which is accurate in terms of anatomy and mechanical properties, was found to be comparable to a porcine model in regards to participant satisfaction as well as face validity. CONCLUSIONS: The 3D printed airway model is able to be accurately scaled to various sizes and simulate the mechanical properties of the desired age group. The 3D printed model provides an excellent alternative to animal models in terms of practicality, logistics of use, and anatomical accuracy.