PDA Journal of Pharmaceutical Science and Technology最新文献

The risk for virus contamination in biotechnology products (e.g., monoclonal antibodies, fusion proteins, or antibody-drug conjugates) derived from mammalian cell lines is a safety concern that must be evaluated from the early stages of development. The regulatory requirement for virus clearance that assesses the capacity of purification processes to remove endogenous and adventitious viruses is aimed at mitigating viral safety risk. A virus clearance database, containing virus clearance study data from biological license applications and investigational new drug submissions, has been maintained by the Food and Drug Administration's Center for Drug Evaluation and Research for over 15 years. Herein, an update is provided with regard to the impacts of process changes on the virus clearance during the product development cycle of biotechnology drug products based on the investigational new drug submissions received between January 1986 through March 2024. The current data demonstrated continuous robust removal of retroviruses and parvoviruses by chemical inactivation and virus-retentive filtration unit operations, respectively. Additional virus removal was supported by inclusion of one or more chromatography processes unit operations. For these processes, interactive process parameter effects were investigated for impacts on the reported virus clearance. The data reported here demonstrated that process- and product- specific considerations needed to be evaluated on a case-by-case basis to achieve robust and effective virus clearance for mammalian-cell-derived biotechnology products.

The antimicrobial effectiveness test assesses the performance of the preservatives and/or antimicrobial substances added to multiuse sterile or nonsterile dosage forms to protect these products from microbiological growth. In this study, insulin products underwent the European Pharmacopoeia and the United States Pharmacopeia antimicrobial preservative effectiveness tests at both room and refrigerated temperatures. Notably, a psychrotolerant strain, Serratia marcescens, originally isolated from a refrigerated pharmaceutical product, was included in the antimicrobial effectiveness testing. When evaluated against the compendial requirements, both neutral protamine Hagedorn and regular insulin stored at room temperature successfully met the European Pharmacopoeia-A criteria and the United States Pharmacopeia standards. However, although both formulations stored under refrigeration conformed to the United States Pharmacopeia criteria, they failed to satisfy the European Pharmacopoeia-A criteria at contact times of <7 days. The reductions in Serratia marcescens counts were the same at both incubation temperatures. This study indicated that for sterile multidose vials, performing the antimicrobial effectiveness test at both room and refrigerated temperatures might give a more accurate indication of antimicrobial preservative efficacy.

In 2019, the BioPhorum Development Group Viral Clearance Workstream performed a collaborative retrospective analysis to evaluate packed bed chromatographic resin performance after repeated cycling for two commonly used chromatography steps in biopharmaceutical manufacturing: protein A and anion exchange. Key variables evaluated in the assessment included virus type, resin type, number of reuse cycles, and virus challenge. This paper has been amended to include additional commentary on the ICH Q5A revision adopted in November 2023. In this retrospective analysis of viral clearance data on naïve versus cycled resin, powered by the availability of decades' worth of accumulated industry data, clearance capability was not negatively impacted by resin cycling. This finding is consistent with publications showing that surrogates for viral clearance capabilities could be employed in lieu of testing of viral clearance of cycled resins for protein A and anion exchange chromatography. The rigorous analysis of the retrospective data supports the view that viral clearance studies for cycled protein A and anion exchange resins are not necessary, provided that appropriate cleaning methods are applied during repeated use of chromatography columns. In agreement with this paper, ICH Q5A(R2) acknowledges that used resin studies are not required for protein A. Used resin evaluation is still required for other chromatography steps; however, with appropriate justification, prior knowledge may be used in place of product-specific studies.

Vial and syringe filling by peristaltic pump has been widely implemented by contract manufacturing organizations and biopharmaceutical companies. Filling volume is commonly considered a critical quality attribute related to the aseptic filling process, and the variation needs to be well controlled to guarantee the safety, efficacy, and consistency of drug products. However, the criteria for justifying the filling variation and underlying mechanisms that affect the variability are not fully revealed quantitatively in the literatures. This study selected filling accuracy, filling process capability, and filling precision as three criteria for evaluating the filling process performance with four statistical indexes: Relative Error Mean, Critical Control Limit (Cpk ≥ 1.33), Relative Standard Deviation, and Relative Moving Range Mean. The impact of liquid properties, pump tubing sizes, and pump settings on these indexes was investigated using a bench-top system with a peristatic pump and a high-precision balance. The results showed that the viscosity, target filling volume, pump tubing size, pump speed, acceleration/deceleration rate, and suck-back had a statistically significant influence on the filling volume variability. Definitive Screening Design was further applied to clarify and visualize the priorities and interaction impact of these factors on filling volume variability. A stepwise approach for filling volume variability optimization and control based on predictive models was established and verified for drug product solution with viscosity between 1-23 cp and target filling volume between 0.2-2.0 mL.

This paper is the result of a round-robin activity run by the Technical Committee TC12, Pharma Packaging, of the International Commission on Glass (ICG). The study was motivated by a concern about the risk that the depyrogenation treatment of glass vials, when performed in an abnormal way that deviates from the usual procedure, may have a negative impact on the hydrolytic resistance of the container inner surface after filling with the drug product, for example, by increasing the release of leacheables and/or the propensity to delamination. The study was executed by using 10 mL clear type I borosilicate glass vials representing four different compositions. For the applied depyrogenation process, extreme parameters were chosen with maximum temperature up to 400°C, exposure times up to 72 hours, and different amounts of residual water inside as starting conditions. Those treated samples were tested in seven different laboratories as a round-robin test. A large amount of data was obtained, which clearly indicate that the hydrolytic resistance performance of the Type I borosilicate glass vials is not affected even by such extreme depyrogenation conditions (e.g., 400°C, 72 hours, and not perfectly dried inside). This is an important and useful result, both for glass and pharma companies, based on the 12,000 analytical data collected during the interlaboratory activity.

In silico modeling of subcutaneous injections is a promising tool to derisk and optimize the development of injections systems and improve preliminary understanding of the injectability of drugs. Such modeling can be leveraged early in development, prior to pre-clinical studies, to reduce testing burden and effectively predict aspects such as the time and forces required for full dose delivery into tissue and the tissue-injectate-device interactions. In this work, we address the three main in silico pillars (primary container, injection device, and tissue) that are necessary to simulate a parenteral injection. We showcase how their modeling can be combined and applied to various delivery systems and injection conditions to enable appropriate systems and parameters selection to achieve desired performance. Case studies of viscous drugs in PFS/AI and wearable injection systems with non-rigid component properties are presented to highlight the theoretical treatment of interfaces, the critical inputs required to achieve accurate predictions, the insights gained, and the good agreement between model predictions and experimental results.

We're starting to see a huge shift in the healthcare industry towards sustainability, with stakeholders throughout the sector aiming to drive down emissions and reduce environmental impacts. This graphic focuses on device design, and applies to any sector of the industry. It looks at every phase of a product's lifecycle, and breaks these down into focal points and design opportunities for footprint reduction.The ultimate goal in sustainability is The Circular Economy, the definition of which is the reduction, capture, and reuse of all embodied resources into an indefinite loop, with minimal negative external effects. The graphic illustrates how the journey to circularity can be achieved through considered design at every one of those lifecycle phases. It examines opportunities within raw materials, manufacturing, transport, use, and end-of-life, considering not just technical approaches but business model development and user behaviours as well, aiming to cohesively target a cradle-to-cradle system. Even for products and services where full circularity is not realistic, it identifies multiple opportunities for good design to reduce emissions and perhaps ease the journey to circularity in the future.

Challenges in the manufacturing of high-concentration antibody formulations have seldom been discussed. These are observed mainly from late downstream operations where the antibody gets concentrated to its final strength to final fill finish processing and containerization of the product. The present paper summarizes the challenges typically observed in manufacturing and processing of high-concentration antibody products and provides turnkey solutions to these typical challenges in order to have a consistent and robust manufacturing process for these products. Immunoglobulin G1 (IgG1) has been used as a model protein for studying the challenges and providing solutions to them. The late downstream challenges, like increased viscosity limiting further concentration, can be resolved by use of viscosity modifying agents in the formulation. Replacement of the conventionally used 'A' screen membranes with 'D' screen or using single pass tangential flow filtration can further provide an in targeting higher concentrations for the same protein with lesser shear and aggregation. Using a 0.5 µm/0.2 µm asymmetric or bilayered membrane instead of the conventional 0.2 µm membrane resulted in better flux during filtration of a high-concentration IgG1 formulation. In-process holding time during the filling operation was optimized to be <60 min based on the nozzle drying time for the high-concentration IgG1 formulation. An appropriate control strategy of replacing filling nozzles and performing periodic fill weight checks was proposed for the fill-finish process of a high-concentration IgG1 formulation.

This work focused on understanding the current practice of the intravitreal injections (IVIs) and existing challenges for both patients and healthcare professionals with the ultimate goal of developing a combination device concept for intravitreal injections. Using a systematic approach, an initial user preference study was initiated that incorporated an online survey designed and conducted with retinologists from the EU countries (n = 25), followed by in-person interviews with national and international KOLs (n = 5). Multiple feasibility studies were conducted with focus on the unmet needs of key users such as handling characteristics and accuracy of the injection volume focusing on potential device solutions to address these unmet needs. Finally, laboratory testing and user experience evaluation of device potential concepts were used to find the best fitting device concept for injections of a fixed dose (0.05 ml) into the eye. Both qualitative evaluation and statistical analysis were used to study significant differences between the results of injection with device and standard of care. Compared to the manual IVI procedure, an automated device has the potential to increase safety for patients, decrease procedure times, allow for integrated data storage and documentation, and reduce costs for medical staff and expensive operating rooms.