PDA Journal of Pharmaceutical Science and Technology最新文献

The technology transfer process varies widely between organizations across the biopharmaceutical industry. This variation amplifies the complexity of transfers and negatively impacts the communication of critical information. Organizations tend to either have their own established inflexible processes or unclearly defined processes that change over time. This lack of standardization is compounded as individual companies redefine their processes to meet changing requirements. This creates inefficiencies and barriers to collaboration between organizations due to dissimilar technology transfer processes. Additionally, the industry is evolving rapidly with companies adopting new and novel processes (e.g., continuous processing, new modalities) to meet the global demand for biopharmaceuticals. As the processes become more complex and divergent, the need for a generic technology transfer process increases. This National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) sponsored paper defines a generic technology transfer process using input from a broad range of subject matter experts from across the industry. This generic definition, which is not specific to any one company or any specific implementation, is provided as a starting point for organizations to build on in the future.

Post-approval changes (PACs) are integral to pharmaceutical product life cycle management, ensuring that the product remains safe, effective, and compliant with evolving standards. However, managing these changes across multiple regulatory jurisdictions remains a challenging endeavor due to diverse regulatory requirements and timelines across national regulatory authorities (NRAs). This results in delays in obtaining approval from NRAs, impacting global supply chains and ultimately jeopardizing timely access to essential medical products by patients. In 2021, the World Health Organization issued the Good Reliance Practices (GReIP) guidance to encourage streamlined PAC review and approval process while maintaining access to quality-assured, safe, and effective medicinal products. NRAs are encouraged to rely on the assessment completed by a reference authority that agrees to provide the outcomes of its regulatory expertise. The ultimate objective of this guidance is to accelerate the overall process for PACs, ultimately fostering more equitable and timely access to medical products by the populations who need them. This approach was tested in a chemistry, manufacturing, and control PAC pilot to determine the feasibility of using the principles of regulatory reliance based on the recommendations outlined in the GReIP with the goal of establishing a predictable, 6-month approval timeframe across multiple NRAs. The design and management of this pilot is described in Gastineau et al. This paper describes the outcomes of the pilot, which demonstrated that regulatory reliance is feasible. Of the 21 NRAs that agreed to participate, 55% were able to complete the review within 6 months; within 10 months, 95% of approvals were received and, after 16 months, all participating countries had approved the PAC. The use of a Q&A SharePoint Tool allowed for visibility of the questions raised and the company responses among the NRAs. Feedback on this reliance pilot was solicited from the participating NRAs and provides further support for future CMC PAC reliance cases.

A cartridge container closure integrity control strategy may leverage a combination of test methods to ensure that drug products in the assembled container system are protected from an exchange with the external environment. These methods provide evidence supporting the suitability of the container closure system; however, some methods involve extended test times, complex setups, subjective interpretation, and are destructive. A method that mitigates such factors was developed to improve upon testing utilized within the control strategy. Reviewing the underlying principles of internal methods and external standards resulted in two potential paths, a force decay method and a constant force method, to improve on the cartridge control strategy using a linear mechanical testing system. The force decay method monitors the force decay signal obtained from applying a predetermined force and holding the displacement constant for a desired time frame. The constant force method monitors the displacement signal obtained from applying a predetermined force and holding the force constant for a desired time frame. Supplementing the experimental data generated by both methods with a finite element analysis along with a first principles derivation of the system response aided in a recommendation to utilize the constant force method for cartridge container closure integrity leak testing. The constant force method was then optimized to attain the best signal response for leak detection and ensure a robust method. The data generated in this article support the viability of using the constant force mechanical container closure integrity test method for improving the in-process container closure integrity testing strategy for solution products.

Elastomeric components such as closures and stoppers play key roles in providing container closure integrity (CCI), supporting a portfolio of injectable combination products and primary containers including needle shields (NSs) in prefilled syringes (PFSs). Upon piercing through the elastomeric (i.e., synthetic rubber) components, the physical interaction between the needle and the deformable elastomer could result in the formation of small, random-shaped particles fragmented and dislodged from the NS material due to cutting processes. This phenomenon, called coring, poses a major risk in drug product contamination, as elastomer particle fragments can potentially be aspirated with the medication and injected into a patient or prevent injection. Here, we present a combined computational and experimental approach to assess the incidence of coring. In particular, we first experimentally characterized the nonlinear finite deformation behavior of five commonly used NS elastomers and calibrated constitutive models. Then, we performed finite element simulations validated with needle insertion experiments to compare the coring behavior of the NS elastomers. We demonstrated that higher maximum failure strain under tension and higher deformation-stiffening properties of the elastomer are contributing factors that attenuate coring and fragmentation. The experimental-numerical framework presented is suitable for quantifying broad correlative and discovering relationships between device properties governing the incidence of coring and fragmentation.

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.