PDA Journal of Pharmaceutical Science and Technology最新文献

Non-sterile drug products represent approximately 30% of annual drug sales. Non-sterile drug products offer therapeutic advantages, manufacturing costs which permit wide patient access, versatility of dosage form and routes of administration which facilitate patient compliance. These advantages have resulted in an increase in the number and nature of non-sterile finished dosage forms. Regulations and standards require the provision of non-sterile drugs to controlled levels of bioburden, the absence of specified microorganisms and the absence of objectionable microorganisms. Thoroughly understanding the microbiological risks and control performance in non-sterile manufacturing is vitally important in the improvement in the quality and compliance of non-sterile manufacturing. Prior publications have reported the magnitude and characteristics for non-sterile product recalls and regulatory compliance shortfalls from 2004 to 2011 and from 2012 to 2019. The purpose of this review is to similarly provide a valuable contemporary update of the microbiologically related quality and compliance issues specifically associated with non-sterile drug products by reviewing drug recalls and Form FDA 483s. This includes evaluation of incidences of microbiological quality and regulatory compliance issues through more detailed abundance analysis. This data and information should assist in the risk assessment and risk management necessary in the manufacture of non-sterile products and beneficial to the pharmaceutical microbiologist.

Ensuring safety of patients using pharmaceuticals and medical devices through chemical characterization requires accurate estimation of extractables and leachables to ensure tolerable risk from unintentional exposure to these chemicals. However, this is complicated by variability in chemical responses, particularly with mass spectrometry methods. High quality relative response factor predictions provide the opportunity for both expedited and more accurate quantitation in extractables and leachables analyses. In-silico prediction models were developed to test a wide variety of compounds, selected utilizing a physicochemical property coverage approach. Three neural network models, and associated sub-models, were applied to both positive and negative ionization modes for Liquid Chromatography Mass Spectrometry, and Gas Chromatography Mass Spectrometry methods. Mean absolute errors across all methods for training data was 0.47 and 0.65 for out-of-sample data, indicating high predictability of response factors for the compounds chosen by the model and a low likelihood that the data was overfit.Model performance was evaluated using a series of chemicals outside the training data set. When tested, predictive accuracy was greater than 60% of known values for 44 of the 49 chemicals tested (90%). This proof-of-concept work shows that sophisticated neural network modeling of response factor data is a potential solution for response factor variation.

Technology transfer from clients to contract development and manufacturing organizations is a complicated process and inclusion of scale-up and scale-down strategies brings additional complexity. These complexities can lead to extended development timelines and significant resource utilizations to meet regulatory compliance. This manuscript presents the implementation of Quality by Design (QbD) principles as a systematic framework to mitigate these challenges and improve technology transfer efficiency. Here I provide a strategic approach to integrate QbD across five key stages of technology transfer: Scope of Work Development, Information Transfer and Failure Mode and Effects Analysis, Technology Transfer and Pilot Runs, Pre-Production Activities, and cGMP Production. By adopting this QbD-driven methodology, companies can achieve more effective knowledge transfer, develop scalable and reproducible processes, and ensure consistent product quality in alignment with regulatory standards.

Advanced technologies in both aseptic filling and environmental monitoring are coming together to improve the resilience and sterility assurance of aseptic processing. Continuous, real-time environmental monitoring using biofluorescent particle counters (BFPCs) to detect viable and nonviable particles during the aseptic filling process for injectable drugs is gaining traction as an accepted alternative to conventional methods such as active air sampling instruments. Evolving regulatory guidance, including EU Annex 1 guidelines, are increasingly recommending the adoption of isolator technology as well as continuous environmental monitoring during GMP processes, including technologies that offer real-time feedback during drug product manufacturing. Computational flow dynamics and airflow visualization studies are additional tools that support the design of equipment and determination of locations for environmental monitoring. The current nutrient culture media growth-based environmental monitoring, rooted in science from 150 years ago, is unable to keep pace with recent technological advances and the ability to immediately react to an out-of-control state. Here we examine the design of an isolator that eliminates human intervention and indirect product contact parts during aseptic fill finish operations and present computational fluid dynamics (CFD) studies verified by airflow visualization, along with the incorporation of BFPCs at critical areas. Also, we report the results of the interference study characterizing the baseline results for detection of total particles (nonviable plus viable) using a BFPC within a robotic gloveless isolator during dynamic and static operating conditions. The results of our study using BFPCs demonstrate that airflow in the robotic gloveless isolator provides protection of critical areas from contamination during the tub peeling process and that the stoppering process in this environment does not generate detectable particles. During dynamic conditions and material transfer, the study demonstrates the design of the robotic gloveless isolator prevents false positives from interfering with materials during normal operations.

Aseptic manufacturing depends on reliable equipment to maintain throughput and protect patients. This study presents a practical, reproducible maintenance engineering method for proactively replacing aging parts before failure; regulatory references are included only as bounded implementation context for execution inside governed (site validated) systems. This study presents a practical, reproducible method for proactively replacing aging parts before failure. The method combines a simple weighted Health Index (HI) that summarizes condition signals such as vibration, temperature, flow, pressure decay, and motor torque with established survival methods (Weibull and Kaplan-Meier) to estimate remaining useful life (RUL). These estimates are converted into clear Green-Yellow-Red maintenance actions and illustrated with a conceptual SAP PM execution workflow for work orders, spare reservation, and traceable recordkeeping under site governanceThe workflow is demonstrated on a vial washer, an upstream step that influences vial cleanliness and particulate control prior to depyrogenation, focusing on components including conveyors, pumps, bearings, seals, spray nozzles, and heaters. Using a simulation dataset to illustrate the full end to end analytics and decision workflow, Weibull fits with shape factor ß in the range of about 1.8 to 2 captured wears out behavior, and Kaplan-Meier pump survival at 24 months was 0.58 (95% CI 0.50 to 0.66). Applying HI together with RUL shifted interventions from unplanned breakdowns to planned stops. Relative to a reactive baseline under the stated assumptions, the scenario results showed 62.5% lower downtime, 84% lower combined maintenance and rejection costs, and 50% fewer batch rejects, with robustness demonstrated through sensitivity tests and 1,000 Monte Carlo runs.Overall, the contribution is a reproducible maintenance engineering workflow (HI + survival-based RUL + decision matrix) with a conceptual CMMS/SAP PM execution mapping for traceable work order initiation when implemented under site governance. The approach is adaptable to existing SCADA and SAP PM infrastructures following validation within the site quality system, with early benefit expected when prioritizing product quality critical components such as seals and spray nozzles.

Developing medicines to serve patients is a complex, highly regulated process in which multiple interdependent factors must be aligned. If one aspect is not thoroughly evaluated, it may adversely affect others and ultimately the final product, leading to delays, additional costs and, in the worst case, market access barriers. This is particularly true for prefilled syringes (PFS) as combination products, where an already challenging market environment is further compounded by intricate regulatory requirements and a highly complex development process.This paper argues that many recurring issues in PFS development are not isolated technical failures, but the consequence of four systemic challenges: diverging regulatory requirements for drugs and devices, division of competencies between drug and device development teams, fragmented supply chains for device components, and non-standardized characterization and evidence generation across stakeholders. Using examples such as break-loose and glide forces, silicone oil, particles, endotoxins, and biocompatibility, the paper illustrates how these challenges manifest as concrete risks along the development pathway, including transitions from vial to syringe and interactions with notified bodies under the MDR. It then outlines system-level strategies to mitigate these risks, including clearer system ownership, integrated risk management and design spaces, earlier and closer collaboration with device experts and suppliers, and more harmonized standards and regulatory expectations. The overall aim is to support a more efficient, predictable and sciencebased pathway to safe, effective and user-appropriate prefilled syringes.

Measuring cellular quality attributes of cell therapy products is crucial because it ensures their safety, purity, potency, identity, and stability. These attributes help determine whether the therapy is effective and consistent across batches. Since cell therapy products are biologically complex, assessing their quality helps maintain lot-to-lot consistency, supports clinical data generation, and ensures compliance with regulatory standards. Additionally, critical quality attributes (CQAs) are essential for monitoring process control and validating the therapyâs effectiveness. Many of these cellular quality attributes are assessed using flow cytometry; however, beyond well-established clinical immunophenotyping assays, the technology remains insufficiently standardized, complicating alignment with Good Manufacturing Practice (GMP) and regulatory expectations. The work outlined here assesses the feasibility of the Accellix Platform for automated cellular sample analysis by analyzing repeatability and reproducibility across sites, operators, and dedicated instruments. The data presented demonstrates the potential of combining cytometry automation with advanced T cell engineering techniques to achieve robust and compliant manufacturing processes for innovative cellular therapies.

One of the most important requirements for a sterile packaging system is container closure integrity (CCI). For vial-based systems comprised of a vial, a hyper-elastic stopper, and a rigid crimp seal, CCI testing is an integral part of the drug development process.  During the vial-capping process, the component dimensions and materials play a critical role in creating a robust and adequate seal that will satisfy CCI. Although these properties are manufactured within certain tolerances there exist lot to lot variabilities and aging effects. If not taken into consideration during initial design, these factors can potentially impact the Residual Seal Force (RSF)  for a container closure system (CCS). Residual Seal Force (RSF) of the vial, while not predictive or causal, is correlated with CCI. For example, is possible that containers with sufficient RSF can contain defects that compromise CCI, including but not limited to fibers, cracks, and folds.A robust and efficient deterministic finite element model capable of predicting RSF for fixed displacement crimping systems was developed for this study. A probabilistic analysis was conducted, and stopper top dimensions (height and outer diameter (OD)) were found to be the most important drivers of seal force magnitude and variation. Seal force was positively correlated with both stopper height and OD. The effect of 2-year accelerated aging of the stopper, prior to assembly, was an increase to material stiffness and corresponding seal force. However, this increase in force was small (~3%). This corresponds well with practical findings where shelf aging is typically associated with increased material stiffness over time as well as an increase in RSF.

The European Qualified Person (QP) holds unique legal responsibility for certifying batch release, ensuring patient safety, and maintaining regulatory compliance. Modern pharmaceutical manufacturing-especially in biologics, ATMPs, and personalized medicinesâgenerates complex, multi-site, data-rich environments that challenge traditional oversight. Artificial Intelligence (AI) offers predictive analytics, anomaly detection, and trend recognition to support decision-making but cannot currently replace the QPâs scientific judgment or legal accountability. The forthcoming Annex 22 introduces Human-in-the-Loop (HITL) frameworks that embed human oversight within AI-supported processes, aligning technological advancement with regulatory control. This review explores evolving QP responsibilities, core and emerging competencies, AI integration within Quality Risk Management (QRM) and GMP frameworks, and ethical considerations, illustrated with practical case studies. By developing AI literacy and applying HITL oversight, QPs can more effectively translate technological potential into transparent, science-based, and patient-centered batch-release decisions.

Good contamination control practices in a controlled manufacturing environment demand consistency, which can be undermined by the common belief that the use of disinfectants alone will control the microbiological risk.  This comes from a legacy misunderstanding that use of a sporicide will correct other control failures.  The use of a sporicide in a cleanroom is not meant to replace good cleaning and broad-spectrum microbial disinfection but to complement broad spectrum efficacy when bacterial spore-formers are a persistent risk to the process .  Along with the rotation of a sporicidal disinfectant, a good balance of microbiological control for incoming materials and good gowning practices reduce the risk of introduction of microbiological contamination into a cleanroom or controlled environment.  Clear understanding of bacterial spore-formers and a risk-based approach to the removal of potential sources of bacterial spore-formers will lead to a good practice for the use of a sporicide in sterile pharmaceutical manufacturing environments.