This study investigates the real-world forces and torques applied by professional healthcare users to the luer cone region of prefilled syringes (PFSs) during typical handling and preparation tasks. While standards such as ISO 11040-4 address mechanical robustness, limited data exist on the magnitude and nature of forces various users actually apply during device useÂinformation that is critical for ensuring patient safety and product reliability. To address this gap, a custom measurement platform replicating a 1.5 mL Luer Lock PFS, instrumented with multi-axis force and torque sensors was developed. Participants (n=60 nurses and retail pharmacists) performed key handling tasks, including unscrewing the tip cap, screwing on a needle, removing the needle cap, and activating the safety needle shield-while applied forces were recorded. Four safety needle types-two hinge-based, one slider-based, and one spring-based retractable mechanism-were included in the evaluation; all safety needles require users to actively deploy the safety guards. Tasks were completed under three instruction conditions: naturalistic use ("actual"), elevated force use ("confident"), and perceived upper-bound force ("maximum acceptable"). The results quantify the range and characteristics of user-applied forces across tasks, needle types, and instructional prompts, providing valuable data to inform technical specifications for luer cone interfaces. In addition, these findings highlight the importance of study design choices such as task selection and instructional prompting when conducting human factors force characterization studies intended to support robust, use-relevant specifications setting. These insights aim to support the development of PFS devices that are both robust and user-friendly, ultimately ensuring the devices designed are suitable for the capabilities of their intended users.
Single-use systems (SUS) have become the dominant technology across the biotechnology and pharmaceutical industry, and viral vector manufacturing is no exception. The standard CQV framework, however, was designed and largely developed for stainless steel, fixed-equipment biopharmaceutical manufacturing. This creates real qualification gaps that the industry is currently solving inconsistently. This article proposes a structured, fit-for-purpose CQV approach built around three pillars specific to single-use Biopharmaceutical facilities: equipment qualification of single-use systems, supplier qualification as the foundation of SUS CQV, and a event-driven requalification strategy for single-use multi-product facilities. The framework is illustrated through a detailed qualification example for a single-use bioreactor and is positioned against the current regulatory landscape, including EU GMP Annex 1, 21 CFR 211.65, PDA Technical Report No 66 and FDA gene therapy CMC guidance.
Chemically crosslinked elastomers such as butyl rubber (IIR) and its halogenated derivatives (BIIR, CIIR) remain the benchmark for parenteral applications due to their exceptional gas barrier properties, chemical resistance, and long-term stability. Emerging materials, including brominated isobutylene-co-para-methylstyrene and thermoplastic elastomers (e.g., SEBS-based materials), offer architectural flexibility and processing advantages but require careful formulation to achieve equivalent sealing and barrier performance. The relationship between polymer composition, viscoelastic behavior, and functional sealing performance is examined using mechanical, thermal, rheological, and analytical characterization techniques. The paper further discusses product-level requirements, including compendial compliance, extractables and leachables (E&L) assessment with USP <1663>/<1664>, biocompatibility, and deterministic CCI testing in accordance with USP <1207> and global regulatory expectations. Special attention is given to time-dependent sealing behavior, residual seal force, pressure-induced stopper movement, and performance under cryogenic storage conditions relevant to advanced biologics and mRNA-based therapies. The evolution of risk-based extractables and leachables strategies, including threshold concepts (SCT, QT, AET) and advances in chromatographic and mass spectrometric methodologies, is also reviewed. Finally, the integration of finite element analysis, viscoelastic modeling, and mass migration simulation is presented as a predictive framework to complement empirical testing, reduce development complexity, and support science-based regulatory justification. Together, material science, analytical characterization, performance testing, and simulation-driven design form a holistic approach to developing robust, compliant, and future-ready elastomeric primary packaging components for sterile pharmaceutical products.
Recently, the pharmaceutical industry has recognized the benefits of assessing moisture by measuring the water activity of the product instead of its total water content. USP <922> has introduced water activity as a metric for determining the free, or "active", water that is available in a pharmaceutical product that can participate in undesired reactions such as hydrolysis or create an environment that supports microbiological growth. Traditional water content determination methods for lyophilized products, such as Karl Fischer titration, are time-consuming and measure the total water content which includes both the "active" and "inactive" water populations. In addition, the destructive nature of Karl-Fischer titration means that the moisture analysis of statistically relevant sample sets of lyophilized drug products is typically avoided, resulting in limited insight into the drying process and creating challenges for accurate determination of moisture specifications for product stability. Moisture assessment using water activity measurements, as mentioned in USP <922>, can be accomplished using newer non-destructive methods such as frequency modulated spectroscopy (FMS) headspace analysis. A moisture sorption isotherm can be used to bridge the measurements between the traditional Karl-Fischer total water content and the headspace water activity by establishing the relationship between the two for a particular drug product.In this study, a lyophilized product already in production was used as a model to evaluate this approach. Using a moisture sorption isotherm generated using a Dynamic Vapor Sorption (DVS) instrument, good correlation of the total water content of the lyophilized product was observed between the experimental Karl Fischer (KF) results and the values inferred from the FMS-Water Activity measurements. Due to the non-destructive nature of the headspace water activity analysis, rapid acquisition of a statistically relevant number of samples from three production batches were compared to demonstrate the robustness of this method for assessing moisture.
This paper reviews USP's proposed consolidation of sterilization informational chapters, particularly revised USP <1229> and <1229.1>, concluding that it creates significant technical gaps and perpetuates redundancies and areas of misalignment with established global standards and guidances for moist heat sterilization. While USP's general goal of streamlining is supported, the revised chapters provide far less depth than ISO 17665:2024 and PDA Technical Reports No. 1 and No. 48, omitting or insufficiently addressing key lifecycle elements such as installation qualification, operational qualification, cycle development, performance qualification, and ongoing control, and other critical topics such as steam quality, biological indicator use, and process lethality. The paper recommends that USP maintain <1229> as an overarching sterilization chapter, delete modality-specific chapters, and instead cross-reference recognized global standards and guidance documents for detailed technical requirements, thereby improving scientific alignment, reducing duplication, supporting regulatory expectations, and making USP sterilization guidance more practical and useful for sterility assurance professionals.
In this article, we present a rapid sterility method with a time to detection of 3 days and a limit of detection (LOD) of 1 CFU for testing both cell-therapy drug products and E. coli DNA plasmid preparations. The new method combines the automated rapid sterility test system BacT/ALERT (bioMérieux) as an enrichment step with PCR detection of viable microorganisms via the ATMP sterile release qPCR assay (Sartorius). Sample preparation protocols for non-filterable cell-therapy drug products and cell-free E. coli DNA plasmid preparations were developed; these include removal of contaminating DNA and PCR inhibitors and the use of a physical lysis step. A validation of the rapid sterility method using the BacT/ALERT system is presented and pre-validation experiments for the full assay are described.
Purified water is critical to the pharmaceutical industry. It is used at various stages of production and is subject to strict quality standards. This paper presents a case study of Pseudomonas aeruginosa microbiological contamination in a Brazilian pharmaceutical company's purified water generation and distribution system. The study investigates the causes of contamination, its microbiological and operational impacts on the production process, and the corrective and preventive measures adopted. The analysis involved examining internal documents, physicochemical and microbiological monitoring records, sanitation procedures, and system qualification reports. The results revealed operational failures during sanitation, mainly due to insufficient Standard Operating Procedures instructions for the aseptic handling of the mixed-bed resin and the risk of recontamination after system opening. The sanitizer that was routinely used, sodium metabisulfite, was ineffective at eliminating the microorganism and was replaced by peracetic acid, which eradicated the P. aeruginosa contamination. However, incompatibility of the new agent with system components was observed, which compromised water quality parameters. In conclusion, effective microbiological control requires efficient sanitizers, well-defined procedures, material compatibility, and alignment with good manufacturing practices. Additionally, the importance of continuous monitoring, a culture of quality, and structured change management to ensure sanitary industrial processes should be emphasized.
Robust process development enhances product quality while reducing time and cost across the product lifecycle. Systematic approaches are necessary to fully understand processes and control sources of variability; however, challenges increase when entering the field of autologous or personalized cell and gene therapies (ex. CAR-T) where each patient brings inherent biological variability. This presentation utilizes a simulated case study that combines Design of Experiments (DOE), mechanistic modeling, machine learning models, and Monte Carlo simulation to illustrate how complex processes can be analyzed in silico alongside benchtop experiments.A screening DOE study defined an efficient experimental space while mechanistic modeling generated critical quality attribute (CQA) outcomes to complement benchtop experimentation. These results trained regression and random forest models which were fed into Monte Carlo simulations. The simulations then quantify how patient-specific versus process-controlled variability contributes to overall outcome variance. Simulations can be repeated under different parameter constraints to ensure variability in patient-inputs can still lead to CQAs that are within acceptable limits.This integrated approach provides a more robust process development than DOE alone. This framework can aid in guiding process optimization and risk assessments both in early-stage process development and in continuous improvement during commercial production.
Pre-Use Post Sterilization Integrity Testing is implemented in sterile filtration applications by drug manufacturers using a risk-based approach with consideration of the stipulation in Eudralex volume 4, Annex 1, of the European Union Good Manufacturing Practice for Sterile Products. During process-specific bacterial retention testing, required as part of sterile filter validation, it is important to simulate the filtration process under evaluation as closely as possible. Worst-case conditions experienced by the process filter during routine use that may impact the process filters' ability to produce a sterile effluent must be accounted for. Given these two facts, do PUPSIT conditions need to be considered during process-specific bacterial retention testing? And if so, how should they be simulated?Performing pre-use post sterilization integrity testing introduces additional mechanical stress on the process filter and a potential new route for the introduction of bioburden into the process fluid flow path related to the filter wetting procedure. We would like to present a risk-based bacterial retention test design that incorporates a pre-use post sterilization integrity testing simulation phase, after a thorough evaluation of the process specific conditions, to rule out impact on efficacy of the sterile filtration process.
The increasing prevalence of biologic therapies requiring high injection volumes has created a need for devices that enable patient self-administration without compromising comfort or adherence. Conventional auto-injectors typically deliver 1-2 mL, necessitating multiple injections for higher doses, which can negatively impact patient experience and compliance. The high-volume auto-injector (HVAI) was developed to address this unmet need by enabling delivery of up to 10 mL in a single injection while maintaining ease of use and minimizing injection burden.A human factors study evaluated HVAI usability across representative user groups, including participants with physical impairments such as reduced hand strength or dexterity, which can make device use challenging. 74 injections were performed with injection times ranging from 21 to 60+ seconds; 69 were successful, five were incomplete. Of the successful injections, 88% met or exceeded a three-second post-injection hold time, the remaining injections with shorter hold times still delivered full doses. All five incomplete injections were classified as wet injections caused by premature device removal before the final indication. Despite the user dexterity impairments, most participants rated the auto-injector as easy to use and reported high confidence in dose delivery, supported by ergonomics and audible/tactile cues. Improvements in completion indicators were suggested.
In response to the FDA's recent policy shift towards conducting unannounced foreign inspections, the global pharmaceutical industry faces new challenges in maintaining a constant state of readiness. This data-driven presentation moves beyond speculation and provides a quantitative analysis of this critical change. Using publicly available data from the FDA's inspection records and data dashboards, we will present a case study analyzing the initial impacts of this policy.
A high-volume IV bag line with variable printing faced ongoing false rejects, prompting deployment of an AI-powered automated visual inspection (AVI) system from concept to production floor. The AVI system learns to distinguish subtle print artifacts from true particulates in real time, preserving print legibility while reducing misclassifications caused by printing variability, bag deformation, and lighting. The program progressed from concept through design, proof-of-concept testing, scale-up, FAT, SAT, and production qualification and validation. The AVI architecture blends deep learning defect detection with high-quality image capture and integrates with existing MES/packaging controls to gate good product and flag anomalies without slowing throughput. Practical design questions were addressed: camera placement, illumination strategies, data management and labeling, and model training and validation. Regulatory alignment (IQ/OQ/PQ, change control, GMP) underpins lifecycle management for AI-enabled inspection, including retraining and performance monitoring. Real-world learnings cover key design choices, maintenance strategies, and deployment milestones to sustain performance in continuous production. Expected outcomes include lower false rejects, improved detection of particulates on challenging flexible bag formats, and enhanced line efficiency while maintaining compliance.
Today's external manufacturing landscape demands more than retrospective audits and subjective traffic-light risk scores. With many CMO and API partners and fragmented oversight processes, quality organizations often discover problems only after they have escalated into supply disruptions or regulatory actions.This session will explore how predictive intelligence can modernize supplier oversight. By unifying structured and unstructured data sources - inspections, deviations, recalls, enforcement documents, audits, batch records, changes - into a single system of intelligence, we can surface early signals of risk. Hazard models and AI-based risk scoring now make it possible to quantify the likelihood of recalls, enforcement actions, or supplier disruptions weeks to months in advance.Real-world use cases will illustrate how large pharma organizations are reducing surprises, better targeting audits, and improving supplier selection decisions. The presentation will highlight the shift from static dashboards to near real-time monitoring, automated alerts, and data-driven next-best-action recommendations.
Effective materials transfer is essential for cleanroom contamination control. Items entering from warehouses or other cleanrooms pose a high risk of introducing fungal and bacterial spores. A robust decontamination procedure is key to minimizing this risk. Options include wiping or spraying items with a sporicide or disinfectant or using vaporized hydrogen peroxide (VHP) pass-through chambers or room decontamination.VHP is especially suitable for sensitive items like electronics and soft metals due to its excellent material compatibility and efficacy.
Detecting microorganisms in pharmaceutical water can be challenging. The current compendial method of plate counts is problematic. Organisms may not grow on the media that is used or may take longer than 7 days to appear on plates. As a result, the use of a bio-fluorescent particle counter (BFPC) offers advantages for the detection of water-borne organisms as their detection is not dependent on traditional culturing methods and is continuous and real-time.For this study, the ability of an online water bioburden analyzer (OWBA), a specific class of BFPC, is challenged to detect different organisms in pharmaceutical-grade water with an accuracy of 0.5 or greater AFU:CFU, variability less than 35% and linearity of r2>0.9025.Based on the results gathered, the OWBA can detect a wide range of organisms with accuracy, precision and linearity, indicating these microorganisms can swim, but they cannot hide!
Bulk lyophilization requires large amounts of material being filled into a bulk tray. Lyophilization cycle development for a bulk configuration normally requires a large amount of solution, typically several hundred milliliters to several liters, to obtain reproducible, representative freeze-drying results. During early development activities, this volume may not be readily available. To avoid devoting large volumes of material to developing a lyophilization cycle, alternative containers may be used, but these containers should be characterized to understand the different heat transfer characteristics and their effect on the final lyophilization cycle. The purpose of this poster is to develop a method to correlate lyophilization cycle development results between bulk trays and alternative containers and demonstrate the ability to complete bulk lyophilization cycle development on a smaller sample size. The vessels were filled with Purified Water, USP and the cycles were interrupted in primary drying and the vessels removed and weighed. Sublimation rate studies were completed in different containers to determine a correlation between Lyoguard trays and different containers to determine the optimal vessel to do small scale studies and develop lyophilization cycles for bulk products with minimal use of product.
