PDA Journal of Pharmaceutical Science and Technology最新文献

{"title":"Issues to Consider in Liquid Extraction Testing of Surfaces for Particulate Matter.","authors":"Klaus Wormuth, Fanny Gaston, Veronique Cantin, Manon Thaüst","doi":"10.5731/pdajpst.2026-000024.1","DOIUrl":"https://doi.org/10.5731/pdajpst.2026-000024.1","url":null,"abstract":"<p><p>Formulation ingredients, process fluids, drug substance, and drug product contact many types of material surfaces during the manufacturing of pharmaceuticals. To achieve the requirements for subvisible and visible particulate matter in final drug products, good manufacturing practice (cGMP) requires control over the cleanliness of contact surfaces with respect to particulate matter. For cell therapy and other aseptic processes where filtration to remove particulate matter may not be possible, particulate matter may accumulate with each process step and pose risks to final drug product purity. Quantitative measurement of particulate matter on contact surfaces provides essential data for risk assessments. Here we address the issues associated with the measurement of surface cleanliness via liquid extraction, and discuss approaches to assessing and reporting surface cleanliness.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148648972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Traditional Statistics to Adaptive Multivariate Models: Exploring the Role of AI in Modern Pharmaceutical Manufacturing.","authors":"Mario Stassen, Matt Schmucki, Francisco Valero, Toni Manzano","doi":"10.5731/pdajpst.2026-000011.1","DOIUrl":"https://doi.org/10.5731/pdajpst.2026-000011.1","url":null,"abstract":"<p><p>Modern pharmaceutical manufacturing increasingly relies on high-frequency, high-dimensional and dynamically evolving data. Traditional statistical tools-such as univariate Statistical Process Control (SPC), Shewhart logic and Nelson's rules-remain valuable for routine monitoring, but are constrained by assumptions of independence, stationarity and linearity. These assumptions are frequently violated in contemporary bioprocesses, leading to inconsistent diagnostics and elevated false-alarm rates. Such limitations have been documented in data-rich manufacturing environments and confirmed in continued process verification initiatives, where repeated univariate rule violations were shown to lack biological relevance.In parallel, regulatory frameworks-including FDA Process Analytical Technology (PAT), ICH Quality by Design (QbD) and the draft EudraLex Annex 22 on Artificial Intelligence (AI)-increasingly emphasize scientifically justified, model-based approaches. This manuscript examines the boundaries of classical statistical methods, the inherently multivariate and dynamic nature of modern pharmaceutical processes, and the role of fixed deterministic and fixed probabilistic AI-based models in addressing analytical gaps. A structured scientific exploration framework is proposed to support evidence-based regulatory acceptance of advanced modelling approaches while improving process understanding, product quality and manufacturing efficiency.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148649035","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gas flow through micro-capillaries - which flow law is most suitable to predict the flow rate through micro-capillaries?","authors":"Christian Proff, Charles E Pierce, Irwann Le Bouquin","doi":"10.5731/pdajpst.2025-000065.1","DOIUrl":"10.5731/pdajpst.2025-000065.1","url":null,"abstract":"<p><p>In pharmaceutical quality control, capillaries are the primary positive controls able to cover a wide range of gas flow rates during Container Closure Integrity (CCI) testing. They serve as the physical benchmarks for analytical methods to demonstrate these can reliably detect defects at or below the critical leak thresholds. However, the predictive reliability of standard gas flow models for capillaries can be undermined by the 'transitional' flow regime. Traditional flow laws, like Hagen-Poiseuille and molecular flow, provide accuracy only at the extremes of the investigated flow rate spectrum, failing to deliver precise results in the range most relevant for the sub-micron defects that define current pharmaceutical safety standards. This study investigates helium flow through capillaries with inner diameters from sub-micron to 25 μm corresponding to the range of leak rates from 10-9 to 10-3 mbar l/s, encompassing the 6·10-6 mbar l/s mentioned in USP<1207>. We evaluated the predictive performance of classical, slip-flow, and modified Knudsen models under differential pressure ranging from 250 mbar to 4000 mbar, specifically comparing behavior at a constant 1000 mbar difference against variable pressure dependencies. Our analysis reveals that model strength is highly context-dependent. At a constant 1 bar pressure difference (ambient vs. vacuum), the slip-flow model was the superior predictor, maintaining a 30% tolerance and outperforming the other flow laws including the modified Knudsen law model by Yoshida et al.. However, for characterizing pressure dependence, simpler models failed to capture the transition from linear ~p in ø0.9 μm to quadratic ~p2 in ø 20 μm capillaries. In this aspect the modified Knudsen model excelled, accurately describing the shift in behavior across the entire diameter range. These results provide a robust framework for CCI testing, enabling industry to select models to simulate specific relevant leak limits under varying environmental and pressure-test conditions.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148284295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Justification and Impact of Reduced Sampling Flow Rates for Total Particle Counting in Grade A Environments.","authors":"Petra Merker, Didier Hélal, Svetlana Kiseleva, Denis Kiselev","doi":"10.5731/pdajpst.2026-000003.1","DOIUrl":"https://doi.org/10.5731/pdajpst.2026-000003.1","url":null,"abstract":"<p><p>The increasing evaluation and adoption of Biofluorescent Particle Counters (BFPCs) for Grade A environments have introduced instruments that operate at lower flow rates, such as 5 L/min, to simultaneously count both viable and total particles. This flow rate differs from the conventional 28.3 L/min referenced in the current EU GMP Annex 1 for total particle counting. The divergence is motivated by the higher effectiveness of viable particle detection achieved with a lower flow rate and by the suppression of a virtual impactor and its associated particle losses.The study provides supportive information for justifying a lower flow rate when sampling in Grade A environments with homogeneous, unidirectional airflow. The performance of two commercially available particle counters was compared to assess whether the lower flow rate is non-inferior in detecting deviations of environmental quality for both 0.5 μm and 5 μm total particles: one operating at the standard flow rate of 28.3 L/min (1 ft³/min) and the other at 2.83 L/min (0.1 ft³/min), representing a proportional flow rate relative to a 5 L/min Biofluorescent Particle Counter.Two distinct experimental setups representing Grade A environments were used: a laboratory-scale microbiological biosafety cabinet (BSC) featuring homogeneous unidirectional airflow at 0.45 m/s, and a custom-built room-sized Grade A chamber equipped with an integrated air purification system and controlled ventilation to simulate full-scale cleanroom conditions. Both setups exposed the particle counters to identical contamination events generated by external ventilators to evaluate performance across different spatial scales and airflow dynamics while maintaining Grade A compliance.The alert thresholds of the two standard particle counters deployed in this study showed a high level of concordance under unidirectional airflow. No consistent preference was observed for one counter over the other in terms of alert precedence. In the BSC setup, the lag time between the two instruments was limited to 1 minute in 96% of cases. Collectively, data from both experimental setups were strongly supportive to demonstrate that operating a particle counter at a lower flow rate is non-inferior to the standard flow rate, maintains equivalent environmental control, and underlines its suitability for application in Grade A zones.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148423171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient-Centric Drug Delivery: Establishing Injection Hold Time Limits for Large Volume Autoinjectors.","authors":"Dana Cabrita, Daniel Miranda, Ankur Kulshrestha","doi":"10.5731/pdajpst.2026-000008.1","DOIUrl":"https://doi.org/10.5731/pdajpst.2026-000008.1","url":null,"abstract":"<p><p>Administering large volumes of medication via subcutaneous or intramuscular injection often requires tradeoffs to balance patient comfort with effective therapeutic outcomes. The shift toward patient-centric drug delivery has driven the development of large-volume autoinjectors (LVAI), enabling self-administration of medications outside clinical settings. However, little research has been conducted to establish an upper limit for autoinjector hold time. Therefore, this study seeks to establish an acceptable upper limit of hold time for most users by evaluating the capability of diverse user groups when performing simulated injection tasks. Using a mockup LVAI (>3mL), participants (N=20; Lay, Chronic Condition, Upper-Extremity impaired) completed two trials with two injections each: Trial A, hold as long as possible, and Trial B, hold for 10 minutes. Trials assessed maximum hold times and performance without progress cues. Grip strength, downward injection force, hold time, and subjective responses were recorded.When instructed, lay participants reliably maintained 10-minute injection time. Participants with chronic conditions and upper extremity impairments demonstrated significantly shorter and more variable hold times. Statistical analysis revealed no significant difference between pre- and postgrip strength, indicating effective fatigue management between trials. Every participant, regardless of group, was able to hold an injection for at least 2 minutes and 18 seconds. Subjective feedback indicated that most participants found 10-minute injections challenging, with a strong indications that durations of 2 minutes or less would be acceptable. Notably, participants were inaccurate in estimating injection duration, with perceived hold times deviating from actual by ~38%.For most users, an acceptable hold time for LVAIs is 2 minutes or less. Longer durations may be feasible but require additional design considerations, such as progress cues, end-of-dose feedback, and ergonomic support, to mitigate physical and mental challenges. Future research should expand to broader populations and balance risk-based factors that can further enhance the development of patient-centric drug delivery systems.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A PAT-aligned framework for installing and operating particle counting systems to detect pre-limit particle-size distribution shifts in ISO-8 (non-sterile) controlled areas.","authors":"Gowtham Nakka, Sakshi Gupta, Kartik Reddy Katti","doi":"10.5731/pdajpst.2026-000013.1","DOIUrl":"https://doi.org/10.5731/pdajpst.2026-000013.1","url":null,"abstract":"<p><p>ISO 14644-1 defines ISO-8 cleanrooms, often found in pharmaceutical manufacturing facilities, by maximum allowable concentrations of airborne particles at specified threshold sizes (commonly ≥0.5 μm and ≥5.0 μm) within a classification particle size range of 0.1-5 μm. For ISO Class 8, though ISO 14644- 1 lists sizes from 0.1 to 5.0 μm, classification commonly uses the operationally relevant limits of ≥0.5 μm and ≥5.0 μm. While ISO classification establishes a compliance boundary, it does not fully leverage modern optical particle counter (OPC) time series data to detect early environmental degradation driven by controllable operational factors in non-sterile areas (traffic, door cycling, material handling, and housekeeping drift). FDA's Process Analytical Technology (PAT) guidance combined with Quality by Design (QbD) principles, promotes timely measurement, enhanced process understanding, and multivariate/statistical approaches to manage variability proactively. This paper proposes a PAT aligned framework for installing and operating particle counting systems in ISO-8 non-sterile controlled areas to detect pre-limit particle size distribution (PSD) shifts. The approach integrates (i) risk-based monitoring network design, (ii) PSD-shift features (coarse to fine ratios, event rate, recovery time, persistence) that translate raw counts into actionable change signals, and (iii) statistical change detection (EWMA/CUSUM) to distinguish transient events from sustained shifts. One thing which is often overlooked is physical collection issues, especially when pulling samples through long tubes or curved lines. Particles at 5 microns or more tend to drop out under those conditions, skewing results noticeably. So this guidance covers considerations for choosing particle counters and where to place ports for truer readings. Instead of waiting until thresholds breach, the system proposed in this article acts earlier using feedback loops tied directly to control actions there by providing a robust continuous monitoring system.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148284341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Using Positive Controls to Define the Defect Detection Range for CCIT Method Development and Validation.","authors":"Ken Victor, Allison Alix Caudill, Peter Grant, Inese Jermakova, James Veale","doi":"10.5731/pdajpst.2025-000071.1","DOIUrl":"https://doi.org/10.5731/pdajpst.2025-000071.1","url":null,"abstract":"<p><p>In recent years, the pharmaceutical industry has moved towards using quality by design (QbD) principles to ensure safety and efficacy in parenteral products. Developing and validating container closure integrity test (CCIT) methods that can be used to confirm inherent package integrity - as well as batch-release and stability sample testing - is an essential aspect of this more holistic approach. To do so, both positive and negative controls are required, both of which should ideally be assembled with container components in a manner mimicking the production samples that are to be tested. The performance of these controls enables the accuracy, precision, limit of detection (LoD), and range of the CCIT method to be defined per the ICH Q2 parameters [1]. The negative controls should contain no known defect. The positive controls should differ from the negative controls only in that they have a well-characterized defect that creates a quantified breach in the container closure integrity (CCI) of the package assembly. When appropriate, \"type controls,\" as defined in USP <1207>, can also be included during CCIT method development [2]. Type controls are intended to qualitatively evaluate the ability of the CCIT method to identify defects that better mimic \"real-world\" defects, including the potential of the product to inhibit the identification of such defects.The first objective of this study was to present a theoretical framework that links the flow-effective size [3] parameterization with the observed gas flow rates for a defect. The second objective was to demonstrate the use of microcapillaries to create defects with a flow-effective size much smaller than the current 2 μm limit of laser-drilled defects. The third objective was to reveal that the flow-effective size associated with 5 and 10 μm laser-drilled defects in glass vials decreased significantly when submerged below a liquid 0.2 μm filtered-water fill.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148284053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Manufacturing CAR T Therapies: A Review of Methods, Controls, and Innovations for Scalable, Accessible Treatments.","authors":"Jose A Caraballo Oramas","doi":"10.5731/pdajpst.2025-000059.1","DOIUrl":"10.5731/pdajpst.2025-000059.1","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T cell therapies have transformed the treatment of hematologic malignancies, providing meaningful clinical outcomes for patients with limited therapeutic options. However, the complexity of these therapies presents significant manufacturing challenges that could affect cost, scalability, and accessibility. Early CAR T production relied on highly manual, variable processes developed in academic settings, whereas current commercial manufacturing has moved toward more structured and standardized platforms. This review examines how that transition unfolded, with particular attention to changes in process design, analytical control strategies, and quality systems that support more robust manufacturing operations. Rather than individual technologies, the literature emphasizes increased levels of maturity in process controls as the defining feature of progress in manufacturing. Improvements in unit operations have helped to enable more predictable scale-out of therapies, reinforcing the role of manufacturing in translating scientific innovation into consistent clinical delivery.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":" ","pages":"328-342"},"PeriodicalIF":0.0,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147475102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peer Review.","authors":"","doi":"10.5731/pdajpst.2026.02613","DOIUrl":"https://doi.org/10.5731/pdajpst.2026.02613","url":null,"abstract":"","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":"80 3","pages":"287"},"PeriodicalIF":0.0,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148219132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Study of LAL and Recombinant Cascade Reagents Methods for Bacterial Endotoxin Testing in Pharmaceutical Products.","authors":"Prasad Thota, Piyush Kumar, Anil Kumar Teotia, Anshika Kaushik, Roshni Rajpali, Manoj Pandey, Meenakshi Dahiya, V Kalaiselvan","doi":"10.5731/pdajpst.2025-000073.1","DOIUrl":"10.5731/pdajpst.2025-000073.1","url":null,"abstract":"<p><p>The bacterial endotoxin method uses amebocyte lysate reagents from the horseshoe crab (<i>Limulus polyphemus</i> or <i>Tachypleus tridentatus</i>) to detect and quantify bacterial endotoxin in injectable medications and medical devices. Two types of recombinant reagents have been introduced by various manufacturers, and the equivalency of their results to those of the natural Limulus amebocyte lysate (LAL) reagents has been recently assessed by the United States, European, and Japanese Pharmacopoeias. Recombinant reagents and amebocyte lysate reagents appear to be highly comparable, according to several investigations. LAL assays are currently the gold standard. LAL is used in vitro for the precise detection of endotoxins and is based on the endotoxin-activated Factor C-mediated clotting cascade. In our quality control laboratory, we tested several categories of drug samples using different compendial methods for detection of bacterial endotoxin that provide reliable and consistent results. Since 2024, a bacterial endotoxin test based on recombinant cascade reagent (rCR)-composed of the endotoxin sensor recombinant Factor C (rFC), Factor B, and pro-clotting enzyme inside of LAL-has been used as an animal-free alternative to LAL. The non-animal-derived reagent rCR uses cloned genes from the genome of the <i>Limulus polyphemus</i> horseshoe crab to detect and measure bacterial endotoxins. In addition to providing ethical and environmental benefits over traditional LAL assays, rCR eliminates interfering horseshoe crab blood components, allowing for extremely specific endotoxin detection. For rCR test performance in a routine setting, a comparative study was conducted of compendial bacterial endotoxin testing by LAL with the alternative animal-free reagent rCR, and the evidence was summarized and presented by analyzing different categories of pharmaceutical products. According to the compendial endotoxin testing requirements, all results were acceptable. When the rCR assay was applied rather than the LAL test, no interference was seen in certain samples. In this study, the rCR and LAL were equivalent and comparable.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":" ","pages":"288-297"},"PeriodicalIF":0.0,"publicationDate":"2026-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147474095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}