PDA Journal of Pharmaceutical Science and Technology最新文献

{"title":"Nonlinear Tissue Permeability Drives Tissue Pressure and Injection Distribution: A Computational Investigation of Subcutaneous Injections.","authors":"Scott Lovald, Shashank Agarwal, Anuradha Radhakrishnan, Vincent Casey, Andrew Rau","doi":"10.5731/pdajpst.2024.012969","DOIUrl":"https://doi.org/10.5731/pdajpst.2024.012969","url":null,"abstract":"<p><p>There is a significant opportunity to expand the understanding of subcutaneous injection mechanics with an aim to increase injectable volume while controlling tissue strain and associated subject pain. Computational modeling can evaluate the mechanics of subcutaneous injections as a supplement to experimental, animal and clinical studies. The objectives of this study are to (1) develop a computational model for subcutaneous injection in tissue, (2) investigate the influence anisotropic tissue permeability has on bolus formation, and (3) explore the effects that injection flow rate and viscosity have on injection flow and tissue strain. Poroelastic models with subsurface flow were implemented in finite element software (COMSOL, ABAQUS). Pore pressure and injectate distribution showed excellent agreement with experimental results when evaluated at multiple injection rates (20 ml/hr, 120 ml/hr and 360 ml/hr). Including the anisotropy of tissue permeability causes the injectate to preferentially spread horizontally, similar to experimentally observed bolus distributions. Cases are presented to provide additional insight into injection mechanics, including variations on the delivery rate, the injection volume, viscosity and the thickness of the subcutaneous layer. The results support the use of computational modeling as a valid tool for understanding tissue strains and injectate distributions for large volume injections.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":"78 4","pages":"516-517"},"PeriodicalIF":0.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046972","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":"Best Practices for Microbial Challenge In-Use Studies to Evaluate the Microbial Growth Potential of Parenteral Biological Products; Industry and Regulatory Considerations.","authors":"Camellia Zamiri, Danielle L Leiske, Patricia Hughes, J Paul Kirwan, Evelyn Der, Emily Cox, Rob Warburton, Monica Goss, Sarah Weiser, Janet Perez-Brown, Ganapathy Gopalrathnam, Jing Liu, Shyam B Mehta, Shebeer Shereefa, Sebastian Specht, Sandra J Aedo, Pierre Goldbach, Feng Jia, Barbara Kuehnle, Scott Page, Liesbeth Voeten, Li Yi, Chen Zhu","doi":"10.5731/pdajpst.2022.012806","DOIUrl":"10.5731/pdajpst.2022.012806","url":null,"abstract":"<p><p>Microbial challenge in-use studies are performed to evaluate the potential for microbial proliferation in preservative-free single-dose biological products after first puncture and potential accidental contamination during dose preparation (e.g., reconstitution or dilution) and storage. These studies, in addition to physicochemical in-use stability assessments, are used as part of product registration to define in-use hold times in Prescribing Information and in the pharmacy manual in the case of clinical products. There are no formal guidance documents describing regulator expectations on how to conduct microbial challenge in-use studies and interpret microbial data to assign in-use storage hold times. In lieu of guidance, US Food and Drug Administration (FDA) regulators have authored publications and presentations describing regulator expectations. Insufficient or unavailable microbial challenge data can result in shortened in-use hold times, thus microbial challenge data enables flexibility for health care providers (HCPs) and patients while ensuring patient safety. A cross-industry/FDA in-use microbial working group was formed through the Innovation & Quality (IQ) Consortium to gain alignment among industry practice and regulator expectations. The working group assessed regulatory guidance, current industry practice via a blinded survey of IQ Consortium member companies, and scientific rationale to align on recommendations for experimental design, execution of microbial challenge in-use studies, and a decision tree for microbial data interpretation to assign in-use hold times. Besides the study execution and data interpretation, additional considerations are discussed including the use of platform data for clinical stage products, closed system transfer devices (CSTDs), transport of dose solutions, long infusion times, and the use of USP <797> by HCPs for preparing sterile drugs for administration. The recommendations provided in this article will help streamline biological product development, ensure consistency on assignment of in-use hold times in biological product labels across industry, and provide maximum allowable flexibility to HCPs and patients while ensuring patient safety.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":" ","pages":"475-500"},"PeriodicalIF":0.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41237601","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":"Worldwide Regulatory Reliance: Launching a Pilot on a Chemistry, Manufacturing, and Control Post Approval Change for a Vaccine.","authors":"Thierry Gastineau, Cynthia Ban, Ana Basso, Franziska Brehme, Ana Luisa Silva, Olivier Faure, Lyne Le Palaire, Priya Persaud, Heraclio Rodriguez","doi":"10.5731/pdajpst.2023.012850","DOIUrl":"10.5731/pdajpst.2023.012850","url":null,"abstract":"<p><p>When an initial marketing authorization of a pharmaceutical product is granted, a substantial number of chemistry, manufacturing, and control (CMC) post approval changes (PACs) have to be managed by the manufacturers. Despite efforts undertaken over the years by multiple regulatory jurisdictions, there is still heterogeneity in terms of regulatory requirements and timelines across national regulatory authorities (NRAs). This creates complexity in managing global CMC PACs, putting the supply of medical products at risk. Regulators have developed regulatory mechanisms that aim at accelerating the reviews and approvals of PACs by NRAs. The World Health Organization (WHO) is supporting the concept of \"reliance\" among NRAs, which are encouraged to rely on the assessment completed by a \"highly performing authority\". The objective is to accelerate the overall process for PACs, ultimately fostering more equitable and timely access to medical products for populations who need them. With the support of Health Canada, WHO, Pan American Health Organization, and the Paul-Ehrlich-Institut, Sanofi has launched a pilot using the principles of reliance for a CMC PAC for a vaccine, with 21 NRAs who accepted to participate in the pilot. The objective of this pilot was to apply these principles to reduce the approval timeline to a maximum of 6 months in all countries after an initial approval is granted by a reference authority. We discuss the opportunities and challenges of implementing reliance principles for CMC PACs. We also describe the pilot experience by sharing initial lessons learned from the Step 1 of this pilot, which consisted of engaging the reference authority and the NRAs.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":" ","pages":"388-398"},"PeriodicalIF":0.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136398658","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":"Sensitization Assessment of Extractables and Leachables in Pharmaceuticals: ELSIE Database Analysis.","authors":"Patricia Parris, Geraldine Whelan, Anders Burild, Jessica Whritenour, Uma Bruen, Joel Bercu, Courtney Callis, Martyn L Chilton, Jessica Graham, Esther Johann, Candice Johnson, Troy Griffin, Martin Kohan, Elizabeth A Martin, Melisa Masuda-Herrera, Brad Stanard, Maureen T Cruz, Lee Nagao","doi":"10.5731/pdajpst.2022.012811","DOIUrl":"10.5731/pdajpst.2022.012811","url":null,"abstract":"<p><p>Quality by design is the foundation of the risk management framework for extractables and leachables (E&Ls) recommended by the Extractables and Leachables Safety Information Exchange (ELSIE). Following these principles during the selection of materials for pharmaceutical product development minimizes the presence of highly toxic substances and decreases the health risk of potential leachables in the drug product. Therefore, in the context of the broad arena of chemicals, it is important to distinguish E&Ls as a subset of chemicals and evaluate this relevant chemical space to derive appropriate analytical and safety thresholds. When considering the health hazards posed by E&Ls, one area presenting a challenge is understanding the sensitization potential and whether it poses a risk to patients. A dataset of E&Ls compiled by ELSIE (n = 466) was analyzed to determine the prevalence and potency of skin sensitizers in this chemical subset and explore a scientifically justified approach to the sensitization assessment of potential leachables in parenteral drug products. Approximately half of the compounds (56%, 259/466) had sensitization data recorded in the ELSIE database and of these, 20% (52/259) are potential skin sensitizers. Only 3% (8/259) of the E&L dataset with sensitization data were considered potent (strong or extreme) sensitizers following in silico analysis and expert review, illustrating that potent sensitizers are not routinely observed as leachables in pharmaceutical products. Our analysis highlights that in silico potency prediction and expert review are key tools during the sensitization assessment process for E&Ls. The results confirm where material selection is anticipated to mitigate the risk of presence of strong and/or extreme sensitizers (e.g., extractable testing via ISO 10993-10), and that implementing thresholds per ICH M7 and/or Masuda-Herrera et al. provides a reasonably conservative approach for establishing the analytical testing and safety thresholds.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":" ","pages":"399-444"},"PeriodicalIF":0.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10253746","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":"Prefilled Ophthalmic syringes - New Possibilities in Terminal Sterilization.","authors":"Bernd Zeiss, Eric Offermann, Annick Gillet, Erik Haghedooren, Markus Bischof","doi":"10.5731/pdajpst.2024.012968","DOIUrl":"https://doi.org/10.5731/pdajpst.2024.012968","url":null,"abstract":"<p><p>In a joint study carried out by Gerresheimer, Sterigenics and Früh, it could be shown that also NO₂ is well suited to terminally sterilize prefilled ophthalmic syringes. In detail 5 topics were addressed: (1) Compare EtO vs. NO₂ penetration into the filled syringe; (2) Analyze gas ingress though 4 different plunger stoppers including silicone oil free and standard rubber plungers; (3) Scrutinize gas ingress through 2 different cap designs based on different elastomer properties; (4) Investigate gas permeation through COP plastic barrels compared to glass; (5) Check if the Tyvek®-layer has an influence on either sterilization.Depending on the needs a suitable sterilization method, packaging and syringe type can be suggested to customers.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":"78 4","pages":"532-533"},"PeriodicalIF":0.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142046973","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":"Comparison of the Cobalt Content in Needles Stainless Steel.","authors":"Laura Berardi","doi":"10.5731/pdajpst.2024.012977","DOIUrl":"https://doi.org/10.5731/pdajpst.2024.012977","url":null,"abstract":"<p><p>Cobalt (Co) alloys are used extensively in a wide range of medical devices due to their biocompatibility, durability, and properties. In 2017 the European Chemical Agency (ECHA) proposed to classify Co metal as a category 1B carcinogen (i.e. presumed to have carcinogenic potential for humans), as a reproductive hazard category 1B (i.e. presumed human reproductive toxicant) and as a category 2 mutagen. Even more, the European Medical Device Regulation (MDR) requires that medical devices contain > 0,1 w/w of substances that are category 1 A and 1B (CMR). As far as the European Medical Device Regulation, it is not specified if the Co content and concentration had to be determined/measured on the entire product or only on the product components. The object of this work is the comparison of Co profile in three different suppliers of stainless-steel needles as is and after being processed (i.e. sterilized) and then provide the proper interpretation and application of MDR requirements. The study and the extractable profile demonstrate the low cobalt content on needles and on a total syringe, thus suggesting to consider the Co content only on the syringe component.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":"78 4","pages":"520-521"},"PeriodicalIF":0.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142047007","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 Novel Combined Approach to Better Predict Sealing Performance of Luer Lock Connectivity.","authors":"Julien Singer, Lucile Gontard, Yetirajendra Daroji, Jimmy Voniez, Nestor Rodriguez, Diana Koschel, William Leverd","doi":"10.5731/pdajpst.2024.012966","DOIUrl":"https://doi.org/10.5731/pdajpst.2024.012966","url":null,"abstract":"<p><p>Luer systems, for example Luer-needle hub with syringe's Luer cone tip and its Luer lock Adapter, are common interface on medical devices. One of the key questions in this application is about the safety guaranty and dose accuracy. It is then crucial to study the sealing between these elements. In this study we combine the use of Finite Element Analysis (FEA) and Multiscale Contact Mechanics (MCM) to analyze the connectivity and sealing performance of a glass syringe and a plastic needle Luer hub.This methodology has been applied before to the contact between glass and rubber and this is the first time that it is used for the contact between glass and plastic materials. The use of FEA allows to calculate the contact pressures and the nominal area of contact. The surface topographies of the two surfaces were measured, over a wide wavelength range (mm to nm). Subsequently, the air and liquid interfacial flow (leakage) is calculated using Persson's MCM theory which considers the roughness and elasto-plasticity of the interfacial surfaces. The theoretical predictions are compared to experimental leak measurements by pressure decay method. Further analysis is conducted, evidencing the key features that are responsible for a good sealing.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":"78 4","pages":"514-515"},"PeriodicalIF":0.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142047005","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":"2024 July/August Editorial.","authors":"","doi":"10.5731/pdajpst.2024.001844","DOIUrl":"https://doi.org/10.5731/pdajpst.2024.001844","url":null,"abstract":"","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":"78 4","pages":"384-385"},"PeriodicalIF":0.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142047004","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":"Establishment of a Single Temperature Incubation Approach for Environmental Monitoring Samples with Focus on Mold Recoveries.","authors":"Alana Poloni, Janete GonÇalves, MÓnica Pereira, Alexander Stoll","doi":"10.5731/pdajpst.2022.012769","DOIUrl":"10.5731/pdajpst.2022.012769","url":null,"abstract":"<p><p>A robust environmental monitoring program is essential to properly estimate and identify microorganisms in cleanrooms, ensuring that microbial contamination remains acceptably low and that a good state of control is maintained in the manufacturing areas. The incubation conditions are important to support optimal microbial recoveries, considering that there is no single culture medium, temperature, and incubation time that can recover all microorganisms. In particular, molds are quite sensitive microorganisms, and some species may have very specific nutritional and environmental needs. In this study, a two-phase approach was used to identify a single incubation-temperature approach that could recover most of the cleanroom microbial flora, with a focus on molds. Phase 1 included a growth promotion study performed in the laboratory using pharmacopeial and in-house strains, comparing different media (Sabouraud Dextrose Agar [SDA] and Tryptone Soy Agar [TSA]) at single or dual incubation-temperature approaches for 5 or 6 days. Phase 2 was based on an in-situ study in which sampling was performed in different areas of a pharmaceutical facility and the recoveries at different incubation conditions were compared. In addition, extension studies of Phase 1 and Phase 2 were performed to get a better understanding of growth requirements for in-house molds. The results showed that an incubation on TSA at 25°C-30°C for 3-4 days was able to recover most tested microorganisms in Phase 1 and a large variety of microorganisms in Phase 2, indicating that the single incubation-temperature is an optimal approach for the recovery of microorganisms in cleanrooms. Exceptions were noted for one strain of the species <i>Cutibacterium acnes,</i> a microaerophilic bacterium for which anaerobiosis and higher temperatures were needed, and two mold strains (<i>Sistotrema brinkmannii</i> and <i>Stereum hirsutum</i>), indicating that those molds required a specific media (SDA) for their proliferation. The results showed that TSA incubated at the single or dual incubation-temperature approach cannot compensate for the absence of SDA for some environmental molds that may be atypical in cleanrooms. Therefore, in addition to TSA, certain monitoring with SDA at, for example, cleanroom entrance points may be beneficial to recover molds with very specific nutritional requirements.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":" ","pages":"312-330"},"PeriodicalIF":0.0,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41237604","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 Method to Investigate Sterilization Processes and the Bacterial Inactivation Resolved in Time and Space.","authors":"Manuel Feurhuber, Thomas Taupitz, Frank Mueller, Carsten Frank, Christoph Hochenauer, Valentin Schwarz","doi":"10.5731/pdajpst.2022.012771","DOIUrl":"10.5731/pdajpst.2022.012771","url":null,"abstract":"<p><p>In this study, a computational fluid dynamics (CFD) model was developed to predict all relevant phenomena occurring during a moist heat sterilization process at a high level of temporal and spatial resolution. The developed CFD model was used to simulate the distribution of, for example, pressure, temperature, and residual air within a large-scale industrial steam autoclave (multiphase flow models), which was not published until now. Moreover, the thermodynamic behavior and distribution of fluids and temperatures inside the sterilization load were simulated and were verified with measurements. Based on the obtained sterilization temperature profiles in connection with the sterilization environment (e.g., non-condensable gases, natural convection), bacterial inactivation could be simulated. A complete moist heat sterilization process was simulated, including all relevant phenomena inside an autoclave chamber and a Peritoneal Dialysis Bag System (PDBS), which represents a complex sterilization item. To verify the simulation results, simulated pressures and temperatures were compared with measurement data for both the autoclave chamber and the PDBS. The results show that the simulated and measured values were in excellent accordance. By using the novel CFD model, the distribution of steam and residual air inside the autoclave chamber, as well as the natural convection inside the sterilization load, could be precisely predicted. To predict the inactivation of <i>Geobacillus stearothermophilus</i> inside different moist heat environments, the CFD model was extended with bacterial inactivation kinetics based on measurement data. The simulation results clearly indicate that our developed CFD model can be used to predict the inactivation kinetics of bacteria, depending on the sterilization temperature profile of the sterilization process as well as the moist heat sterilization environment, and to resolve the kinetics in time and space. Therefore, the developed CFD model represents a powerful tool that might be used in the future to predict, for example, \"worst case\" locations for any given autoclave and sterilization load or any other relevant process parameter, enabling the operator to develop an effective sterilization process.</p>","PeriodicalId":19986,"journal":{"name":"PDA Journal of Pharmaceutical Science and Technology","volume":" ","pages":"331-347"},"PeriodicalIF":0.0,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136398655","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}