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The Case for Apex Vessels
No full textApex vessels are an important element of the dissolution scientist’s toolbox and are frequently used in pharmaceutical drug product development settings. However, their use in development has not translated widely into use in the final approved QC method. This article aims to demonstrate the significant benefit of the apex vessel relative to the standard vessel in overcoming coning for formulations which contain dense insoluble excipients. Industrial case studies outline the benefits imparted by the apex vessel such as improved clinical relevance, more robust and discriminatory methods, and streamlined in vitro bridging strategies.
Furthermore, to understand the impact of apex vessels produced by different dissolution bath manufacturers, an interlaboratory study was performed across 11 partners which demonstrated minimal differences in dissolution performance between partners when a controlled protocol was executed
Towards real-time release of pharmaceutical tablets: 100% in-line control via near-infrared spatially resolved spectroscopy and 3D microwave resonance technology
No full textIn the scope of 100% in-line quality control and real-time release of pharmaceutical tablets, the authors present a flexible inspection module for in-line tablet analysis with integrated multipoint near-infrared (NIR) spectroscopy and 3D microwave resonance technology (3D MRT). Via an industrial case study on Diclofenac Sodium tablets, the abilities of this versatile process analytical technology (PAT) tool are presented. It is demonstrated that the combination of Diclofenac concentration prediction via NIR spectroscopy and mass prediction via 3D MRT allow to estimate the dosage of each individual tablet. Single sample repetition tests were performed on 5 tablets, measured 10 times on three different days. A high accuracy and precision of prediction was shown, with an average standard deviation below 0.5 mg. The inspection run demonstrated the added value of such inspection and sorting strategies based on the calculated dosage of individual tablets
Refractive Index: The Ultimate Tool for Real-Time Monitoring of Solid-Phase Peptide Synthesis. Greening the Process
No full textThis is the OAK Entry for the series of conferences where the content of OAK case 44094 (previously approved) is presented.
Peptides are the basis of many drugs currently in the market and much more entering clinical trials, as well as in preclinical studies. The most part of peptides in both research and industrial modes are synthesized using Solid-Phase Peptide Synthesis (SPPS) processes. A characteristic of this strategy is that the synthetic intermediates are not isolated and not characterized. In this context, the development of a real-time monitoring method would assure an optimal synthetic process. Refractive index (RI) of a liquid has important information about its physical properties and makes it possible to know the composition of any solution. Herein, RI is demonstrated for the first time as a Process Analytical Tool (PAT) that can be used for real-time monitoring of SPPS. The three basic steps involved in this process can be followed up on line: coupling, deprotection and washes. This has consequences for the determination of the end-point of the reactions and the optimization of all synthetic steps. This will impact directly into the consumption of reagents, solvents, and time, making SPPS greener
Introduction video for Manuel Sanchez-Felix
No full textShort video describing Manuel Sanchez-Felix outlining activities of a Control Release Soceity subgroup titled "Education committee on equity, diversity and inclusion
Impact of diabetes status on immunogenicity of trivalent inactivated influenza vaccine in older adults
No full textIndividuals with type 2 diabetes mellitus experience high rates of influenza virus infection and complications. We compared the magnitude and duration of serologic response to trivalent influenza vaccine in adults aged 50-80 with and without type 2 diabetes mellitus. Serologic response to influenza vaccination was similar in both groups: greater fold-increases in antibody titer occurred among individuals with lower pre-vaccination antibody titers. Waning of antibody titers was not influenced by diabetes status
Distinct contributions of partial and full EMT to breast cancer malignancy
No full textEpithelial-mesenchymal transition (EMT) is a transient, reversible process of cell de-differentiation where cancer cells transit between various stages of an EMT continuum, including epithelial, partial EMT, and mesenchymal cell states. We have employed Tamoxifen-inducible dual recombinase lineage tracing systems combined with live imaging and 5-cell RNA sequencing to track cancer cells undergoing partial or full EMT in the MMTV-PyMT mouse model of metastatic breast cancer. In primary tumors, cancer cells infrequently undergo EMT and mostly transition between epithelial and partial EMT states but rarely reach full EMT. Cells undergoing partial EMT contribute to lung metastasis and chemoresistance, whereas full EMT cells mostly retain a mesenchymal phenotype and fail to colonize the lungs. However, full EMT cancer cells are enriched in recurrent tumors upon chemotherapy. Hence, cancer cells in various stages of the EMT continuum differentially contribute to hallmarks of breast cancer malignancy, such as tumor invasion, metastasis, and chemoresistance
A Practical Discussion on Estimating Shelf Life Through Tolerance Intervals.
No full textThis paper is a companion article to the research originally presented in "Estimating Shelf Life through Tolerance Intervals" (Schwenke et al., 21:290, 2020) published in AAPS PharmSciTech where tolerance intervals are introduced as an alternative methodology for estimating pharmaceutical shelf life. An industry stability shelf life example data set was used to demonstrate the proposed methods. Although using industry data does give relevance to examples demonstrating shelf life estimation, measures of how well the proposed methods accurately and effectively estimate shelf life cannot be obtained because the true shelf life values are not known for example data sets. In this current paper, the results of a computer simulation are reported where the tolerance interval estimates of shelf life are compared to theoretically known true shelf life values. Various factors that affect a tolerance interval estimate of pharmaceutical shelf life are investigated. A critical decision factor is the choice of the proportion of the stability distribution allowed out of specification at expiry to define the pharmaceutical risk. The number of stability batches available for shelf life estimation and the storage time at which the estimate is made are also considered in this simulation study. The industry example data are again used as the basis for the simulation study to give relevance to this research
The kinase chemogenomic set (KCGS): An open science resource for kinase vulnerability identification
No full textWe describe the assembly and annotation of a chemogenomic set of protein kinase inhibitors as an open science resource for studying kinase biology. The set only includes inhibitors that show potent kinase inhibition and a narrow spectrum of activity when screened across a large panel of kinase biochemical assays. Currently, the set contains 187 inhibitors that cover 215 human kinases. The kinase chemogenomic set (KCGS), current Version 1.0, is the most highly annotated set of selective kinase inhibitors available to researchers for use in cell-based screens
Use of less-than-lifetime (LTL) durational limits for nitrosamines: Case study of N-Nitrosodiethylamine (NDEA)
No full textThe ICH M7(R1) guideline describes a framework to assess the carcinogenic risk of mutagenic and carcinogenic pharmaceutical impurities following less-than-lifetime (LTL) exposures. This LTL framework is important as many pharmaceuticals are not administered for a patient's lifetime and as clinical trials typically involve LTL exposures. While there has been regulatory caution about applying LTL concepts to cohort of concern (COC) impurities such as N-nitrosamines, ICH M7 does not preclude this and indeed literature data suggests that the LTL framework will be protective of patient safety for N-nitrosamines. The goal was to investigate if applying the LTL framework in ICH M7 would control exposure to an acceptable excess cancer risk in humans. Using N-nitrosodiethylamine as a case study, empirical data correlating exposure duration (as a percentage of lifespan) and cancer incidence in rodent bioassays indicate that the LTL acceptable intake (AI) as derived using the ICH M7 framework would not exceed a negligible additional risk of cancer. Therefore, controlling N-nitrosamines to an LTL AI based on the ICH M7 framework is thus demonstrated to be protective for potential carcinogenic risk to patients over the exposure durations typical of clinical trials and many prescribed medicines