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ICH M10 Bioanalytical Method Validation Guideline-1 year Later
The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) adopted Guideline M10 entitled \"Bioanalytical Method Validation and Study Sample Analysis\" in May 2022. In October 2023, approximately one year after the adoption of the ICH M10 guideline, a \"Hot Topic\" session was held during the AAPS PharmSci 360 meeting to discuss the implementation of the guideline. The session focused on items the bioanalytical community felt were challenging to implement or ambiguous within the guideline. These topics included cross-validation, parallelism, comparative bioavailability studies, combination drug stability, endogenous analyte bioanalysis, and dilution QCs. In addition, the regulatory perspective on the guideline was presented. This report provides a summary of the Hot Topic session.
Graphical Abstract
Journal Article
Extended Stability for Parenteral Drugs
Get the support you need to safely extend dating of parenteral drugs beyond the usual 24-hour limit--minimizing waste, lowering medication costs, and enabling optimal patient administration schedules at alternate infusion sites. The new seventh edition features the inclusion of monographs expanded beyond home infusion to be inclusive of all clinical settings where parenteral drugs are stored or compounded.
eBook
Repetitive stability study of remdesivir/cyclodextrin complex on the international space station
Stability assessment of drugs in space is particularly important for future missions. In space there are multiple factors, such as the variability of the conditions (radiation, microgravity, vacuum etc.) that could affect the reliability and reproducibility of the data. Therefore, we investigated the stability of an anti-Covid drug formulation, Remdesivir (RDV) sulfobutylether-beta-cyclodextrin (SBECD) complex, in two separate flight experiments on the International Space Station (ISS). While HPLC/MS studies revealed no degradation of the cyclodextrin excipient in any of the samples investigated in both missions, RDV purity analysis of the RDV/SBECD complex after the first mission revealed different stabilities and altered degradation in space and on Earth. This latter interesting finding was not supported by the second mission, where no differences in the drug stabilities were identified. This anomaly highlighted the importance of standardization together with increased control of the variable parameters during the entire space missions and the terrestrial control experiments.
Journal Article
PTBP1 modulation of MCL1 expression regulates cellular apoptosis induced by antitubulin chemotherapeutics
Myeloid cell leukemia sequence 1 (MCL1), an anti-apoptotic BCL2 family protein, is a key regulator of intrinsic apoptosis. Normal cells require strict control over MCL1 expression with aberrant MCL1 expression linked to the emergence of various diseases and chemoresistance. Previous studies have detailed how MCL1 expression is regulated by multiple mechanisms both transcriptionally and translationally. However, characterization of the post-transcriptional regulators of
MCL1
mRNA is limited. Polypyrimidine tract binding protein 1 (PTBP1) is a known regulator of post-transcriptional gene expression that can control mRNA splicing, translation, stability and localization. Here we demonstrate that PTBP1 binds to
MCL1
mRNA and that knockdown of PTBP1 upregulates MCL1 expression in cancer cells by stabilizing
MCL1
mRNA and increasing
MCL1
mRNA accumulation in cytoplasm. Further, we show that depletion of PTBP1 protects cancer cells from antitubulin agent-induced apoptosis in a MCL1-dependent manner. Taken together, our findings suggest that PTBP1 is a novel regulator of
MCL1
mRNA by which it controls apoptotic response to antitubulin chemotherapeutics.
Journal Article
Stability Evaluation of the Biosimilar Monoclonal Antibody Using Analytical Techniques
Determination of the drug substance (DS) and drug product (DP) stability is especially important for biosimilar monoclonal antibodies since it can affect the quality, efficacy, and safety of the drugs. The main objective of this study was to determine the stability of the biosimilar candidate (TUR01) using state-of-the-art (current) analytical techniques.
Analytical techniques used in this study were isoelectric focusing on capillary electrophoresis, capillary electrophoresis-sodium dodecyl sulfate, size exclusion chromatography-ultra-high performance liquid chromatography, binding affinity, and physicochemical and microbiological tests. DS was kept in polyethylene terephthalate copolyester, glycol modified (PETG) bottles at ≤-65.0°C and 5.0 ± 3.0°C for 18 months, where the pre-filled syringe stability study was conducted at 5.0 ± 3.0°C for 24 months and 25.0 ± 2.0°C/60% ± 5 relative humidity (RH) for 6 months. The accelerated condition for DS was accepted as 5.0 ± 3.0°C, while it was 25.0 ± 2.0°C for the DP.
The results indicated that TUR01 DS was stable when it was stored under long-term storage conditions at ≤-65°C and at 5 ± 3°C at least 18 months. Also, TUR01 DP was stable at 5 ± 3°C for 24 months and at 25 ± 2°C with 60.5% RH for 2 months without any significant changes.
State-of-the-art analytical techniques proved to be invaluable tools for evaluate the stability of the TUR01 DS and drug product.
Journal Article
miR-346 Controls Release of TNF-α Protein and Stability of Its mRNA in Rheumatoid Arthritis via Tristetraprolin Stabilization
TNF-α is a major cytokine implicated in rheumatoid arthritis. Its expression is regulated both at the transcriptional and posttranscriptional levels and recent data demonstrated that miRNAs are implicated in TNF-α response in macrophages. LPS-activated FLS isolated from RA patients express TNF-α mRNA but not the mature protein. This prompted us to look for miRNAs which could be implicated in this anti-inflammatory effect. Using a microarray, we found two miRNAs, miR-125b and miR-939 predicted to target the 3'-UTR of TNF-α mRNA, to be up-regulated in RA FLS in response to LPS, but their repression did not restore mature TNF-α expression in FLS. We showed previously that miR-346, which is upregulated in LPS-activated FLS, inhibited Btk expression that stabilized TNF-α mRNA. Blocking miR-346 reestablished TNF-α expression in activated FLS. Interestingly, transfection of miR-346 in LPS-activated THP-1 cells inhibited TNF-α secretion. We also demonstrated that TTP, a RNA binding protein which inhibited TNF-α synthesis, is overexpressed in activated FLS and that inhibition of miR-346 decreases its expression. Conversely, transfection of miR-346 in LPS-activated THP-1 cells increased TTP mRNA expression and inhibited TNF-α release. These results indicate that miR-346 controls TNF-α synthesis by regulating TTP expression.
Journal Article
ASHP Injectable Drug Information
Our new ASHP® Injectable Drug Information(tm) remains the gold standard for information on compatibility, stability, storage, and preparation of parenteral drugs. For the first time ever, ASHP® Injectable Drug Information(tm) is available as an eBook with new and expanded information. The 2021 edition features 18 new monographs, and nearly 200 new references for a total of over 24,000 total compatibility pairs.
eBook
Involvement of the Cdc42 Pathway in CFTR Post-Translational Turnover and in Its Plasma Membrane Stability in Airway Epithelial Cells
Cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that is expressed on the apical plasma membrane (PM) of epithelial cells. The most common deleterious allele encodes a trafficking-defective mutant protein undergoing endoplasmic reticulum-associated degradation (ERAD) and presenting lower PM stability. In this study, we investigated the involvement of the Cdc42 pathway in CFTR turnover and trafficking in a human bronchiolar epithelial cell line (CFBE41o-) expressing wild-type CFTR. Cdc42 is a small GTPase of the Rho family that fulfils numerous cell functions, one of which is endocytosis and recycling process via actin cytoskeleton remodelling. When we treated cells with chemical inhibitors such as ML141 against Cdc42 and wiskostatin against the downstream effector N-WASP, we observed that CFTR channel activity was inhibited, in correlation with a decrease in CFTR amount at the cell surface and an increase in dynamin-dependent CFTR endocytosis. Anchoring of CFTR to the cortical cytoskeleton was then presumably impaired by actin disorganization. When we performed siRNA-mediated depletion of Cdc42, actin polymerization was not impacted, but we observed actin-independent consequences upon CFTR. Total and PM CFTR amounts were increased, resulting in greater activation of CFTR. Pulse-chase experiments showed that while CFTR degradation was slowed, CFTR maturation through the Golgi apparatus remained unaffected. In addition, we observed increased stability of CFTR in PM and reduction of its endocytosis. This study highlights the involvement of the Cdc42 pathway at several levels of CFTR biogenesis and trafficking: (i) Cdc42 is implicated in the first steps of CFTR biosynthesis and processing; (ii) it contributes to the stability of CFTR in PM via its anchoring to cortical actin; (iii) it promotes CFTR endocytosis and presumably its sorting toward lysosomal degradation.
Journal Article
Preformulation of a liquid dosage formulation of captopril for pediatric use: drug-excipient compatibility and stability studies
Currently, medications used in children are typically modified from pharmaceutical dosage forms designed for adults. Captopril is widely adapted to liquid formulations for use in hospitals. Its stability in the aqueous medium is reduced since it undergoes oxidation producing captopril disulfide (its main metabolite). The aim of this formulation study was to suggest favorable conditions for the development of a stable captopril formulation. The compatibility between the drug and excipients was evaluated by differential scanning calorimetry analysis (DSC). For studies in solution, different formulations were prepared according to a factorial design varying EDTA concentration, water purity and pH. The resultant formulations were stored at 60°C and analyzed over a twelve-day period using HPLC. The DSC curves obtained suggested, although not conclusive to elucidation, interactions of captopril with citric acid and sucralose. The stability study of these solutions revealed that the variables significantly influenced captopril content, which degraded at zero order kinetics and rates differing by a factor of up to 7 times, where pH proved the most influential factor. Interactions between variables were observed. Therefore, development of a stable captopril formulation is feasible provided EDTA and a buffering agent is used at suitable concentrations (0.08% and pH 3.85).
Journal Article