Pharmaceutical Quality Control
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Clinical trials in oncology are important tools to identify and establish new effective drugs for cancer treatment. Since the development of the concept of precision oncology, a huge number of multi-centric biomarker-driven clinical trials have been performed and promoted by either academic institutions or pharmaceutical companies. In this scenario, the role of pathologists is essential in multiple aspects, with new challenges that should be addressed. In this position paper of the European Society of Pathology, the role of pathologists as contributors to the design of the clinical trial, as local collaborators, or as members of central review laboratories is discussed. Moreover, the paper emphasizes the important role of pathologists in guiding methods and criteria of tissue biomarker testing in the biomarker-driven clinical trials. The paper also addresses issues regarding quality control, training, and the possible role of digital pathology.
- MeSH
- klinické zkoušky jako téma * MeSH
- laboratorní medicína normy metody MeSH
- lidé MeSH
- nádorové biomarkery * analýza MeSH
- nádory * patologie farmakoterapie MeSH
- patologové * MeSH
- společnosti lékařské MeSH
- výzkumný projekt normy MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Geografické názvy
- Evropa MeSH
INTRODUCTION: In a previously published randomised, placebo-controlled trial, 800 mg/day of pharmaceutical-grade chondroitin sulfate (CS) was shown to be superior to placebo in reducing pain and improving function over 6 months in patients with symptomatic knee osteoarthritis (OA). The aim of the current post hoc analyses was to evaluate the cost-effectiveness of CS compared with placebo in a European perspective using individual patient data from this clinical trial. METHODS: Patients with knee OA randomised to CS or placebo were followed up at 1, 3 and 6 months. The algo-functional Lequesne index was used to derive the EuroQol Five-Dimension Five-Level (EQ-5D-5L) score based on a validated formula. The EQ-5D-5L scores at each time point were used to calculate the changes in quality-adjusted life years (QALYs) with the area under the curve method. Costs were assessed using the average price of CS in the countries where the original study took place and where CS is currently marketed. The costs of CS in three countries were then used (i.e. the Czech Republic, Italy and Switzerland). The incremental cost-effectiveness ratio (ICER) threshold for CS to be considered cost-effective was set at 91,870 EUR per QALY (equivalent to the usually recommended threshold of US $100,000). The study used an intention-to-treat population, i.e. patients who received one dose of the study drug, and imputed missing values using the basal observation carried forward method. RESULTS: No significant differences in baseline characteristics were observed between the CS group (N = 199) and the placebo group (N = 205). The mean cost of CS for 6 months of treatment was 194.74 EUR. After 6 months of treatment, CS showed a mean ICER of 33,462 (95% CI 5130-61,794) EUR per QALY gained, indicating cost-effectiveness compared with placebo. The acceptability curve for cost-effectiveness shows that the CS treatment is likely to be cost-effective compared with placebo, with a 93% probability when the ceiling ratio is set at 91,870 EUR per QALY gained. CONCLUSIONS: These results highlight the role of CS as a cost-effective therapeutic option in the management of OA. However, further studies taking into account the use of other healthcare resources are warranted for a more complete understanding.
- MeSH
- analýza nákladové efektivity MeSH
- analýza nákladů a výnosů * MeSH
- artróza kolenních kloubů * farmakoterapie ekonomika MeSH
- chondroitinsulfáty * terapeutické užití ekonomika MeSH
- kvalitativně upravené roky života * MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- randomizované kontrolované studie MeSH
- Geografické názvy
- Česká republika MeSH
- Itálie MeSH
- Švýcarsko MeSH
Úvod: Erektilní dysfunkce (ED) je vysoce prevalenční porucha, která významně ovlivňuje kvalitu života mužů i jejich partnerek. Inhibitory fosfodiesterázy typu 5 (PDE5i), zejména sildenafil, tvoří základní linii farmakologické léčby ED. Tradiční tabletová forma však může být u části pacientů spojena s pomalejším nástupem účinku, vyšším výskytem nežádoucích účinků a sníženou adherencí. Inovativní léková forma – orálně rozpustný film (ORF) s obsahem sildenafilu – byla vyvinuta s cílem tyto limity překonat. Metodika: Článek shrnuje dostupná klinická a farmakokinetická data o účinnosti, bezpečnosti a pacientské preferenci nové lékové formy sildenafilu ve formě ORF. Zohledněna jsou randomizovaná kontrolovaná hodnocení, farmaceutické studie a zkušenosti z klinické praxe. Výsledky: Sildenafil ve formě ORF vykazuje srovnatelnou účinnost jako klasická tableta, přičemž dosahuje rychlejšího nástupu účinku díky částečnému vstřebávání přes sliznici dutiny ústní. Při dávce 50 mg bývá dosaženo optimálního terapeutického efektu u většiny pacientů, což může snižovat výskyt nežádoucích účinků. Léková forma rovněž umožňuje diskrétní užití bez nutnosti zapíjení, čímž zvyšuje komfort a adherenci pacientů. Závěr: ORF s obsahem sildenafilu představuje moderní a klinicky přínosnou alternativu v léčbě ED. Jeho využití může být zvláště vhodné u pacientů s preferencí rychlého nástupu účinku, u osob s dysfagií nebo u těch, kteří upřednostňují diskrétní formu užití. Další výzkum by měl ověřit přínosy této formy v běžné klinické praxi a její vliv na dlouhodobou adherenci a spokojenost pacientů.
Introduction: Erectile dysfunction (ED) is a highly prevalent disorder that significantly affects the quality of life of men and their partners. Phosphodiesterase type 5 inhibitors (PDE5i), particularly sildenafil, form the first line of pharmacological treatment for ED. However, the traditional tablet form may be associated with a slower onset of action, a higher incidence of adverse effects, and reduced adherence in some patients. An innovative drug form - an orally dissolvable film (ORF) containing sildenafil - has been developed to overcome these limitations. Methodology: The article summarizes the available clinical and pharmacokinetic data on the efficacy, safety, and patient preference of the new sildenafil dosage form as an orally dissolving film. Randomized controlled trials, pharmaceutical studies, and clinical experience are taken into account. Results: Sildenafil in ORF form shows comparable efficacy to the classic tablet, with a faster onset of action due to partial absorption through the oral mucosa. At a dose of 50 mg, the optimal therapeutic effect is achieved in most patients, which may reduce the incidence of adverse effects. The dosage form also allows for discreet use without the need for water, thereby increasing patient comfort and adherence. Conclusion: An orally dissolvable film containing sildenafil represents a modern and clinically beneficial alternative in the treatment of ED. Its use may be particularly suitable for patients who prefer a rapid onset of action, those with dysphagia, or those who prefer a discreet form of administration. Further research should verify the benefits of this form in routine clinical practice and its impact on long-term adherence and patient satisfaction.
- MeSH
- aplikace orální MeSH
- aplikace sublinguální MeSH
- erektilní dysfunkce * farmakoterapie MeSH
- inhibitory fosfodiesterasy 5 aplikace a dávkování farmakokinetika terapeutické užití MeSH
- lidé MeSH
- sildenafil citrát aplikace a dávkování farmakokinetika terapeutické užití MeSH
- způsoby aplikace léků MeSH
- Check Tag
- lidé MeSH
Annotation of multiple regions of interest across the whole mouse brain is an indispensable process for quantitative evaluation of a multitude of study endpoints in neuroscience digital pathology. Prior experience and domain expert knowledge are the key aspects for image annotation quality and consistency. At present, image annotation is often achieved manually by certified pathologists or trained technicians, limiting the total throughput of studies performed at neuroscience digital pathology labs. It may also mean that simpler and quicker methods of examining tissue samples are used by non-pathologists, especially in the early stages of research and preclinical studies. To address these limitations and to meet the growing demand for image analysis in a pharmaceutical setting, we developed AnNoBrainer, an open-source software tool that leverages deep learning, image registration, and standard cortical brain templates to automatically annotate individual brain regions on 2D pathology slides. Application of AnNoBrainer to a published set of pathology slides from transgenic mice models of synucleinopathy revealed comparable accuracy, increased reproducibility, and a significant reduction (~ 50%) in time spent on brain annotation, quality control and labelling compared to trained scientists in pathology. Taken together, AnNoBrainer offers a rapid, accurate, and reproducible automated annotation of mouse brain images that largely meets the experts' histopathological assessment standards (> 85% of cases) and enables high-throughput image analysis workflows in digital pathology labs.
An increasing resistance of microbes to antibiotics, the emergence of multidrug-resistant and extremely resistant strains, and the long time needed to develop new antibiotics are driving the search for additional sources of antibacterial agents. The aim of the study was to compare the efficacy of Czech honeys with already available pharmaceutical agents containing medicinal honey, and to perform basic biochemical analysis of Czech samples, including detection of undesirable chemical substances. The results showed strong antibacterial activity of Czech honeydew honeys compared to the control group, especially against G+ pathogens, with an average MIC of 9.44% compared to 17.54%, and comparable activity against G- of 16.48% versus 16.66%. In addition to the strong antibacterial activity, this study confirmed the safety and quality of Czech honeys and helped to select the character of a possible source for in vivo testing and subsequent clinical trials.
- Publikační typ
- časopisecké články MeSH
Transferring an existing marketed pharmaceutical product from batch to continuous manufacturing (CM) without changes in regulatory registration is a challenging task in the pharmaceutical industry. Continuous manufacturing can provide an increased production rate and better equipment utilisation while retaining key quality attributes of the final product. Continuous manufacturing necessitates the monitoring of critical quality attributes in real time by appropriate process analytical tools such as near infra-red (NIR) probes. The present work reports a successful transfer of an existing drug product from batch to continuous manufacturing process without changing the formulation. A key step was continuous powder blending, whose design and operating parameters including weir type, agitation rate, dynamic hold-up and residence time were systematically investigated with respect to process repeatability. A NIR-based multivariate data model for in-line composition monitoring has been developed and validated against an existing quality control method for measuring tablet content uniformity. A continuous manufacturing long-run with a throughput of 30 kg/h (approx. 128,000 tablets per hour), uninterrupted for 320 min, has been performed to test and validate the multivariate data model as well as the batch to continuous process transfer. The final disintegration and dissolution properties of tablets manufactured by the continuous process were found to be equivalent to those manufactured by the original batch process.
- MeSH
- blízká infračervená spektroskopie metody MeSH
- farmaceutická chemie metody MeSH
- farmaceutická technologie * metody MeSH
- pomocné látky chemie MeSH
- prášky, zásypy, pudry chemie MeSH
- příprava léků metody MeSH
- řízení kvality MeSH
- rozpustnost MeSH
- tablety * MeSH
- uvolňování léčiv MeSH
- Publikační typ
- časopisecké články MeSH
The transfer from batch-based to continuous tablet manufacturing increases the quality and efficiency of processes. Nonetheless, as in the development of a batch process, the continuous process design requires optimization studies to ensure a robust process. In this study, processing of a commercially batch-manufactured tablet product was tested with two continuous direct compression lines while keeping the original formulation composition and tablet quality requirements. Tableting runs were conducted with different values of process parameters. Changes in parameter settings were found to cause differences in tablet properties. Most of these quality properties could be controlled and maintained within the set limits effortlessly already at this stage of studies. However, the API content and content uniformity seemed to require more investigation. The observed content uniformity challenges were traced to individual tablets with a high amount of API. This was suspected to be caused by API micro-agglomerates since tablet weight variability did not explain the issue. This could be solved by adding a mill between two blenders in the process line. Overall, this case study produced promising results with both tested manufacturing lines since many tablet properties complied with the test result limits without optimization of process parameter settings.
Levothyroxine is a drug with a narrow therapeutic index. Changing the drug formulation composition or switching between pharmaceutical brands can alter the bioavailability, which can result in major health problems. However, the increased adverse drug reactions have not been fully explained scientifically yet and a thorough investigation of the formulations is needed. In this study, we used a non-targeted analytical approach to examine the various levothyroxine formulations in detail and to reveal possible chemical changes. Ultra-high-performance liquid chromatography coupled with a data-independent acquisition high-resolution mass spectrometry (UHPLC-DIA-HRMS) was employed. UHPLC-DIA-HRMS allowed not only the detection of levothyroxine degradation products, but also the presence of non-expected components in the formulations. Among these, we identified compounds resulting from reactions between mannitol and other excipients, such as citric acid, stearate, and palmitate, or from reactions between an excipient and an active pharmaceutical ingredient, such as levothyroxine-lactose adduct. In addition to these compounds, undeclared phospholipids were also found in three formulations. This non-targeted approach is not common in pharmaceutical quality control analysis. Revealing the presence of unexpected compounds in drug formulations proved that the current control mechanisms do not have to cover the full complexity of pharmaceutical formulations necessarily.
- Publikační typ
- časopisecké články MeSH
Background and Objectives: The enteric form of omeprazole is one of the most commonly prescribed medications. Similarly to Europe, Kazakhstan relies on the localization of pharmaceutical drug production as one of its primary strategies to ensure that its population has access to affordable and good-quality medicines. This study comprehensively describes the technologically available development of bioequivalent delayed-release omeprazole. Materials and Methods: Various regimes and technological parameters were tested on laboratory- and production-scale equipment to establish a technical process where a functional and gastro-protective layer is essential. According to the ICH guidance on stability testing and Kazakhstan local rules, stability studies were conducted under conditions appropriate for climate zone II. The comparison of the rate and extent of absorption with subsequent assessment of the bioequivalence of the generic and reference drugs after a single dose of each drug at a dose of 40 mg was performed. Results: The quantitative and qualitative composition and technology of producing a new generic enteric form of omeprazole in capsules were developed and implemented at the manufacturing site of solid forms. Dissolution profiles in media with pH 1.2 and 6.8 were proven. During the accelerated six-month and long-term twelve-month studies, the developed formulation in both packaging materials at each control point passed the average weight and mass uniformity test, dissolution test, acid-resistance stage test, buffer stage test, impurity assay, and microbiological purity test and met all the specification criteria. A bioequivalence study in 24 healthy volunteers compared against the innovative drug showed the bioequivalency of the new generic system. The obtained values from the test and reference products were 1321 ± 249.0 ng/mL and 1274 ± 233 ng/mL for Cmax, 4521 ± 841 ng·h /mL and 4371 ± 695 ng·h /mL for AUC0-t, and 4636 ± 814 ng·h /mL and 4502 ± 640 ng·h /mL for AUC0-∞. Conclusions: Using affordable technologies, a bioequivalent generic delayed-release formulation of 20 and 40 mg omeprazole has been developed.
- MeSH
- klinické křížové studie MeSH
- lidé MeSH
- omeprazol * chemie MeSH
- terapeutická ekvivalence MeSH
- tobolky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Evropa MeSH
This study was designed to assess both the quality and cost aspects of various branded and generic formulations of angiotensin receptor blockers, specifically Irbesartan, Losartan Potassium, Olmesartan Medoxomil, Telmisartan, and Valsartan. The collected samples underwent distinct quality evaluations using the methods outlined in different global Pharmacopoeias (British Pharmacopoeia/European Pharmacopoeia, Indian Pharmacopoeia and United States Pharmacopoeia). These drugs were characterized using Fourier-Transform Infrared Spectroscopy and Nuclear Magnetic Resonance techniques, while their quality and concentration were analysed using High Performance Liquid Chromatography. The release profile of the drugs was examined through dissolution testing. Additionally, a cost comparison analysis was carried out by determining the prevailing market prices of the drugs. The evaluated branded and generic angiotensin receptor blockers were found to meet the established standards for impurities, active drug content, and dissolution as set by these Pharmacopoeias, indicating their optimal quality. Notably, the generic drugs exhibited significantly lower costs compared to their branded counterparts. This study confirms that the quality of generic angiotensin receptor blockers is equivalent to that of their branded counterparts. Consequently, these findings support the practicality of utilizing generic drugs as a more economically sustainable and cost-effective approach to managing diseases, especially those of chronic nature.
- Publikační typ
- časopisecké články MeSH
