Requirements For Registration Of Pharmaceuticals Research Articles

Nonclinical Profile of PF-06952229 (MDV6058), a Novel TGFβRI/Activin Like Kinase 5 Inhibitor Supports Clinical Evaluation in Cancer.

The development of transforming growth factor βreceptor inhibitors (TGFβRi) as new medicines has been affected by cardiac valvulopathy and arteriopathy toxicity findings in nonclinical toxicology studies. PF-06952229 (MDV6058) selected using rational drug design is a potent and selective TGFβRI inhibitor with a relatively clean off-target selectivity profile and good pharmacokinetic properties across species. PF-06952229 inhibited clinically translatable phospho-SMAD2 biomarker (≥60%) in human and cynomolgus monkey peripheral blood mononuclear cells, as well as in mouse and rat splenocytes. Using an optimized, intermittent dosing schedule (7-day on/7-day off/cycle; 5 cycles), PF-06952229 demonstrated efficacy in a 63-day syngeneic MC38 colon carcinoma mouse model. In the pivotal repeat-dose toxicity studies (rat and cynomolgus monkey), PF-06952229 on an intermittent dosing schedule (5-day on/5-day off cycle; 5 cycles, 28 doses) showed no cardiac-related adverse findings. However, new toxicity findings related to PF-06952229 included reversible hepatocellular (hepatocyte necrosis with corresponding clinically monitorable transaminase increases) and lung (hemorrhage with mixed cell inflammation) findings at ≥ targeted projected clinical efficacious exposures. Furthermore, partially reversible cartilage hypertrophy (trachea and femur in rat; femur in monkey) and partially to fully reversible, clinically monitorable decreases in serum phosphorus and urinary phosphate at ≥ projected clinically efficacious exposures were observed. Given the integral role of TGFβ in endochondral bone formation, cartilage findings in toxicity studies have been observed with other TGFβRi classes of compounds. The favorable cumulative profile of PF-06952229 in biochemical, pharmacodynamic, pharmacokinetic, and nonclinical studies allowed for its evaluation in cancer patients using the intermittent dosing schedule (7-day on/7-day off) and careful protocol-defined monitoring. SIGNIFICANCE STATEMENT: Only a few TGFβRi have progressed for clinical evaluation due to adverse cardiac findings in pivotal nonclinical toxicity studies. The potential translations of such findings in patients are of major concern. Using a carefully optimized intermittent dosing schedule, PF-06952229 has demonstrated impressive pharmacological efficacy in the syngeneic MC38 colon carcinoma mouse model. Additionally, a nonclinical toxicology package without cardiovascular liabilities and generally monitorable toxicity profile has been completed. The compound presents an acceptable International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use S9-compliant profile for the intended-to-treat cancer patients.

Development and Validation of a Simple UV-HPLC Method to Quantify the Memantine Drug Used in Alzheimer's Treatment.

Memantine, a non-competitive NMDA receptor antagonist, is used to treat Alzheimer's disease. Therefore, loading memantine in nanoparticles (NPs) could be an essential tool to improve the treatment effectiveness while reducing drug toxicity. Even though some approaches have been described to quantify memantine, none reported optimized methods using high-performance liquid chromatography resorting to ultraviolet detection (UV-HPLC) to determine encapsulation in NPs. The present research developed a HPLC method using pre-column derivatization for quantitatively analyzing memantine hydrochloride in NPs. Memantine was derivatized using 9-fluorenylmethyl chloroformate (FMOC). The developed method was fully validated regarding suitability, specificity, linearity, sensitivity, precision, accuracy, and robustness according to the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines. The retention time of memantine was 11.393 ± 0.003 min, with a mean recovery of 92.9 ± 3.7%. The new chromatographic method was validated and found to respond linearly over 5-140 μg/mL, with a high coefficient of determination. Intraday precision lay between 3.6% and 4.6%, and interday precision between 4.2% and 9.3%. The stability of memantine was also tested at 4 °C and -20 °C, and no signs of decay were found for up to 6 months. The new method was properly validated and proved simple, sensitive, specific, accurate, and precise for determining memantine encapsulation efficiency in lipid NPs. Greenness was evaluated, presenting a final score of 0.45. In the future, this methodology could also be applied to quantify memantine in different nanoformulations.

Time-efficient HPLC Validation Methodology for the Qualitative Analysis of 68Ga PSMA-11 in Routine Clinical Usage under Isocratic Method

Background: Prostate-specific membrane antigen (PSMA) has shown to be a promising agent for prostate cancer imaging under PET-CT. With the automation in radiolabeling with 68Ga, using iTG 68Ge/68Ga generator, it has helped introduce various new diagnostic agents and achieve good manufacturing practices (GMP) simultaneously. However, before any radiopharmaceutical is put into clinical usage, it should always be checked for its radiochemical purity and other quality parameters before injecting in the patient. Chromatography techniques such as Gas Chromatography (GC), High-Performance Liquid Chromatography (HPLC), and Thin-Layer Chromatography (TLC) are the most frequently utilized separation technique for purity analysis. A rapid quality control HPLC based methodology was required for radiopharmaceuticals. Aim & Objective: In our current setting, we conducted quality control analysis and standardized and validated HPLC method for the routine quality check of 68Ga-PSMA-11. Materials and Methods: The QC of 68Ga PSMA-11 was performed under ITLC and HPLC. Results: Linearity, accuracy, precision and specificity were assessed and quantified in accordance with International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (Q2 (R1) ICH) guidelines, which can be implemented in resource-limited settings to check the quality. Conclusion: The current HPLC based methodology is rapid, with a retention time of 2.24 min, rendering it a favorable analytical standard operating procedure for QC analysis of 68Ga-PSMA-11.

New RP-HPLC method for the simultaneous determination of process yield and percentage of encapsulation of Gallein in albumin nanoparticles

A study was performed for the development and validation of a method of High Performance Liquid Chromatography (HPLC) for the identification and simultaneous quantification of Gallein and Human Serum Albumin (HSA). In addition, this work presents the development and physicochemical characterization of this new pharmaceutical formulation of HSA nanoparticles loaded with Gallein for potential use in the treatment of Alzheimer’s disease.The method was developed with the purpose of determining the performance of the synthesis process of nanoparticles and the efficiency of encapsulation of the drug in the nanosystem. The HPLC mobile phase consisted of ACN:H2O:TEA:H3PO4 (50:49.8:0.1:0.1 v/v/v) pumped at a flow rate of 0.8 mL/min, isocratic mode, and the measurement were carried out at 220 nm. Chromatographic runs were performed on a C18 column (150 × 4.60 mm; 5 μm size particles). The HPLC-method was validated following the International Conference on Harmonisation (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines and was used to simultaneously quantify the two components of the nanoformulation. Thus, the values obtained through the validated method were 43 % for drug encapsulation efficiency (% EE) and the synthesis performance (% yield) was 96 %.Moreover, the nanoformulation was characterized by DLS, the results showed that the average particle size was 217 nm, with a PDI of (0.085 ± 0.005) and a potential Z of −29.7 mV.Therefore, the developed method has proven useful in providing accurate simultaneous measurements of HSA and Gallein from albumin nanoparticles. It is advantageous since it is able to reduce the time and facilitate the determination of Gallein encapsulation efficiency and yield of albumin nanoparticles.

UPLC-TQD-MS/MS Method Validation for Quality Control of Alkaloid Content in Lepidium meyenii (Maca)-Containing Food and Dietary Supplements.

Lepidium meyenii Walp. (Brassicaceae), also known as Maca or Peruvian ginseng, is a common ingredient in food supplements with many claimed health benefits, such as improved endurance, increased energy level, and enhanced sexual properties. Due to potential toxicity of its chemicals, including alkaloids, some regulatory authorities, e.g., in Belgium, Germany, the United States, expressed concerns about the safe consumption of Maca root. However, due to the lack of commercial standards, no established analytical method currently exists for this purpose. The current project focuses on the quantitative determination of potentially toxic alkaloids from Maca. The current study presents the first analytical method for quality control of alkaloid content in Maca-containing food and dietary supplements, assessing the presence of 11 major compounds belonging to three different classes, i.e., imidazole, β-carboline, and pyrrole alkaloids. An accurate, rapid, and sensitive UPLC-TQD-MS/MS method is reported, which was fully validated according to the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and SANTE/11312/2021 guidelines. To ensure the method's applicability and practicability in the absence of primary standards, validation of secondary standards (SSs) alongside primary standards (PSs) was also conducted for imidazole alkaloids. As a result, in Maca raw powder, total alkaloid content was found to vary from 418 to 554 ppm (mg/kg). Furthermore, all quantified imidazole alkaloids were ascertained to be the major alkaloids with the total content from 323 to 470 ppm in Maca raw powder, followed by the β-carboline and pyrrole alkaloids. It was also observed that the commercial preparation of finished products affects the total alkaloid content, evidenced by the large variation from 56 to 598 ppm. Ultimately, from a regulatory point of view, it seems advisible not to request the complete absence of the alkaloids but to impose a maximum level based on safety considerations. In addition to the analytical method, a low-cost, simple, and scalable synthetic scheme of macapyrrolins A, C, and G was reported for the first time.

Method validation and characterization of stress degradation products of azelastine hydrochloride using LC-UV/PDA and LC-Q/TOF-MS studies.

Azelastine HCl is a second-generation H1 -receptor antagonist approved by the US Food and Drug Administration (US FDA) for treating seasonal allergic rhinitis and non-allergic vasomotor rhinitis. This study encompasses the validation of a liquid chromatography-ultra violet photo diode array (LC-UV/PDA) method for the drug and its extension to liquid chromatography/quadrupole time-of-flightmassspectrometry (LC-Q/TOF-MS) studies for identification and characterization of various stress degradation products of the drug. Stress degradation of azelastine HCl was undertaken under the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) prescribed conditions of hydrolytic, photolytic, oxidative, and thermal stress. The degraded drug solutions were analyzed using Ultra Performance Liquid Chromatography (UPLC) employing a C18 (100 × 4.6mm; 2.6μ, Kinetex) column by isocratic elution. Detection wavelength was 241 nm. The degradation products were identified and characterized using UPLC-MS/TOF studies, and an attempt was made to isolate one of the degradation products by solvent extraction. The drug was found to significantly degrade under acidic/alkaline/neutral photolytic, oxidative, and alkaline hydrolytic conditions. Six degradation products (I-VI) were identified through LC-Q/TOF-MS studies that were adequately resolved from the drug with the developed UPLC method. All degradation products (I-VI) were ionized in the total ion chromatogram (TIC) in the LC-MS studies, and these were identified and characterized, and the degradation pathway of the drug was postulated. One of the oxidation products isolated from the degraded drug solution was characterized through differential scanning calorimetry, Fourier-transform infrared spectroscopy, and nuclear magnetic resonance spectral data. Six degradation products generated from stress degradation studies on azelastine HCl were adequately resolved through LC-UV/PDA studies followed by method validation. These were successfully identified and characterized through LC-Q/TOF-MS studies, and the degradation pathways for the generation of these products from the drug have been postulated.

Development and Greenness Assessment of Analytical Quality by Design Optimised Eco-friendly UV Spectrophotometric Methods for Analysis of Two Natural Antioxidants in Pure and Formulation

Utilizing analytical quality by design and green analytical chemistry principles, the present work introduces simple, robust, and environmentally benign UV methods. Two separate spectrophotometric methods were developed for the estimation of Silybin and Curcumin, where solvent, scan speed, and sampling interval are the estimated critical parameters. The detection was carried out at absorption maxima of 288nm for Silybin and 419nm for Curcumin with ethanol. To determine the critical method variables, a risk assessment was carried out using an Ishikawa diagram. Developed spectrophotometric methods were validated according to the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Q2 (R1) guidelines. The proposed methods showed good predictability and robustness. The new methodologies were found to be green according to the analytical greenness metric approach and software, the green analytical procedure index, and analytical eco-scale tools in comparison to the existing methods.

Application of QbD based approach in development and validation of RP-HPLC method for simultaneous estimation of methotrexate and baicalin in dual-drug-loaded liposomes.

The present study delineates the development of a novel, rugged and sensitive stability-indicating risk-based HPLC method for the concurrent estimation of methotrexate (MTX) and baicalin (BCL) in dual-drug-loaded-nanopharmaceuticals based on an analytical quality-by-design approach. Preliminary screening trials along with systemic risk analysis were performed, endeavouring to explicate the critical method attributes, namely pH, percentage of orthophosphoric acid and percentage of acetonitrile, that influence the critical quality attributes. Box-Behnken design was utilized for the optimization of the tailing factor as the response for MTX and BCL in a short run time. The chromatographic conditions were optimized by performing 17 experimental runs using design expert software. The chromatographic conditions were selected after the analysis of the optimized zone within the confines of the design space: water:acetonitrile adjusted to a pH of 3.0 with 0.05% orthophosphoric acid (60:40, %v/v) was the mobile phase, the flow rate was 1.0ml/min and an analytical C18 column was used at an isobestic wavelength of 282 nm. Furthermore, the optimized method was validated in accordance with the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines and was found to be within the prescribed limits. Therefore, the developed reversed-phase-high-performance liquid chromatography method has a high degree of practical utility for synchronous detection of MTX and BCL in pharmaceutical nano-dosage forms such as protein-based nanoparticles, nanocrystals, polymeric nanoparticles and metallic nanoparticles in in vivo and in vitro studies.

A Technical Overview of the Pharmaceutical Development Process and Best Practices

The pharmaceutical development process is the foundation for the production of safe, effective, and highquality medications. This article explores the complex stages of pharmaceutical development, starting with the significance of selecting appropriate drug substances and excipients, formulation development, and establishing robust manufacturing processes. The integration of Quality by Design (QbD) principles and advanced risk management strategies is discussed as a means to optimize development and ensure regulatory compliance. By adhering to the guidelines outlined by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use considerations (ICH) guideline Q8 (R2) on pharmaceutical development, pharmaceutical companies can enhance product quality, reduce variability, and ensure the consistent delivery of therapeutic products to the market.

Alternative analytical methods for ibrutinib quantification in pharmaceutical formulation: A statistical comparison

Abstract Ibrutinib is a drug used for the treatment of marginal zone lymphoma, mantle cell lymphoma, lymphocytic leukemia, chronic graft, and Waldenstrom macroglobulinemia. A simple, sensitive, and fast liquid chromatographic and spectrophotometric method for the quantification of ibrutinib in pharmaceutical forms and bulk was developed and validated. The chromatographic technique was developed using an ODS 3 C 18 (250 mm × 4.6 mm i.d., 5 µm) column. The mobile phase was a mixture of 0.1% trifluoroacetic acid in water and acetonitrile (50/50, v/v) at a flow rate of 1.0 mL·min−1. Eluent detection was carried out at a wavelength of 260 nm using a ultraviolet detector. The retention time of ibrutinib was found to be 5.27. On the other hand, Ibrutinib was determined using a spectrophotometric technique by measuring the absorbance of the solutions at a wavelength of 260 nm. The developed techniques were validated in accordance with the protocols outlined in International conference on harmonisation of technical requirements for registration of pharmaceuticals for human (ICH) guidelines Q2(R1). Correlation coefficients for both methods were greater than 0.999 in the concentration range of 5–30 mg·mL−1. The relative standard deviation values were low in intraday and interday precision tests. The accuracy of the developed techniques ranged 99.74–100.23% for the chromatographic method and 99.32–100.76% for the spectrophotometric method. The limits of detection and quantitation were 0.90 and 2.80 µg·mL−1 for the chromatographic method and 1.10 and 3.20 µg·mL−1 for the spectrophotometric method. The developed and validated analytical methods can be safely used in quality control tests for the determination of the amount of ibrutinib in pharmaceutical products.

Systematic review of spontaneous reports of myocarditis and pericarditis in transplant recipients and immunocompromised patients following COVID-19 mRNA vaccination

ObjectivesTo determine whether spontaneous reporting rates of myocarditis and pericarditis differed in immunocompromised patients compared with the whole population overall, and in terms of demographics, vaccine dose and time-to-onset.DesignSystematic review...

Analytical quality by design based on design space in reversed-phase-high performance liquid chromatography analysis for simultaneous estimation of metformin, linagliptin and empagliflozin.

Employing the Quality by Design paradigm through this work helped conclude the method operable design region for optimizing the high performance liquid chromatography (HPLC) assay using Design of Experiments and response surface methodology to obtain a good resolution and determination of all analysed compounds and to achieve a suitable analysis time. A deep understanding of the quality target product profile, analytical target profile and risk assessment for parameters that affect the method performance led to developing an accurate, precise and cost-effective method. Quality risk management principles were applied for determining the critical method parameters affecting the simultaneous determination of metformin hydrochloride (MET), linagliptin (LIN) and empagliflozin (EMP) by reversed-phase HPLC . The ternary mixture was successfully resolved in 5 min with a linearity range of (0.1–600) µg ml−1 for MET and (0.05–50) µg ml−1 for LIN and EMP. The newly developed method was validated according to the International Council for Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines. Good agreement was observed with the assay results of the reported UPLC one. To evaluate the greenness of the proposed method, an analytical Eco-Scale method was used.

Experimental and computational studies of enantioseparation of three profen enantiomers with a focus on quantification of the enantiomeric impurities present in the corresponding enantiopure S-profen drugs

A rapid reversed-phase high performance liquid chromatographic (HPLC) methodology for chiral separation of three profen compounds has been developed and then applied to enantiomeric impurity testing of their corresponding enantiopure drugs. The assay is specific, allowing quantitation of the enantiomeric impurities at levels of 0.0078%, 0.0105%, and 0.0416% relative to S-ibuprofen, S-naproxen, and S-ketoprofen, respectively. In order to gain a better insight into the chiral recognition mechanisms of chiral profens on an FLM Chiral NQ(2)-RH column, molecular docking studies were carried out using AutoDock 4.0 software. It was found that hydrogen bonding, hydrophobic interactions, and π-π stacking were all involved in stereoselective interactions, and the calculated binding energy (BE) obtained reflected the binding strength of each enantiomer interacting with a chiral selector. The higher the BE value, the harder it was to elute the corresponding enantiomer, which also accorded with the enantiomer elution order observed in the actual enantiomeric separation. Additionally, thermodynamic analysis revealed that the enantioseparation process at 15–40°C was driven mainly by entropic contributions. The methodology was further validated according to the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline Q2 (R1) and proved to be sensitive, linear, precise, and accurate for determining R-profen impurities in three commercially available single-enantiomer S-profen drugs. As expected, in the case of products acquired in actual pharmacies, the levels of all of the monitored impurities were found to be lower than the allowable impurity limits.

Development of a method for simultaneous screening of four natural-derived steroids and their analogues used as dietary supplements via liquid chromatography-quadrupole-time of flight mass spectrometry and liquid chromatography-tandem mass spectrometry

Natural-derived steroids and their analogues are present in various plants and insects. To minimize the chance of missing a positive doping test and avoiding potentially serious health problems, adequate screening methods are necessary for the detection of a wide range of natural-derived steroids and their analogues in dietary supplements. In this study, an accurate and simple liquid-chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to determine and quantify the natural-derived steroids and their analogues according to the International Conference on Harmonization of technical Requirements for Registration of Pharmaceuticals for Human Use guidelines. The validation results indicating excellent extraction efficiency and low matrix effects show that the LC-MS/MS method is reliable for the detection of natural-derived steroids and their analogues. In addition, we established the ion fragmentation of turkesterone and ion fragmentation of four natural-derived steroids and their analogues. The validated method was applied to 60 dietary supplements purchased online and in person from international vendors in 2020. Ecdysterone and 5α-hydroxylaxogenin were detected respectively in 3 and 14 of 60 dietary supplements. Especially, a high amount of 5α-hydroxylaxogenin, an FDA-unapproved ingredient, was detected in two of dietary supplements (44.4 and 32.3 mg/g). This component should be controlled since it may cause unexpected side effects if administered excessively. Thus, this method will be helpful for the continuous control and supervision of unlicensed dietary supplements containing natural-derived steroids and their analogues.

Development of an analytical method for the determination and quantification of n-nitrosodimethylamine in olmesartan by HPLC-MS/MS

In this study, a simple, rapid, and highly sensitive analytical method has been developed and validated for the detection, separation, and quantification of N-nitrosodimethylamine in the active pharmaceutical ingredient olmesartan medoxomil, as well as in manufactured tablets and marketed tablets, using high-performance liquid chromatography-mass spectrometry. Chromatographic separation was achieved using the Agilent Eclipse XDB-C18 column (5 m × 4.6 mm × 150 mm) with a binary gradient with water as mobile phase A and 0.1 % formic acid in methanol as mobile phase B, flow rate 0.5 mL/min, B. Due to the presence of polar groups, N-nitrosodimethylamine is successfully ionized and quantified in positive atmospheric pressure chemical ionization mode using multiple reaction monitoring. The method was validated according to International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use guidelines, evaluating the limit of detection and quantification, a good signal-to-noise ratio, and an excellent regression coefficient greater than 0.995 were found. The accuracy (expressed as recovery) of the method was performed in triplicate obtaining satisfactory results between 80 and 104 %, with a precision (%RSD) of 0.34 – 1.50 %. The method can be used routinely for the determination and quantification of N-nitrosodimethylamine in olmesartan.

Comparative study of Regulatory requirements of Drug Product in Emerging market

Registration of Pharmaceutical drug product in Emerging Market is most demanding task. Regulatory requirements are harmonized in regulated countries by Common technical document (CTD) filing, while there is diversity of requirements in emerging markets. International conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) has brought regulatory authorities and pharmaceutical industries of US, Japan and Europe together for various aspects of drug registration but there are is no such harmonized guideline for emerging market except Association of Southeast Asian Nations (ASEAN) and Gulf Co-operation Council (GCC) where harmonization exist in clusters with their mutual concern. The optimization and harmonization requirements has become mandatory and can be examined by the incidence of higher cost involved in availability of drugs, quality requirement of premise and research and development, regional registration requirements. Quality, Safety and Efficacy data has significance importance in dossier registration. Pharmaceutical Industries has to comply with regulatory requirement in Emerging market and for betterment of public Health and safety.
 The review also explains a brief about different regulatory requirement for Registration of drug product in Emerging market and comparative data for registration of dossier application in Emerging market.

HPLC-MS method for simultaneous quantification of the antiretroviral agents rilpivirine and cabotegravir in rat plasma and tissues

The antiretroviral agents rilpivirine (RPV) and cabotegravir (CAB) are approved as a combined treatment regimen against human immunodeficiency virus (HIV). To fully understand the biodistribution of these agents and determine their concentration levels in various parts of the body, a simple, selective and sensitive bioanalytical method is essential. In the present study, a high performance liquid chromatography method with mass spectrometry detection (HPLC-MS) was developed for simultaneous detection and quantification of RPV and CAB in various biological matrices. These included plasma, skin, lymph nodes, vaginal tissue, liver, kidneys and spleen, harvested from female Sprague Dawley rats. The suitability of the developed method for each matrix was validated based on the guidelines of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) on bioanalytical method validation. Analytes were extracted from biological samples employing a simple one-step protein precipitation method using acetonitrile. Samples were analysed using an Apex Scientific Inertsil ODS-3 column (4.6 mm × 250 mm, 5 µm particle size), maintained at 40 °C, on a HPLC system coupled with a single quadrupole MS detector. RPV was detected at a mass-to-charge ratio (m/z) of 367.4 and CAB at 406.3. Separation was achieved using isocratic elution at 0.3 mL/min with a mixture of acetonitrile and 0.1% (v/v) trifluoroacetic acid in water (81:19, v/v) as the mobile phase. The run time was set at 13 min. The presented method was selective, sensitive, accurate and precise for detection and quantification of RPV and CAB in all matrices. The developed and validated bioanalytical method was successfully employed for in vivo samples with both drugs simultaneously.

Management of validation of HPLC method for determination of acetylsalicylic acid impurities in a new pharmaceutical product

The work mainly focused on a validation of the method for determining the content of salicylic acid and individual unknown impurities in new pharmaceutical product—tablets containing: 75, 100 or 150 mg of acetylsalicylic acid and glycine in the amount of 40 mg for each dosage. The separation of the components was carried out by means of HPLC, using a Waters Symmetry C18 column (4.6 × 250 mm, 5 μm) as the stationary phase. The mobile phase consisted of a mixture of 85% orthophosphoric acid, acetonitrile and purified water (2:400:600 V/V/V). Detection was carried out at a wavelength of 237 nm, with a constant flow rate of 1.0 ml min−1. In order to verify the method, linearity, precision (repeatability and reproducibility), accuracy, specificity, range, robustness, system precision, stability of the test and standard solution, limit of quantification and forced degradation were determined. Validation tests were performed in accordance with ICH (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use) guidelines. The method was validated successfully. It was confirmed that the method in a tested range of 0.005–0.40% salicylic acid with respect to acetylsalicylic acid content is linear, precise and accurate.

Critical Analysis of cGMP Large-Scale Expansion Process in Bioreactors of Human Induced Pluripotent Stem Cells in the Framework of Quality by Design.

Human induced pluripotent stem cells (hiPSCs) are manufactured as advanced therapy medicinal products for tissue replacement applications. With this aim, the feasibility of hiPSC large-scale expansion in existing bioreactor systems under current good manufacturing practices (cGMP) has been tested. Yet, these attempts have lacked a paradigm shift in culture settings and technologies tailored to hiPSCs, which jeopardizes their clinical translation. The best approach for industrial scale-up of high-quality hiPSCs is to design their manufacturing process by following quality-by-design (QbD) principles: a scientific, risk-based framework for process design based on relating product and process attributes to product quality. In this review, we analyzed the hiPSC expansion manufacturing process implementing the QbD approach in the use of bioreactors, stressing the decisive role played by the cell quantity, quality and costs, drawing key QbD concepts directly from the guidelines of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use.

Study of the compatibility of oral magnesium oxide preparations sold in Japan with the ICH-Q3D guideline for elemental impurities.

Magnesium oxide has been widely used as an antacid and constipation remedy. Currently in Japan, magnesium oxide preparations manufactured by five medical companies are marketed as prescribed generic drugs. In this study, we focused on metal elemental impurities present in 330 mg magnesium oxide tablets manufactured by each of these companies. The content of such impurities was determined by atomic absorption spectrometry and inductively coupled plasma mass spectrometry. We confirmed whether the content conformed to the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use, Guideline for Elemental Impurities (ICH-Q3D) based on the 30% control threshold. The content of these impurities varied among the five products (preparations A-E), but in all cases met the oral permitted daily exposure (PDE) criteria stipulated in ICH-Q3D. In 5 lots of preparation C and all lots of preparation D, the equivalent cadmium (Cd) intake for a daily maximum dosage of 2 g was higher than the 30% control threshold of 1.5 µg/day. By cluster analysis, preparations A-E were classified into preparations A + B and C + D + E and/or preparations A + B, C + D and E. The present study showed that all 5 preparations sold in Japan meet the PDE value standard of ICH-Q3D, and that preparations A and B meet the 30% control threshold. It is important that for preparations failing to meet the criteria, further improvements need to be sought, and impurities in magnesium oxide preparations need to be monitored to ensure their safety.