STABILITY INDICATING ASSAY DEVELOPMENT AND METHOD VALIDATION OF VALGANCICLOVIR HCL BY UV-VISIBLE SPECTROPHOTOMETRY

The objective of the present study was to develop and validate stability indicating method to generate reliable, precise, cost effective UV-VIS spectroscopy method and accurate data for dutasteride regardless of whether it is for acceptance, release, stability or pharmacokinetic study. The solvent used was methanol and the absorption maximum λ max of the drug was found to be at 241nm. A linear response was observed in the range of 1-100µg/ml. Linear regression of absorbance on concentration gave the equation y = 0.0194x + 0.0099 with a regression co-efficient (R2) of 0.997. The method was then validated for different parameters as per the ICH guidelines. Dutasteride was subjected to stress degradation under different conditions as recommended by ICH guidelines. The degradation studies were carried out by using the developed method. The method is useful for the determination of dutasteride in bulk and pharmaceutical formulations

Stability studies form a crucial aspect of the pharmaceutical development process and play a vital role in establishing the quality, safety and efficacy of the drug product. The core objective of a stability study is to ascertain the shelf-life of a drug product and to understand how best to design the drug product and its container-closure system so as to ensure that the same maintain suitable physical and chemical properties during the proposed shelf-life period. Since stability studies are inherently crucial to the lifecycle of a pharmaceutical formulation, the process and its requirements are subject to stringent regulations and specifications by regulatory authorities around the globe. A multitude of guidelines have been published in this regard by various regulatory authorities entailing concepts, techniques and protocols associated with stability testing, with the aim of aiding drug manufacturers generate accurate and viable stability data. Most of these guidelines, however, are based on the International Council for Harmonisation (ICH) stability guidelines and have been adapted by individual regulatory authorities to complement the climatic conditions of the respective regions, two such examples being the United States Food and Drug Administration (USFDA) and the Gulf Cooperation Council (GCC). Therefore, the present work aims to briefly discuss the stability guidelines applicable in each region and identify any similarities and differences, whilst examining the documentation requirements related to stability studies as well as the dossier requisites to be adhered to during drug product registrations.

Objective: The main objective of the present work is to develop an efficient, unique, reliable Reverse Phase High Performance Liquid Chromatography (RP-HPLC) method for the simultaneous quantification of Amoxicillin (AMX), Clarithromycin (CTM) and Lansoprazole (LPZ) in bulk and pharmaceutical formulations. 
 Methods: The chromatographic separation was achieved by using Kinetex column C18 (100 x 4.6 mm, 2.6 µm) with Buffer (2.5 g of hexane sulphonic acid and 1ml of Triethylamine which are added to 1000 ml of HPLC water and adjusted its pH at 5.0 with Ortho phosphoric acid) and acetonitrile in the ratio of 70: 30 (%v/v) as a mobile phase at flow rate of 1.0 ml/min. The column effluents were monitored by a photodiode array detector at wavelength predetermined at 240 nm.
 Results: The method produced reliable results at optimized chromatographic conditions. The method was linear at concentration range of 15-225 µg/ml of AMX, 15-225 µg/ml of CTM and 0.9-13.5 µg/ml of LPZ with regression coefficients of 0.9999, 0.9999, and 0.9999 respectively. The retention times of AMX, CTM, LPZ were obtained as 1.513, 3.124, 3.770 min respectively. Results obtained for system suitability, precision, LOD and LOQ were in acceptable range and were validated according to the guidelines of the International Council for Harmonization (ICH).
 Conclusion: The proposed method was validated in accordance with ICH and all the obtained results were found satisfactory and were successfully applicable to the analysis of the bulk and the pharmaceutical formulations.

Background: Favipiravir is an influenza antiviral medication. DEM Avigan is the commercial name for a pyrazine carboxamide derivative. Aim: According to the guidelines framed by ICH - International Council for Harmonisation, the present method was developed and validated for the system suitability, specificity, linearity, precision, limit of quantification and limit of detection, accuracy, & robustness. Results: All the results obtained were within the acceptable range. This method was used to better separate the peaks of Favipiravir and its three impurities. The retention times and squared correlation coefficient values of Impurity-1, Impurity-2, Favipiravir & Impurity-3 were obtained at 1.998, 3.223, 4.438 & 7.052 min and 0.9993, 0.9995, 0.9998 & 0.9997 respectively. Conclusion: Thus, the results show that the suggested RP-HPLC method for separating three contaminants with Favipiravir was effective and may be utilised in routine pharmaceutical analysis and quality control. Forced degradation was carried out under different stress conditions thus proving as stability indicating as per ICH guidelines.

After multiple drugs were removed from the market secondary to drug‐induced torsade de pointes (TdP) risk, the International Council for Harmonisation (ICH) released guidelines in 2005 that focused on the nonclinical (S7B) and clinical (E14) assessment of surrogate biomarkers for TdP. Recently, Vargas et al. published a pharmaceutical‐industry perspective making the case that “double‐negative” nonclinical data (negative in vitro hERG and in vivo heart‐rate corrected QT (QTc) assays) are associated with such low probability of clinical QTc prolongation and TdP that potentially all double‐negative drugs would not need detailed clinical QTc evaluation. Subsequently, the ICH released a new E14/S7B Draft Guideline containing Questions and Answers (Q&As) that defined ways that double‐negative nonclinical data could be used to reduce the number of “Thorough QT” (TQT) studies and reach a low‐risk determination when a TQT or equivalent could not be performed. We review the Vargas et al. proposal in the context of what was contained in the ICH E14/S7B Draft Guideline and what was proposed by the ICH E14/S7B working group for a “stage 2” of updates (potential expanded roles for nonclinical data and details for assessing TdP risk of QTc‐prolonging drugs). Although we do not agree with the exact probability statistics in the Vargas et al. paper because of limitations in the underlying datasets, we show how more modest predictive value of individual assays could still result in low probability for TdP with double‐negative findings. Furthermore, we expect that the predictive value of the nonclinical assays will improve with implementation of the new ICH E14/S7B Draft Guideline.

The founding industry members (European Federation of Pharmaceutical Industries and Associations [EFPIA], Japanese Pharmaceutical Manufacturers Association [JPMA], and Pharmaceutical Research and Manufacturers of America [PhRMA]) of the International Council for Harmonisation (ICH) have a 25-year track record of the contribution to ICH. Given that further globalization of ICH is expected, we should value this legacy and maintain the current ICH culture and its principles of "benefit to the patients first" and "science-based approach," through which industry members would ensure transparency and objectivity in their ICH activities. In order to maintain and develop the culture of the ICH and its current momentum, a 2-way approach is important: (1) sharing common views through dialogues among leaders of each industry association, such as through the Industry Executive Council, and (2) spreading the values through grassroots activities involving wider stakeholders in global forums such as DIA, as platforms for sharing the knowledge, views, and culture of ICH across the globe.

I read with discomfort the original commentary by C. Michael White, PharmD, FCP, FCCP, in the Journal of Clinical Pharmacology. “Preventing a New Tuskegee: Food and Drug Administration Oversight of Overseas Research Must Match That in the United States” concludes that the regulatory agency of the United States has a responsibility for the oversight of all international clinical research. The conclusion ignores that each sovereign country has their own regulatory agencies, with separate investigational new drug application processes and independent oversight of research conducted on their soil. Further, the introductory title sensationally conflates the horrible Tuskegee experiments with the fiduciary responsibilities of the US Food and Drug Administration (FDA) to regulate safe clinical trials.1 In 1990, the International Council for Harmonization (ICH) brought together the international regulatory authorities, ensuring that safe, effective, quality therapeutics are developed and registered in the most resource-efficient manner. The ICH participating agencies ensure that clinical trials conducted in one ICH region can be used in other ICH regions, by setting common standards on science and ethics, called Good Clinical Practice (GCP).2 ICH guidelines have been adopted into international law in some countries and our FDA, which is an ICH participating authority, uses the ICH for guidance to guarantee that proper oversight meets recognized global standards. Without mention of this important ICH/GCP guard rail for new drug applications, the commentary drops an opinion not rooted in fact or international law. The commentary wrongly suggests that the regulation of all international clinical research is the purview of the USA, which is not the edict of the FDA.3 Most concerning, the title asserts a willful intent to harm subjects, whether directed or ignored by the FDA. The author fails to opine the link between FDA ignorance of GCP and the lack of informed consent, with the intentional harm introduced by not providing treatment to the men infected with a bacterium. The Tuskegee Syphilis Study (1932) predated the Nuremberg Code, the Helsinki Declaration, and the ICH/GCP guidance that the FDA originally accepted in 1997. A historical outline of the development of the current FDA is beyond the scope of this letter; however, blindly suggesting a causal link between introducing harm to subjects, by failing to obtain informed consent and, worse, causing illness without remedy or regulation by the FDA, is a broad stroke of imagination and requires corrective discussion.

The International Council for Harmonisation (ICH) E6(R2) (International Council for Harmonisation (ICH). ICH harmonised guideline: integrated addendum to ICH E6(R1): guideline for good clinical practice E6(R2). 2016. https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf. Accessed 5 Dec 2019) introduced Quality Tolerance Limits (QTLs) to the industry, and in doing so, modernized quality control for clinical trials. QTLs provide measured feedback on clinical trial parameters previously only used by statistical and clinical functions to track trial progress toward endpoints. Elevating these measures as part of the Quality Management System (QMS) provides greater visibility across clinical trial functions and the enterprise as well as to measures that are important indicators of the state of participant protection and reliability of trial results. In support of this new requirement, TransCelerate developed a framework to guide industry sponsors and their agents in implementing QTLs. This QTL Framework is intended to aid industry’s ability to improve the quality of clinical research through the implementation of QTLs in a way that helps protect trial participants and reliability of trial results while meeting Health Authority (HA) expectations. The framework is intended to maximize efficiency and minimize confusion in the implementation of QTLs. The framework includes proposed approaches for implementation of QTLs for a clinical trial as defined in Section 5.0.4 and 5.0.7 of ICH E6(R2) (International Council for Harmonisation (ICH). ICH harmonised guideline: integrated addendum to ICH E6(R1): guideline for good clinical practice E6(R2). 2016. https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf. Accessed 5 Dec 2019) and considerations for setting thresholds.

Minoxidil is an anti-hypertensive agent and Tofacitinib citrate is a Janus-kinase inhibitor but there are various articles proving their efficacy in the treatment of Alopecia. An effort is made in order to formulate gel for topical use containing Minoxidil and Tofacitinib citrate for the treatment of Alopecia areata. Objective: The aim of study is to establish and validate a sensitive, selective and precise, method capable of accurately detecting Minoxidil and Tofacitinib citrate in both their raw form and pharmaceutical formulations, adhering strictly to the guidelines outlined by the International Council for Harmonisation (ICH). Method: A UV-spectrophotometric method was devised to simultaneously determine the concentrations of Minoxidil and Tofacitinib citrate. The method underwent validation across various parameters including Linearity, Accuracy, Precision, Repeatability, LOD, LOQ, Robustness, and Ruggedness. A double-beam UV-spectrophotometric technique was developed to simultaneous estimation of the levels of Minoxidil and Tofacitinib citrate. This method was then rigorously validated using various parameters including linearity, accuracy, precision, repeatability, detection limit (LOD), quantification limit (LOQ), robustness, and ruggedness. Results: In the Methanol solvent, Minoxidil exhibits its peak absorbance at 258nm, while Tofacitinib citrate displays its maximum absorbance at 290nm. The concentration range of 2-10µg/mL for both analytes adheres to Beer's law, indicating their reliable quantification potential. For Minoxidil, the Limits of Detection (LOD) and Limits of Quantification (LOQ) stand at 0.537µg/mL and 1.628µg/mL, respectively. Tofacitinib citrate, on the other hand, exhibits LOD and LOQ values of 0.427µg/mL and 1.294µg/mL, respectively. In the assessment of their presence in a topical gel formulation, recovery rates ranging from 50.00% to 150.00% were observed for both Minoxidil and Tofacitinib citrate. Conclusion: The method proposed demonstrates selectivity, specificity, precision, accuracy, ruggedness, and robustness, rendering it suitable for routine analysis of Minoxidil and Tofacitinib citrate in both bulk form and pharmaceutical dosage formulations.

A Risk-Based Approach to Evaluate and Control Elemental Impurities in Therapeutic Proteins

Objective: In the present research, the plant oil of Gaultheria procumbens (family: Ericaceae), an extensively utilized ethnic drug to treat arthritis and get rid of pain, was selected to formulate Micro Emulsions (MEs). The objective of this research was to examine the suitability of gaultheria oil in formulating MEs containing Non-Steroidal Anti-Inflammatory Drug (NSAID) for topical use. Methods: A new water-in-oil Piroxicam Micro Emulsions (PMs) consisting of gaultheria oil, tween 20 and Poly Ethylene Glycol (PEG) 600 were formulated using D-optimal design expert software for optimization of formulation and also to enhance the loading capacity of a model NSAID piroxicam has been demonstrated. The pseudo-ternary phase drawing has been depicted on a constant surfactant/co-surfactant (S-mix) ratio (1:1). Then the prepared PMs were evaluated for percentage (%) transmittance, pH determination, refractive index (RI), viscosity measurement, % drug content, particle size, zeta potential, in vitro cumulative drug release and stability studies. Results: The pre-formulation studies showed high solubility of drug (piroxicam) with gaultheria oil, tween 20 and PEG 600, thereby confirming its suitability for formulation. Fourier Transform Infrared Spectroscopy (FTIR) proved drug excipient compatibility by retaining the characteristic peaks even after formulation. D-optimal design expert software was proved to be beneficial in the formulation and optimization process and matched the experimental results. Optimized Piroxicam Micro Emulsion (PM) formulation PM 8 showed satisfactory results regarding % transmittance (98.84±1.04), pH (7.41±0.01), RI (1.4421±0.002), viscosity (469.53±0.61), % drug content (96.32±0.19), particle size (185.5 nm±0.24 nm), zeta potential (-25.34±0.51), in vitro cumulative drug release in 6 h (42.62 %±0.11 %) and 12 h (86.42 %±0.21 %). The drug release kinetics study showed a zero-order release mechanism confirmed by Korsmeyer-peppas model. Stability studies as per International Council for Harmonization (ICH) guidelines demonstrated the stability of PM 8 for its physical appearance, phase separation, % transmittance, pH and % drug content for 90 d. Conclusion: Thus, it can be concluded that the present investigation study can be beneficial for improved loading of model NSAID piroxicam in the interfacial film of PM with gaultheria oil as a promising vehicle aimed at the topical conveyance of drugs in the management of arthritis.

The simultaneous measurement of paracetamol, chlorpheniramine maleate, and caffeine in a pharmaceutical formulation was accomplished through the development and validation of a precise, accurate, and robust high performance liquid chromatography (HPLC) method. Using an optimized mobile phase composition of (Methanol: Buffer, pH 4.0), a flow rate of 1.0 mL/min, and detection at a wavelength of 215 nm, the chromatographic separation was accomplished on a (4.6 mm x 15 cm, 5 µm, L1) column. For every analyte, the method showed outstanding linearity over the concentration ranges of “80–120%”, with correlation coefficients (R 2 ) continuously surpassing 0.997. While intra and inter day precision produced relative standard deviations below 2%, accuracy was validated with recovery values between “98%–102%”. Robustness was confirmed by altering critical parameters, demonstrating the method's reliability under various analytical conditions. The Method can be used for routine quality control, stability testing, and regulatory compliance of pharmaceutical tablet formulations containing paracetamol, chlorpheniramine maleate, and caffeine. The method was validated according to International Council for Harmonisation (ICH) guidelines. The results highlight the method's potential to enhance pharmaceutical quality testing and analytical precision, thereby improving patient safety and ensuring regulatory compliance.

Peramivir is a neuraminidase inhibitor that serves as a transition state analogue for influenza neuraminidase, inhibiting the formation of new viruses in infected cells, and has been approved for intravenous administration. To validate an HPLC method used to identify the degraded products of the antiviral drug peramivir. Herein, we report the identification of compounds formed after the degradation of peramivir through acid, alkali, peroxide, thermal, and photolytic degradation. At the level of toxicology, a technique was devised for the isolation and measurement of peramivir. A sensitive and reliable LC-tandem mass spectrometry technique for the quantitative measurement of Peramivir and its impurities was developed and verified in order to comply with the recommendations made by the International Council for Harmonisation (ICH). The proposed protocol was in the 50-750 µg/mL range. Relative Standard Deviation values of less than 2.0% indicated good recovery in the range of 98.36-102.57%. Within the studied range, the calibration curves demonstrated good linearity and, in addition, the fitting of correlation coefficient was more than 0.999 for every impurity. Quantitative analysis of contaminants revealed the high efficiency at a low level. Given its ability to separate degradation products, quantitative analysis is used to detect and quantify known and unknown impurities and degradants in the peramivir drug substance during routine analysis and stability studies. No significant degradation was found in peroxide and photolytic degradation studies. An HPLC method was developed and put to the test in order to analyze the behavior of the impurities of peramivir as they degraded when subjected to the stress conditions suggested by the ICH. Peramivir was found to be stable under peroxide and photolysis conditions but not stable or degradable when exposed to the acid, base, and thermal stress conditions. The method developed was extremely precise, linear, accurate, robust, and rugged. As a result, this technology has the potential to be used in the medication production process for regular impurity analysis as well as for the stability analysis of peramivir.

This article analyses the setting of global pharmaceutical standards in the International Council for Harmonization (ICH) and the implementation of these global standards in the European framework of pharmaceutical regulation. It thereby highlights the conflict between the publicprivate nature of the ICH process and the European administrative law principle of independence of public regulators. While the ICH is a public-private partnership between regulatory authorities and pharmaceutical industry associations, in the regulation of pharmaceuticals in the European Union public regulators are subject to a strict requirement of independence from the industry they are regulating. Nonetheless, the ICH standards are implemented into the regulatory framework for pharmaceuticals in the European Union, although the standard-setting process on the global level fundamentally contradicts the procedural standards of EU administrative law. In this regard, the article calls for a more coherent approach for the EU’s participation in global standard-setting bodies and the implementation of global standards in the EU.

Oligonucleotide therapeutics (ONTs) are a growing class of nucleic acid-based therapies with the potential to treat a variety of diseases through several different mechanisms of action (MoA). The most prevalent MoA entails the inhibition of therapeutically relevant levels of protein expression via mRNA degradation, exemplified by numerous approved ONTs. ONTs have unique physicochemical properties, pharmacokinetic characteristics, and MoAs that are distinct from other drug classes. The result can be a disconnect between the administered dose, plasma drug concentrations, pharmacodynamics, and toxicity. Thus, ONT development poses unique scientific and regulatory challenges that are not fully addressed by current International Council for Harmonisation (ICH) guidelines. The complexity of ONT development has recently been recognized with the acceptance of the new ICH topic proposal "ICH S13-Nonclinical Safety Evaluation of Oligonucleotide-based Therapeutics." In preparation for the ICH S13 Step 2 public consultation period, the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) DruSafe ONT Working Group convened to identify and discuss key considerations for ONT development, and to communicate areas where regulatory clarity and harmonization are most needed. Specifically, these include strategies to assess off-target toxicities, safety pharmacology, general toxicity studies, First-In-Human dose selection, genotoxicity studies, reproductive and developmental toxicity studies, carcinogenicity assessments, and the appropriate use of a surrogate molecule in development. The intended goals of this paper are to provide a means for communicating input towards the ICH process and to provide a resource for assisting with the public review of the draft ICH S13 Guidance.