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The research study investigated the biosorption behavior of Pb(II) ions by treated and untreated biomass of B. subtilis. At initial biosorption conditions, the biosorption efficiency was found to be 36.75%. At the optimized experimental conditions, control biomass showed maximum biosorption efficiency of 58.04% where the biomass was treated with different chemicals. The biomass treated with formaldehyde showed the highest efficiency of 80.9% which was further optimized and attained maximum efficiency of 89.8% for Pb(II) ions. SEM (Scanning Electron Microscope) and EDX (Energy dispersive X- ray) analysis evaluates the structural and elemental changes that occurred as a result of biosorption. Functional groups that are involved in biosorption were revealed by FTIR (Fourier Transform Infrared spectroscopy). Kinetic data showed the best fit with the pseudo second-order model. Effective removal of lead ions from industrial contaminated water sources by pretreatment biomass of B. subtilis elucidates its potential use as biosorbent for metal remediation..

In the present study, initially Aspergillus niger was tested for biosorption of Pb(II) ions and then studied the effect of pretreatment for enhanced biosorption. It was found that the maximum biosorption potential was achieved with citric acid treatment (70.56 %) in comparison with the biomass without treatment (65.46 %) at a biosorbent dose of 20 mg/L, pH 4, 100 rpm, 37 ºC for 8 h. The optimized conditions for treated Aspergillus niger were determined by optimizing the biosorption parameters such as pH, temperature, biomass dose, incubation time and agitation speed. This study indicates that the citric acid treated Aspergillus niger is an effective biosorbent for removal of lead (II) at optimized conditions with the maximum biosorption potential of 83.6 % as compared to previous reported work. SEM-EDX and FTIR analysis showed the structural variations and the functional groups involved in lead biosorption, respectively. Biosorption kinetics showed that pseudo second order kinetic model as the better fit.

The study carried out here was focused on developing conventional monolithic controlled release matrix tablet of Atorvastatin calcium using carbomer as release controlling polymer. This system ensures the drug release at the alkaline pH region where the drug has got maximum solubility. Further the study was concentrated on comparing the impact of gelling agent polyvinyl pyrrolidone on drug release. Quality by design tools were considered during formulation development and the polymer concentrations were optimized adopting the statistical tool, design of experiments (DoE). The optimized formulation of present study exhibited desired controlled drug release characteristics in the alkaline pH conditions and at acidic environment the drug dissolution was minimal as intended.

Objectives Leflunomide (LFNM) is a drug that belongs to isoxazole derivatives and has immunosuppressive and anti-inflammatory activities. A literature search confirms that there is no method reported for the simultaneous estimation of LFNM and its related impurities A and B in pharmaceutical dosage forms or in bulk drug. Hence the present work aimed to develop a simple stability indicating RP-HPLC method for the separation and quantification of LFNM and its impurities A and B. Materials and methods Systematic trials of method conditions like mobile phase ratio, pH, flow rate, stationary phase, and detector wavelength were performed for the simultaneous analysis of LFNM and its related impurities A and B. The developed method was validated as per the ICH guidelines including forced degradation studies in different stress conditions. Results Optimized separation was achieved on a Thermo Scientific Hypersil ODS C18 column (250 mm×4.6 mm; 5 μm id) using mobile phase composition of acetonitrile, methanol, and 0.1 M sodium perchlorate in the ratio of 40:30:30 (v/v), pH 4.6, at a flow rate of 1.0 mL/min in isocratic elution. UV detection was carried out at a wavelength of 246 nm. Well-resolved peaks were observed with high numbers of theoretical plates, lower tailing factor, and reproducible relative retention time and response factor. The method was validated and all the validation parameters were found to be within the acceptance limits. Stability tests were done through exposure of the analyte solution to five different stress conditions, i.e. 1 N HCl, 1 N NaOH, 3% H2O2, thermal degradation of powder, and exposure to UV radiation. The method can successfully separate the degradation products along with both the impurities studied. The % degradation was also found to be less. Conclusion The method developed for LFNM is simple and precise and can be applied for the separation and quantification of LFNM and its related impurities in bulk drug and pharmaceutical formulations.

Objective of the present research work is to develop a sensitive, selective and accurate new RPHPLC method with UV detection and determination for estimation of Nevirapine (NVP)and its impurities in bulk drug. The separation and quantification was achieved with Kromosil C18 isocratic column, (150 mm × 4.6 mm i.d., particle size 3.5 µm, maintained at ambient temperature), HPLC system (Peak LC P7000), a mixture of 20% acetonitrile, 80% buffer (sodium per chlorate) (v/v), at pH of 4.8 and the flow rate was set at 1.0 ml/min. and UV detection at 220 nm. The retention time for NVP, Impurity-A and Impurity-B were found to be 5.5, 7.8, 3.4 min respectively. The method was validated for Linearity, Accuracy, and Precision. The Limit of detection of NVP, Impurity-A and Impurity-B were found to be 0.03, 0.03, 0.03(µg/ml) respectively.

Objective: Vinorelbine (VNRB) is a chemotherapeutic drug used to treat non-small cell lung cancer and breast cancer. Literature survey reveals that there are no reverse-phase high-performance liquid chromatography (RP-HPLC) methods reported for the estimation of VNRB in spiked human plasma. Hence, the present work aimed to develop a simple and efficient RP-HPLC method for the estimation of VNRB in human plasma.Methods: Specimen preparation for the measurement of VNRB was performed through liquid-liquid extraction using methanol as extracting solvent and reconstructed with mobile phase. Paclitaxel (PCTX) was used as internal standard. HPLC method was optimized and validated as per the US FDA bioanalytical guidelines. VNRB and internal standard were separated on Kromasil® C18 (250×4.6 mm; id 5 μ) using acetate buffer (pH=5.9) and methanol in the ratio of 85:15 (v/v) at 1 ml/min flow rate. Eluted compounds were recorded using UV detector at 235 nm.Results: The retention time of PCTX and internal standard was found to be 4.3 and 9.0 min, respectively. The analytical measuring ranges were found to be 5–750 ng/ml (r2>0.9998). The method was found to be simple, accurate, precise, and stable and there is no interference of plasma matric components.Conclusion: The described HPLC method allows for the measurement of total and free PCTX in both plasma and cord blood and can utilize for the estimation of drug in pharmacokinetic studies.

Decitabine is an anti-cancer chemotherapy drug. This article describes method development and method validation of related substances of Decitabine (a- decitabine, a-isomer, methyl 4-chlorobenzoate, s-isomer, O-Acetyl and unknown impurities) in decitabine drug substance and finished dosage forms by using a high Performance liquid chromatography. In this high performance liquid chromatography, the resolution was achieved on Inertsil ODS 3V, 250×4.6 mm, 5µm column with a gradient elution at a flow rate of 1.2 mL/min using a mobile phase A as Ammonium acetate buffer solution and mobile phase B as water: acetonitrile (10:90% v/v) at wavelength 254 nm by an UV detector. The method was validated in the concentration range of 0.7 ppm to 7.1 ppm, 1.2 ppm to 11.0 ppm, 1.2 ppm to 10.9 ppm, 1.2 ppm to 11.0 ppm, 1.2 ppm to 10.9 ppm and 0.8 ppm to 7.7 ppm for related substances of a- decitabine, a-isomer, methyl 4-chlorobenzoate, s-isomer, O-Acetyl and Decitabine respectively. The obtained recovery was in between 90.0 % to 110.0 % and the % RSD was not more than 10.0. The HPLC method is suitable, specific, linear, accurate, precise, stability indicating and robust which may be useful for the routine and stability analysis for determination of related substances in Decitabine drug substance and finished dosages.

Pharmaceutical industry has been emerging rapidly for the last decade by focusing on product Quality, Safety, and Efficacy. Pharmaceutical firms increased the number of product development by using scientific tools such as QbD (Quality by Design) and PAT (Process Analytical Technology). ICH guidelines Q8 to Q11 have discussed QbD implementation in API synthetic process and formulation development. ICH Q11 guidelines clearly discussed QbD approach for API synthesis with examples. Generic companies are implementing QbD approach in formulation development and even it is mandatory for USFDA perspective. As of now there is no specific requirements for AQbD (Analytical Quality by Design) and PAT in analytical development from all regulatory agencies. In this review, authors have discussed the implementation of QbD and AQbD simultaneously for API synthetic process and analytical methods development. AQbD key tools are identification of ATP (Analytical Target Profile), CQA (Critical Quality Attributes) with risk assessment, Method Optimization and Development with DoE, MODR (method operable design region), Control Strategy, AQbD Method Validation, and Continuous Method Monitoring (CMM). Simultaneous implementation of QbD activities in synthetic and analytical development will provide the highest quality product by minimizing the risks and even it is very good input for PAT approach.

The pharmaceutical industry is emerging as a significant industrial sector with tremendous potential for providing innovative drugs to treat life-threatening diseases as well as for providing economical generic alternatives of supreme quality. Hence this sector is not only responsible to provide the much desired boost to the health of the society, especially of the developing countries, but also it is a competitive yet profitable sector from a business perspective. Currently, the primary focus of the pharmaceutical industry is to raise the bar for the quality, safety and efficacy of the drug products that are made available in the global market place. Product quality, price of raw materials [API (active pharmaceutical ingredient) and excipients] and market return competition are vital factors that determine the longevity or existence and profitability of a company in the crowded pharmaceutical market. . Hence these critical factors receive special consideration from drug product manufacturers. Active Pharmaceutical Ingredient (API) is the primary constituent of a pharmaceutical drug product that governs the final cost of the drug product as well as the commercial profit earned by the company. Most of the major generic drug manufacturing companies have their own API manufacturing facility and hence may not prefer to screen independent API suppliers as part of their generic drug development plan to procure additional API. Contradictorily, the generic drug manufacturers who do not synthesize the API themselves are dependent on external and independent API manufacturers for procurement of the API. Such generic drug manufacturing companies have to select suitable API suppliers by adapting a risk aversive approach. This article presents an informed and comprehensive discussion on the primary and alternate API supplier selection processes for generic drug products manufacturing firms. This API supplier selection process can be categorized into several stages which include preliminary assessment, documents review, samples analysis, onsite or offsite audit, results evaluation and final approval or rejection. This API selection process includes the anticipated product specific risk assessment with relation to API characteristics, specifications, analytical results, document review observations and inspection results. A generic drug product manufacturing company can choose an alternative API supplier or change the existing API supplier either during the development phase or after development of the drug product. Generic drug product manufacturing companies should rework on development activities if any API supplier change happens during the development phase. API supplier change or addition of an alternative API supplier has to be followed as per SUPAC guidance for US market and VARIATION filing procedures for European market.

A novel high speed, high resolution Reverse phase-UPLC method was developed for the quantification of related substances in Febuxostat drug substance. The separation of drug from the possible impurities was achieved on a Halo C18 column. The innovative approach of using stationary phase with sub 2 μ particles provides a comprehensive combination of selectivity and speed. 10 mM mono basic potassium phosphate buffer at pH 2.7 and acetonitrile mixture was selected as mobile phase. Flow rate and detection were kept at 0.8 mL/min and 320 nm respectively. The developed UPLC method was subjected to validation parameters. System precision, accuracy, specificity, limit of detection, limit of quantification and linearity were established as per the guidelines recommended by ICH. Stability indicating nature of the method was also performed by exposing the sample under various conditions like acid, base, peroxide and photo stability exposures. Total analysis run time 7.0 minutes indicates the speed and cost saving initiation of the developed method. Using the method one can carry out the quantitative estimation of related substances in Febuxostat drug substance, further the same method can be adopted for determination of drug substance assay also.

Generic drug product (GDP) competition for market existence and profitability has become a challenging task for the manufacturers. All the generic players are putting intensive efforts to enter the market with competitive price and consistent drug product (DP) quality. The generic firms have to manage the delicate balance between the cost and quality of raw materials, especially the active pharmaceutical Ingredient (API) for market survival. Major Pharma companies have adopted the merger and acquisition strategies with API manufacturers to withstand the competition and price erosion. Still the majority firms don’t have their own API manufacturing facility. Since the finished product cost is majorily driven by API, the supplier selection plays prominent role in the generic profitability as well as quality. The supplier screening and selection includes extensive evaluation and comparison of documents, quality and cost. As part of risk mitigation strategy many generic manufactures prefer to include additional or alternate sources for API supplier. This exercise could be triggered anytime during the DP life cycle. The authors have tried to share the view on supplier change process at various stages of product lifecycle and related regulatory authority requirements and expectations. Generic products have been targeted majorly for US and Europe regions and same is being focused here. These two regulatory bodies have almost similar requirement for supplier selection and change, except difference in procedural approaches. The regulatory requirements may vary for each phase of generic product life cycle. At the development stage, the supplier change may not significantly fall into regulatory umbrella. Generally development phase comes under relatively less regulatory scruitiny than CTD submission or post approval phase. The dossier review and post approval phase have almost similar regulatory requirements. All the post approval changes shall be routed through SUPAC filing in US and VARIATION filing procedures in Europe.

Development and Comparative Assessment of Hydrocolloid Based Against Wax Based Gastro Retentive Bilayered Floating Tablet Designs of Atorvastatin Calcium Using Qbd Approach Atorvastatin calcium is one of the most widely prescribed lipid lowering drug and due to its acidic degradation properties the bioavailability reported is only 12-14% when administered orally. The gastro retentive floating tablets of Atorvastatin calcium had shown enhanced bioavailability compared to conventional immediate release dosage forms. The study presented here was focused on comparing the physicochemical properties of two different bilayered controlled release gastro retentive buoyant formulation designs of Atorvastatin calcium tablets. The buoyancy layer for first formulation was swelling hydrocolloid based (HPMC) against the second formulation design which was non swellable wax (HCO) based. The drug release characteristics, kinetic models, buoyancy characteristics and stability were compared between the two formulation designs. Apart the DoE (22 factorial design) studies were carried out to understand the impact and range of release controlling agents in drug layer against the dissolution profile in pH 4.5 acetate buffer. The buoyancy properties were observed to be consistent and stable in case of HPMC based buoyancy system, where as the wax based formulation design had shown tendencies for layer seperation at higher agitation speeds.

A simple, sensitive and accurate analytical method for related substances of Voriconazole has been developed and validated by using RP-UPLC technique. The developed analytical procedure was validated as per ICH recommendations. Analysis was performed on a HALO C18 (100 × 2.1 2.7 μ) column. 20 mM ammonium formate adjusted the pH to 4.5 with formic acid was selected as buffer. Acetonitrile was used as organic modifier in the mobile phase composition. A simple gradient was applied in the method. Flow rate of mobile phase was kept at 0.4 ml per min. Column compartment temperature was maintained at 45°C. Injection volume was set at 1 μL with an auto sampler maintained the temperature at 10°C. Detection of all the components was monitored at 254 nm by photodiode array detector. Developed method satisfies the system suitability criteria, peak integrity, and resolution for the parent drug and its related substances. The proposed method was validated for Specificity, precision, accuracy, linearity, limit of detection and quantification. Forced degradation studies were conducted to assess stability indicating nature of the method under acidic, basic, oxidative and photolytic conditions. Run time less than 7.0 minutes indicating that the method is cost effective and productive; it can be successfully applied for testing of related substances in drug substance and assay of drug substance in routine quality control analysis and stability testing.

Periodic Testing (PT) or Skip Testing (ST) is an important and widely discussed concept for the purpose of cost saving in the generic pharmaceutical industry where widespread expenditure is a necessity. As there is no particular/ appropriate/apropos guideline recommending the implementation of the PT or ST concept so pharmaceutical companies implement it depends on their vendor qualification procedure and other aspects. All pharmaceutical industries have their internal Standard Operating Procedure (SOP) for the implementation of periodic or skip testing. These tests can be implemented for Active Pharmaceutical Ingredients (APIs), excipients, packing materials and inprocess testing of finished products analysis. Implementation of PT or ST for API, excipient and packaging material can be approached according to SOPs which would be available for an audit by the regulatory agencies. However, the implementation of PT for in-process testing of finished product can be undertaken only after seeking concurrence from the agency either during the review of a marketing authorization application or after approval of the application. A suitable supplement or variation needs to be submitted to the agency for its review if PT is to be implemented for in-process testing. This article explains the periodic testing/skip testing approach for in-process samples, APIs, excipients and packing materials.

New High-performance liquid chromatographic bio-analytical method has been developed and validated for the simultaneous analysis of Trifluridine (TFD) and Tipiracil (TPC) in human plasma. The combination of TFD and TPC are used in the treatment of unresectable advanced or recurrent colorectal cancer. The method was developed with UV detector (at 260 nm wave length), Intersil ODSC 18 column (250 mm × 4.6 mm×5μ), at flow rate of 1.0mL/min. The mobile phase consisted of 15% NaClO4 buffer (PH 4.5 v/v), 85% Methanol. The retention times of TFD and TPC are 3.4 min and 7.4 min respectively. The method was developed and validated in terms of selectivity, precision, linearity, accuracy, LOQ, LOD and stability study. The proposed method can be applicable for pharmacokinetic studies using HPLC or LC-MS.

Stability studies are playing main role in the pharmaceutical industry. Stability studies for pharmaceutical drug products are having all guidelines like ICH, USFDA, EMEA, WHO and etc. Hold time study data shall give the assurance the maximum allowable hold times for bulk and in-process drug products. Generally one lot can be used for validating hold times if any inconsistency results were observed then another two lots can be used for this study. Major hold study required stages are mixing, blending, lubrication, binder solution, coating solution, uncoated tablets, coated tablets, filled capsules, syrup solution, power for injection, liquid injection, bulk creams/ointments/gels. Hold study samples need to pack with the regular used poly ethylene bags, sterilized containers, HDPE or Glass containers. Hold samples need to store at GMP conditions i.e. where the lot or stage holds in the manufacturing area. All the regulatory agencies also may expect the hold time study at critical stages to understand the trend of degradation during holding at in-process stages.