01 1ICBio Clinical Research Pvt Ltd
02 1QUINTA-ANALYTICA s.r.o
01 2Valsartan
01 1HPLC/MS/MS
02 1LSMS/MS
01 1ng/mL
02 1ng/ml
01 1Human Plasma
02 1Blank
What is Valsartan?
Valsartan is an angiotensin-receptor blocker (ARB) medicine that
may be used to treat a variety of cardiac conditions including hypertension, diabetic nephropathy and heart failure.
What is valsartan’s mechanism of action?
Valsartan lowers blood pressure by antagonizing the renin-angiotensin-aldosterone system (RAAS). Valsartan belongs to a class of antihypertensive agents called angiotensin II receptor blockers (ARBs), prescribed for patients with high blood pressure, congestive heart failure and to reduce death for people with left ventricular dysfunction after having had a heart attack.
Valsartan has a unique mechanism of action which significantly differs from that of other ACE inhibitor (Angiotensin-converting enzyme) drugs, which block the conversion of angiotensin I to angiotensin II.
Millions of Americans take valsartan medications daily which are one of the many valsartan generic medicines currently available in market. Recently, some generic versions of valsartan were found to contain an impurity that doesn’t meet FDA’s safety standards. Hence it’s mandatory to keep track of Valsartan recall updates from the FDA.
According to the latest FDA statement, the FDA currently has a major operation underway to investigate and address this troubling finding which is a valsartan impurity. This investigation is led by a dedicated task force of experts focused solely on tracking new developments and information coming in from Valsartan manufacturers and suppliers. This multidisciplinary team of chemists, toxicologists, medical doctors, pharmacists, investigators, communication specialists, and analytical lab staff coordinates across the FDA, and acts on the newest available information including tracking updates on the valsartan recall, diovan recall, and the FDA has also issued a valsartan generic recall list with the names of valsartan suppliers, valsartan manufacturers whose valsartan products are under recall and also another list of products which are not recalled. Find Valsartan Impurity related updates on PharmaCompass. The global recall alert is also applicable for valsartan combination drugs such as Diovan (Hydrochlorothiazide and Valsartan) and Entresto (Sacubitril and Valsartan). Follow all updates on the valsartan NDMA impurity problem through PharmaCompass so that you get all the updated information on time from trusted sources.
N-Nitrosodimethylamine (NDMA) impurity of valsartan, also known as dimethylnitrosamine, is a semi-volatile organic chemical (sartan impurity), produced as by-product of several industrial processes and present at very low levels in certain foodstuffs, especially those cooked, smoked, or cured. NDMA is water-soluble, yellow in color, and it has little or no taste and odor. N-Nitrosodimethylamine is toxic to the liver and other organs, and is a probable human carcinogen. It is also used to create cancer in rats for cancer research.
The valsartan impurity (NDMA) story began in June, when the drug company Prinston Pharmaceuticals raised the concern that its active pharmaceutical ingredient supplier, Zhejiang Huahai Pharmaceutical, found small but unacceptable amounts of N-nitrosodimethylamine (NDMA) impurity in the valsartan active pharmaceutical ingredient. The company alerted the FDA's Center for Drug Evaluation and Research (CDER).
Valsartan impurity Analytical Testing (NDMA) is found in water and some foods at trace levels, and is potentially carcinogenic. The next step for regulators was to find the companies affected by contaminated API and suggest product recalls.
While the cause of the impurity is not yet clear, the agency believes "a combination of conditions, which include certain chemicals, processing conditions and production steps, could lead to formation of the NDMA impurity Testing in valsartan. We believe that these risks are introduced through a specific sequence of steps in the manufacturing process of valsartan, where certain chemical reactions are needed to form the active ingredient."
The US Food and Drug Administration said it found an additional "unexpected Valsartan NDMA impurity " in three lots of Torrent Pharmaceuticals' recalled valsartan drug.
Several pills that contain valsartan, have been under a voluntary recall since July. The drugs were tainted with N-nitrosodimethylamine, or NDMA impurity Testing of valsartan that is considered a possible carcinogen by the US Environmental Protection Agency.
FDA said that three lots of the drugs made by Torrent Pharmaceuticals were contaminated with a second impurity, N-Nitrosodiethylamine in valsartan, or NDEA, which is also a suspected human carcinogen. The agency began testing the recalled products and the pills that have not been recalled for the substance after it learned that Zhejiang Huahai Pharmaceuticals found NDEA impurity in valsartan active ingredient.
What are the bioanalytical methods used in the development and validation of Valsartan?
Basically, Bioanalytical Method Validation (BMV) means the methods used to check and prove the validity or accuracy of chemical substances like Valsartan API. Global Bioanalytical Method Validation guidelines for Valsartan are applied to bioanalytical methods that are used for the quantitative determination of Valsartan generic forms or their metabolites to ensure that valsartan generic consumed as therapeutic products are free from valsartan impurities or valsartan related impurities. Valsartan Bioanalytical Method Validation guidelines are also applicable for the bioanalytical method validation of small molecules. Various process used in detecting valsartan impurities are Valsartan analytical methods, NDMA Analytical Testing.
Valsartan Impurity NDMA (N-Nitrosodimethylamine), a contaminant in water and meat samples, has recently been identified as a contaminant in valsartan API. NDMA Validation or NDMA impurity validation in valsartan. Its presence has to be regulated or tested as it is a probable human carcinogen which means the presence of NMDA in medicines poses risks of getting cancer. Since July 2018, there has been a global investigation into valsartan API production due to the detection of N-Nitrosodimethylamine in valsartan supplier like Zhejiang Huahai Pharmaceuticals, China.
The FDA and the European Medicines Agency reported that Zhejiang Huahai Pharmaceuticals (ZHP) had found Valsartan impurity NDEA in several batches of its valsartan API after which all global drug regulatory agencies immediately began retesting all valsartan API and Bioanalytical Method Validation documents to detect valsartan impurities or valsartan related impurities, including both recalled products and those currently marketed in the United States, for NDMA and nitrosodiethylamine (NDEA) impurities in valsartan. Post the alert, there has been an increased interest in valsartan lawsuits based on the investigation reports conducted on some of the marketed valsartan generic forms.
Various types of valsartan impurities are Valsartan Related Compound A, Valsartan Related Compound B, Valsartan Related Compound C and Valsartan Methyl Ester,Valsartan USP Impurity A, Valsartan USP Impurity B, Valsartan USP Impurity C, Valsartan Ethyl Ester etc.
N-Nitrosodimethylamine impurity (Valsartan Impurity NDMA) is a known environmental contaminant. For context, it is found in water and foods including meats, dairy products and vegetables. The removal of N-Nitrosodimethylamine (NDMA Testing or NDMA Analytical Impurity Testing) from water is extremely important step before it is used in the production of Valsartan API. As reported in this paper, “Metal-Catalyzed Reduction of N-Nitrosodimethylamine with Hydrogen in Water”, Environ. Sci. Technol. 40, 23, 7329-7335 the authors state that N-nitrosodimethylamine (NDMA) in water used in valsartan production like in drug sample prepared by valsartan manufacturers has to be destructed rapidly using stronger, more efficient methods because current alternative treatment methods are relatively inefficient.
Global pharmaceutical companies are now designing specific Valsartan Bioanalytical methods or Valsartan Impurity testing or NDMA method development for generic medicines following the global alert on Valsartan. Apart from ensuring GMP compliance and top-notch quality, pharmaceutical companies need to test high throughput active pharmaceutical ingredient samples for the presence of Valsartan NMDA or N-nitrosodiethylamine impurity (NDEA).
The FDA has presented a validated method for Valsartan generic forms are free of valsartan impurities. It is the gas chromatography-mass spectrometry (GC/MS) headspace method for manufacturers and regulators to utilize fully for detecting NMDA impurity. According to the latest method presented by FDA, out of other Bioanalytical Method Validation of Valsartan processes, specifically the GC/MS Headspace Method was selected for Detection of NDMA. The Valsartan Impurity N-nitrosodimethylamine (NMDA) investigation document states that Valsartan Impurity NMDA is an impurity which is classified as a probable human carcinogen and is believed to have been introduced into the finished products as a result of the manufacturing process of the drug substance. Valsartan validation service providers. The limit of Quantitation used in Valsartan impurity validated methods for detection of NMDA Valsartan impurity is 0.3 ppm. Hence, if the valsartan drug substance samples exceed this value or contain valsartan impurities, it presents a significant challenge in its utilization.
Bioanalytical validation methods of Valsartan Impurity play a significant role in evaluation and interpretation of bioavailability, bioequivalence, pharmacokinetic, and toxicokinetic studies. In which different parameters like accuracy, precision, selectivity, sensitivity, reproducibility, and stability are performed. Valsartan analytical methods, Valsartan Bioanalytical Method Development & Validation Service providers CROs / CDMOs have vast experience in Validated methods for Active Pharmaceutical Ingredients (APIs) for a variety of platforms including HPLC ( High Performance Liquid Chromatography ), RP-HPLC (Reverse Phase- High Performance Liquid Chromatography), RP-UPLC (Reverse Phase- Ultra Performance Liquid Chromatography), LC/MS/MS, GC/MS or GC/FID, ICP/MS, and ligand binding assays (ELISA or other cell-based assays). As both an in vivo and analytical CRO, they support bioanalytical method development & validation of valsartan services of a variety of Active Pharmaceutical Ingredients (APIs) / Drugs. Bioanalytical methods and validation studies for Valsartan are typically conducted under GLPs, where product release and stability tests follow GMP quality requirements.
NDMA method Development and validation or NDMA Validation is the process used to confirm that the analytical procedure employed for a specific test is suitable for its intended use. NDMA method Development and validation Results from method validation can be used to judge the quality, reliability and consistency of analytical results; it is an integral part of any good analytical practice. It is the process of defining an analytical requirement, NDMA Analytical and confirms that the method under consideration has performance capabilities of NDMA Characterization consistent with what the application requires. NDMA bioanalytical method Development and validation is within specification, working correctly and adequately calibrated is fundamental to the method validation process. NDMA Bioanalytical method development carrying out the studies by using NDMA Suppliers perform NDMA Testing Service Providers must be competent in the analysis and NDMA Characterization under study and have sufficient knowledge of the method/analysis to draw conclusions from the observations as the validation work proceeds by using NDMA Testing Service Providers. NDMA Bioanalytical method development is Quite often method validation evolves from method development and so the two activities are often closely tied, with the validation study employing the techniques and steps in the analysis NDMA Method development service providers as defined by the method development. Analytical methods need to be validated or revalidated. NDMA Validation Development and NDMA Analytical In many cases, methods are developed and validated in service laboratories that are specialized in this task. NDMA validated methods or validated methods for NDMA is critical tool for accessing valsartan. NDMA Process Development is the method is transferred to the routine analytical laboratory, care should be taken that the method and its critical parameters are well understood by the workers in the departments who apply the method NDMA Isolation and Identification. NDMA Process Development or A detailed validation protocol and NDMA Validation technique a documented procedure for method implementation and good communication between the development and operation departments are equally important. Valsartan method development and validation is an essential tool to process NDMA impurity assessment in a drug substance. ICH provides a guideline for NDMA testing or NDMA Analytical testing. NDMA Analysis or NDMA Valsartan Analysis is to be done in GMP/GLP certified laboratory where company has to perform NDMA testing by using NDMA analytical testing methods in valsartan by using NDMA bioanalytical methods. NDMA Bioanalytical method development is performed by using HPLC/LC-MS methods. NDMA contamination in valsartan is carcinogenic which has been found in studies done on Rat/Mice. FDA Recalls valsartans from vrious manufacturers due to presence of NDMA levels or NDMA impurity levels in valsartan. NDMA isolation or NDMA identification is needed for manufacturers to re-launch drug in market.
NDMA Validation Method, NDMA Isolation and Identification If the method is used by a number of departments, it is recommended to verify method validation parameters and to test the applicability and usability of the method in a couple of these departments before it is distributed to other departments. NDMA Isolation Technique, NDMA Validation technique In this way, problems can be identified and corrected before the method NDMA Identification is distributed to a larger audience. NDMA Isolation and Identification If the NDMA Analytical method is intended to be used by just one or two departments, an analyst from the development department should assist the users of the method during initial operation. NDMA Validation Development method should be encouraged to give constant feedback on the applicability and usability of the method to the development department. The latter should correct problems if any arise.
Validated routine methods NDMA Assay are transferred between laboratories at the same or different sites when contract laboratories offer services like NDMA Assay, NDMA Analytical Testing Assay for routine analysis in different areas or when products are manufactured in different areas. NDMA Testing Assay When validated routine methods are transferred between laboratories and sites, their validated state should be maintained to ensure the same reliable results in the receiving laboratory. NDMA impurity testing and NDMA Analytical Testing means the competence of the receiving laboratory to use the method should be demonstrated through tests, for example, repeat critical method validation experiments and run samples in parallel in the transferring and receiving laboratories.
Limit of Quantification (LOQ) Lower limit of quantification.
For Valsartan, the Development and Validation of RP-HPLC method for NDMA quantification and NDMA Purification including its NDMA validation technique for Pharmaceutical Formulations is of utmost importance. Research by KS Rao, N Jena, and MEB Rao (J Young Pharm. 2010 Apr-Jun; 2(2): 183–189) reported a stress testing method of valsartan carried out under acidic, alkaline, oxidative, thermal, and photolytic conditions. The authors presented a stability-indicating HPLC assay method used in the development and validation methods of valsartan in bulk drug and pharmaceutical dosage forms and to remove valsartan impurities. The valsartan impurity testing method was based on an isocratic RP-HPLC on Waters 2695 using Symmetry C18 (250mm × 4.6mm × 5?) column with the mobile phase consisting of 0.02 mM sodium dihydrogen ortho-phosphate, with the pH adjusted to 2.5 using ortho-phosphoric acid (solvent A), and acetonitrile (solvent B) in the ratio of 58:42 %v/v. NDMA validation for Valsartan analytical methods. NDMA validation or NDMA purification is proposed isocratic RP-HPLC method for Bioanalytical testing of Valsartan and Valsartan impurity testing was validated as per ICH guidelines and the authors found it to be suitable for the quality control of valsartan in bulk and pharmaceutical dosage forms as well as the stability-indicating studies.
As both an in vivo and analytical CRO, they support bioanalytical method development & validated methods of valsartan. Bioanalytical studies for Valsartan are typically conducted under GLPs, where product release and stability tests follow GMP quality requirements. NDMA Validated Methods which the requirements for valsartan purification processes can be discussed on a per-project basis so that the supplied valsartan API conforms to international standards and is ensured of free from valsartan impurities. Removal of NDMA and NMDA is one of the core processes involved in bioanalytical chromatographic methods of valsartan API production.
Bioanalytical testing techniques used in Validation of Valsartan: Commonly used Bioanalytical chromatographic methods in validation testing for Valsartan are as follows: Hyphenated techniques: A hyphenated technique is combination or coupling of two different analytical techniques with the help of proper interface. NDMA Validated Methods and Mainly chromatographic techniques are combined with spectroscopic techniques to ensure a validated method for valsartan purification is used, for e.g. LC–MS (liquid chromatography–mass spectrometry); GC–MS (gas chromatography–mass spectrometry); CE–MS (capillary electrophoresis–mass spectrometry) Liquid Chromatography-Mass Spectrometry (LC-MS/MS or LC-MS-MS): Bioanalytical liquid chromatography-mass spectrometry or Bioanalytical Mass
Spectrometry is a technique that uses liquid chromatography with the mass spectrometry. LC-MS or LC-MS-MS and rapid and sensitive high performance LC/MS/MS for valsartan is commonly used validated method for valsartan impurity testing in laboratories for the quantitative and qualitative estimation of Valsartan impurity, conduct additional analysis to check valsartan bioavailability and check the presence of valsartan related impurities. Valsartan analytical testing methods. LC-MS has played an important role in evaluation and interpretation of bioavailability, bioequivalence and pharmacokinetic details of Valsartan. NDMA Validated Methods which is also used in the quantitative analysis of valsartan impurities and in validation methods for valsartan.
The gas chromatography-mass spectrometry (GC/MS) method provided by FDA is being used in pharmaceutical companies and API manufacturing firms using the latest validated methods for ensuring the quality and accuracy of valsartan APIs. NDMA Analytical Method,Through LC-MS biological samples are determined throughout all phases of method development of NDMA and its salts in research and quality control. NDMA Levels in Valsartan and HPLC (high performance liquid chromatography) & Gas chromatography are also important for the analysis of valsartan drug substances.
Chromatographic separations and valsartan impurity testing using RP-HPLC and RP-UPLC methods are considered as rapid stability indicating methods which depend on the samples to be analyzed. The chromatographic procedure used during bioanalytical testing method for valsartan is important for the systemic approach to LC-MS/MS method development.
GAS CHROMATOGRAPHY-MASS SPECTROMETRY (GC-MS) Gas chromatography–mass spectrometry (GC-MS) is a method that combines the features of gas-liquid chromatography and mass spectrometry to identify different Valsartan salts within a test sample. Applications of GC-MS include drug detection, fire investigation, environmental analysis, NDMA Analytical Method, valsartan cancer risk testing, and Method Validation of Valsartan, valsartan impurity testing and also developing the same for other drug products. NDMA Analytical Testing or NDMA testing, The fundamental bioanalytical method validation parameters include precision and accuracy, sensitivity. Another innovative bioanalytical method validation technique is solid phase extraction bioanalysis or SPE bioanalysis. Valsartan analytical testing methods. NDMA Analytical Method or NDMA testing ,There are many optimization and validation studies on valsartan have been carried out for the assessment of SPE for Valsartan, including those for valsartan impurity testing and characterization. Valsartan impurity validation service providers. NDMA Analytical Method, A sensitive, specific bioanalytical method provided by Bioanalytical Service Providers is critical for a reliable pharmacokinetic experiment. A Bioanalytical Service Provider must ensure that all valsartan impurities have been removed and the API is up to the standards for therapeutic use.
Valsartan Impurity Testing involves Comparative assessment of bioanalytical method validation several different techniques such as Method Transfer of valsartan, Partial Validation of valsartan, and Cross Validation of bioanalytical methods for valsartan and other Chromatographic techniques, especially, high performance liquid chromatography (HPLC) for valsartan assay coupled with different detection systems like LC-MS/MS bioanalysis method development, valsartan analytical impurity testing methods, validation, and sample analysis and RP-HPLC and RP-UPLC techniques are some of the preferred techniques, routinely employed in bioanalytical laboratories as compared to any other method of analysis owing to their precision, accuracy, reliability and applicability to large-scale analysis. Valsartan Impurity Testing Companies. Valsartan Validation, the goal of Valsartan Impurity Testing is to determine whether the obtained data for valsartan impurity testing across different valsartan API samples are comparable. NDMA Validated Methods and Valsartan analytical impurity testing methods.ND Cross validation assay is another valsartan impurity testing process and also include method transfer techniques consists of analysis of quality control samples (either spiked, incurred samples, or both), assayed under the different experimental conditions or different sites with validated methods of Valsartan testing, as appropriate for ensuring minimal or absence of valsartan cancer risk.
What are the Essential Attributes of Bioanalytical Methods used in the Development and Validation of Valsartan API?
Limit of detection (LOD) and limit of quantification (LOQ) are two important performance characteristics in bioanalytical method validation. Limit of Quantification (LOQ) - the detection limit, lower limit of detection, or LOD, is the lowest quantity of a substance that can be distinguished from the absence of that substance according to a standard confidence level. Valsartan Impurity Testingand NDMA testing Services. Method validation service providers.The estimation of baseline noise can be quite difficult for bioanalytical validation methods, if matrix peaks elute close to the analyte peak.
Upper limit of quantification (ULOQ)
The upper limit of quantification (ULOQ) is the maximum analyte concentration of a sample that can be quantified with acceptable precision and accuracy (bias). Bioanalytical method companies.In general, the ULOQ value of Valsartan is identical with the concentration of the highest calibration standard and becomes an important reference point for valsartan validation process.
The same set of samples for Valsartan API should be measured by both analytical sites or using the two different Bioanalytical methods. NDMA Analytical Testing and NDMA method Development and validation, As notified by the FDA, cross validation should be performed in advance of study samples being analyzed in valsartan samples so that valsartan impurities are removed in the primary steps of manufacturing in small throughput and large throughput samples. NDMA Analytical Testing, It is recommended that the following rationale should be used in deciding how best to perform the cross validation method for valsartan or NDMA Validated Methods.
Valsartan NDMA impurity can be detected using both gas and liquid chromatography. Global pharmaceutical companies perform a wide variety of NDMA
impurity testing methods and validated methods for valsartan on numerous valsartan products to take care of all valsartan impurity testing challenges and comply with international Bioanalytical NDMA method validation guidelines of valsartan, NDMA testing or NDMA Validated Methods a validated method for valsatan analysis is Quality By Design(QbD) development of bioanalytical method is a novel method for the analysis of drug products extensively used in the industries for removal of valsartan impurities.
High performance liquid chromatography (HPLC) is one of the most accurate methods widely used for the quantitative & qualitative analysis of Valsartan to remove valsartan impurities. Valsartan impurity testing and is used for determining Valsartan stability. Stability indicating HPLC methods are used to separate various drug related impurities that are formed during the synthesis or manufacture of Valsartan. NDMA Analytical testing During bulk drug manufacturing of valsartan, tackling the presence of valsartan impurities can be challenging as the valsartan intermediates have complex chemical structures whose effects may not be known. NDMA Validated Methods and Method validation service providers. Various research laboratories are pursuing in-depth characterizations on Valsartan impurities NDMA and NMDA and NDEA to understand the Valsartan impurities structure, Valsartan impurities physical and chemical properties and the cytotoxic effects of Valsartan impurities on clinical samples. Other research groups are conducting studies on refining valsartan impurity testing methods.
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