Drug Metabolite Impurities, Pathways & Analytical Techniques

 Metabolites are the intermediate products of metabolic reactions catalyzed by various enzymes that naturally occur within cells. The term metabolite is usually used for small molecules.

Metabolites forms may be integral or pharmacological and formed during the natural biochemical process of degrading and eliminating the compounds from chemical compounds. It is important to know how the drug products are metabolized and what are its probable side effects. e.g. Sugars are metabolites into fructose or glucose, which are both present in the metabolic pathways.

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Evaluation of Photodegradation Pathways

 Photostability study provides useful information about the handling and packing of drug substance and drug products.

Most of the drug substances are light-sensitive hence during formulation it may degrade at the time of processing, manufacturing, and storage. Due to photodegradation, there may be a chance loss of potency, impact on efficiency, and harmful biological properties.

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Patenting in the Indian Pharmaceutical Industry

 Indian Pharmaceutical Industry is considered highly progressive in the field of drug manufacturing and technology. Today India has the global presence in the field of generic drugs and hence protecting the new drugs combinations and its process by means of intellectual property rights (IPR).

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Impurity Profiling in Drug Development

 Impurities in pharmaceuticals are unwanted chemicals that remain with the active pharmaceutical ingredients (APIs) or develop during formulation or upon aging of both API and formulation. In the pharmaceutical industry, an impurity is considered as any other inorganic or organic material, or residual solvents other than the drug substances, or ingredients, that arise out of synthesis or unwanted chemicals that remains with APIs. The presence of these unwanted chemicals even in trace amount may influence the efficacy and safety of pharmaceutical product.

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Forced Degradation Studies for Drug Substances and Drug Products- A Regulatory Considerations

 Various regulatory guidance is available which provides useful definitions and general comments about degradation studies. However, guidance concerning the scope, timing, degradation condition, and best practices for degradation studies is very general. Various issues related to stress testing are addressed in numerous guidance documents but not always in the context of stress testing. Therefore, stress-testing conditions should be realistic and not excessive.

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Potential Impurities in Drug Substance & Drug Products

 Potential impurities are the substance which are formed during the reaction or already present in the form of starting materials, by-products, or intermediate products. Potential Impurities have no therapeutic value and are potentially harmful.  Therefore, they need to be controlled.

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Nitrosamine Impurities Trace in Metformin

 Metformin is a prescription drug used to control high blood sugar in patients with type 2 diabetes. The Regulatory agency announced that traces of Nitrosamine present in generic drug substances and drug products, further FDA and EMA investigation also led to the detection of these Nitrosamine impurities in low levels of NDMA impurity in Metformin.

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Nitrosamine Impurity: A Regulatory Perspective

 

The Regulatory agency announced that Nitrosamine impurities N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) are said to be present in generic drug substances and drug product, especially in angiotensin II receptor blockers (ARBs) and belong to a family of analog compounds referred to as the sartans. Further FDA and EMA investigation also led to the detection of these Nitrosamine impurities in Pioglitazone and the low level of NDMA impurity found in Metformin.

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Nitrosamine Impurities Traces in Ranitidine

 Ranitidine is a histamine-2 blocker, which decreases the amount of acid created by the stomach. Prescription ranitidine is approved for multiple indications, including treatment and prevention of ulcers of the stomach and intestines and treatment of gastroesophageal reflux disease. The FDA and EMA investigation also led to the detection of N-nitrosodimethylamine (NDMA) levels in some Ranitidine products.

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Good Manufacturing Practice (GMP) Considerations for Responding to COVID-19 Infection in Employees in Drug & Biological Products Manufacturing

 In June 2020, FDA released Guidance for Industry (GFI) entitled “Good Manufacturing Practice Considerations for Responding to COVID-19 Infection in Employees in Drug and Biological Products Manufacturing”. FDA is issuing this guidance to provide recommendations to drug and biological product manufacturers regarding:

• Manufacturing controls to prevent contamination of drugs,
• Risk assessment of SARS-CoV-2 as it relates to drug safety or quality,
• Continuity of manufacturing operations.
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EMA Issues Guidance to Avoid Nitrosamine Impurities

 European Medicines Agency’s (EMA) issues guidance to avoid Nitrosamine in human medicines. EMA continue to monitor the presence of nitrosamine impurities in medicines, in co-operation with regulators from outside the European Union (EU), and to work with marketing authorisation holders to find rapid solutions to address any adverse findings. EMA carried out a review Article 5(3) from September 2019 to June 2020, the guidance to marketing authorisation holders, how to avoid the presence of nitrosamine impurities in human medicines. The CHMP has asked marketing  authorisation holders to review their medicines for the possible presence of nitrosamines and test all products at risk, as mentioned in theguidance and review their manufacturing processes to identify and, if necessary, mitigate the risk of presence of nitrosamine impurities in three steps. The European medicines regulatory network has agreed to extend the deadline to complete step 1  to 1^st October 2020.This follows reports of the challenges encountered in meeting the original deadline of 26 March 2020, and the impact of the severe restrictions in place to combat the COVID-19 pandemic. The European medicines regulatory encourages marketing authorisation holders to submit the outcome of step 1 before 1^st October 2020 if they complete the risk evaluation or identify a risk in their products. Marketing authorisation holders should inform the national competent authorities as soon as possible if tests confirm the presence of nitrosamine, irrespective of the amount detected, assess the immediate risk to patients to take appropriate action to avoid or minimise the exposure of patients to nitrosamines. The European medicines regulatory network plans to complete this exercise by 26 September 2022.

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Genotoxic Potential Alert Chemical Structures

 Chemical structures are helpful to plan to classify compounds into their types that will alert them to potential material. The computer software’s e.g., MultiCASE’s M case, Accelrys’s Topcat, or LHASA’s DEREK is available for forecasting the probable toxicity of drug impurities on the basis of it is chemical structure. It is predictive and may not be factual, they will give hint of which one would be confirmed from the toxicity studies. Performing Ames bacterial mutagenicity testing after software provides a structural alert. Results from the Ames test are considered more definitive than the in silico data.

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The Role of Patents in the Pharmaceutical Industry

 

The pharmaceutical industry has a major role in the past decades in developing new technology in the field of product and process development. Further technology advancement in the pharmaceutical field developed new life-saving drugs and to protect the inventions Intellectual property rights IPR has played a significant role. The term “Intellectual Property Rights” refers to the legal rights granted with the aim to protect the creations of the intellect. These rights include Industrial Property Rights e.g. Patents, Industrial Designs, Trademarks, and Copyright.

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Recent update on Nitrosamine Impurities by EP and US Pharmacopoeia

 

The European Pharmacopoeia (Ph. Eur.) published its new general chapter on the analysis of N-nitrosamine impurities inactive substances (2.4.36) for a 3-month public consultation in Pharmeuropa 32.2. The closing date for public comments was 30th June 2020. Given the exceptional circumstances due to the COVID-19 pandemic, would like to remind stakeholders to provide comments before the end of June to contact their respective national pharmacopeia Authority (NPA) or the EDQM as soon as possible so as to announce their intent to comment. The general chapter on the analysis of N-nitrosamine impurities inactive substances (2.4.36) will remain available in the Pharmeuropa archives issue 32.2 and comments to be sent no later than 31^st August 2020, comments after this date will be too late for consideration.

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Chemistry for The Formation of Nitrosamines

 Nitrosamines, or more correctly N-nitrosamines, refer to any molecule containing the nitroso functional group. These molecules are of concern because nitrosamine impurities are probable human carcinogens. Although they are also present in some foods and drinking water supplies, their presence in medicines is nonetheless considered unacceptable.

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Veeprho’s Exclusive Services – Impurity Isolation and Purification

  Isolation and Purification of Known and Unknown Impurities from milligram to gram scale, which is performed by our talented team of scientists who always provide high quality products. We have executed most critical isolation and purification projects from drug product, API and structure elucidation of the appropriate project.

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Synthesis, Isolation, & Characterisation of Impurities

 

Synthesis of impurity with the predicted structure is tough and it may involve multistep synthesis. Hence for the synthesis of complex structures impurity, systematic and thoughtful consideration was involving. In-depth route design and scouting exercise performed. A systematic literature search using search tools such as SciFinder, Beilstein, and online access to most of the international journals in chemistry.

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Overview & Determination of Enantiomeric Impurities

 

An enantiomer can be named by the direction in which it rotates the plane of polarized light. An optical isomer can be named by the spatial configuration of its atoms. Clockwise rotation of the light traveling toward the viewer is labelled (+) or R (in Latin Rectus for right) also termed as d-isomer i.e. dextrorotatory enantiomer. Its mirror-image is labelled (−) or S (in Latin Sinister for left) also termed as l-isomer i.e. levorotatory enantiomer. 

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Peptides and Probable Degradation Pathways

 These are naturally occurring biological molecules. peptides are made up of smaller molecular sequences of amino acids. When a molecule consists of 2 to 50 amino acids it is called a peptide. They are classified by the number of amino acid components in the sequence, called amino acid residues. Tripeptides have three amino acid residues while tetrapeptides have four. A polypeptide is formed when the chain of amino acid links exceeds several dozen in length.

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Elemental Impurities in Pharmaceutical Products

 Elemental impurities in drug substance and drug products may arise from several sources; they may be residual catalysts that were added intentionally in the synthesis or may be present as impurities (e.g., through interactions with processing equipment or container/closure systems or by being present in components of the drug product). Elemental impurities do not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled within acceptable limits. Long term exposure even to low concentrations of impurities can cause many adverse health effects and even toxicity.

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Use of DSC in Pharmaceuticals Drug Characterisation

 Differential scanning calorimetry (DSC) measures the difference between the heat flow to the sample and the reference pan that flows undergo with a controlled temperature program. Heat flow corresponds to transmitted power and is estimated in watts (W). The change in enthalpy after absorbing the energy is term as an endothermic reaction and when the sample releases the energy is termed as an exothermic reaction.

Different thermal events measured by DSC such as crystallization, the onset of oxidation, melting, cure reaction, and heats of transitions i.e. enthalpy.

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Residual Solvents in Pharmaceuticals

 Numerous organic solvents were utilized in the synthesis of drug substances or drug products. These organic solvents have poisonous properties also harmful to the environment. During manufacturing, it’s very difficult to get rid of organic solvents completely from the finished product. If organic solvents aren’t removed completely from the finished product then the quality and safety of the product is at risk and finally unsafe to the consumer.

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The Role of Total Quality Management (TQM)

 Total Quality Management (TQM) is a management approach for an organization to continuously improve the quality of the manufactured products and to have long term success through customer satisfaction. TQM is a strategic management tool that can be used for improving the competitiveness, effectiveness, and flexibility of the whole organization and to survive in the increasingly competitive market.TQM is a multidimensional approach that essentially requires adherence to all quality practices in the areas of pharmaceutical products like Quality by design (QbD), Quality risk management (QRM), and six sigma, etc along with the regulatory guidelines. 

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Analytical Balance – Working Range

 Analytical balances are the key instrument of quantitative analysis. It is used to accurately weighing of samples and standards. it is one of the primary activities of the analysis. The balances are able to provide accurate measurements. Due to the extremely sensitive nature of these instruments, there are several factors that can cause them to give erroneous readings.

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Review on Mass Balance

 Mass balance in the pharmaceutical analysis is very much important. It is representing the degradative losses of parent drug compare well with the measured increase in the degradation products. Equally, if one observes, for example, a 10% loss of parent drug but only measures a 2 % increase in degradation products, it is expected that additional degradation products formed are not accurately determined by the present method(s).

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Reference Standards, Types, Uses, Preparation & Qualification:

 

A reference standard material is defined as highly purified compound that is well characterized by FDA (US Food and Drug Administration) or company or laboratory. Reference standards are highly characterized specimens of drug substances, excipients, reportable impurities, degradation products, compendial reagents, and performance calibrators by USP (US Pharmacopeia). Reference standards are used to determine quantitative data (such as assay and impurity), qualitative data (such as identification test), and calibration (such as melting point standard). Therefore, the quality and purity of the reference standards are crucial to achieve scientifically valid results

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Review on Drug Master File (DMF)

 Drug master file (DMF) is a submission to Food and Drug and Administration (FDA) and is a kind of confidential document which contains detailed information about the facilities, processes, manufacturing, processing, packaging, and storing of human drug products. In DMF the details mentioned may be used to support an (IND) Investigational New Drug Application,( NDA) New Drug Application, (ANDA) Abbreviated New Drug Application.

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Separation of Closely Eluting Impurities by Selecting Appropriate Stationary Phase

 

HPLC column is the heart of HPLC hence selecting the appropriate stationary phase is the most important part of method development. The selection of the stationary phase plays an important role in selectivity. There are numbers of regulatory queries on the inappropriate resolution between closely eluting impurity hence it is important to develop the suitable stability-indicating analytical method. There are more complex drug products hence analytical scientists need to develop the specific, accurate, precise and robust method to attain the optimum resolution between closely eluting impurities.  Adequate resolution and recovery between the closely eluting peaks are the definitive goals for good chromatography. The resolution, means the distance between the center of two peaks measured by the retention time or volume divided by the average width of the individual peaks.

USFDA recommends the resolution should be more than 2. If there are closely eluting peaks in the method then it is essential to give minimum resolution criteria between the two peaks.

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