Pharma Analytical

Chemical stability of pharmaceutical molecules is most important as it has impact on the safety and efficacy of the drug products. Stress testing or forced degradation is an analytical tool to study  the behaviour of the products as well as to understand the resolving power of  the analytical method used. Stress testing reveals the quality of  pharmaceutical products exposed over the time period as well as different environmental conditions viz.,  heat, hydrolysis, oxidation, photolytic etc. ICH guideline defines stress testing as: Studies undertaken to elucidate the intrinsic stability of the drug substance. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing. Stress studies provides more valuable information about the degradation impurities, called as degradants, which are likely to form during the shelf life of the product lifecycle in a very short period compared to...

Data integrity is one of the most talked in the pharmaceutical industries in the recent past as regulators have issued  multiple FDA Warning Letters and EU GMP Noncompliance Reports about the failures of  integrity of key electronic records. Good practices like documentation, record keeping and data integrity are the  essential components  of the quality system in a GMP environment to protect and ensure the quality of the product and hence  safety of the patient. FDA has focused intensely on  data integrity issues since 2010 and issued  many warning letters to pharmaceutical companies  related to poor electronic data integrity. The warning letters issued  to drug manufacturers related to data integrity were 2 in 2010, 8 in 2013, 12 in 2014, 13 in 2015, 16 in 2016 etc and is increasing continuously. The deficiencies found in recent cases of electronic data integrity are 1. Disabling of software audit trail functions 2. Inadequate user privileg...

The concept of quality by design (QbD) in pharmaceutical industry has been introduced to enhance robust manufacturing process and to facilitate product quality. Quality is built in the product and process by design and scientific approach. As the number of  out-of-trend (OOT) results, out-of-specification (OOS) results are increasing in pharmaceutical industry and the current quality system is unable to address the growing concern,  a strategy to make a robust manufacturing process is felt and a cocept if QbD has emerged. FDA has implemented the QbD concept first in drug formulation manufacturing processes as the finished drug products are directly consumed by the patients and any variation in the quality will adversaly affect the safety of the patients. Similar to robust product development, an equally important analytical methods employed to test the quality of product must be robust and capable of producing accurate results.  The benefits of implementing AQbD are 1.con...

Impurities are any organic material besides the drug substances and excipients that may be present as an unwanted guest in the drugs.  The presence of these impurities even in small amounts may influence the efficacy and safety of the drug products.  Hence ICH, International Council on Harmonization, framed guidelines for identification, reporting and qualification levels of these impurities in different forms of the drugs as mentioned below.  1. Impurities in New Drug Substances in Q3A (R2) 2. Impurities in New Drug Products in  Q3B (R2) 3. Guideline for Residual Solvents in Q3C (R5) 4. Guideline for Elemental Impurities in Q3D These guidelines are adopted by US, Europe and Japanese Regulatory authorities.  ICH provides detailed information of acceptable level of impurities in the drugs based on maximum daily dosage calculated per day. Beyond certain level, the drug cannot be approved as such by the Regulatory agencies.  Regulatory agencies basically look...

Elemental impurities are traces of metals carried from raw materials, residual catalysts, manufacturing equipments, process water, excipients, containers that can be observed in finished drug products.  These elemental impurities do not have any therapeutic effect  and is harmful to patients due to their toxicity beyond certain limit. The presence of trace elements were tested classically by using USP's Heavy metals test,  <231> , which uses as a colorimetry test by forming as a sulphide precepitate with elements. In the last decade, PDE (permitted daily exposure) of almost all elements are found which leads to monitor and  control the individual elements in the drugs by measuring their level by using modern instruments like ICP OES, ICP MS etc. ICH developed a  guideline specifically on Elemental impurities as Q3D and list the PDE values for each element. Based on PDE value and the route of administration ( orals, parenteral, nasal)  values are diffe...

History of Nitrosamine Impurities In July 2018, USFDA has alerted healthcare professionals  to   withdraw the drug, valsartan, from the market due to the presence of   an impurity, N-nitrosodimethylamine (NDMA). This impurity is highly toxic and is considered as  a "probable human  carcinogen"  meaning it can cause cancer.  Nitrosamines are classified by the ICH M7(R1) Guideline as Class 1 impurities, “ known mutagenic carcinogens ,” based on both rodent carcinogenicity and mutagenicity data Other Nitrosamine Impurities The investigation of NDMA in valsartan leads to the  detection of some more nitrosamine impurities in  drugs viz., N-nitrosodiethylamine (NDEA), N -nitrosodiisopropylamine (NDIPA), N – nitrosoethylisopropylamine (NEIPA), N -nitroso-N-methyl-4-aminobutyric acid (NMBA) etc. Mechanism of Formation Nitrosamines are formed when nitrites, which can be formed from nitrates, react with a secondary or tertiary amine to p...