ICH M9: Biopharmaceutics Classification System-based Biowaivers On October 19, 2016, the International Council for Harmonisation (ICH) has announced a new guideline, M9: Biopharmaceutics Classification System (BCS)-based Biowaivers, providing recommendations to support the biopharmaceutics classification of medicinal products. The Biopharmaceutics Classification System (BCS) is a system classifying a drug substance (API) based on its minimum aqueous solubility in the pH range of 1–7.5, dose and human fraction absorbed or intestinal membrane permeability. The Biopharmaceutics Classification System (BCS) is the result of continuous efforts in mathematical analysis for the elucidation of the kinetics and dynamics of the drug process in the gastrointestinal tract (GIT) for NDA (New Drug Application) and ANDA (Abbreviated New Drug Application) filings and biowaivers. Bcs classification system • 1. BIOPHARMACEUTICS CLASSIFICATION SYSTEM • Contents• Introduction• Overview of the Classification system• Applications• Conclusion• References • Introduction ۞Biopharmaceutics Classification System (BCS)♥ Scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability What is the need for a classification based on biopharmaceutics of the drug? Its importance in determining bioavailability • ORAL ROUTE♠ Route of choice for the formulators Continues to dominate the area of drug delivery technologies. LIMITATIONS Absorption and Bioavailability in the milieu of gastrointestinal tract. Limitations more prominent with the advent of protein and peptide drugs compounds emerging as a result of combinatorial chemistry and the technique of high throughput screening • API structure salt form and excipients Bioavailability of drug is determined byextent of drug solubility and permeability drug solubility drug product quality attributes • Biopharmaceutics Classification System Guidance provided by the U.S. Food and Drug Administration for predicting the intestinal drug absorption The fundamental basis established by Dr. Gordon Amidon Distinguished Science Award (Aug ’06,FIP) First introduced into regulatory decision-making process in the guidance document on Immediate Release Solid Oral Dosage Forms: Scale Up And Post Approval Changes • Drug development tool that allows estimation of the contributions of 3 major factors, that affect oral drug absorption from immediate release solid oral dosage forms Dissolution Solubility Intestinal permeability. Bcs classification system • 1. BIOPHARMACEUTICS CLASSIFICATION SYSTEM • Contents• Introduction• Overview of the Classification system• Applications• Conclusion• References • Introduction ۞Biopharmaceutics Classification System (BCS)♥ Scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability What is the need for a classification based on biopharmaceutics of the drug? Its importance in determining bioavailability • ORAL ROUTE♠ Route of choice for the formulators Continues to dominate the area of drug delivery technologies. LIMITATIONS Absorption and Bioavailability in the milieu of gastrointestinal tract. Limitations more prominent with the advent of protein and peptide drugs compounds emerging as a result of combinatorial chemistry and the technique of high throughput screening • API structure salt form and excipients Bioavailability of drug is determined byextent of drug solubility and permeability drug solubility drug product quality attributes • Biopharmaceutics Classification System Guidance provided by the U.S. Food and Drug Administration for predicting the intestinal drug absorption The fundamental basis established by Dr. Gordon Amidon Distinguished Science Award (Aug ’06,FIP) First introduced into regulatory decision-making process in the guidance document on Immediate Release Solid Oral Dosage Forms: Scale Up And Post Approval Changes • Drug development tool that allows estimation of the contributions of 3 major factors, that affect oral drug absorption from immediate release solid oral dosage forms Dissolution Solubility Intestinal permeability. INTRODUCTION The FDA’s Biopharmaceutics Classification System(BCS) is based on the work of Amidon and coworkers with the core idea being that in vitro methodology, centrally embracing permeability and solubility, with qualifications related to pH and dissolution, may qualify drug products for a waiver of in vivo bioequivalence studies. The objective of the BCS is to predict in vivo performance of drug products from in vitro measurements of permeability and solubility. In 2005, Wu and Benet recognized that for drugs exhibiting high intestinal permeability rates the major route of elimination in humans was via metabolism, while drugs exhibiting poor intestinal permeability rates were primarily eliminated in humans as unchanged drug in the urine and bile. They proposed that a biopharmaceutics drug disposition classification system (BDDCS) could serve as a basis for predicting the importance of transporters in determining drug disposition, as well as in predicting drug-drug interactions. The major differences between BCS and BDDCS relate to their purpose and the measurement for classification as depicted in. The purpose of BCS is to characterize drugs for which products of those drugs may be eligible for a biowaiver of in vivo bioequivalence studies. The purpose of BDDCS is to predict drug disposition and potential drug-drug interactions in the intestine and the liver, and potentially the kidney and brain. Both BCS and BDDCS use solubility as one of the two classification criteria. The solubility parameter utilized may be called the FDA solubility, that is, an estimate of the ability of the drug at its highest dose strength to completely dissolve in 250 ml of water over a pH range between 1 and 7.5 at 37°C. For a drug to be considered highly soluble in the two classification systems, the drug from its highest strength regulatory approved dosage form must go completely into solution at its lowest solubility over this pH range in 250 ml of water. As we have recently noted, FDA solubility is a property of the drug in a formulation and is not an intrinsic property of the active pharmaceutical ingredient itself. Abcd 2 full movie mp4 download 2015. The second classification parameter, and where the two systems differ, is related to intestinal permeability. Who Bcs ClassificationIn BDDCS, predictions are based on intestinal permeability rate, which was found to be related to extent of drug metabolism. In BCS, biowaivers are based on the extent of intestinal absorption, which in a number of cases does not correlate with intestinal permeability rate. THE BCS AND ITS USE IN DRUG DEVELOPMENT The BCS characterizes drugs into four classes according to their FDA solubility and permeability as depicted in. In 2000, the FDA promulgated the BCS system as a science-based approach to allow waiver of in vivo bioavailability and bioequivalence testing of immediate-release solid oral dosage forms for Class 1 high solubility, high permeability drugs when such drug products also exhibited rapid dissolution. This waiver is based on a triple-tier rationale where: a) high solubility insures that drug solubility will not limit dissolution, and thus absorption, b) high permeability insures that drug is completely absorbed during the limited transit time through the small intestine, and c) rapid dissolution insures that the gastric emptying process is the rate-limiting step for absorption of highly soluble and highly permeable drugs. Drug sponsors are allowed to use mass balance, absolute bioavailability, or human intestinal perfusion studies to demonstrate high permeability. The FDA Guidance, however, also recommends possible methods not involving human subjects including in vivo or in situ intestinal perfusion in a suitable animal model, and/or in vitro permeability methods using excised intestinal tissues or monolayers of suitable epithelial cells,, usually the Caco-2 cell system. However, some studies have shown that in vitro cellular permeability criteria recognized in the FDA’s BCS guidance may not always correctly predict the extent of drug absorption in humans –. The Biopharmaceutics Classification System (BCS) as defined by the FDA after Amidon et al. In 2010, the European Medicine’s Agency (EMA) revised its bioequivalence guideline stating that demonstration of complete absorption in humans is preferred for biowaiver of BCS Class 1 drug applications rather than measures of high permeability. The criteria for complete absorption in the EMA Guidline is ≥85% measured extent of absorption in humans based either upon absolute bioavailability or mass balance studies. The correlation between intestinal permeability rate and the extent of absorption in humans came from the results of in vivo studies with 34 drugs and endogenous substances, where a good correlation was observed between jejunal permeability from human intestinal perfusion studies and the fraction of the oral dose absorbed in humans. However, in these early human intestinal perfusion studies, no drugs were investigated that subsequently showed a discordance between cellular system permeability rates and the extent of absorption in humans. It is now generally recognized by the FDA, the EMA and the research scientists in the field that high cellular permeability rates do correctly predict a high extent of absorption.
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