biopharmaceuticals classification system and biowaiver
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The Biopharmaceutical Classification System (BCS) categorizes drug substances based on aqueous solubility and intestinal permeability to aid in drug development and in vivo pharmacokinetics predictions. The FDA guidelines expand the application of BCS and allow for biowaivers—exemptions from costly bioavailability and bioequivalence studies—for certain drug formulations, particularly immediate-release oral dosages that meet specific solubility and permeability criteria. BCS classification comprises four classes, each indicating varying levels of permeability and solubility, ultimately affecting drug absorption and development strategies.
biopharmaceuticals classification system and biowaiver
- 1. NOTES ON BCS AND BIOWAIVER Introduction The Biopharmaceutical classification system (BCS) is a scientific framework for classifying a drug substance based on its aqueous solubility and intestinal permeability. The BCS is a useful tool for decision making in the discovery and early development of new drug. It allows for the prediction of in vivo pharmacokinetics of oral immediate-release (IR) drug products by classifying drug compounds into four classes based on their solubility related to dose and intestinal permeability in combination with the dissolution properties of the dosage form. Biopharmaceutical Classification System (BCS) guidance was provided by US Food and Drug Administration (FDA), to improve the efficiency of drug product development process. The Biopharmaceutical Classification System (BCS) is a system to differentiate the drugs on the basis of their solubility and permeability. It is a guide for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration. BCS is based on scientific framework describing three rate limiting steps in oral absorption. The three necessary steps for a drug to be absorbed are: (1) Release of drug from dosage forms; (2) Maintenance of dissolved state through Gastro-intestinal (G.I) tract; (3) Permeation through G.I. membrane into hepatic circulation. Concept behind BCS The in-vivo performance of orally administered drugs depends upon their solubility and tissue permeability characteristics. The release rate or solubility of the drug substance will not be a parameter if the absorption of the drug is permeation rate limited and in such cases the in vitro dissolution study can be used to demonstrate the bioavailability (BA) or bioequivalence (BE) of the drug product through in vitro - in vivo correlation (IVIVC). On the other hand if absorption of the drug is dissolution rate limited that means the drug in the gastrointestinal fluid passes freely through the bio-membranes at a rate higher than it dissolves or is released from the dosage form. The specifically designed in-vivo study will be required in such a case, to access the absorption rate, and hence its bioavailability and to demonstrate the
- 2. bioequivalence ultimately. Such a drug substance is a good candidate for controlled delivery provided they qualify in terms of their pharmacokinetics and pharmacodynamics for controlled release development. Also if a drug itself is having low solubility and a slow dissolution rate, the release will automatically get slower and the dosage form need not have an in-built release retardation mechanism, rather the absorption will now be governed by the gastric emptying rate. Therefore, the dosage form must be able to restrain within the absorption window for a sufficient time so that absorption can take place. In such case, a hydro-dynamically balanced (floating) system or a mucoadhesive dosage form will serve the purpose. Hence the BCS can work as guiding tool for the development of various oral drug delivery technologies. Purpose of the BCS Guidance 1. Expands the regulatory application of the BCS and recommends methods for classifying drugs. 2. Explains when a waiver for in vivo bioavailability and bioequivalence studies may be requested based on the approach of BCS. Objective of BCS 1. To improve the efficiency of the drug development and review process by recommending a strategy for identifying expendable clinical bioequivalence test. 2. To recommend a class of immediate-release (IR) solid oral dosage forms for which bioequivalence may be assessed based on in vitro dissolution tests. 3. To recommend methods for classification according to dosage form dissolution along with the solubility–permeability characteristics of the drug product. Classes of Biopharmaceutical Classification System
- 3. Class I - High Permeability, High Solubility: Those compounds are well absorbed and their absorption rate is usually higher than excretion. The drugs of this class exhibit high absorption number and high dissolution number. The rate-limiting step is drug dissolution, and if dissolution is very rapid, then the gastric-emptying rate becomes the rate-determining step. They dissolverapidly when presented in immediate release form, and are also transported across the gut wall. Class II – High Permeability, Low Solubility: These drugs have a high absorption number but a low dissolution number. In vivo drug dissolution is then a rate limiting step for absorption except at a very high dose number. These drug exhibited variable bioavailability and need the enhancement in dissolution for increasing the bioavailability. These compounds are suitable for design the SR and CR formulations. In vitro- in vivo correlation (IVIVC) is usually expected for class II drugs. Class III - Low Permeability, High Solubility: The absorption is limited by the permeation rate but the drug is solvated very fast. Drug permeability is the rate-limiting step for drug absorption, but the drug is solvated very quickly. These drugs exhibit a high variation in the rate and extent. of drug absorption. Since the dissolution is rapid, the variation is attributable to alteration of physiology and membrane permeability rather than the dosage form factors. Class IV - Low Permeability, Low Solubility: Those compounds have a poor bioavailability. Usually they are not well absorbed over the intestinal mucosa and a high variability is expected.The drugs of this class are problematic for effective oral administration. Fortunately, extreme examples of Class IV compounds are the exception rather than the rule, and these are rarely developed and marketed. Examples of Drugs belonging to different Classes of BCS Class I: Chloroquine, Diltiazem, Metoprolol, Paracetamol, Propranolol, Theophylline Class II: Carbamezapine, Danazol, Glibenclamide, Ketoconazole, Nifedipine, Phenytoin Class III: Acyclovir, Atenolol, Captopril, Cimetidine, Metformin, Ranitidine Class IV: Cyclosporin A, Furosemide, Ritonavir, Saquinavir, Taxol, Ellagic acid Parameters of BCS The drugs are classified in BCS on the basis of following parameters: 1. Solubility 2. Permeability 3. Dissolution The class boundaries for the parameters are: Solubility class boundaries- It is based on the highest dose strength of an
- 4. immediate release product. A drug is considered highly soluble when the highest dose strength is soluble in 250 ml or less of aqueous media over the pH range of 1 to 7.5. The volume estimate of 250 ml is derived from typical bioequivalence study protocols that prescribe administration of a drug product to fasting human volunteers with a glass of water. Permeability class boundaries- It is based indirectly on the extent of absorption of a drug substance in humans and directly on the measurement of rates of mass transfer across human intestinal membrane. Alternatively non- human systems capable of predicting drug absorption in humans can be used (such as in-vitro culture methods). A drug substance is considered highly permeable when the extent of absorption in humans is determined to be 90 % or more of the administered dose based on a mass-balance determination or in comparison to an intravenous dose. Dissolution class boundaries- An immediate release product is considered rapidly dissolving when no less than 85 % of the labelled amount of the drug substance dissolves within 15 minutes using USP Dissolution Apparatus - I at 100 RPM or Apparatus - II at 50 RPM in a volume of900 ml or less in the following media: 0.1 NHCl or simulated gastric fluid or pH 4.5 buffer andpH 6.8 buffer or simulated intestinal fluid. Drug Properties that determine BCS classification
- 5. BCS Biowaiver The term biowaiver is applied to a regulatory drug approval process when the dossier (application) is approved based on evidence of equivalence other than through in vivoequivalence testing. Biowaiver means to obtain waive off for carrying out expensive and time consuming BA and BE studies. A biowaiver has been regarded as an official approval of the waiver for conducting a bioequivalence study in the context of an application for drug approval process. The BCS-based biowaivers apply during pre- (IND/ NDA and ANDA) and post approval phases. BCS-based biowaivers are applicable for immediate-release solid oral dosage formulations containing one or more of the API(s) mentioned above if the required data ensure the similarity of the submitted pharmaceutical product and the appropriate pharmaceutically equivalent comparator product. BCS- based biowaiver has become an important and cost-saving tool in approval of generic drugs. Criteria for BCS based biowaiver Biowaiver are based on the Biopharmaceutics (BCS) classification of the active ingredient. Currently BCS class I and some class III compounds are eligible for biowaivers. • The drug substance should be highly soluble and highly permeable. • An IR drug product should be rapidly dissolving. • The drug should not be a narrow therapeutic index drug. • Excipients used in the dosage form should have been used previously in FDA approved IR solid dosage forms. • For waivers of an in vivo relative bioavailability study, dissolution should be greater than 85% in 30 min in the three recommended dissolution media (acidic media, such as 0.1 N HCl or Simulated Gastric Fluid USP without enzymes, a pH 4.5 buffer; and a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes). For waivers of in vivo bioequivalence, test and reference products should exhibit similar dissolution profiles under the dissolution test conditions defined for rapidly dissolving products. Two dissolution profiles may be considered similar when compared using the f2 metric (f2 > 50) .When both the test and the reference products dissolve 85 % or more of the label amount in < 15 minutes, in all three dissolution media recommended above, a profile comparison is unnecessary. Exceptions BCS-based biowaivers are not applicable for the following: 1) Narrow Therapeutic index: This guidance defines narrow therapeutic range drug products as those containing certain drug substances that are subject to
- 6. therapeutic drug concentration or pharmacodynamic monitoring, and/or where product labelling indicates a narrow therapeutic range designation. Examples include digoxin, lithium, phenytoin, theophylline, and warfarin. Because not all drugs subject to therapeutic drug concentration or pharmacodynamic monitoring are narrow therapeutic range drugs, applicant should contact the appropriate review division to determine whether a drug should be considered to have a narrow therapeutic range. 2) Products Designed to be Absorbed in the Oral Cavity: A request for a waiver of in-vivo BA/BE studies based on the BCS is not appropriate for dosage forms intended for absorption in the oral cavity (e.g., sublingual or buccal tablets)