Bcs Classification Database
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To provide sponsors of new drug submissions with the information necessary to comply with Division 8 of the Food and Drug Regulations ( Regulations) with respect to Biopharmaceutics Classification System (BCS) based biowaivers for comparative bioavailability studies to be used in support of the safety and efficacy of a drug. This information is applicable to all submission types where comparative bioavailability studies would normally provide pivotal evidence in support of the safety and efficacy of a product. In vivo human data collected for the purpose of submission to Health Canada should be collected in accordance with generally accepted clinical practices that are designed to ensure the protection of the rights, safety and well-being of subjects. They should be collected in compliance with the good clinical practices referred to in Division 5 of the Regulations and described in the International Conference on Harmonisation (ICH) Guidance (Topic E6) on Good Clinical Practice. The principles of Good Manufacturing Practice as indicated in Part C, Division 2 of the Regulations should be adhered to wherever applicable. Absorption - the uptake of substance from a solution into or across tissues. Absorption can include passive diffusion, facilitated passive diffusion (with a carrier molecule), and active transport.
Critical dose drug - drugs where comparatively small differences in dose or concentration lead to dose- and concentration-dependent, serious therapeutic failures and/or serious adverse drug reactions which may be persistent, irreversible, slowly reversible, or life threatening, which could result in hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, or death. Adverse reactions that require significant medical intervention to prevent one of these outcomes are also considered to be serious. See Health Canada guidance document Comparative Bioavailability Standards: Formulations Used for Systemic Effects (22 May 2012) Dose solubility volume (DSV) - the highest therapeutic dose (milligrams) divided by the solubility of the substance milligrams/millilitres (mg/mL) at a given pH and temperature. For example, if a drug substance has a solubility of 31 mg/mL at pH 4.5 (37°C) and the highest dose is 500 mg, then DSV = 500 mg / 31 mg/mL = 16 mL at pH 4.5 (37°C). Highest dose - the highest approved therapeutic dose for the drug substance in Canada.
If not currently approved in Canada, the highest proposed dose is applicable. Rapidly dissolving product - a product in which not less than 85% of the labelled amount is released within 30 minutes or less during a product dissolution test under the conditions specified in this guidance.
Very rapidly dissolving product - not less than 85% of the labelled amount is released within 15 minutes or less during a product dissolution test under the conditions specified in this guidance. High solubility: A drug substance is classified as highly soluble if the highest therapeutic dose of the drug substance is completely soluble in 250 mL or less of aqueous media over the pH range of 1.2-6.8 at 37 ± 1°C, that is ( i.e.)., DSV less than or equal to (≤) 250 mL over the pH range. Low solubility: A drug substance is classified as a low solubility compound if the highest therapeutic dose of the drug substance is not completely soluble in 250 mL of aqueous media at any pH within the pH range of 1.2-6.8 at 37 ± 1°C, i.e., DSV greater than 250 mL at any pH within the range.
Absolute bioavailability studies: Studies comparing the bioavailability of at least the highest dose of the drug substance from an orally administered aqueous solution, or an immediate-release tablet or capsule without excipients that are known to affect absorption, with an intravenous dose. The extent of absorption should be measured through serial blood sampling using a sampling protocol designed to characterize at least 80% of the area under the time-plasma concentration curve to infinity (AUC I).
The study population should be properly characterized and a sufficient number of volunteers should be included in order to obtain a reliable estimate of absolute bioavailability. Mass balance studies: Mass balance studies are conducted to determine the disposition of a drug substance following oral administration. For the purposes of assessing absorption, quantification of the parent compound excreted in the urine, as well as Phase 1 oxidative and Phase 2 conjugative metabolites excreted in the urine or feces can be used. The parent compound excreted in faeces, or metabolites produced through reduction or hydrolysis should not be included due to uncertainty of their origin unless the sponsor can demonstrate that those metabolites did not result from degradation or metabolism in the gut prior to absorption.
Mass balance data will support the classification of a highly absorbed drug substance if the sum of the urinary recovery of the parent compound and the urinary and fecal recovery of Phase 1 oxidative and Phase 2 conjugative metabolites of the parent compound account for greater than or equal to (≥) 85% of the administered dose. Mass balance studies used to establish extent of absorption should be designed to thoroughly characterize the in vivo disposition of the drug substance in a sufficient number of volunteers to obtain meaningful estimates. The product is a low dose form, when the tablet/capsule strength is 5 mg or lower and/or the drug substance forms 2% weight per weight (w/w) or less of the total mass of the tablet/capsule content; or. When the chosen manufacturing process is prone to variability and/or scale-up difficulties ( e.g. Direct compression process for manufacturing a low dose product); complex ( e.g. Use of coating technology to add the drug substance to inert granules, lyophilisation, microencapsulation); and/or uses new technologies ( e.g.
Well-established excipients in usual amounts should be employed in the proposed drug product. A description of the function and a justification for the relative amount of each excipient is required. Excipients that might affect the bioavailability of the drug substance e.g., mannitol, sorbitol, or surfactants, should be identified. These critical excipients should not differ qualitatively or quantitatively between the test product and reference product and should be within 10% of the amount measured in the reference product batch(es) used in comparative testing.
Amount: One unit of the strength for which a biowaiver is requested Methodology: Basket apparatus (USP I) or paddle apparatus (USP II) Agitation: Basket apparatus at 100 revolutions per minute (rpm) or paddle apparatus at 50 rpm (if coning is observed for both Test and Reference products, speed may be increased, for example, to 75 rpm. However results with the lower speed should also be reported). Dissolution media: Aqueous buffers at pH 1.0 - 1.2, 4.5, and 6.8 Volume of media: ≤ 900 mL Sampling times: For example, 5, 10, 15, 20 and 30 minutes Temperature of media: 37 ± 1°C Replicates: Not less than 12 units per batch per pH medium. At least 12 units should be used for each profile determination.
Mean dissolution values can be used to estimate the similarity factor, f2. To use mean data, the percent coefficient of variation at the earlier point should be not more than 20% and at other time points should be not more than 10%.
Because f2 values are sensitive to the number of dissolution time points, only one measurement should be included after 85% dissolution of the test and reference products. Compilation of historical data is not acceptable. When equivalence to a reference product for one strength in a series of strengths is established on the basis of a BCS-based biowaiver, a waiver from the requirement for conducting studies with other strengths cannot then be granted based on the proportionality principles as described in the TPD policy Bioequivalence of Proportional Formulations - Solid Oral Dosage Forms (1996). Other strengths in the product line should conform to the requirements for a BCS-based biowaiver in comparison to the pharmaceutically equivalent reference product of the same strength. The sponsor shall provide complete information on the critical quality attributes of the drug substance and finished product for both the test and reference product including, but not limited to: polymorphic form and enantiomeric purity; and any information on bioavailability or bioequivalence problems with the substance or drug product, including literature surveys and sponsor derived studies. All study protocols including standards, quality assurance and testing methods should be appropriately detailed and validated according to current regulatory guidance's and policies. A full description of the analytical methods employed, including validation, should be provided.
A detailed description of all test methods and solutions, including test and reference batch information unit dose (mg and%), batch number, manufacturing date and batch size where known, expiry date, and any comments examined is required. The dissolution report should also include information on the dissolution conditions such as apparatus, de-aeration, filtration process during sampling, volume, etcetera. The drug substance is identical to that in reference product. The drug substance is not a critical dose drug. The drug substance should be BCS class I or III.
Highest therapeutic single dose is soluble in 250 mL aqueous media between pH 1.2 and 6.8. For class I requirements: At least 85% of highest therapeutic oral dose absorbed, based on absolute bioavailability determination in humans or mass balance data. Data from in vitro models considered supportive in estimating extent of absorption.
For class III requirements: Less than 85% of highest therapeutic oral dose absorbed, based on absolute bioavailability determination in humans or mass balance data. Data from in vitro models considered supportive in estimating extent of absorption.
Product contains BCS Class I or III drug substance, which is identical to that in the reference product. Immediate-release, solid oral pharmaceutical drug product, with no buccal or sublingual absorption, intended to deliver drug to the systemic circulation.
Dosage form is the same as the reference dosage form. Fixed-dose combination products may be eligible for a biowaiver when all drug substances contained in the product and the product itself meet the defined criteria. A biowaiver for an individual drug component in a fixed-dose combination product may be justified if these criteria are met and there is no interaction between the drugs in the combination product. Batches tested for biowaiver should meet the same requirements that a biobatch is expected to meet (that is, as in in vivo studies).
For higher risk products, at least one commercial scale batch should be tested and meet the biowaiver requirements. Higher risk drug products include those made with potent drugs (drug substance is ≤ 2% w/w of total mass of dosage form) and those with known difficulties in scale-up or which use complex or new technologies in their manufacture. Excipients:. For products with BCS class I drug substances, excipients affecting bioavailability should be same as in reference product. For products with BCS class III drug substances, excipients should be qualitatively the same and quantitatively very similar to the reference product.
In aqueous media at pH 1.2, 4.5 and 6.8, the test and reference products should be very rapidly dissolving for products containing BCS Class III drug substances, and either very rapidly or similarly rapidly dissolving for products containing BCS Class I drug substances.
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.
Bcs Classification System Database
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.