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Definitions of Terms

Agglomerates: Agglomerates consist of large particles formed by the joining or binding together of primary particles whose original identity can still be visible in the final agglomerate form.

Apparatus 1: A rotating mesh (40 mesh standard) basket in a hemispherical vessel.

Apparatus 2: A rotating paddle in a hemispherical vessel.

Apparatus 3: A reciprocating cylinder in a cylindrical vessel.

Apparatus 4: A media flow through cell.

Apparatus 5: A rotating paddle over a disk in a hemispherical vessel.

Apparatus 6: A rotating cylinder in a hemispherical vessel.

Apparatus 7: A reciprocating holder in a cylindrical vessel.( disk, cylinder, pointed rod, spring holder, angled disk)

Batch: A specific quantity of a drug or other material produced according to a single manufacturing order during the same cycle of manufacture and intended to have uniform character and quality, within specified limits (21 CFR 210.3(b)(2)).

Batch formula (composition): A complete list of the ingredients and their amounts to be used for the manufacture of a representative batch of the drug product. All ingredients should be included in the batch formula whether or not they remain in the finished product (Guideline for Submitting Documentation for the Manufacture of and Controls for Drug Products, FDA February 1987).

Bioavailability: The rate and extent to which the active drug ingredient or therapeutic moiety is absorbed from a drug product and becomes available at the site of drug action (21 CFR 320.1(a)).

Biobatch: A lot of drug product formulated for purposes of pharmacokinetic evaluation in a bioavailability/bioequivalency study. This lot should be 10% or greater than the proposed commercial production batch or at least 100,000 units, whichever is greater.

Bioequivalent drug products: Pharmaceutical equivalents or pharmaceutical alternatives whose rate and extent of absorption do not show a significant difference when administered at the same molar dose of the therapeutic moiety under similar experimental conditions, either single dose or multiple dose. Some pharmaceutical equivalents or pharmaceutical alternatives may be equivalent in the extent of their absorption but not in their rate of absorption and yet may be considered bioequivalent because such differences in the rate of absorption are intentional and are reflected in the labeling, are not essential to the attainment of effective body drug concentrations on chronic use, or are considered medically insignificant for the particular drug product studied (21 CFR 320.1(e)).

Biopharmaceutics classification system: a scientific framework for classifying drug substances based on their aqueous solubility and intestinal permeability. When combined with the dissolution of the drug product, the BCS takes into account three major factors that govern the rate and extent of drug absorption from IR solid oral dosage forms: dissolution, solubility, and intestinal permeability. According to the BCS, drug substances are classified as follows:

Class 1: High Solubility – High Permeability

Class 2: Low Solubility – High Permeability

Class 3: High Solubility – Low Permeability

Class 4: Low Solubility – Low Permeability

In addition, IR solid oral dosage forms are categorized as having rapid or slow dissolution. Within this framework, when certain criteria are met, the BCS can be used as a drug development tool to help sponsors justify requests for biowaivers

CR: Controlled release.

Convolution: Prediction of plasma drug concentrations using a mathematical model based on the convolution integral.

Correlation: As used in this guidance, a relationship between in vitro dissolution rate and in vivo input (absorption) rate. 21

Deaggregation: The state in which small aggregates are no longer intact.

Deconvolution: Estimation of the time course of drug input (usually in vivo absorption or dissolution) using a mathematical model based on the convolution integral.

Development: Establishing an in vitro/in vivo correlation.

Drug product: A finished dosage form, e.g., tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients (21 CFR 314.3(b)).

Disintegration: The state in which the dose form is no longer intact except for small aggregates.

Disintegration test: USP .

DR: Delayed release.

ER: Extended release.

Extended release dosage form: A dosage form that allows a reduction in dosing frequency as compared to that presented by a conventional dosage form, e.g., a solution or an immediate release dosage form.

Evaluation: In the context of in vitro/in vivo correlation, a broad term encompassing experimental and statistical techniques used during development and evaluation of a correlation which aid in determining the predictability of the correlation.

F2: A similarity factor used to compare multipoint dissolution profiles.

Formulation: A listing of the ingredients and composition of the dosage form.

In vitro/in vivo correlation: A predictive mathematical model describing the relationship between an in vitro property of an extended release dosage form (usually the rate or extent of drug dissolution or release) and a relevant in vivo response, e.g., plasma drug concentration or amount of drug absorbed.

In vivo dissolution: The process of dissolution of drug in the gastro-intestinal tract. In vitro release: Drug dissolution (release) from a dosage form as measured in an in vitro dissolution apparatus.

In vivo release: In vivo dissolution of drug from a dosage form as determined by deconvolution of data obtained from pharmacokinetic studies in humans (patients or healthy volunteers).

Level A correlation: A predictive mathematical model for the relationship between the entire in vitro dissolution/release time course and the entire in vivo response time course, e.g., the time course of plasma drug concentration or amount of drug absorbed.

Level B correlation: A predictive mathematical model for the relationship between summary parameters that characterize the in vitro and in vivo time courses, e.g., models that relate the mean in vitro dissolution time to the mean in vivo dissolution time, the mean in vitro dissolution MDT vitro ‘ I 4 o (M 4 & M(t)) dt M 4 23 time to the mean residence time in vivo, or the in vitro dissolution rate constant to the absorption rate constant.

Level C correlation: A predictive mathematical model of the relationship between the amount dissolved in vitro at a particular time (or the time required for in vitro dissolution of a fixed percent of the dose, e.g., T %) and a summary parameter that characterizes the in vivo time 50 course (e.g., C or AUC). Max.

Lot: A batch, or a specific identified portion of a batch, having uniform character and quality within specified limits or, in the case of a drug product produced by continuous process, a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits (21 CFR 210.3(b)(10)).

Mean absorption time: The mean time required for drug to reach systemic circulation from the time of drug administration. This term commonly refers to the mean time involved in the in vivo release and absorption processes as they occur in the input compartment and is estimated as MAT = MRT – MRT oral i.v.

Mean in vitro dissolution time: The mean time for the drug to dissolve under in vitro dissolution conditions.

Mean residence time: The mean time that the drug resides in the body. MRT may also be the mean transit time. MRT = AUMC/AUC. Narrow therapeutic index drugs: Drugs having, for example, less than a two-fold difference in the minimum toxic concentrations and the minimum effective concentrations (21 CFR 320.33 (c)).

MR: Modified release.

Nonrelease controlling excipient (noncritical compositional variable): An inactive ingredient in the final dosage form that does not significantly affect the release of the active drug substance.

Occluded: Drug substance that is not collected or analyzed due to adsorption, absorption, and containment in the dosage form.

Occlusion: The point in a dissolution profile in which drug substance is no longer is released into the media.

Occultation: The point in a dissolution profile in which drug substance release rate is slowing to the occlusion point.

PCA: Principle Component Analysis.

PLS: Partial Least Squares regression analysis.

PR: Prolonged release.

Predictability: Verification of the model’s ability to describe in vivo bioavailability results from a test set of in vitro data (external predictability) as well as from the data that was used to develop the correlation (internal predictability).

Percent prediction error: %PE = [(Observed value - Predicted value) / Observed value] x 100

Release controlling excipient (critical compositional variable): An inactive ingredient in the final dosage form that functions primarily to extend the release of the active drug substance from the dosage form.

Release mechanism: The process by which the drug substance is released from the dosage form. Release rate: Amount of drug released per unit of time as defined by in vitro or in vivo testing. Statistical moments: Parameters that describe the characteristics of the time courses of plasma concentration (area, mean residence time, and variance of mean residence time) and of urinary excretion rate.

SR: Sustained release.


Literature Cited: Guidance for Industry: Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations, U.S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), September 1997, BP 2

Dissolution Discussion Group, Volume 1, A user’s perspective on Dissolution.

Guidance for Industry. Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. U.S. Department of Health and Human Services. Food and Drug Administration,Center for Drug Evaluation and Research (CDER), August 2000, BP

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