Wednesday, October 7, 2015
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)).
Convolution: Prediction of plasma drug concentrations using a mathematical model based on the convolution integral. For example, the following convolution integral equation may be used to predict the plasma concentration (c(t)) resulting from the absorption rate time course (r ): abs c(t) = I0 c* (t-u) rabs(u) du t The function c represents the concentration time course that would result from the instantaneous * absorption of a unit amount of drug and can be estimated from either i.v. bolus data, oral solution, suspension or rapidly releasing (in vivo) immediate release dosage forms.
Correlation: As used in this guidance, a relationship between in vitro dissolution rate and in vivo input (absorption) rate.
Deconvolution: Estimation of the time course of drug input (usually in vivo absorption or dissolution) using a mathematical model based on the convolution integral. For example, the 22 absorption rate time course (rabs) that resulted in the plasma concentrations (c(t)) may be estimated by solving the following convolution integral equation for r : abs c(t) = I0 c* (t-u) rabs(u) du t The function c represents the concentration time course that would result from the instantaneous * absorption of a unit amount of drug and is typically estimated from either i.v. bolus data, oral solution, suspension or rapidly releasing (in vivo) immediate release dosage forms.
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)).
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.
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 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., T50%) and a summary parameter that characterizes the in vivo time course (e.g., Cmax or AUC)
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 = MRToral - MRTi.v
Mean in vivo dissolution time: For a solid dosage form: MDT = MRT - MRT . This solid solid solution reflects the mean time for drug to dissolve in vivo.
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)).
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 from the dosage form.
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.
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)).
Convolution: Prediction of plasma drug concentrations using a mathematical model based on the convolution integral. For example, the following convolution integral equation may be used to predict the plasma concentration (c(t)) resulting from the absorption rate time course (r ): abs c(t) = I0 c* (t-u) rabs(u) du t The function c represents the concentration time course that would result from the instantaneous * absorption of a unit amount of drug and can be estimated from either i.v. bolus data, oral solution, suspension or rapidly releasing (in vivo) immediate release dosage forms.
Correlation: As used in this guidance, a relationship between in vitro dissolution rate and in vivo input (absorption) rate.
Deconvolution: Estimation of the time course of drug input (usually in vivo absorption or dissolution) using a mathematical model based on the convolution integral. For example, the 22 absorption rate time course (rabs) that resulted in the plasma concentrations (c(t)) may be estimated by solving the following convolution integral equation for r : abs c(t) = I0 c* (t-u) rabs(u) du t The function c represents the concentration time course that would result from the instantaneous * absorption of a unit amount of drug and is typically estimated from either i.v. bolus data, oral solution, suspension or rapidly releasing (in vivo) immediate release dosage forms.
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)).
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.
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 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., T50%) and a summary parameter that characterizes the in vivo time course (e.g., Cmax or AUC)
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 = MRToral - MRTi.v
Mean in vivo dissolution time: For a solid dosage form: MDT = MRT - MRT . This solid solid solution reflects the mean time for drug to dissolve in vivo.
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)).
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 from the dosage form.
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.
