STUDY SUBMISSION AND DRUG REVIEW

PROCESS

WWW.DULOMIX.COM 1

❖The contents of New Drug Applications (NDAs) and Abbreviated New Drug Applications

(ANDAs) are similar in terms of the quality of manufacture (Table 16-14).

❖ The submission for an NDA must contain safety and efficacy studies as provided by

animal toxicology studies, clinical efficacy studies, and pharmacokinetic/bioavailability

studies. For the generic drug manufacturer, the bioequivalence study is the pivotal study in

the ANDA that replaces the animal, clinical, and pharmacokinetic studies.

WWW.DULOMIX.COM 2

➢The investigator should be sure that the study has been properly designed, the objectives
are clearly defined, and the method of analysis has been validated (ie, shown to measure
precisely and accurately the plasma drug concentration).

➢The results are analyzed both statistically and pharmacokinetically

➢These results, along with case reports and various data supporting the validity of the
analytical method, are included in the submission.

➢ If necessary, an FDA investigator may inspect both the clinical and analytical facilities
used in the study and audit the raw data used in support of the bioavailability study.

➢For ANDA applications, the FDA Office of Generic Drugs reviews the entire ANDA as
shown in below Fig.

➢ If the application is incomplete, the FDA will not review the submission and the
sponsor will receive a Refusal to File letter.

WWW.DULOMIX.COM 3

WWW.DULOMIX.COM 4

WWW.DULOMIX.COM 5

WWW.DULOMIX.COM 6

THE BIOPHARMACEUTICS

CLASSIFICATION SYSTEM (BCS)

WWW.DULOMIX.COM 7

THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM (BCS)

• The BCS is 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. These factors are 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

WWW.DULOMIX.COM 8

• A theoretical basis for correlating in vitro drug dissolution with in vivo bioavailability

was developed by Amidon et al (1995). This approach is based on the aqueous solubility

of the drug and the permeation of the drug through the gastrointestinal tract. The

classification system is based on Fick’s first law applied to a membrane:

Jw=PwCw

where Jw is the drug flux (mass/area/time) through the intestinal wall at any position and

time, Pw is the permeability of the membrane, and Cw is the drug concentration at the

intestinal membrane surface.

This approach assumes that no other components in the formulation affect the membrane

permeability and/or intestinal transport.

WWW.DULOMIX.COM 9

For regulatory purposes, drugs are classified according to the BCS in accordance with the solubility,

permeability, and dissolution characteristics of the drug (US-FDA, CDER, 2000b).

Solubility

• An objective of the BCS approach is to determine the equilibrium solubility of a drug under

approximate physiologic conditions. For this purpose, determination of pH–solubility profiles over

a pH range of 1–8 is suggested.

• The solubility class is determined by calculating what volume of an aqueous medium is sufficient to

dissolve the highest anticipated dose strength.

• A drug substance is considered highly soluble when the highest dose strength is soluble in 250 mL

or less of aqueous medium over the pH range 1–8. The volume estimate of 250 mL is derived from

typical bioequivalence study protocols that prescribe administration of a drug product to fasting

humanW vWoWl.DuULnOtMeIXe.COrsM with a glass (8 oz) of water. 10

Permeability
• Studies of the extent of absorption in humans, or intestinal permeability methods, can be used to

determine the permeability class membership of a drug.

• To be classified as highly permeable, a test drug should have an extent of absorption >90% in
humans. Supportive information on permeability characteristics of the drug substance should also
be derived from its physical–chemical properties (eg, octanol: water partition coefficient).

• Some methods to determine the permeability of a drug from the gastrointestinal tract include

(1) in vivo intestinal perfusion studies in humans;

(2) in vivo or in situ intestinal perfusion studies in animals;

(3) in vitro permeation experiments using excised human or animal intestinal tissues; and

(4) in vitro permeation experiments across a monolayer of cultured human intestinal cells. When
using these methods, the experimental permeability data should correlate with the known extent-of-
absorption data in humans.

• After oral drug administration, in vivo permeability can be affected by the effects of efflux and
absorpWtWivWe.D UtLrOaMInX.CsOpMorters in the gastrointestinal tract, by food, and possibly by the various exci1p1 ients
present in the formulation.

Dissolution

• The dissolution class is based on the in vitro dissolution rate of an IR drug product under

specified test conditions and is intended to indicate rapid in vivo dissolution in relation to

the average rate of gastric emptying in humans under fasting conditions.

• An IR drug product is considered rapidly dissolving when not less than 85% of the label

amount of drug substance dissolves within 30 minutes using USP Apparatus I (see Chapter

14) at 100 rpm or Apparatus II at 50 rpm in a volume of 900 mL or less in each of the

following media: (1) acidic media such as 0.1 N HCl or simulated gastric fluid USP

without enzymes, (2) a pH 4.5 buffer, and (3) a pH 6.8 buffer or simulated intestinal fluid

USP without enzymes.

• The FDA is in the process of revising the BCS guidance to permit biowaivers for generic

formulations of Class 3 drugs (Mehta, 2014).
WWW.DULOMIX.COM 12

Biopharmaceutics Drug Disposition Classification System

• The major aspects of BCS are the consideration of solubility and permeation.

• According to BCS, permeability in vivo is considered high when the active drug is systemically

absorbed ≥90%.

• Wu and Benet (2005) and Benet et al (2008) have proposed modification of the BCS system

known as the Biopharmaceutics Drug Disposition Classification System (BDDCS), which takes

into account drug metabolism (hepatic clearance) and transporters in the gastrointestinal tract for

drugs that are orally administered.

• For BCS 1 drugs (ie, high solubility and high permeability), transporter effects will be minimal.

• However, BCS 2 drugs (low solubility and high permeability), transporter effects are more

important. These investigators suggest that the BCS should be modified on the basis of the extent

of drug metabolism, overall drug disposition, including routes of drug elimination and the effects
WWW.DULOMIX.COM 13

of efflux, and absorptive transporters on oral drug absorption.

REFERENCES

Applied Biopharmaceutics and Pharmacokinetics, 7th edition

Basic pharmacokinetics-Sunil Jambekar

WWW.DULOMIX.COM 14

WWW.DULOMIX.COM 15