REGULATORY GUIDELINES FOR DISSOLUTION TESTING OF IR DOSAGE FORMS

:

REGULATORY GUIDELINES FOR DISSOLUTION TESTING OF IR SOLID ORAL DOSAGE FORMS pavan devineni KVSR SCOPS

Introduction:

Introduction This guidance is developed for IR dosage forms and is intended to provide… General recommendations for dissolution testing Approaches for setting dissolution specifications related to biopharmaceutical characteristics of the drug substance Statistical methods for comparing dissolution profiles A process to help in determining when dissolution testing is sufficient to grant a waiver for an in vivo bioequivalence study

Introduction:

Introduction Provides recommendations for dissolution tests that help in ensuring continuous drug product quality and performance after post approval changes This document is intended to complement… IR-scale-up and post-approval changes Chemistry , manufacturing & controls In-vitro dissolution testing In-vivo bioequivalence documentation

Background:

Background Drug absorption from a solid dosage form after oral administration depends on…. release of drug substance from drug product dissolution or solubilization of the drug under physiological conditions permeability across the GIT Basing on this criteria, in-vitro dissolution studies may be relevant to the prediction of in-vivo performance of drug product

Background:

Background In-vitro dissolution tests for IR solid oral dosage forms are used to; assess the lot-to-lot quality of a drug product Guide development of new formulations Ensure continuing product quality and performance after certain changes in formulation , manufacturing processes , site of manufacture etc. solubility , permeability , dissolution and pharmacokinetic parameters of drug product should also be considered in defining dissolution test specifications

Biopharmaceutics classification system:

Biopharmaceutics classification system Based on drug solubility and permeability , the following BCS is recommended; Case-1 : High solubility-High permeability drugs Case-2 : Low solubility-High permeability drugs Case-3 : High solubility-Low permeability dugs Case-4 : Low solubility-Low permeability drugs This classification can be used as a basis for setting dissolution specifications and also to achieve IVIVC

Slide 7:

BCS suggests the RLS for different cases as follows; Case-1 : gastric emptying Case-2 : drug dissolution Case-3 : permeability of drug Case-4 : both dissolution and permeability Class-4 drugs cause significant problems for oral drug delivery

Setting dissolution specifications:

Setting dissolution specifications For NDA’s The dissolution specifications should be based on acceptable clinical , pivotal bioavailability and/or bioequivalence batches For ANDA’s/AADA’s The performance of acceptable bioequivalence batches of drug product

Slide 9:

Three categories of dissolution test specifications for IR drug products are described in this guidance Single-point specifications Routine quality control tests(for highly soluble and rapidly dissolving drugs) Two-point specifications 1. For characterizing the quality of drug product 2. Routine quality control tests(for slow dissolving or poorly water soluble drug products) Dissolution profile comparison 1. For accepting product sameness under supac - related changes

Slide 10:

2. To waive bioequivalence requirements for lower strengths of dosage form 3. To support waivers for other bioequivalence requirements In future , a two-point assay may be useful , both to characterize a drug product & serve as quality control specification

Approaches for setting dissolution specifications for a new chemical entity:

Approaches for setting dissolution specifications for a new chemical entity The dissolution characteristics of the drug product should be developed based on consideration of the pH solubility profile and pKa of the drug substance The partition coefficient may be useful in selecting the dissolution methodology and specifications The dissolution specifications are established in consultation with biopharmaceutics and CMC review staff

Slide 12:

If the formulation intended to be marketed differs from drug product used in clinical trials , dissolution & bioequivalence studies between 2 formulations are recommended Dissolution testing should be carried out under mild test conditions in basket method(50/100rpm) or paddle method(50/75rpm) , at 15 min interval For rapidly dissolving products , generation of an adequate sampling at 5-10 min interval may be necessary

Slide 13:

For BCS class 1 & 3 drugs- single-point dissolution test specification of NLT 85% (Q=80%) in 60 minutes or less is recommended For BCS class 2 drugs- two-point dissolution specifications , one at 15 mts (dissolution range) and other at a later point (30,45,60) to ensure 85% dissolution is recommended The product is expected to comply with dissolution specifications throughout its shelf life

Approaches for setting dissolution specifications for generic products:

Approaches for setting dissolution specifications for generic products USP drug product dissolution test available A dissolution profile at 15 min interval or less using USP method for test and reference products(12 units each) is recommended USP drug product dissolution test not available , dissolution test for reference listed NDA drug product available A dissolution profile at 15 min intervals or less is recommended for the reference and test products(12 units each)

Slide 15:

USP drug product dissolution test not available , dissolution test for reference listed NDA drug product not available Comparative dissolution testing using test and reference products under a variety of test conditions is recommended(different dissolution media , apparatus 1 & 2 , agitation speeds)

Special cases:

Special cases Two-point dissolution test For poorly water soluble drug products , dissolution testing at more than one time point is recommended to ensure in-vivo product performance Two-tiered dissolution test Two-tiered dissolution testing in simulated gastric fluid with or without pepsin or simulated intestinal fluid with or without pancreatin is recommended to ensure batch to batch product quality

Mapping or response surface methodology :

Mapping or response surface methodology Mapping is defined as a process for determining the relationship between CMV and a response surface derived from an in vitro dissolution profile and an in vivo bioavailability data set CMV includes changes in formulation , process , equipment , materials , and methods for the drug product that can significantly affect in vitro dissolution The goal is to develop product specifications that will ensure bioequivalence of future batches prepared within the limits of acceptable dissolution specifications Several experimental designs are available to study the influence of CMV on product performance

Slide 18:

One approach to study and evaluate the mapping process includes; 1. Prepare 2 or more dosage formulations using CMV to study their in vitro dissolution characteristics 2. Test the products with fastest and slowest dissolution characteristics along with the standard or the to be marketed dosage form 3. Determine bioavailability of the products and in-vitro-in-vivo correlation The products with extreme range of dissolution characteristics are found to be bioequivalent to the standard or to be marketed dosage form , future batches with dissolution characteristics between these ranges should be equivalent to one another

In vitro-In vivo correlation:

In vitro-In vivo correlation For highly water soluble IR products using currently available excipients and manufacturing technology , an IVIVC may not be possible For poorly water soluble products , it is possible Dissolution as a quality control tool for predicting in-vivo performance of a drug product is significantly enhanced if an IVIVC is established To achieve IVIVC , at least 3 batches that differ in the in-vivo as well as in-vitro performance should be AVAILABLE If the batches show differences in in-vivo performance , in-vitro test conditions are modified to correspond with in-vitro data to establish IVIVC If no changes are observed in in-vivo performance of batches , and if the in-vitro performance is different , the test conditions are modified to achieve same dissolution profiles.

Validation & verification of specifications:

Validation & verification of specifications Confirmation by in-vivo studies need validation of an in-vivo system Two batches with different in-vitro profiles should be prepared , tested in-vivo If the 2 products show different in-vivo characteristics , then system is validated If not results are interpreted as verifying the dissolution specifications Thus either validation or verification of dissolution specifications has to be confirmed

Dissolution & SUPAC-IR:

Dissolution & SUPAC-IR The SUPAC-IR guidance defines the levels of changes , recommended tests and documentation to ensure product quality and performance of reference and test in: components & composition site of manufacturing scale of manufacturing process & equipment changes Depending on level of changes , SUPAC-IR guidance recommends different levels of in-vitro dissolution test or in-vivo bioequivalence tests For formulation changes , additional dissolution testing in several media is recommended For process and manufacturing site changes , only dissolution testing is sufficient

Slide 22:

This guidance recommends dissolution profile comparisons to ensure PRODUCT SAMENESS between reference and test Biowaivers In addition to regular quality control tests , comparative dissolution tests have been used to waive bioequivalence requirements for lower strengths of a dosage form For biowaivers , a dissolution profile should be generated and evaluated Biowaivers are generally provided for multiple strengths after approval of BE studies performed on lower strengths

Dissolution testing conditions Apparatus selection : :

Dissolution testing conditions Apparatus selection :

Agitation:

Agitation RANGE : 25 TO 100 RPM FOR BASKET METHOD : 50 to 100 RPM FOR PADDLE METHOD : 50 TO 75 RPM BELOW 25 RPM : INCONSISTENCY OF HYDRODYNAMICS ABOVE 150RPM :TURBULANCE

Slide 25:

Dissolution media Buffered aqueous solutions with pH range 1.2 to 6.8 are used surfactants like SLS , tween80 , CTAB are used for poorly soluble drugs simulated gastric fluids with or without pepsin and simulated intestinal fluids with or without pancreatin are used to establish IVIVC Volume 500-1000mL with 900mL as most commonly maintained volume Volume can be raised between 2 and 4 liters Temperature Oral dosage forms : 37 +/- 0.5 c Suppositories : 38 +/- 0.5 c Transdermal patches : 32 +/- 0.5 c Deaeration Sonication , helium sparging