USP s Perspective on Drug Product Performance Test

Transcription

1 USP s Perspective on Drug Product Performance Test

2 Course Overview 1. The concept of in vitro dissolution Definition and application 2. Compendial dissolution/ drug release testing 3. Method development selection of test conditions 4. Dissolution method assessment IVIVC(R) 5. Setting specifications 6. Product/ profile comparison product similarity/ interchangeability 7. Analytical instrument qualification 8. Validation the dissolution test

3 Disclaimer Because USP text and publications may have legal implications in the U.S. and elsewhere, their language must stand on its own. The USP shall not provide an official ex post facto interpretation to one party, thereby placing other parties without that interpretation at a possible disadvantage. The requirements shall be uniformly and equally available to all parties. In addition, USP shall not provide an official opinion as to whether a particular article does or does not comply with compendial requirements, except as part of an established USP verification or other conformity assessment program that is conducted separately from and independent of USP's standard-setting activities. Certain commercial equipment, instruments or materials may be identified in this presentation to specify adequately the experimental procedure. Such identification does not imply approval, endorsement, or certification by USP of a particular brand or product, nor does it imply that the equipment, instrument or material is necessarily the best available for the purpose or that any other brand or product was judged to be unsatisfactory or inadequate.

4 Dissolution Rate The dissolution rate of a drug from the solid state is defined as the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid id/ lid interface, temperature, t and solvent composition

5 Goals of a Dissolution Test Predict the bioavailability surrogate parameter of the therapeutic ti efficacy Indicate the robustness of the dosage form drug product related safety Sensitive to variations in the manufacturing process which have critical influence on the dosage form performance Quality control tool to ensure the uniformity of a product within 1 batch among various batches

6 The Dissolution Test The dissolution procedure is a performance test applicable to majority of dosage forms It is one test in a series of tests that constitutes the dosage form s public specification (tests, procedures for tests, acceptance criteria) The procedure should be appropriately discriminating, capable of distinguishing ishing significant changes in a composition or manufacturing process that might be expected to affect in vivo performance

7 Noyes-Whitney Equation dm dt = k ( C C) s M amount of drug dissolved t time k dissolution coefficient Cs concentration of drug in stagnant layer C concentration of drug in bulk solvent Cs-C concentration gradient

8 Nernst-Brunner Equation Modified Noyes-Whitney Equation dm D A k ( C C) = s dt h M amount of drug dissolved t time D diffusion coefficient of drug A surface area of drug particle k dissolution rate constant h thickness of stagnant layer Cs concentration of drug in stagnant layer C concentration of drug in bulk solvent Cs-C concentration gradient

9 Sink Conditions Sink conditions exist when the volume of the dissolution medium is at least 3 times greater than the volume required to make a saturated drug solution dm D A = dt h k C s Overall dissolution rate increases with increased surface area A By maintaining A constant, the dissolution rate can be conveniently determined (Note that C S and k are constant at a given temperature for each solvent, unstirred)

10 Intrinsic Dissolution Rate Constant Intrinsic dissolution rate constant k (cm/s) varies from drug to drug and is a function of the diffusion coefficient D (cm 2 /s) of the drug and the thickness of liquid film, l (cm) k = D l As the agitation intensity is increased, the thickness of the film decreases progressively k is therefore a function of the test

11 Dissolution in the Context of Bioavailability TABLET DISINTEGRATION GRANULES DISAGGREGATION DRUG PARTICLES IN SUSPENSION DRUG IN SOLUTION IN GI FLUIDS SYSTEMIC ABSORPTION

12 Dissolution Pathway Initial Exposure of the Tablet dissolved drug dissolution tablet = Drug particle

13 Dissolution Pathways # Drug molecules release

14 S-Shaped Dissolution Curve Solid Dosage Forms 100% e.g. occlusion % Dru ug Dissolv ved Mechanical Lag + Wetting Dissolution 0% De-aggregation Disintegration Time

15 Dissolution Profiles e.g. Apparatus 1 and 2 (cumulative results)

16 Dissolution Profiles e.g. Apparatus 3 and 4 (fractioned vs. cumulative)

17 Factors Influencing Dissolution Physico-chemical properties of the drug substance solubility particle size Formulation characteristics of the dosage form Wettability Diffusion Release mechanism Swelling Erosion Diffusion De-complexation

18 Factors Influencing Dissolution Apparatus choice Media composition Agitation Volume

19 Bioavailability of Solid Oral Dosage Forms Bioavailability is the rate and extent to which the drug substance or Active Pharmaceutical Ingredient (API) is absorbed from the drug product and becomes available at the site of action exemplified for disintegrating immediate release solid dosage forms: Solid oral dosage form Disintegration Solid Dissolution Drug in Absorption particles solution Drug in the body

20 Dissolution/ Drug Release Test Dosage forms requiring dissolution/drug release test Tablets Capsules Suspensions Ointments Creams Suppositories Transdermals Implants Medicated gums and others

21 Goals of a Dissolution Test Predict the bioavailability surrogate parameter of the therapeutic efficacy Indicate the robustness of the dosage form drug product related safety Sensitive to variations in the manufacturing process which have critical influence on the dosage form performance

22 Goals of a Dissolution Test Quality control tool to ensure the uniformity of a product Within one batch Among various batches

23 Dissolution Testing. Dissolution assesses the performance of drug products To be effective, the test should be: Predictive - relationship to in vivo response Comparative - prediction only possible with comparative tests Discriminatory - comparison only possible with discriminatory tests Reproducible - discrimination only possible with reproducible tests

24 Significance of Dissolution Testing Important in the early stages of formulation development It can be an indicator of in vivo performance Extensively used for testing product stability Serves as a quality control test by providing evidence of the product s physical consistency and manufacturing process Serves as a quality assurance tool for batch to batch consistency and intra-batch homogeneity

25 Significance of Dissolution Testing It is a critical regulatory and compendial requirement in the testing of solid dosage forms Provides data facilitating initial approval, scale-up and post-approval changes Assists regulatory agencies in making approval decisions pertaining to minor process and formulation changes In combination with the BCS characterization allows Biowaivers

26 Dissolution Testing Dissolution testing is comparative Formulation to formulation Fresh product to aged product Batch to batch Old process to new process Innovator to generic