The Dissolution Procedure: Development and Validation

[Pages:24]The Dissolution Procedure: Development and Validation

Based on: as published in Pharmacopoeial Forum, Vol. 31 (5), 2005

Dr. Elisabeth Krug Lilly Forschung GmbH Germany

Dissolution ? Outline

General considerations for dissolution procedures

Medium In vivo ? In vitro correlation Apparatus Agitation Sinkers Study Design Observations Sampling Filters Assay Validation Analysis Acceptance Criteria

Dr. Elisabeth Krug

Company Confidential

2

Dissolution ? General Considerations

?Dissolution is a performance test, applicable to many dosage forms

?It yields data to allow an accept/reject decision ?One test amongst a series of others ?The USP provides the following General Chapters:

Disintegration Drug Release Dissolution

Medium Apparatus/Agitation Rate Study Design Assay Acceptance Criteria

Dr. Elisabeth Krug

Company Confidential

3

Dissolution ? General Considerations

What is needed? Apparatus, medium, and test conditions

How should the acceptance criteria look like? Should be representative for multiple batches with the same nominal composition and manufacturing process

What are the requirements for a dissolution procedure? ?Must provide a method rugged and reproducible as well as transferable ?Must be appropriately discriminating, i.e. capable of distinguishing significant changes in a composition or manufacturing process that might be expected to affect in

vivo performance

Dr. Elisabeth Krug

Company Confidential

4

Dissolution ? General Considerations

the discriminating method...

Differences in vitro for batches without differences in vivo ? What to do?

? Carefully evaluate whether the procedure is too sensitive or appropriately discriminating

? Assess the results from multiple batches that represent typical variability in composition and manufacturing parameters

? Intentionally vary manufacturing parameters (lubrication, blend time, compression force, drying parameters)

Dr. Elisabeth Krug

Company Confidential

5

Dissolution ? General Considerations

... more requirements for the dissolution procedure

?

? ? ?

?

?

Reflection of relevant changes in the drug product over time caused by temperature, humidity, photosensitivity, and other stress No significant analytical solution stability problems should be associated with the test Not highly variable: RSD > 20% at 10 min or less

RSD > 10% at later time point Identify sources of variability:

Formulation (API, excipients, manufacturing process, poor CU, process inconsistency, film coat, capsule shell aging, hardening or softening of dosage forms) Test procedure artifacts (coning, tablet sticking, air bubbles etc.)

Dr. Elisabeth Krug

Company Confidential

6

Dissolution ? Outline

General considerations for dissolution procedures

Medium

In vivo ? In vitro correlation Apparatus Agitation Sinkers Study Design Observations Sampling Filters Assay Validation Analysis Acceptance Criteria

Dr. Elisabeth Krug

Company Confidential

7

Medium Dissolution ?

? Criteria for Selection

? Physical and chemical data for:

?drug substance ?Solubility and solution state stability as a function of pH ?Evaluation of influence of buffer, pH value and surfactants

?dosage unit ?Release mechanism (immediate, delayed, modified) ?Disintegration rate as affected by hardness, friability, presence of solubility enhancers, other excipients

Dr. Elisabeth Krug

Company Confidential

8

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