Quality Assurance of Pharmaceuticals - A Compendium of Guidelines and Related Materials - Volume 1
(1997; 248 pages) [French] View the PDF document
Table of Contents
Open this folder and view contentsIntroduction
Open this folder and view contents1. National drug regulation
Close this folder2. Product assessment and registration
View the documentGuidelines for the assessment of herbal medicines1,2
Open this folder and view contentsStability of drug dosage forms1
Open this folder and view contentsGuidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms1
Close this folderMultisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability1
View the documentIntroduction
View the documentGlossary
Open this folder and view contentsPart One. Regulatory assessment of interchangeable multisource pharmaceutical products
Open this folder and view contentsPart Two. Equivalence studies needed for marketing authorization
Open this folder and view contentsPart Three. Tests for equivalence
View the documentPart Four. In vitro dissolution tests in product development and quality control
View the documentPart Five. Clinically important variations in bioavailability leading to non-approval of the product
View the documentPart Six. Studies needed to support new post-marketing manufacturing conditions
View the documentPart Seven. Choice of reference product
View the documentAuthors
View the documentReferences
View the documentAppendix 1. Examples of national requirements for in vivo equivalence studies for drugs included in the WHO Model List of Essential Drugs (Canada, Germany and the USA, December 1994)
View the documentAppendix 2. Explanation of symbols used in the design of bioequivalence studies in humans, and commonly used pharmacokinetic abbreviations
View the documentAppendix 3. Technical aspects of bioequivalence statistics
Open this folder and view contents3. Distribution
Open this folder and view contents4. The international pharmacopoeia and related activities
Open this folder and view contents5. Basic tests
Open this folder and view contents6. Laboratory services
Open this folder and view contents7. International trade in pharmaceuticals
Open this folder and view contents8. Counterfeit products
Open this folder and view contents9. Training
View the documentSelected WHO publications of related interest
View the documentBack cover

Part Four. In vitro dissolution tests in product development and quality control

In vitro dissolution tests are useful in product development and in monitoring the batch-to-batch consistency of the manufacturing process following approval of marketing. Such tests are also used to check the consistency of the release characteristics of a dosage form during storage. Dissolution testing may also provide a useful check on a number of characteristics of the dosage form, including:

- the particle size distribution, state of hydration, crystal form and other solid state properties of the active ingredients;

- the mechanical properties of the dosage form itself (water content, resistance to crushing force for tablets, integrity of the shell for capsules and coated tablets, etc.).

When used in product quality control, information on in vitro dissolution should be provided in the documentation submitted with the application for marketing authorization. In vitro dissolution tests and quality control specifications should be based either on suitable compendial specifications or on the in vitro performance of the test batches used to generate material for the equivalence study. Where sufficient full-scale process validation batches are not prepared in the immediate post-approval period, several batches (two or three are recommended) of the test product should be manufactured in the preapproval period in accordance with standard, consistent, well documented procedures. Two of these batches should contain at least 100 000 units or 10% of the intended production batch, whichever is larger. The third, if prepared, may be smaller (e.g. 25 000 units). The use of smaller batches should be justified. Material from these test batches is used to provide material both for dissolution studies and for equivalence testing. Physiologically relevant media and test conditions should be used for dissolution tests on these batches. When selecting the test methods to be used, it is recommended that widely used compendial methods (“paddle” and “basket”) should be used initially and other methods (“flow-through cell”, etc.) tried if these fail to demonstrate sufficient discriminatory power. Dissolution profiles are recommended, even when a single-point compendial dissolution test is available. For immediate-release pharmaceutical products, a single-point dissolution test may be used for quality control purposes. Specifications for the dissolution performance of batches subsequently manufactured will be based on the results of the dissolution tests performed on the test batches. While it is undisputed that the value of dissolution testing will be increased if the test results can be shown by in vivo studies to reflect important changes in formulation and/or the manufacturing process, the practical problems involved are still under discussion. It is not recommended that the dissolution specification should be made less stringent on the basis of the performance of the test batches beyond the point where equivalence between the test material used in the equivalence study and production batches subsequently manufactured can no longer be assumed.

The following data should be recorded and included in the documentation submitted with the application for marketing authorization:

(a) comparative dissolution results for the test and reference pharmaceutical products after intervals appropriate for the products and conditions under investigation (a minimum of three sampling times is normal);

(b) for each sampling time, the observed data, individual values, the range and the coefficient of variation (relative standard deviation).

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