New policy for dissolution and disintegration testing in Ph. Eur. monographs
Over the last few years, the European Pharmacopoeia (Ph. Eur.) has been elaborating monographs on medicinal products containing chemically defined active substances, applicable to immediate-release solid dosage forms (tablets, capsules).
These monographs include a mandatory test for dissolution or disintegration. However, in justified and authorised cases, manufacturers may propose another procedure and/or, where appropriate, different acceptance criteria as part of their marketing authorisation application. This is indicated in the monographs by the sentence:
The tablets comply with the test and the acceptance criterion described below, unless otherwise justified and authorised.
Since the result of the dissolution test may be affected by the formulation and/or the manufacturing process, the Ph. Eur. Commission launched a substantive examination of users’ expectations with regard to this test in medicinal product monographs.
Users in the pharmaceutical industry, the licensing authorities, national pharmacopoeias and OMCLs, for example, were therefore invited to participate in a survey in January 2019.
Three options were proposed:
- keep a mandatory dissolution test in the monographs;
- include a dissolution test as an example in the monographs;
- do not include a dissolution test since the dosage form monographs on Tablets (0478) and Capsules (0016) contain the requirement to carry out such a test, in addition to the prescriptions of guideline ICH Q6A.
Based on the results of the survey and on experience gained by other pharmacopoeias elaborating such monographs, a compromise was found and adopted at the 168th session of the European Pharmacopoeia Commission (November 2020). The latter decided that a dissolution or disintegration test will be included in each medicinal product monograph on an immediate-release solid dosage form.
The details of the scope of such a test and the conditions for its use in a marketing authorisation application will be included in the General Notices (Chapter 1 of the Ph. Eur.). An excerpt is shown below:
“In line with the relevant guidelines applied nationally or regionally (such as the ICH Q6A guideline) and with the relevant Ph. Eur. dosage form monograph, a suitable product-specific dissolution test has to be proposed by the applicant for routine quality control to confirm batch-to-batch consistency. This test must be described in the MAA for submission to the competent authority, unless there is data justifying the replacement of the dissolution test by a disintegration test (see below). The demonstration of the suitability of the dissolution test has to be made by the applicant to the satisfaction of the competent authority.
Where appropriate, a dissolution test is described in an individual monograph on a medicinal product. In such cases, the applicant may either select the monograph dissolution test or develop an in-house dissolution test as the product-specific dissolution test. In any case, the applicant has to demonstrate the suitability of the selected test to the satisfaction of the competent authority.
If an in-house dissolution test is proposed, justification for not selecting the monograph dissolution test and demonstration of compliance with the monograph dissolution test is normally not requested in the MAA.
However, when tested, the medicinal product has to comply with the monograph dissolution test, unless otherwise justified by the applicant.
Where a given medicinal product does not comply with the monograph dissolution test and this product is approvable by a competent authority, then the competent authority shall bring this to the attention of the Ph. Eur. Commission so it can review the monograph and revise it where appropriate.”
Consequently, the following monographs have been revised to delete the sentence in italics mentioned above and to add a footnote referring to the General Notices:
- Deferiprone tablets (2986)
- Dronedarone tablets (3038)
- Lacosamide tablets (2989)
- Raltegravir chewable tablets (2939)
- Raltegravir tablets (2938)
- Regorafenib tablets (3023)
- Riociguat tablets (3079)
- Rivaroxaban tablets (3021)
- Rosuvastatin tablets (3008)
- Sitagliptin tablets (2927)
- Sorafenib tablets (3022)
- Ticagrelor tablets (3097)
These monographs and the revised General Notices will be published in Supplement 10.6.
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