Main Deficiencies Concerning the European Marketing Authorization: Part II
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0092-8615/2001 Copyright 0 2001 D N lnformation ~ Association Inc.
Printed in the USA. All rights reserved.
MAIN DEFICIENCIES CONCERNING THE EUROPEAN MARKETING AUTHORIZATION: PART I1 YVONNELEGRAS,PHD, PHARMD Aventis Pharrna S.A., Antony cedex. France
This paper discusses a representative sample of the main deficiencies identified by European agencies in the “Chemical, Pharmaceutical arid Biological documentation” of Marketing Authorization Applications for chemical active substances. The plan followed in the paper is that of the European Part Ilfile. Each deficiency is illustrated by examples. Specific European references are listed, as well as new texts. The paper also comments on the presentation of the pharmaceutical dossier and expert report. Key Words: Deficiencies; Marketing Authorization Application; Europe; Chemistry, Manufacturing, and Controls part; Regulatory affairs
THE AIM OF THIS paper is to highlight the main deficiencies found in European Marketing Authorization Applications concerning part I1 or “Chemical, Pharmaceutical and Biological documentation” of the file for an active chemical substance, without pretending to be exhaustive. These deficiencies constitute a representative sample of the most frequent questions asked by European agencies. The term “should,” employed in this paper, indicates recommendations that are expected to apply unless shown to be inapplicable or replaced by an alternative demonstrated to provide at least an equivalent level of quality assurance. The plan followed is that of the European Part I1 file.
manufacturing materials. Attention should be focused on the following problems:
CONCERNING CHAPTER 11-A-1: COMPOSITION OF THE MEDICINAL PRODUCT The medicinal product composition includes active substances, excipients, and auxiliary Reprint address: Dr. Yvonne Legras, Aventis Pharma S.A., 20, Avenue Raymond Aron. 92165 Antony cedex, France.
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1. Active substance a. The expression of the active substance (AS) quantity should be written as an anhydrous base form for a salt, a hydrochloride, a hydrate, and so forth (Table 1). The amount should be fixed and not variable depending upon the dosage strength. The active ingredient calculation related to the strength should be given in the composition table, and b. An under- or over-age should be stated below the composition table. It should be emphasized that in Europe, only manufacturing overages are tolerated to compensate for manufacturing losses. For example, a shelf-life and manufacturing Vitamin D overage of up to 9% should be split into 5% corresponding to manufacturing losses and 4% relating to stability, which should be justified in terms of specific product characteristics. Thus, for active substances well-known to be unstable, such as some vitamins
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Ytronne Legras
358 TABLE 1 Examples of Presentation of Active Substance Quantity Compound AS-1 AS-2 AS-3, 3 H20
TABLE 3 Examples of Qualitative Composition of Complex Excipients
Applicant’s
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