TITLE IV

MANUFACTURE AND IMPORTATION
Article 46
The holder of a manufacturing authorization shall at least be obliged:
1. to have at his disposal the services of staff who comply with the legal requirements existing in the Member State concerned both as regards manufacture and controls;
2. to dispose of the authorized medicinal products only in accordance with the legislation of the Member States concerned;
3. to give prior notice to the competent authority of any changes he may wish to make to any of the particulars supplied pursuant to Article 41; the competent authority shall, in any event, be immediately informed if the qualified person referred to in Article 48 is replaced unexpectedly;
4. to allow the agents of the competent authority of the Member State concerned access to his premises at any time;
5. to enable the qualified person referred to in Article 48 to carry out his duties, for example by placing at his disposal all the necessary facilities;
6. to comply with the principles and guidelines of good manufacturing practice for medicinal products and to use only active substances, which have been manufactured in accordance with good manufacturing practice for active substances and distributed in accordance with good distribution practices for active substances. To this end, the holder of the manufacturing authorisation shall verify compliance by the manufacturer and distributors of active substances with good manufacturing practice and good distribution practices by conducting audits at the manufacturing and distribution sites of the manufacturer and distributors of active substances. The holder of the manufacturing authorisation shall verify such compliance either by himself or, without prejudice to his responsibility as provided for in this Directive, through an entity acting on his behalf under a contract.
The holder of the manufacturing authorisation shall ensure that the excipients are suitable for use in medicinal products by ascertaining what the appropriate good manufacturing practice is. This shall be ascertained on the basis of a formalised risk assessment in accordance with the applicable guidelines referred to in the fifth paragraph of Article 47. Such risk assessment shall take into account requirements under other appropriate quality systems as well as the source and intended use of the excipients and previous instances of quality defects. The holder of the manufacturing authorisation shall ensure that the appropriate good manufacturing practice so ascertained, is applied. The holder of the manufacturing authorisation shall document the measures taken under this paragraph;
7. to inform the competent authority and the marketing authorisation holder immediately if he obtains information that medicinal products which come under the scope of his manufacturing authorisation are, or are suspected of being, falsified irrespective of whether those medicinal products were distributed within the legal supply chain or by illegal means, including illegal sale by means of information society services;
8. to verify that the manufacturers, importers or distributors from whom he obtains active substances are registered with the competent authority of the Member State in which they are established;
9. to verify the authenticity and quality of the active substances and the excipients.
Substituted by Directive 2011/62/EU of the European Parliament and of the Council of 8 June 2011 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products (Text with EEA relevance).