Revision of Directive 2001/83/EC - Consequences for the API Industry

GMP News No. 401

31 March 2004

Revision of Directive2001/83/EC –
Consequences for the API Industry

The Directive of the European Parliament and of the Council amendingDirective 2001/83/EC on the Community Code relating to medicinal productsfor human use has been accepted by the Parliament in December last yearand by the Council in the beginning of March 2004 and will be effectivefrom March 31, 2004, on*1

There are three major consequences for the API manufacturers:

(A) APIs have to be manufactured in accordance to Annex 18 EG GMPGuide:

The EG GMP Guide obliges pharmaceutical companies to purchase APIs fromapproved suppliers only. The amended Directive increases the pressure onthe pharmaceutical company: according to article 46f the pharmaceuticalcompany is obliged "(…) to use as starting materials only activesubstances, which have been manufactured in accordance with the detailedguidelines on good manufacturing practice for starting materials (comment:reference is made to the Annex 18 to the EU GMP Guide). This point shallalso be applicable to certain excipients, the list of which as well as thespecific conditions of application shall be established by a Directiveadopted by the Commission in accordance with the procedure referred to inArticle 121(2).

Annex 18 to the EU GMP Guide can be found here:

(B) Annex 18 of the EU GMP Guide (GMP for APIs) becomes mandatory forthe EU:

Article 47
The principles of good manufacturing practice for active substances usedas starting materials referred to in point (f) of Article 46 shall beadopted in the form of detailed guidelines. (…)

(C) Inspections at the premises of API manufacturers may be carriedout:

Article 111
The competent authority may also carry out unannounced inspections at thepremises of manufacturers of active substances used as starting materials,or at the premises of marketing authorisation holders whenever itconsiders that there are grounds for suspecting non-compliance with theprinciples and guidelines of good manufacturing practice referred to inArticle 47. These inspections may also be carried out at the request of aMember State, the Commission or the Agency.

In order to verify whether the data submitted in order to obtain aconformity certificate comply with the monographs of the EuropeanPharmacopoeia, the standardisation body of the nomenclatures and thequality norms within the meaning of the Convention relating to theelaboration of the European Pharmacopoeia (European Directorate for thequality of Medicinal Products) may ask the Commission or the Agency torequest such an inspection when the starting material concerned is thesubject of a European Pharmacopoeia monograph.

The competent authority of the Member State concerned may carry outinspections of starting material manufacturers at the specific request ofthe manufacturer himself.

Unfortunately the different wordings of 'APIs' in Annex 18 and in theDirective may cause confusion: Annex 18 uses the word 'activepharmaceutical ingredient', the amended Directive uses 'startingmaterial'.

Dr Barbara Jentges

*1: Many thanks to Dr Chris Oldenhof fromDSM, Netherlands, for the link and the latest information on the newDirective.


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