Revision of the Directive 91/356/EEC

GMP News No. 211

GMP News 
3 July 2002

Revisionof the Directive 91/356/EEC

The "Commission Directive 91/356/EEC of 13 June 1991 laying down theprinciples and guidelines of good manufacturing practice for medicinalproducts for human use" formulates - as can be gathered from theslightly long-winded title - the basic framework for the GoodManufacturing Practice for human drugs. It entered German law as GermanOperation Ordinance for Pharmaceutical Entrepreneurs(Pharmabetriebsverordnung) in 1994.

In the subordinate document "ECGuideline for a Good Manufacturing Practice for Medicinal Products"with its now 18 Annexes, comprehensive guidelines are presented andsometimes revised in order to take the technical and scientific progressinto account. A recent revision concerned Annex 13, which deals with the"Manufacture of Investigational Medicinal Products" (see Newsof 8 March 2002). The modifications that are suggested in the documentand have been released for comment regard a stricter implementation of theGMP principles to the manufacture of investigational medicinal productsand correspond to the requirements of the Directive 2001/20/EC on theimplementation of GCP in the conduct of clinical trials. These regulationshave now been included in analogy into the GMP Directive. The thus createdrevision of the 91/356/EEC document was published as Draft Proposal on 2May 2002 and released for comment until 2 August 2002.

In the following you will find somecharacteristic examples of the changes.
In order to clarify expressly how one has to proceed in the manufacture ofinvestigational medicinal products, additional formulations have beeninserted, requiring e.g. validated processes and data processingsystems.
Furthermore the text requires that "the function of qualitycontrol shall be established and maintained distinct from otherfunctions." The responsibility shall lie with a person who isindependent of production.
The retention period for samples (bulk formulated products,finished drug products, packaging components for finished drug products)is clearly defined.
Different passages of the document contain detailed regulations for the triangleconstituted by manufacturer, importer and sponsor, above all inview of complaints or recalls during clinical trials.

The draft revision of the Directive isembedded in a modified network of regulations some of which have beenpublished only recently.
The two most important new Directives to which the document referscontinually are the

"Directive 2001/83/EC... of 6 November 2001 ...on the Community code relating to medicinal products for human use"

and the already mentioned

"Directive 2001/20/EC... of 4 April 2001 ...relating to the implementation of good clinical practice in the conduct ofclinical trials on medicinal products for human use."

The second Directive regulates theconduct of clinical trials, the first one strives for a harmonisation ofthe different regulations of the individual states in the EuropeanEconomic Area regarding all categories of medicinal products for humanuse, and thus also investigational medicinal products.

This revision of the Directive 91/356/EECis the consequence of both the "GCP Directive" 2001/20/EC andthe revision of Annex 13 to the GMP Guideline. This shows very clearlythat the manufacture of investigational medicinal products is the focus ofGMP attention and that any grey zones in the manufacture ofinvestigational medicinal products have been eliminated in thecorresponding regulations.

The revised draft directive can bedownloaded here:

The Revision of Annex 13 can bedownloaded from this address:

Dr Gerhard Becker



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