Draft Revision of EU Annex 2 For Biologicals Out For Comment

The European Commission has published a revised draft of Volume 4, Annex 2, “Manufacture of Biological Medicinal Substances and Products for Human Use.”  This revision is taking place due in part to the need to include an increased range and complexity of biological products, and new products such as advanced therapy medicinal products.  This guidance is required for these new products to meet the requirements of Article 5 of Regulation 1394/2007 and to align with details in Directive 2009/120/EC.

Many final biological products are actually active substances. However, Directive 2004/23/EC on Human Tissue and Cells covers only the donation, procurement and testing of the tissues and cells, which become the “biological active substances” for many biological medicinal products.  This guidance seeks to clarify further requirements, and takes into account that biological processes are inherently less predictable and more variable than chemical manufacturing processes.

Up until now, pharmaceuticals have been classified for regulatory purposes by their method of manufacture.  The Annex along with companion guidelines will now give further guidance on the manufacturing of biologics by defining two different aspects, as noted in the draft:

a) Stage of manufacture – for biological active substances to the point immediately prior to their being rendered sterile, the primary guidance source is Part II. Guidance for the subsequent manufacturing steps of biological products are covered in Part I. For some types of product (e.g. cell-based products) all manufacturing steps need to be conducted aseptically.

b) Type of product – this annex provides guidance on the full range of medicinal substances and products defined as biological.

These two aspects are shown in a table giving examples to help manufacturers define what is needed for their specific products.  The draft guidance notes that “the level of GMP increases in detail from early to later steps in the manufacture of biological substances but GMP principles should always be adhered to. The inclusion of some early steps of manufacture within the scope of the annex does not imply that those steps will be routinely subject to inspection by the authorities.”

The annex is divided into two main parts:

Part A contains supplementary guidance on the manufacture of biological medicinal substances and products, from control over seed lots and cell banks through to finishing activities, and testing.

Part B contains further guidance on selected types of biological medicinal substances and products.

The initial concept paper for this draft was released in May 2005, and the first public consultation took place beginning in March 2008.  Significant changes have been made as a result of this consultation.  Public consultation on this revision will take place until July 15, 2010.

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Manufacture of Biological Medicinal Substances and Products for Human Use