As already announced with the GMP News from 12 September 2012, the new Annex 2 of the EU GMP Guide becomes effective on 31 January 2013. In the review period of about five years the volume increased from 5 to 32 pages. Already the draft for the second public consultation phase in 2010 (see GMP News from 29 April 2010) indicated the comprehensive modifications and additions intended with the revision. The tremendous developments in the area of biopharmaceutical products - especially the developments in the area of transgenic products and Advanced Therapy Medicinal Products (ATMP) - urgently required a review. The first significant modification already becomes obvious in the name of this Annex. In its 2004 version it only comprised "Biological Medicinal Products", while the new version now also covers "Biological Active Substances". In a new table the Annex shows what products and what production steps are concerned. Here it starts with the extraction of certain products as, e.g. urine based products and master cell banks.
To take into consideration the diversity of biological products the new Annex 2 is separated in two parts. Part 1 comprises the general requirements relative to the issues
2. Premises and Equipment
6. Starting and raw materials
7. Seed lot and cell bank system
8. Operating Principles
9. Quality control
The structure is basically the same as before. The number of sub items - and this also means the covered details - has increased from 43 to 70, though. And not only the number increased, but also the gathered details of requirements for each sub item is a lot more comprehensive. For instance, the section on premises and equipment defines specifications with regard to requirements for design of buildings and processes with much more detail. It also extensively describes specifics - e.g. in the production of a "Multi Product Facility" under item 8.
According to the now included new types of biological products, the section on starting and raw materials is almost completely new or revised and complemented with an extensive part on human tissue and cells as starting materials. The same applies to the section "Operating Principles" in the first part of the Annex.
Many of the "modern" biological medicines are - in addition to the GMP Guidelines - also subject to specific guidelines and statues. Among these are the Gene Technology Law and the Tissue Act. Compared to the previous version, the many references to respective guidelines and specifications for the particular products (as e.g. Annex 14 for blood, tissue guideline etc.) are quite helpful for the reader.
Part 2 of the revised Annex 2 covers the special requirements with regard to the origin or respectively to the type of product. The following groups are addressed:
1. Animal sourced products
2. Allergen products - materials manufactured by extraction from natural sources as well as by recombinant DNA technology
3. Anmal Immonosera products
5. Recombinant products
6. Monoclonal antibody products
7. Transgenic animal products
8. Transgenic plant products
9. Gene therapy products
10. Somatic and xenogeneic cell therapy products and tissue engineered products
The third part comprises a glossary with the terms used in the Annex 2 and that are most important and possibly in need of explanation
To find out more please see the "Annex 2 - Manufacture of Biological active substances and Medicinal Products for Human
A document comparing the previous Annex 2 version from 2004 with the revised version as well as a comparison of the draft from 2010 and the final version from 2012 is available for ECA members in the members' area of the ECA website.
Please note that the seminar "GMP Compliance for Biopharmaceuticals with the Workshop GMP for ATMP" scheduled in Heidelberg, Germany, from 10-12 October will address this issue in more detail.
Axel H. Schroeder
CONCEPT HEIDELBERG ( a service provider entrusted by the ECA Foundation)