European Commission publishes revised Version of EU GMP Guideline Annex 2

In November, the European Commission adopted the "New Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products" as the new stand-alone regulation of GMP for ATMPs. With coming into force of that document, the current Annex 2 ("Manufacture of Biological active substances and Medicinal Products for Human Use" of EudraLex Volume 4 - EU guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use) were not the leading guidance for GMP for ATMP any longer. Therefore, a revision of Annex 2 was necessary, eliminating the ATMP relevant parts.

According to the commission the reasons for revision are the following:
"Reasons for changes: Annex 2 of the GMP Guide has been revised as a consequence of the adoption of the Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products pursuant to Article 5 of Regulation (EC) 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004.1 Deadline for coming into operation: 26 June 2018."

On this occasion, several minor updates of references to relevant documents and wordings were implemented. Following you will find a brief summary of the leading changes:

Scope:
Current version:
This annex provides guidance on the full range of active substances and medicinal products defined as biological.
Revision:
This annex provides guidance on the full range of active substances and medicinal products defined as biological, with the exception of Advanced Therapy Medicinal Products ("ATMPs"), as defined in Article 1(1) of Regulation (EC) No 1394/20071 . The ATMPs are not covered by the present guideline. Manufacturers of ATMPs should refer to the Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products referred to in Article 5 of the above quoted Regulation.
 
Current version:
In certain cases, other legislation is applicable to the starting materials:
(a) Tissue and cells used for industrially manufactured products (such as medicinal products):
Revision:
In certain cases, other legislation is applicable to the starting materials. For example,
(a) Tissue and cells used as starting materials for medicinal products:…

In the following Table 1. Illustrative guide to manufacturing activities within the scope of Annex 2 and sections, all ATMP relevant parts and wordings were eliminated - for example:

Animals:
Current version:
19 (b) Animal tissues and cells derived post-mortem and from establishments such as abattoirs: examples include xenogeneic cells from animal tissues and cells, feeder cells to support the growth of some ATMPs, abattoir sources for enzymes, anticoagulants and hormones (sheep and pigs).
Revision:
19 (b) Animal materials derived post-mortem and from establishments such as abattoirs: examples include abattoir sources for enzymes, anticoagulants and hormones (sheep and pigs).

Production:
Current version:
30. For cell based ATMPs where production batches are frequently small the risk of cross-contamination between cell preparations from different donors with various health status should be controlled under defined procedures and requirements.
Revision:
30. For medicinal products from cells and tissues where production batches are frequently small the risk of cross-contamination between cell preparations from different donors with various health status should be controlled under defined procedures and requirements.

In the chapter of Starting and raw materials, the part about donation, procurement and testing of cells and tissues was enlarged:
Current version:
36. For human tissues and cells used as starting materials for biological medicinal Product:
Revision:
36. The donation, procurement and testing of human tissues and cells used as starting or raw materials should be in accordance with Directive 2004/23/EC.18 360 Traceability for human tissues and cells used as starting materials for biological medicinal products should be maintained from the donor to the batch of a finished medicinal product. Appropriate arrangements should be made between the manufacturer and the supplier of tissues and cells regarding the transfer of health donor information that may become available after the supply of the starting material and which may have an impact on the quality or safety of the medicinal product manufactured therefrom.

The section 44. of the chapter Seedlot and cell bank system was completely deleted:
Current Version:
"
Cell based medicinal products are often generated from a cell stock obtained from limited number of passages. In contrast with the two tiered system of Master and Working cell banks, the number of production runs from a cell stock is limited by the number of aliquots obtained after expansion and does not cover the entire life cycle of the product. Cell stock changes should be covered by a validation protocol.”
Revision:
- no section 44. -

An example for the update of relevant guidelines which will be referenced in the Annex 2 revision will be section 23 in the chapter Animals:
Current version:
Note should be taken of Council Directive 86/609/EEC on the approximation of laws, regulations and administrative provisions of the Member States regarding the protection of animals used for experimental and other scientific purposes as regards requirements for animal quarters, care and quarantine. Housing for animals used in production and control of biological active substances and medicinal products should be separated from production and control areas.
Revision:
Note should be taken of Directive 2010/63/EU on the protection of animals used for scientific purposes . Housing for animals used in production and control of biological active substances and medicinal products should be separated from production and control areas.

To get an overview about all major and minor changes, please read the revised version of EU GMP Annex 2: Manufacture of Biological Medicinal Products for Human Use.

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