Revision of Annex 1 "Manufacture of Sterile Medicinal Products" published for Comments

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10-12 December 2024

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On 20 December, the European Commission published the long-awaited revision draft of Annex 1 "Manufacture of Sterile Medicinal Products" of the EU Guideline for good manufacturing practice for drug products and drug substances. The guideline published in 1971 had last been revised in parts in 2008.

The present draft is the first complete revision of the guideline. Amongst other things, it was designed to pay credit to new issues like quality risk management as well as new technologies and procedures. A new structure was developed in close collaboration by the WHO and PIC/S in order to maintain a sensible linkage with their standards and recommendations and thereby reach globally agreed standards.

Overall, the document grew significantly. While Annex 1 consisted of 16 pages since its last revision in 2008, the new document with its additions and changes now amounts to 50 pages. It was attempted to give the Annex a clear structure with a sensible sequence of its content sections. This is reflected by the following table of contents:

Section Number	General Overview
1. Scope	Additional areas (other than sterile medicinal products) where the general principles of the annex can be applied.
2. Principle	General principles as applied to the manufacture of medicinal products.
3. Pharmaceutical Quality System (PQS)	Highlights the specific requirements of the PQS when applied to sterile medicinal products.
4. Personnel	Guidance on the requirements for specific training,knowledge and skills. Also gives guidance to the qualification of personnel.
5. Premises	General guidance regarding the specific needs for premises design and also guidance on the qualification of premises including the use of barrier technology.
6. Equipment	General guidance on the design and operation of equipment.
7. Utilities	Guidance with regards to the special requirements of utilities such as water, air and vacuum.
8. Production and specific Technologies	Discusses the approaches to be taken with regards to aseptic and terminal sterilisation processes. Also discusses different technologies such as lyophilisation and Blow Fill Seal (BFS) where specific requirements may be required. Discusses approaches to sterilization of products, equipment and packaging components.
9. Viable and non-viable environmental and process monitoring	This section differs from guidance given in section 5 in that the guidance here applies to ongoing routine monitoring with regards to the setting of alert limits and reviewing trend data. The section also gives guidance on the requirements of Aseptic Process Simulation.
10. Quality control (QC)	Gives guidance on some of the specific Quality Control requirements relating to sterile medicinal products.
11. Glossary	Explanation of specific terminology.

The section order changed significantly. The information on clean room classifications (following the new ISO 14644 standards) and their qualification follows after the general section on premises. However, while particle sizes ≥ 5 μm had been removed for the qualification of rooms as in ISO 14644, they were maintained in recommended limits for the monitoring of non-living particles.

There is a new chapter on "Utilities", meaning the required equipment and/or other materials that may come into contact with a product or influence it directly. The section covers water systems, steam used for sterilization, compressed gas and vacuum and cooling systems.

On round about 16 pages, the chapter "Production and specific technologies" now more comprehensibly covers "Terminally sterilized products" and "Aseptic preparation", "Finishing of sterile products" and the variations of sterilisation including filtration.

Moreover, several sections address issues like Form-Fill-Seal (FFS) and Blow-Fill-Seal (BFS) technologies as well as Single Use Systems (SUS).

The section about media fill formerly called Processing now appears under a new name. Under the headline Aseptic Process Simulation (APS), the term media fill only appears once. However, the requirements are described on four pages.

More comprehensive information on the new contents can be found directly in "Annex 1 Manufacture of Sterile Medicinal Products". Information on the commentation, which is possible until 20 March, 2018 can be found on the EC's website: "Targeted stakeholders consultation on the revision of annex 1, on manufacturing of sterile medicinal products, of the Eudralex volume 4" .

In this context, please also note the Annex 1 Conference on 8/9 May, 2018 in Berlin.