The draft of the new Annex 1 is open to consultation

The new Annex 1 of the GMPs on the "Manufacture of Sterile Medicinal Products" has been published by the European Commission and is currently open to consultation until 20 March 2018. The structure of the document has been revised compared to the previous version

Giuliana Miglierini

15 January 2018

The European Commission (EC) published on December 20th, 2017 the first complete revision of Annex 1 “Manufacture of Sterile Medicinal Products” of the EU Guideline for Good Manufacturing Practice (GMP) for drug products and drug substances. The draft is currently open to consultation until 20 March 2018. You can download it from this link.
The interested parties can provide their feedback by e-mail, writing to the address SANTE-REVISION-ANNEX-1@ec.europa.eu. It is also possible to send comments by post to the address “Directorate-General for Health and Food Safety, Unit SANTE B/4, BE-1049 Brussels”. In any case, the subject line should contain the reference “Targeted Public Consultation – Revision of annex 1 of EU GMP Guide”.
The template to be used for comments can be downloaded from the consultation web page, together with the instructions to fill it with relevant information for individuals or companies/organisations.

The structure of the new Annex 1

The revision of Annex 1 has been long waited, as since its original publication in 1971 the pharmaceutical technology has deeply evolved and new methods for production and analytical controls are now available and need to be considered in the relevant GMP regulations. This can be acknowledged by the fact that the new Annex 1 is a 50 pages long document, far more complex than the 16 pages old version (2008), and it includes many completely new clauses.
The GMP-GDP Inspectors Working Group of the European Medicines Agency started the revision in 2014 and drafted the final text of the new Annex 1 upon several steps of consultation of the interested parties and in collaboration with the World Health Organisation and PIC/S (Pharmaceutical Inspections Co-operation Scheme).
The new Annex 1 follows the Quality Risk Management (QRM, ICH Q9) principles typical of the modern pharmaceutical life cycle. The structure of the document has been completely revised to follow a logical flow and now includes specific sections discussing the requirements of Pharmaceutical quality systems (PQS, ICH Q10), the characteristics of single use and barrier technologies such as Rabs or isolators, and of the different type of sterilisation process, including form-fill-seal, blow-fill-seal and lyophilisation processes. The high level structure of the new Annex 1 is the following:

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 lyophilization 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 document’s scope can be also extended to specific cases of the manufacturing of not-sterile medicinal products, that are discussed at the beginning of the new guideline.
The environmental control and monitoring requirements now ask to check the ≥ 5 µm particles during routine testing only of non-living particles, and not during qualification of the clean rooms.
Attention is also deserved to the qualification and validation of both terminal sterilisation and aseptic process (including simulation of this last one, where media fill is also included), and to cleaning validation.
The new Annex 1 might have an impact on manufacturing activities, as it requires to move towards a more holistic vision of the entire process based on a robust risk assessment for each step of the process and on the availability of the supporting documentation for all decisions. Among the main new points to be considered, the document introduces the requirement of a formal contamination control strategy and a cleanroom classification to be run according to the new ISO 14644 standards.

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