EU GMP Annex 1 revisited.
What's new?

In sight of the holiday period, the long awaited draft of Annex 1, Manufacture of Sterile Medicinal Products was published on 20 December 2017. The EU GMP and PIC/S Annex 1 has long been the GMP bible for manufacturers of sterile medicines and consequently for Advipro, who has a focus on validation and certification activities in and around sterile manufacturing processes.

The original version was partially revised in 1996, 2003 and 2007. However, there has not been a complete review of the document since it was originally issued. So with more than 10 years now passed, the changes in technologies and the significant updates in GMP following the adoption of the ICH Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality Systems) guidelines, it is fair to say not a revision, but a complete rewrite was necessary.

A rewrite, …

A rewrite, is exactly what they have done. The update not only contains substantial additional detail on practically every topic in the 2007 version, it went from a 16-page document to a document with no less than 50 pages! There are also a lot of new topics included and the concept of risk management is embedded into the entire document.

What’s the impact?

In all fairness, a lot of the changes to annex 1 have been part of current industry best practices for some time now. Nevertheless, the pharmaceutical industry will have to prepare for several potential changes, such as:

  • New requirements for barrier technologies (RABS and isolators) with respect to room classification and integrity testing.
  • Difference between limits for routine particle measurements and initial/periodic clean room classification.
  • Inclusion of requirements with regards to new technologies such as single use equipment, process water systems,…
  • The potential intent to mandate HEPA/ULPA filtration in all classified areas (including Grade D).
  • Potentially additional requirements for cleanroom classification (beyond ISO requirements) in critical areas.
  • Significant enhancements to expectations for a 100% visual inspection.
  • The expectation for a formal contamination control strategy, including quality risk management and comprehensive trending of aseptic quality parameters.
  • The expectation for a formal aseptic operator qualification program and aseptic process simulation activities.
  • Possible new requirements for container closure integrity validation.
  • The expectation for adequately trained personnel in aseptic gowning and aseptic practices (Aseptic Process Simulation)

Advipro can contribute

With new and more strict requirements regarding cleanroom classification and aseptic operator qualification, Advipro can assist you with cleanroom certification activities according current expectations. Also, with our unique training centre, The GxP Academy, which has an operational GMP cleanroom up to grade A/B classification. Advipro can offer customized operator qualification trainings without the possible risk of contaminating the actual process at your facility.

Final thoughts

The revision of Annex 1 is, as expected, a extensive rewrite of the previous 2007 version. With a focus on application of QRM to sterile manufacture and the addition of some new technologies this draft provides an extensive guidance document for the industry on manufacture of sterile medicinal products.

Of course, this is still a draft and comments can be submitted until 20 March 2018. So my advice is to print out this new revision and don’t let it sit on your desk for weeks but read through it and see how it will affect you or your organisation.

In the weeks to come, Advipro will follow up on the topic with an in depth analysis of the significant changes to the Annex 1 for the industry so follow us on social media and visit our website.


26/01/2018 – Glenn Van Doninck, Project Support Engineer at Advipro