21.02.2018 |

LOGFILE No. 07/2018 – What's new in the draft of Annex 1 of the EU GMP Guidelines? – Part 1

What's new in the draft of Annex 1 of the EU GMP Guidelines? – Part 1

6 minutes reading time

A commentary by Ruven Brandes and Fritz Röder

On 20 December 2017, the European Commission published the long-awaited draft of Annex 1 “Manufacture of Sterile Medicinal Products” of the EU GMP Guide. A public consultation period will run until 20 March 2018.

What’s new in the draft? Our authors Ruven Brandes and Fritz Röder have carried out a detailed analysis. You will learn what topics and requirements it holds for you, as well as what problems remain and which are entirely new.

Almost three years after the announcement of a revision of Annex 1, a new draft has now been published. The annex has long been the “GMP bible” for manufacturers of sterile medicinal products, but at nearly 10 years since the last review, an update is more than overdue.

In January 2015, the EMA published a concept paper, in which some examples of grounds for the revision were given:

  • The global acceptance and implementation of ICH Q9 (Quality Risk Management) and ICH Q10 (Pharmaceutical Quality System) which were not taken into consideration in the last revision in 2007.
  • Advances in sterile production technology which were not adequately taken into consideration in the last revision.
  • Ambiguities and contradictions were not corrected or cleared up in the 2008 revision.
  • Acknowledgement that Annex 1 is used beyond sterile manufacturing and the scope and/or the title must be changed in order to take this use into account.
  • Facilities, equipment and processes for the production of sterile medicinal products which re-quire new GMP guidelines. One example of this is the revision to the Ph. Eur. monograph on the production of water for injection.

Figure 1 illustrates the reasons for why Annex 1 of the EU GMP Guidelines urgently needed to be reviewed. The numerous changes to the European and American guidelines in recent years must be harmonised with the new Annex 1.

Figure 1: Guideline factors in the revision of Annex 1

The new draft of the annex is not the first revision. Already for 2015, a draft was announced in the concept paper. However, there were delays to the schedule and the draft was initially postponed again because the changes were so extensive that detailed and long discussions of the individual points were required. Overall, therefore, not much happened for a long time.

New Annex 1 (PIC/S and EU): not only a revision – a complete new version!

The reporter for the sub-working group of the EMA’s GMDP Inspectors Working Group for Annex 1, Andrew Hopkins, has indicated multiple times in the last 18 months in a variety of presentations what is in store for the manufacturers. This revision to Annex 1 should not be a selective revision – it is one of the more comprehensive revisions since the implementation of Annex 1 in the 1970s. It is true!

  • A total of 269 articles (compared with 127 in the 2007 version) were elaborated or revised, without taking the many small lists within individual articles into account.
  • More than 100 new articles were drafted.
  • 14 articles were not carried over from the previous version.
  • 70 articles were updated such that this update is likely to have a significant effect on some manufacturers.
  • Only approx. 40 of the original 127 articles have remained practically unchanged.

New focus - Quality Risk Management (QRM)

QRM was named as a major driver for change and incorporated as never before in a GMP document. The word “risk” is used 92 times, in comparison with 20 times in the previous version. There are 15 separate references to “QRM” and “risk management”.

In order to put the focus on “Quality Risk Management”, the Pharmaceutical Quality System (PQS) was introduced. The new system should predominantly concentrate on the following points:

  • Integration of a risk management system into the product life cycle
  • Emphasis on experts’ process know-how
  • Obligatory root cause analysis in the event of errors
  • Separate process paths (manufacturing and finished medicinal products) with regard to con-tainers, etc.
  • Sufficient exchange of information between all parties who are involved in the release process
  • OOS investigations should not only concern the affected batch, but should also be extended to other batches.

A few potential “changes” have emerged …

In the concept paper, it was determined that there were no adverse impact on industry with respect to either resources or costs. The authors question this. The implementation of this Annex 1 will result in higher costs, even if there are only a few changes which are not already part of the current best practices.

Changes which are likely to lead to discussion, in the authors’ opinion, are the following:

  • The clear expectation of a formal, complete contamination control strategy. It is expected that a formal document or dossier which reflects the control strategy across the facility for minimising contamination in relation to sterile production is available.
  • Potential additional requirements for cleanroom classification - beyond the ISO requirements - in critical areas.
  • The potential aim of employing HEPA/ULPA filters in all classified areas (including grade D). This phrasing is not clear and will doubtlessly be discussed in the consultation phase.
  • An authorised occupancy list for material in air locks. The question arises of how this should look and how many lists there should be – validated?
  • Reference is made to technical observations in critical areas – in addition to windows , cameras can/should also be used – data protection?
  • The cleaning process for the cleanroom should be validated, which should be seen as positive!
  • Significant changes to the expectations of the various types of sterilisation. For example, the verification of biological indicators (BIs) is required before use. Detailed information about the equipment and records for sterilisations and autoclaves are likewise newly included. These requirements have already been implemented for some time – required by EN 285.
  • Significant changes to the expectations for visual inspection – defects must be recorded and captured in a defect library throughout the life cycle.
  • The sterility test applied to the finished product should only be regarded as the last in a series of control measures by which sterility is assured. What does the overview of the control strat-egy look like in order to be able to comprehend the evaluation in its entirety?

But there are also lots of new little details…

In comparison with the 2008 version, the draft of Annex 1 has crucial additional details on practically every topic. For this reason, the number of articles has more than doubled. In addition to the potential “changes” listed above, the compliance department can adapt to new details on the following topics:

  • Missing or displaced stoppers - microbial ingress studies to determine the acceptable stopper height displacement
  • Cleanroom clothing type and management (mandatory wearing of sterile face masks and sterile eye coverings in A/B and yes: disposable socks!)
  • Moist heat sterilisation
  • Trending of the results for environmental monitoring
  • Personnel supervision/qualification – gowning: supervision by the quality unit – note on quali-ty oversight
  • Isolators
  • Blow-Fill-Seal (BFS) technology , both rotary and shuttle-type equipment
  • Air flow pattern studies - with simultaneous validation across the entire A-surface
  • Aseptic process simulation (APS) (media fill)
  • Lyophilisation
  • Sterility test

There are also some new topics…

With more than 100 new articles, there are of course new topics. The most relevant are:

  • Single use technologies
  • Aseptic operator qualification
  • Application of quality risk management
  • Cleaning validation for cleanroom surfaces
  • Water systems - biofilm strategy
  • Pure steam
  • Utilities
  • Cooling systems
  • Compressed gasses
  • Closed systems

Next week, you’ll read in the second part of the detailed analysis which problems remain and which are even new, a comparison with the FDA Aseptic Guide and concluding thoughts on the new draft.


Concept paper on the revision of annex 1 of the guidelines on good manufacturing practice – manufacture of sterile medicinal products (EMA/INS/GMP/735037/2014)

Annex 1 – Manufacture of Sterile Medicinal Products (Consultation Document)




Ruven Brandes
Wirtschaftsgenossenschaft deutscher Tierärzte eG (WDT), Garbsen, Germany
Email: rbconsulting@gmx.eu

Fritz Röder
Merck KGaA, Germany
Email: roederfritz@googlemail.com