17.03.2016 |

LOGFILE No. 11/2016 – What does the new Annex 1 have in store for us?

What does the new Annex 1 have in store for us?

by Thomas Peither, Maas & Peither AG

For some time there have been predictions concerning a new Annex 1 on sterile production in the EU GMP Guide. The rumours were confirmed at the ISPE Europe Annual Meeting 2016. For instance, the scope is to be expanded to include non-sterile products.


The draft is scheduled for publication in the autumn of 2016

"The current draft is presently before the GMP/GDP Inspectors Working Group (IWG) of the EMA and the PIC/S", according to Andrew Hopkins of the MHRA (= Medicines & Healthcare products Regulatory Agency, London). The draft will be released for public consultation in the autumn – if all goes according to plan.

Unfortunately, as Andrew Hopkins indicated in his talk (ISPE Europe Annual Meeting 2016 of 7 - 9 March 2016) in Frankfurt am Main, "according to plan" has not yet happened. Originally, the draft was expected to be at the IWG and PIC/S by October of 2015. However, the entire schedule was delayed by six months and now the document is not to be presented to the public until autumn.

The sixth revision of Annex 1 is not piecemeal. The multitude of regulatory changes requires the most extensive and thorough revision since the first publication took place in 1972.

Revision is urgently needed

The main reasons for the revision are:

  • For a general review from the last version of 2009
  • To take principles of Quality Risk Management (QRM) into account
  • To use new technologies such as closed single-use and disposable systems
  • To meet manufacturers' increasing wishes to stay abreast of the state of the art
  • To include innovations in production and testing that have appeared since 2009

Chapter 5 and Annex 15 make additional demands

The current version of Chapter 5 in the EU GMP Guide calls for taking microbiological risks in non-sterile production into consideration as well.

EU GMP Guide 5.10: "At every stage of processing products and materials should be protected from microbial and other contamination."

EU GMP Guide 5.20: „A Quality Risk Management process, which includes a potency and toxicological evaluation, should be used to assess and control the cross-contamination risks presented by the products manufactured. Factors including; facility/equipment design and use, personnel and material flow, microbiological controls, physico-chemical characteristics of the active substance, process characteristics, cleaning processes and analytical capabilities relative to the relevant limits established from the evaluation of the products should also be taken into account. The outcome of the Quality Risk Management process should be the basis for determining the necessity for and extent to which premises and equipment should be dedicated to a particular product or product family.“

5.21 calls for mitigating the risk of cross-contamination with the aid of technical and organisational measures. Pursuant to 5.21 the pharmaceutical manufacturer must test the effectiveness of this measure periodically according to set procedures.

Microbiological tests are likewise described in the new Annex 15 of the EU GMP Guide. All of this must be taken into account in the new Annex 1.

Additional changes result from the new version of ISO 14644:2015, which is already available in English.

IWG and PIC/S work closely together

The challenge was that not only the requirements and reservations of the supervisory authorities, but also those from the industry had to be met. Added to that were efforts to correctly understand these topics first, before they are implemented in the new version.

What has happened up to now? The concept paper was introduced to the IWG in September of 2014. This was followed by inclusion of the PIC/S and public consultation. A first draft was made in the subgroup, where it was discussed again. A second review is nearing completion. Therefore, the draft can soon proceed to the IWG and PIC/S.

Annex 1 applies to more than merely sterile products

What will change in the new Annex 1?

  • Annex 1 will be completely restructured.
  • The principles of risk management will be incorporated.
  • System operators should be distanced from the product and new technologies used.
  • Environmental and process monitoring

The new Annex 1 is not intended solely for sterile/aseptic products; therefore, a scope has also been added. It will be interesting to see what other products Annex 1 will also apply to – ointments, biotechnological products.

A separate chapter has also been devoted to the Pharmaceutical Quality System (PQS), utilities and environmental and process monitoring. The PQS in particular will take up the requirements from Chapter 1 of the EU GMP Guide and deal with the main quality processes of change management, root cause analyses and CAPA.

Virtually everyone expected that quality risk management would lead to changes in this Annex, too. The risk analyses are often very weak and are frequently approached incorrectly, according to Andrew Hopkins; this is where appropriate assistance is needed.

The system operator must be distanced from the product

We all know that human beings represent one of the most critical elements in the production of medicinal products. After all, we carry around as many miniscule living beings on our skin as there are people on earth. Therefore, common sense dictates that more (new) technolo-gies be used to mitigate this contamination risk.

This is why we shall encounter these technical solutions once more in Annex 1: RABS (= Restricted Access Barrier System), isolators, closed single-use and disposable systems, aseptic connections. Thus the riskbased approach also relates to the avoidance of problems through the appropriate use of technology.

Environmental and process monitoring

Environmental and process monitoring up to now have often been separate areas of responsibility. This situation should now come to an end. The Annex may bundle the various monitoring tools. The monitoring of living organisms and non-living particles is to be combined using process simulation.

The toolbox should cover all aspects and be used accordingly.

Monitoring here is viewed as being part of the QRM, since QRM is also intended to serve to newly define and/or improve monitoring. In this connection it is also important that trends be recognised early. Therefore, trending will also be included in Annex 1. Process simulation (Media Fill) should also be mentioned here.

Q&A for WFI

There will be no waiting for the new WFI requirements from the Ph.Eur; instead, the IWG will compile a Questions & Answers document for implementing new possibilities for WFI production. Thus, whilst the two documents are not interdependent, they will be linked together through the Q&A document.


Andrew Hopkins' remarks arouse curiosity about the new Annex 1 on sterile and aseptic production. It is to be hoped that the requirements are practicable and can be implemented. However, we must still be patient.


1. Andrew Hopkins, Regulatory Highlights (Annex 1), ISPE Europe Annual Meeting 2016, Frankfurt
2. Andrew Hopkins, EU GMP Guideline Changes Annex 1, ISPE Europe Annual Meeting 2016, Frankfurt


Thomas Peither
Maas & Peither AG, Karlstrasse 2, 79650 Schopfheim, Germany