26.02.2019 | LOGFILE Feature 07/2019

A Summary of the GMP DIALOGUE at the GMP-BERATER Tage 2018

Annex 1 - Sterile and Aseptic Production Facing New Challenges

Annex 1 - Sterile and Aseptic Production Facing New Challenges

8 min. reading time | by Dr. Sabine Paris


The new Annex 1 of the EU GMP Guide is to be finalised in December 2018. The publication is planned for spring 2019. Which changes will surely come, where is there still a need for discussion? Where are your ambiguities?

In the following, you can read a summary of the questions and answers that arose during the discussion at our GMP conference, the GMP-BERATER Tage 2018. GMP inspector Dr Rainer Gnibl and Fritz Röder, Senior Manager Validation, Qualification & Engineering at Merck KGaA, responded to questions from interested GMP Publishing customers.

What is new in the draft of Annex 1?

The draft Annex 1 of the EU GMP Guide does not turn the "sterile world" upside down. But it does come up with some innovations and clarifications, which can be complex in the technical implementation.

In many aspects, the new Annex is more detailed than the current version. The sections on sterilisation, sterile filtration, "Form Fill Seal" and "Blow Fill Seal" as well as on lyophilisation are very detailed and give concrete instructions for action. New sections have been inter alia added on "Finishing", "Closed Systems" and "Single Use Systems".

Overall, the document is relatively difficult to read, as individual topics are taken up in different places, e.g. monitoring. The comments on "Sterilisation" should also be read in full. Single passages alone do not help, then important information is missing.

New is an explicit demand for a "Contamination Control Strategy". The control strategy should define control measures (technical and organisational) by means of quality risk management (QRM). The Annex lists the individual elements which must at least be documented. The elements themselves are nothing new. Anyone who manufactures sterile or aseptic products already has, for example, appropriate rooms and equipment, trained personnel and process validation. New is the holistic consideration of all process and environmental factors and the consolidation of the associated data in one document (see below).

The draft highlights very well the differences between classification, qualification and monitoring of clean rooms. These are points that have often been unclear so far and have led to discussions.

For the first time, concrete time intervals are specified for requalification. In future, grade A/B zones must be requalified every 6 months at the latest, C/D zones every 12 months at the latest.

The demand for QRM runs through the entire Annex. Critical aspects that should be included in the risk assessment are included in ABC lists. In this way, a structure is defined that facilitates risk assessment.

What is the difference between clean room classification and qualification?

The draft of Annex 1 defines the classification as follows (5.23):

Classification is a method of assessing the level of air cleanliness against a specification for a clean room or clean area device by measuring the airborne particle concentration. The classification is part of the qualification of a clean area.

The qualification therefore includes the classification of the room, but goes even further. Among other things, the quality of the walls, lighting and ventilation are also taken into consideration for the qualification. However, it certainly does not make sense to review these aspects every six months as part of the requalification process.

What is required for the requalification?

The maintenance of the qualified status of the clean rooms must in future be demonstrated at regular intervals (see above) or after changes to the equipment. Particles and microbiology should always be measured/tested. It is not required that all filter tests or smoke studies must be repeated. Rather, it is necessary to determine in a risk-beneficial manner which tests should be carried out in detail in order to prove the appropriateness of the premises.

Will HEPA filters also have to be installed in grade D clean rooms in the future?

The draft of the new Annex 1 requires that HEPA or ULPA filters be installed in all clean rooms. This also includes the grade D rooms.

Manufacturers who previously had no HEPA or ULPA filters in grade D rooms will have to retrofit.

What exactly does “Contamination Control Strategy” mean?

In the future, it is expected that a document implemented in the QM system will be written, which will bring together the individual components with relevance for sterility assurance.

A risk-based strategy is to be developed. For this purpose, it makes sense to carry out a gap analysis that brings together the most diverse elements of the pharmaceutical quality system and technical elements. The evaluation should lead to the implementation of measures that can close identified gaps.

In the document, the manufacturer should try to include links and references in order not to rewrite all qualification documents.

The Contamination Control Strategy must be regularly reviewed and adjusted.

What's new regarding personal hygiene, disinfection and airlocks?

In cleanroom grade D, appropriately disinfected shoes or overshoes must be worn. Grade C requires appropriately disinfected or sterilised shoes or overshoes. In the A/B area, a sterile face mask and sterile eye coverings will have to be worn in the future, i.e. a complete face cover.

The adjective "appropriate" means that the manufacturer himself has to make specifications, e.g. on the basis of monitoring data. It is not stipulated that the shoes have to be disinfected every time they go out and in.

A new requirement is the disinfection of drains. What the exact procedure looks like must be defined by each manufacturer. A definition could be, for example, that as a rule only the cover of the drain is cleaned and disinfected and the drain is completely opened at regular intervals as part of the requalification.

Disinfectants should be shown to be effective for the duration of their in use shelf-life. The critical aspects of contact time, type of application and surface on which the disinfectant is utilised should be evaluated. The requirement for the use of several disinfectants makes it clear that a sporocidal agent must also be used in any case.

Typically, airlocks for personnel are separate to those used for material. In addition, separate airlocks for entering and leaving the clean areas are recommended as generally desirable. However, both formulations (no "should"!) leave room for deviating concepts.

Only materials and equipment that have been included as part of the qualification list should be allowed to be transferred into the grade A/B area via the air lock or pass through. This requirement increases the documentation and establishes a systematic procedure. You must also specify how materials that are not on the list can be brought into the clean area.

Microbial monitoring: What has changed here?

In the table of permissible limits, the footnote is omitted which said that averages can be calculated. So far, for example, one of three tests in grade A rooms could be >1 CFU/m3 if the average result was lower than the limit value of 1. In the future every test from ≥ 1 will be a deviation.

How is the new requirement for PUPSIT (pre-use, post-sterilisation integrity test) to be evaluated?

The draft of Annex 1 requires an additional integrity test after sterilisation of the filter before using the sterile filter (PUPSIT). This new requirement met with strong criticism from industry. PUPSIT itself may increase the risk to the integrity and the complexity of the aseptic process by requiring the installation of additional aseptic connections, thus increasing the product contamination risk.

The PDA suggests emphasizing the need for risk assessment and reduction or replacement of the use of this specific method, depending on the risk assessment outcome.

The terms "serial filtration", "filter train" and "redundant sterilizing filter" were newly introduced. The final Annex 1 should also clarify whether PUPSIT is also required for all filters of the "filter train" (which would be almost impossible in practice) and how a "redundant" filter is to be defined. The actual necessity of additional filters should also be questioned. Isn't my process so safe after all?

Must an M-descriptor (as mentioned in EN ISO 14644) be used in the future for the measurement of ≥ 5 µm particles?

The new Annex 1 will no longer require the measurement of ≥ 5 µm particles for the classification of rooms. Only the particles ≥ 0.5 µm are to be measured. This is parallel to the valid EN ISO 14644-1 of 2015. However, for monitoring purposes, measurement of the 5 µm particles is still required in order to detect deviations at an early stage.

An M-descriptor can be used for the measurement of ≥ 5 µm particles, but is not a must.

Will there be a transitional period for the new Annex 1?

A transition period such as in a law or a directive is not usual for an annex to the EU GMP Guidelines. It is expected that the date for coming into operation will be 6 months after publication. In practice, there will de facto be a longer transitional period until all new requirements are implemented and actually queried by the authorities. In any case, it is advisable to start implementation as soon as possible after announcement of the final document. During GMP inspections you should draw attention to activities already carried out.


  • The draft of Annex 1 of the EU GMP Guidelines does not turn the "sterile world" upside down. However, some innovations will be complex to implement technically.
  • The demand for QRM runs through the entire document.
  • The differences between classification, qualification and monitoring are well worked out.
  • For the first time, concrete time intervals are specified for the requalification.
  • The total documentation effort increases. For example, a new "Contamination Control Strategy" is required.

Recommended reading

Comparison of the EU GMP Guide Annex 1 - Version 2008 to Draft 2017, Fritz Röder, Maas & Peither GMP-Verlag, 1st edition 2018

Sabine Paris


Sabine Paris, PhD
Senior GMP Expert / Chief Editor of the GMP Compliance Adviser
E-Mail: sabine.paris@gmp-publishing.com