Annex 1 modified

GMP News No. 127

GMP News
20 August 2001

Annex 1 modified *** Annex 1 modified *** Annex 1 modified

On June 7, 2001 the EC announced the modification of paragraph 42 of Annex 1 ("Supplementary and revised guidelines for the manufacture of sterile medicinal products").

What does paragraph 42 of Annex 1 deal with?

It is the paragraph that defines standards for media fills in aseptic methods.

And what is new about it?

The revised version now requires the inclusion of various interventions performed routinely in production of media fills. In addition, worst case situations are also to be covered within the media fills.

Also new is the definitive requirement for the initial validation by means of three consecutive runs per shift as well as the revalidation after significant changes:

  • to the ventilation system (HVAC)

  • to the number of personnel shifts.

The other original instructions with respect to a revalidation (changes to the equipment and/or the process) remain unchanged.

The intervals for a periodic revalidation are now given as: every six months.

Now "zero contamination" is given as the target of the media fills, in addition every contamination should be investigated. The acceptance criterion for the contamination rate of less than 0.1% with a 95% confidence interval is, however, still valid, despite the "zero contamination" requirement.

The requirement for the establishment of alert limits and action limits is also new. These two terms have been included along with "media fill" in the glossary of the EC-GMP Guide.

The alert limit is that limit which informs one at an early stage if the normal conditions have been deviated from. This deviation then leads to an investigation without definitive corrective actions necessarily having to be taken.

According to the glossary, when the action limit is exceeded an immediate search for the error should be initiated, followed by the initiation of corrective action.

At FDA, too, the topic of media fill is becoming more and more the focus of inspections. Among other things, lack of training in aseptic production is meanwhile already the fifth most frequent topic of warning letters (internal evaluation of the fiscal year 2000 by Concept Heidelberg, see GMP-News of July 18, 2001).

Where can one now get help with the topic of media fill?

ISO 13408-1 gives very detailed criteria for the aseptic production of medicinal products. This standard contains, inter alia, the information included in the modifications of paragraph 42. For instance, in this standard you also find concrete information about interventions which should be simulated during media fills as well as information about the contents of media fill records. It also describes alert and action limits on the basis of the 0.1% contamination rate as well as instructions for dealing with failed media fills.

ISO 13408-1 is, of course, also known at FDA.

However, this standard is already undergoing revision again.

Please click here if you want to download the new Annex 1.

Sven Pommeranz, 


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