Epilogue to the CONCEPT HEIDELBERG Seminar: Cleanroom Technology in the Focus of the New Guidances "EU GMP Guide Annex 1" and "Aseptic Guide" by the FDA (Held in Mannheim on 4 November 2003)

GMP News No. 420

GMP News
24 May 2004

Epilogue to the CONCEPT HEIDELBERG Seminar: Cleanroom Technology in the Focus of the New Guidances "EU GMP Guide Annex 1" and "Aseptic Guide" by the FDA (Held in Mannheim on 4 November 2003)

The New Requirements: Analogies and Differences

The FDA published a new draft of the Aseptic Guide practically at the same time as the latest version of Annex 1 to the GMP Guide of the European Union came into force.

On the whole, these two documents are largely congruent - as to the GMP philosophy anyway, but also in many details. With one important exception: the requirements on particles ≥ 5 μm.

The changes in the revised version of Annex 1 to the EU GMP Guide focus on these large particles. However, these are still not an issue for the FDA: the Agency does not see any need for regulation.

The new draft of FDA's Aseptic Guide is clearly based on the international standards for cleanroom technology: the families of standards EN ISO 14644 and 14698. The European Annex 1, however, goes its own way with regard to particles ≥ 5 μm. This sets a questionable example: in an era of consistent internationalisation of the pharmaceutical business, such a lack of willingness to join the international harmonisation of the regulatory requirements can hardly represent a step in the right direction.

The international harmonisation also of the pharmaceutical regulations still has to remain the aim - an aim that is already pursued consistently on the level of cleanroom standards, i.e. the basis for the implementation of GMP requirements on cleanroom technology.

Practical Consequences of the Requirements on Large Particles

Whether they are comprehensible or not: for the time being, the pharmaceutical industry will have to get along with the new European requirements on particles ≥ 5 μm. From a mathematical viewpoint, the new limit for these large particles is a step in the right direction. Operationally, however, this will not bring about many changes: one extremely strict requirement has been replaced by another, not less strict requirement. It takes great efforts to prove its consistent implementation. Whether these efforts are justified from the risk perspective, remains an open question. And, unfortunately, the new specifications also leave some questions unanswered.

One thing that should be clarified by the authorities is the specification that the sample volume has to be 1 m3 of air. Does this requirement concern every sampling point in grade A/B areas separately, or can it likewise be interpreted as the sum of all sample volumes taken in one working area? On this point, unanimity among the European authorities seems to be lacking [1].

Another question that needs to be answered is whether the volume of 1 m3 of air has to be sampled by means of a single continuous measurement - with the results being printed out only after the discrete particle counter has analysed this air volume: this means one measured value every 36 min! Such a long sampling period would neutralise an advantageous capability of the discrete particle counter, which distinguishes it from microbiological sampling: that of providing immediate information about the particle state, to which the personnel can react without delay. If, in contrast to this, the total sample volume of 1 m3 can be considered to represent the sum of 36 individual 1-minute measurements of 1 ft3 = 28.3 lit each, the immediate information is not lost! Some inspectors interpret it in this way - but does this justify the assumption that all authorities will accept this interpretation?

Such questions are left unresolved by the imprecise new passages in Annex 1.

The seminar could not clear up uncertainties of this kind. So it is to be hoped that the authorities will soon meet the need for clarification.

Call for Action on the Part of the Industry

The pharmaceutical industry will have to review its procedures for the qualification and the process monitoring of cleanroom systems for the manufacturing of sterile medicinal products. However, in doing so, it should by no means sacrifice the strengths of the previous strategies on the altar of new specifications. One complex question will have to be answered: Which measures should be triggered off if single values exceed the limits for large particles? One will never be able to avoid the occurrence of large particles completely - so how can their relevance be interpreted from the viewpoint of product risk?

With regard to the scope for interpreting the new requirements, it is in any case advisable to discuss the revised procedures with the competent authority and to have them approved by it.

Preparing for FDA Inspections

Those who are familiar with the authorities on both sides of the Atlantic often hold the opinion that sites that have successfully passed an inspection by a European authority also have a very good chance of passing an FDA inspection. In the context of the above-mentioned facts, this can only be confirmed: With the specifications for particles ≥ 5 μm, the European Commission goes beyond the FDA requirements - in all other points the requirements coincide to a large extent. On both sides of the Atlantic, today, risk analysis is assigned a central role - everything else follows from it. All those who know their risks, control them and can provide convincing proof of doing so have created a sound basis for inspections by any of the two authorities.

Budapest: 5 Compliance Seminars


14-18 June 2004, Budapest, Hungary
5 compliance seminars, all of which can be booked separately, take place from 14-18 June in Budapest. 
The topics are:
> Cleanrooms
> Water Systems
> Project Management
> Pharmaceutical Engineering
> GMP Design of Equipment

Dr Hans H. Schicht, Seminar Moderator

[1] Fairchild St.: May 2003 revision of the Annex 1 to the EU GMP Guide: A case of "ratcheting up" regulatory standards or "just a misunderstanding"? GMP Review 2 (2003) 3, 5-7.


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