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

24 May 2004

Epilogueto the CONCEPTHEIDELBERG Seminar: Cleanroom Technology in the Focus of the NewGuidances"EU GMP Guide Annex 1" and "Aseptic Guide" by the FDA(Held in Mannheim on 4 November 2003)

The New Requirements: Analogies andDifferences

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

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

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

The new draft of FDA's Aseptic Guide is clearly based on theinternational standards for cleanroom technology: the families of standards ENISO 14644 and 14698. The European Annex 1, however, goes its own way withregard to particles ≥ 5 μm. This sets a questionableexample: in an era of consistent internationalisation of thepharmaceutical business, such a lack of willingness to join theinternational harmonisation of the regulatory requirements can hardlyrepresent a step in the right direction.

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

Practical Consequences of theRequirements on Large Particles

Whether they are comprehensible or not: for the time being, thepharmaceutical industry will have to get along with the new Europeanrequirements on particles ≥ 5 μm. From a mathematicalviewpoint, the new limit for these large particles is a step in the rightdirection. Operationally, however, this will not bring about manychanges: one extremely strict requirement has been replaced by another,not less strict requirement. It takes great efforts to prove itsconsistent implementation. Whether these efforts are justified from therisk perspective, remains an open question. And, unfortunately, the newspecifications also leave some questions unanswered.

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

Another question that needs to be answered is whether the volume of 1 m3of air has to be sampled by means of a single continuous measurement - with theresults being printed out only after the discrete particle counterhas analysed this air volume: this means one measured value every 36 min!Such a long sampling period would neutralise an advantageous capability ofthe discrete particle counter, which distinguishes it frommicrobiological sampling: that of providing immediate informationabout the particle state, to which the personnel can react without delay.If, in contrast to this, the total sample volume of 1 m3can be considered to represent the sum of 36 individual 1-minutemeasurements of 1 ft3= 28.3 lit each, the immediate information is not lost! Someinspectors interpret it in this way - but does this justify the assumptionthat all authorities will accept this interpretation?

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

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

Call for Action on the Part of theIndustry

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

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

Preparing for FDA Inspections

Those who are familiar with the authorities on both sides of theAtlantic often hold the opinion that sites that have successfully passedan inspection by a European authority also have a very good chance ofpassing 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 FDArequirements - in all other points the requirements coincide to a largeextent. On both sides of the Atlantic, today, risk analysis is assigned acentral role - everything else follows from it. All those who know theirrisks, control them and can provide convincing proof of doing so have created asound basis for inspections by any of the two authorities.

Dr Hans H. Schicht, Seminar Moderator

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


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