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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changes: one extremely strict requirement has been replaced by another,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.
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