Re Stability issues related to shipping
1. ICHQ1A [R2] section 2.2.7 requires stability under storage and
time conditions sufficient to cover storage, shipment and use-so this
is the regulatory basis for the requirement
2. The best way to do this is during the development phase and
include it as a separate section in the development report as
required by ICH Q8
3. As to details, current ICH just has general requirements for one
off testing during the development phase. For guidance purposes
however I would refer you to an older document-The FDA Guidance for
Industry 1998-Stability testing of drug substances and drug products.
Although this has been replaced by ICH what was excellent was that it
gave specific requirements for different dosage forms and it gives
details of thermal cycling [sometimes mistakenly called freeze and
thaw]
I quote from the guidance-----
A study of the effects of temperature variations particularly if
appropriate for the shipping and storage conditions of certain drug
products should be considered...........As part of the stress
testing.\the phackaged drug product should be cycled through
temperature conditions that simulate the changes likely to be
encountered......
Suggestions regarding thermal cycling is given.
4. My experience is that thermal cycling-three cycles normally, is
much more revealing than any accelerated testing-obviously Arrhenius
is inapplicable .
5. The testing is always related to physical changes in the product
rather than simple chemical assay---so for example for tablets it is
things like hardness, friability, disintegration and particularly
dissolution that would require testing.
Regarding the response of the regulatory authorities-as usual it
depends on the authority-and on the individual. My experience is that
if it is included in the development report in a reasonable way there
should be no problems. If it was ignored completely, then some
reviewers in countries who dont experience dramatic temperature
changes will probably not pick it up.
I trust that provides everything you require
Dr. Malcolm Ross
Generapharm-Training and Consultancy
Basel, Switzerland
m.ross@generapharm.eu
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