Hi - there was an interesting query last week from Poland about this
as follows:
Dear Colleagues,
I would like to ask you for advice. Do you have any ideas how to
designed stability studies for bulks?
My questions concern:
- Holding Time for bulk tablets and
- influence of transport conditions (temperature \ humidity) on drug
product quality\shelf life.
- Are there any guidelines specifying how stability studies for bulk
products (granulate, cores and film coated tablets) should be
designed\performed? (I mean temperature, humidity range, testing
period required)
I checked GMP and CPMP guidelines and found nothing :-( ?
There is a small piece on on-going stability in Chapter 6 of NtA Volume 4:
http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-4/pdfs-en/2005_10_chapter_6.pdf
and
CPMP/ICH/2736/99 says:
2.2.7. Storage Conditions
The long term testing should cover a minimum of 12 months' duration
on at least three primary batches at the time of submission and
should be continued for a period of time sufficient to cover the
proposed shelf life. Additional data accumulated during the
assessment period of the registration application should be submitted
to the authorities if requested. Data from the accelerated storage
condition and, if appropriate, from the intermediate storage
condition can be used to evaluate the effect of short term excursions
outside the label storage conditions (such as might occur during
shipping).
- Is it possible to predict, how storage of bulk product in bin for
some period of time or transport conditions, influence drug product
shelf life\its stability? Do we have to perform any specific
stability experiments? Is it acceptable to use a known data set
(results obtained at ACC, LT conditions) to infer information about
future data? Is it acceptable to use satistics for calculating
allowed Holding Time or influence of transport conditions on drug
product shelf life?
Can I use for such calculation: Arrhenius equation and this way
predict influence on above mentioned factors on drug product
stability and its shelf life? Is this proceed acceptable from
regulatory point of view?
P.S.
Please find enclosed to this e-mail some literature data.
http://www.medscape.com/viewarticle/472699
Kind Regards
Aleksandra
Aleksandra Zaborska
Regulatory Affairs Specialist
I have a few thoughts on this, as follows:
In my experience, bulk storage containers have been used for storage
of intermediate products that are retested before use in final
manufacture so assuming they comply with specification they can be
used.
As far as bulk packing of tablets in containers is concerned, I
haven't seen any specific legislation so I'm going to take a flyer
and make a guess!
If the product is to be packed elsewhere into finished product
primary and secondary packaging I would expect that a bulk container
could be used but the materials used in the containers packaging
would have to undergo the same types of analysis as the primary
packaging used in the finished product. CoAs, methods of analysis and
validation would be needed to support their use. I assume the product
is only contained within bulk containers for a relatively short
period of time during the manufacture and packaging process (moving
from one site to another).
Stability data will need to be generated on the bulk packed product
to cover the longest period of time expected to be exposed (at
real-time conditions). The FPS tests would be applied to the bulk
packed product; I'd also assume the same principles apply: 3 batches,
ICH conditions. Therefore the holding time of bulk-packed tablets
could be as long as the shelf life of the product, or longer if the
packaging materials offer a better barrier (don't see the point in
that though).
I do have experience in the bulk shipping of tablets from India to
the UK. In this situation the bulk packed tablets were exposed to
widely varying temperatures and humidity. To assess the suitability
of the transport method we included logs within sample batches
recording temperature and humidity. This data was then available for
provision to any Agency questioning the integrity of the shipping
process. This type of data may be required for submission; the number
of batches and the conditions I'd expect to be dictated by the
extremity of the conditions experienced during shipping.
If the concern relates to intermediates or uncoated cores, I'd expect
some retesting before use in the next manufacture stage but whether
this needs to be every batch, one in three, one in ten, etc, I don't
know and I suspect depends on how extreme the shipping conditions
are. With retesting of intermediates it might be possible to forgo
testing of the packaging materials if the supplier of the drum is
able to confirm its properties and the type of container is commonly
used for bulk packaging.
And:
See CHMP note for guidance on start of shelf life for drug product -
hold time for bulk tablets. Can also propose stability data to
justify if hold time is long.
Also use stability and validation data to justify transportation
(specific transportation study may be required) under defined
conditions and controls etc.
3rd one - this is part of dev pharm and validation general guidance
and depends on dosage form, excipients and importantly API
characteristics (ie. sensitivity to light, moisture, air etc etc).
I hope that this information proves useful. I'll continue to forward
our comments as they come in.
Kind Regards,
Pete
Peter Lassoff, Pharm.D.
Vice President, Europe
PAREXEL Consulting
Peter.Lassoff@parexel.com
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