John and Tony!
The inspector was right in enquiring about the product stability at the low temp of 15 C!
John, what was the dosage form? The formulation?
Some products such as some liquid formulations may undergo physical changes (turbid, opalescent, increased number of subvisible particles, etc,,,) when cooled to 15 C. Knowing this phenomenon and if found to be temporary will lead to accounting for it in the storage label and in the instructions for use.
The thermal cycling study (e.g. between -10C and 25C) mentioned by John refers usually to testing at end of the incubation period and generally does not monitor the intermediate behavior/appearance during the on-going thawing process.
The fact that the excursions between 15C and 30 C are allowed in the USP definition does not relieve you from actually verifying the behavior of your product at these "extremes" (15C and 30C) just as you would do after excursions at 40C. On the contrary, the designation "CRT" implies that the stability of your drug product at 15C, 30C and 40C have been investigated or at least addressed.
John, your Inspector surely expected to see a short-term stability study at 15C as part of the so-called "stability studies to support shipping/distribution". These studies are more and more undertaken in addition to the formal storage stability programs as defined in ICH Q1A.
Raphael (Raphy) Bar, Ph.D.
From: Pharmaceutical Stability Discussion Group [mailto:[log in to unmask]] On Behalf Of Tony Cundell
Sent: Friday, March 24, 2017 6:00 PM
To: [log in to unmask]
Subject: Re: [PSDGLIST] Stability data to support excursions to 15°C
This is a brainless request. Does the audit have any concept on the relationship between temperature and chemical reactions and microbial growth?
On Fri, Mar 24, 2017 at 8:56 AM, McGrath, John (QA) <[log in to unmask]>
> Hi Stabilitarians,
> We have drug product labelled per CRT : "Store at 25°C excursions
> permitted 15°C to 30°C".
> An inspector requested to see our stability data to support 15°C.
> We have stability data at 30°C but not at 15°C.
> Our thermal cycling data (-10°C) has no aging.
> Has anyone else faced questions supporting 15°C on product label?
> Based on our 25/60 data, does Mean Kinetic Temperature idea not
> support "excursions 15C to 30C" or is there other guidance?
> Thank You
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