There is regulatory requirement that the cumulative time a frozen pharmacokinetic sample has been thawed – from the time it’s removed from the freezer to the time it’s returned – be documented. Freeze/thaw cycle data is not deemed sufficient alone, since a study sample might have been thawed for extended period of time.
Surprisingly, bioanalytical reference standards (drug and the internal standard) kept at sub-ambient temperatures has not been the focus of regulatory agencies. During the course of a study, the reference standard might be removed from the freezer or refrigerator 6 or more times during method development, method validations (including long-term matrix and solution stabilities) and study sample analyses. Not having a similar tracking system for reference standards that might degrade over extended exposure to room temperature, could easily put the entire study at risk.
The suppliers of reference materials that specify the material’s storage at sub-ambient temperatures do not, on the whole, provide any guidance on how long the standard may be exposed to ambient conditions over the course of its use. It seems somewhat disconcerting that the integrity of the reference standard that the entire study is based upon, is not ever questioned.
At KCAS, we employ more stringent documentation requirements and offer them as suggestions for best practices in dealing with sub-ambient reference materials:
RECEIPT AT ROOM TEMPERATURE. Ironically, reference materials that clearly state storage at refrigerator or freezer conditions may be shipped at room temperature. When this situation occurs, the Sponsor should always be notified in writing. If the standard cannot be resent due to limited supply and is used for study conduct, the study reports need to reflect this deviation. Only two companies (USP and Cerilliant), to my knowledge, that ship sub-ambient standards at room temperature have stability data to bridge transient shipments at ambient temperature.
TRACKING SYSTEM. Documenting the total time sub-ambient standards are outside of recommended storage temperature is straight-forward policy, but rarely done within industry. Anecdotal evidence shows that users of these standards may lack diligence in re-securing the standards promptly at their prescribed temperature. By employing a strong sample tracking system, compliance improves.
STANDARD INTEGRITY. Since suppliers rarely provide guidance on how long a sub-ambient reference material can be kept at room temperature, the question remains: How do we document standard integrity? Comparing the response of the standard in prepared solution form against the stock solution can be misleading. One recommendation is to portion off an aliquot at the first use to keep for later comparison. In the case of a biologic standard, where freeze/thaw cycles should be avoided, the entire standard should be aliquoted into multiple portions, so all subsequent uses of the standard undergo the same number of freeze/thaw cycles.
Thoughtful attention to the use and documentation of sub-ambient standards should be in place at any laboratory, in particular for GLP study conduct. KCAS understands how important of proper storage and use of all reference standards is and we believe this sets us apart from other laboratories.
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