The Irish Medicines Board (IMB) has drafted a document titled: Guidance Note on Control and Monitoring of Storage and Transportation Temperature Conditions for Medicinal Products. The document can be accessed at the following address: http://www.imb.ie/uploads/publications/8123404_Draft_IMB_Guidance_Temp_monitoring.pdf
The closing date for provision of comments to the IMB is January 27, 2006.
Heavy on recommendations and detail for validation requirements of equipment and processes. Solid documentation and training are also stressed. A bit ambiguous when it comes to storage definitions. My comments are as follows: I would be interested to hear what you think.
Overall, pleased to see this document closely mirrors PDA TR39 in many respects, in that it strongly emphasizes validation requirements for storage facilities, equipment and packaging, and qualifying distribution practices and processes and that the IMB advocates thorough documentation, procedures and training. Most of my comments are suggestions for clarity.
Page 4, paragraph 4:
"...validation is required in order to assess the worst-case condition." While it is generally accepted and understood that conditions within the distribution chain can vary, and that the environment changes significantly according to season, and that other variables can have an influence on cold-chain distribution, it is not possible to ascertain "worst-case" conditions. It is not practical, or even possible to validate packages in distribution to an indefinable, unquantifiable limit. Rather, a determination can be made through empirical or historical data - or better yet, by recent data collection, the range and limits of environmental influences. From those ranges and limits, a statistically relevant determination and confidence level of acceptance of the anticipated extremes within the distribution environment can be made.
The terms "worst-case" and "worst-case scenarios" are frequently referenced in this document. Each instance could be changed to more clearly and quantifiably define the authors intent.
For example: Section 3.1, Page8, bullet point 9: "the location of recording sensors/probes with respect to potential worst-case scenarios identified during temperature mapping studies" could read: recording sensors/probes are to be placed in locations with the greatest temperature variability as determined by temperature mapping studies.
Section 3.4 Freezers
There is no reference to tolerance or accuracy for the temperature recording equipment for freezers - as is mentioned for refrigerators.
There is no reference in the validation of freezers that addresses defrost cycle duration or temperature limits and if excursions in storage temperature, outside that of the product, are allowable or acceptable during the defrost cycle.
The assumption that storage at -20°C and -60°C are the same, as mentioned in a previous comment submitted, is not clearly understood among those performing stability studies, particularly when it comes to biologics. Some large molecule, long protein strand biologics are known to be sensitive to long-term storage at certain low temperatures. For example: They may perform acceptably when stored at -20°C and at -80°C but produce a variability in results at temperatures in between, -30°C to
-50°C. The stability of the drug is unaffected at these "pass through" temperatures but unstable after long dwell exposure.
I agree with the previous comments; omit the reference which describes freezing as "any temperature below 0°C". It is confusing in that it is a description and not a definition. If it is necessary to provide a definition for freezing, the use of a recognized standard can be made such as USP's -25°C to -10°C.
3.5 Transportation - cold chain products
In addition to route and time of transportation, mode of transportation is equally significant and should also be considered when arranging cold-chain distribution.
"The receiver should place the products in an appropriately refrigerated area immediately upon receipt."
It is unclear as to whether the goods should be unpacked from their distribution packaging first, or not.
Refrigeration upon receipt of small parcels in insulated shippers with gel packs, could negatively impact the product contents to where the internal temperatures of the package(s) are driven below the minimum allowable. Thus, putting the product at risk.
This should be considered as part of the overall cold-chain validation. Receipt, unloading and storage time limits should be determined, proceduralized and verified in actual practice by the "responsible person."
Page 12, paragraph 4:
"The maximum length of time for which the product is maintained within the required temperature range within the insulated container should be determined. This time period must be determined for "Worst Case" conditions, i.e. the extremes of temperature..."
Again, worst case can be substituted with "expected extremes" or "anticipated extremes". Something that is finite, definable, documentable and defendable.
Goods transported in representitives' vehicles, by postal services (and ambulances, etc., not mentioned in this document) have unique environmental exposure outside the scope of "normal" distribution. For clarity, it should be addressed and in actual practice it will likely require separate validation.
3.5.2 paragraph 2:
Is this grammatically correct?. "Temperatures within loads of products at risk from freezing..." shouldn't it be "...at risk of freezing..."
paragraph 5:
"This includes temperature mapping within the container or transit van to determine hot/cold spots and under "Worst Case" conditions, i.e. when the container/van is loaded to capacity and at the extremes of seasonable temperatures."
If it were only that easy and clear-cut. Numerous trailer/van mapping studies have shown that capacity loads are not necessarily the extreme condition and extremes of seasonal temperatures is an indefinable moving target and cannot be calendarized. Clearer instruction without changing the intent could read: taking into account load variation, and anticipated extremes in seasonal temperatures.
(What little is known and documented regarding trailer mapping shows that trailer condition, travel duration, travel direction, changes in altitude, road heat, sun, wind, and floor heat generated by friction from tire rotation, all contribute to the performance of, and temperature variability within the trailer.)
3.6 Returns "
The IMB position is that cold chain products may only be returned to saleable stock where there is no reasonable possibility that the cold chain has been compromised." What is reasonable? Without documented evidence how can this be determined?
It is unclear as to what is meant by the use of "a unique monitoring device attached to the product" . Does this mean a temperature data logger? An RFID tag? An imbedded chemical indicator? There are inherent problems with any of these options and they do not provide a practical solution.
It sounds to me the IMB's position on the matter is no position.They do know of anyone who can meet their requirements listed but they don't say you can't return goods.
Section 4: Controlled Ambient Temperature Storage
The phrase "Controlled Ambient Temperature Storage" serves no other purpose other than to title this section. It is defined but not used anywhere else within the document. For purposes of clarity, it should be changed to eliminate the contentious and ambiguous tem "ambient". The definition for controlled ambient temperature storage is more succinct, and the title could read: "Storage for Products Not Requiring Cold Storage or Freezing", with a subsequent definition for room temperature and controlled room temperature as determined and limited by their calculation of MKT.
Paragraph 3:
Controlled Room Temperature should be defined. The term "Ambient Temperature" is unacceptable as it is arbitrary and can mean any temperature, but "Room Temperature" can be acceptable if defined by temperature limits (such as USP)
The recent proliferation of shipments identified as 'controlled ambient' is misleading and misguided. Although the intent is to protect the package contents from extremes in temperature, 'controlled ambient' implies that the environment through which the package travels is controlled, when ,in fact, the environment within the package is being controlled - or buffered - against extremes. "Protect from exposure to extremes in temperature" is what is intended and should say so.
