Regulatory Open Forum

Hi Everyone,

If I define the storage condition as room temperature, that seems easy. In accelerated aging (per ASM F1980) the T_RT will be set 25 Celsius, and in real time the devices will kept in a typical 20-25 celsius room temperature range.

But what to do if the storage condition has an upper and lower limits, say -10 to 40 celsius?  Will the T_RT in accelerated again be set to 40 Celsius? and how do I validate in the lower limit?

And more challenging is how to validate in real time the entire range -10 to 40 celsius?

Also, I'd appreciate hearing some risk based consideration for setting storage condition with upper and lower limits.

Thanks,

Shimon 

For accelerated aging testing based on the ASTM F1980 standard, the TRT (Test Reference Time) should typically be set to the upper limit of the storage condition. In this case, it would be appropriate to set the TRT to 40 degrees Celsius.

One approach is to utilize environmental chambers or storage facilities equipped with temperature control systems that can accurately maintain the desired temperature range. minimum of 3 lots have to be tested, One approach is to utilize environmental chambers or storage facilities equipped with temperature control systems that can accurately maintain the desired temperature range. Temperature monitoring systems can also be employed to ensure that the storage conditions remain within the specified range throughout the real-time testing duration.

upper and lower limits need to be set and it's important to have stability data to support it, especially the lower limit, freeze thaw may be required based on what is the device. temperature range selection it's better to get study data for   +/-5 to make sure that kind of deviation is acceptable, if not it has to be mentioned on the label.

Hi Everyone,

If I define the storage condition as room temperature, that seems easy. In accelerated aging (per ASM F1980) the T_RT will be set 25 Celsius, and in real time the devices will kept in a typical 20-25 celsius room temperature range.

But what to do if the storage condition has an upper and lower limits, say -10 to 40 celsius?  Will the T_RT in accelerated again be set to 40 Celsius? and how do I validate in the lower limit?

And more challenging is how to validate in real time the entire range -10 to 40 celsius?

Also, I'd appreciate hearing some risk based consideration for setting storage condition with upper and lower limits.

Thanks,

Shimon 

For accelerated aging testing based on the ASTM F1980 standard, the TRT (Test Reference Time) should typically be set to the upper limit of the storage condition. In this case, it would be appropriate to set the TRT to 40 degrees Celsius.

One approach is to utilize environmental chambers or storage facilities equipped with temperature control systems that can accurately maintain the desired temperature range. minimum of 3 lots have to be tested, One approach is to utilize environmental chambers or storage facilities equipped with temperature control systems that can accurately maintain the desired temperature range. Temperature monitoring systems can also be employed to ensure that the storage conditions remain within the specified range throughout the real-time testing duration.

upper and lower limits need to be set and it's important to have stability data to support it, especially the lower limit, freeze thaw may be required based on what is the device. temperature range selection it's better to get study data for   +/-5 to make sure that kind of deviation is acceptable, if not it has to be mentioned on the label.

Hi Everyone,

If I define the storage condition as room temperature, that seems easy. In accelerated aging (per ASM F1980) the T_RT will be set 25 Celsius, and in real time the devices will kept in a typical 20-25 celsius room temperature range.

But what to do if the storage condition has an upper and lower limits, say -10 to 40 celsius?  Will the T_RT in accelerated again be set to 40 Celsius? and how do I validate in the lower limit?

And more challenging is how to validate in real time the entire range -10 to 40 celsius?

Also, I'd appreciate hearing some risk based consideration for setting storage condition with upper and lower limits.

Thanks,

Shimon 

Hi,

I agree with the TRT based on the upper limit. It is even part of some notified body checklists to proove that the calculation of accelerated aging time is based on the delta between accelerated aging temperature and TRT.

However, I am not aware about a standard or formula to conduct this calculation for negative temperatures. Can you point me into the right direction how such a calculation or evaluation could be conducted? 

Thanks,

Michael

For accelerated aging testing based on the ASTM F1980 standard, the TRT (Test Reference Time) should typically be set to the upper limit of the storage condition. In this case, it would be appropriate to set the TRT to 40 degrees Celsius.

One approach is to utilize environmental chambers or storage facilities equipped with temperature control systems that can accurately maintain the desired temperature range. minimum of 3 lots have to be tested, One approach is to utilize environmental chambers or storage facilities equipped with temperature control systems that can accurately maintain the desired temperature range. Temperature monitoring systems can also be employed to ensure that the storage conditions remain within the specified range throughout the real-time testing duration.

upper and lower limits need to be set and it's important to have stability data to support it, especially the lower limit, freeze thaw may be required based on what is the device. temperature range selection it's better to get study data for   +/-5 to make sure that kind of deviation is acceptable, if not it has to be mentioned on the label.

Hi Everyone,

If I define the storage condition as room temperature, that seems easy. In accelerated aging (per ASM F1980) the T_RT will be set 25 Celsius, and in real time the devices will kept in a typical 20-25 celsius room temperature range.

But what to do if the storage condition has an upper and lower limits, say -10 to 40 celsius?  Will the T_RT in accelerated again be set to 40 Celsius? and how do I validate in the lower limit?

And more challenging is how to validate in real time the entire range -10 to 40 celsius?

Also, I'd appreciate hearing some risk based consideration for setting storage condition with upper and lower limits.

Thanks,

Shimon 

Thank you Michael for your input.

As far as I understand this, aging is accelerated by higher temperatures. That is why you usually only test your upper temperature limit. Lower temperature is expected to slow down the aging processes... this is the whole idea behind ASTM F1980 standard. 

However, in some special cases too low temperature might be damaging to the device.  In such a case, I assume, analysis of materials comes into play and may need to do a more complex real time study to cover both ends of the temperature range.

Shimon

Original Message:
Sent: 14-Jul-2023 16:54
From: Michael Hottner
Subject: Validation of storage condition in a shelf life study

Hi,

I agree with the TRT based on the upper limit. It is even part of some notified body checklists to proove that the calculation of accelerated aging time is based on the delta between accelerated aging temperature and TRT.

However, I am not aware about a standard or formula to conduct this calculation for negative temperatures. Can you point me into the right direction how such a calculation or evaluation could be conducted? 

Thanks,

Michael

------------------------------
Michael Hottner
Köln
Germany

Original Message:
Sent: 14-Jul-2023 10:05
From: Rajeswari Devanathan
Subject: Validation of storage condition in a shelf life study

For accelerated aging testing based on the ASTM F1980 standard, the TRT (Test Reference Time) should typically be set to the upper limit of the storage condition. In this case, it would be appropriate to set the TRT to 40 degrees Celsius.

One approach is to utilize environmental chambers or storage facilities equipped with temperature control systems that can accurately maintain the desired temperature range. minimum of 3 lots have to be tested, One approach is to utilize environmental chambers or storage facilities equipped with temperature control systems that can accurately maintain the desired temperature range. Temperature monitoring systems can also be employed to ensure that the storage conditions remain within the specified range throughout the real-time testing duration.

upper and lower limits need to be set and it's important to have stability data to support it, especially the lower limit, freeze thaw may be required based on what is the device. temperature range selection it's better to get study data for   +/-5 to make sure that kind of deviation is acceptable, if not it has to be mentioned on the label.

------------------------------
Raje Devanathan
Amerisource Bergen
TPIreg, Innomar Strategies
Senior Manager - Regulatory Affairs, Medical Devices
rdevanathan@tpireg.com
3470 Superior Court
Oakville ON L6L0C4
Canada

Original Message:
Sent: 14-Jul-2023 01:23
From: Shimon Vaknin
Subject: Validation of storage condition in a shelf life study

Hi Everyone,

If I define the storage condition as room temperature, that seems easy. In accelerated aging (per ASM F1980) the T_RT will be set 25 Celsius, and in real time the devices will kept in a typical 20-25 celsius room temperature range.

But what to do if the storage condition has an upper and lower limits, say -10 to 40 celsius?  Will the T_RT in accelerated again be set to 40 Celsius? and how do I validate in the lower limit?

And more challenging is how to validate in real time the entire range -10 to 40 celsius?

Also, I'd appreciate hearing some risk based consideration for setting storage condition with upper and lower limits.

Thanks,

Shimon 

Hi Shimon<o:p></o:p>

You are right. It is very material-dependent.<o:p></o:p>

The Arrhenius equation used in ASTM F1980 is a good predictor of the aging behavior of typical medical devices and sterile barrier systems stored at room temperature, but there are limits to how far it can be extrapolated.<o:p></o:p>

Some further reading if you're curious about the general problem:<o:p></o:p>

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398581/<o:p></o:p>

https://www.osti.gov/servlets/purl/1361646<o:p></o:p>

Some materials can be irreversibly damaged by a single excursion to a high or low temperature, crystallizing or melting, regardless of age. Some structures are damaged by cycling between high and low temperatures, with the materials expanding and contracting. Humidity levels, light exposures, pH and other factors can also be significant. Sometimes vibration or shocks from handling at extreme temperatures may have an effect.<o:p></o:p>

You can't test everything, but an analysis of your product and its expected conditions of storage, handling, and use can help you guess the likely failure modes so you can decide what to focus on.<o:p></o:p>

Thank you Michael for your input.

As far as I understand this, aging is accelerated by higher temperatures. That is why you usually only test your upper temperature limit. Lower temperature is expected to slow down the aging processes... this is the whole idea behind ASTM F1980 standard. 

However, in some special cases too low temperature might be damaging to the device.  In such a case, I assume, analysis of materials comes into play and may need to do a more complex real time study to cover both ends of the temperature range.

Shimon

Hi,

I agree with the TRT based on the upper limit. It is even part of some notified body checklists to proove that the calculation of accelerated aging time is based on the delta between accelerated aging temperature and TRT.

However, I am not aware about a standard or formula to conduct this calculation for negative temperatures. Can you point me into the right direction how such a calculation or evaluation could be conducted? 

Thanks,

Michael

For accelerated aging testing based on the ASTM F1980 standard, the TRT (Test Reference Time) should typically be set to the upper limit of the storage condition. In this case, it would be appropriate to set the TRT to 40 degrees Celsius.

One approach is to utilize environmental chambers or storage facilities equipped with temperature control systems that can accurately maintain the desired temperature range. minimum of 3 lots have to be tested, One approach is to utilize environmental chambers or storage facilities equipped with temperature control systems that can accurately maintain the desired temperature range. Temperature monitoring systems can also be employed to ensure that the storage conditions remain within the specified range throughout the real-time testing duration.

upper and lower limits need to be set and it's important to have stability data to support it, especially the lower limit, freeze thaw may be required based on what is the device. temperature range selection it's better to get study data for   +/-5 to make sure that kind of deviation is acceptable, if not it has to be mentioned on the label.

Hi Everyone,

If I define the storage condition as room temperature, that seems easy. In accelerated aging (per ASM F1980) the T_RT will be set 25 Celsius, and in real time the devices will kept in a typical 20-25 celsius room temperature range.

But what to do if the storage condition has an upper and lower limits, say -10 to 40 celsius?  Will the T_RT in accelerated again be set to 40 Celsius? and how do I validate in the lower limit?

And more challenging is how to validate in real time the entire range -10 to 40 celsius?

Also, I'd appreciate hearing some risk based consideration for setting storage condition with upper and lower limits.

Thanks,

Shimon 

Hi Everyone,

If I define the storage condition as room temperature, that seems easy. In accelerated aging (per ASM F1980) the T_RT will be set 25 Celsius, and in real time the devices will kept in a typical 20-25 celsius room temperature range.

But what to do if the storage condition has an upper and lower limits, say -10 to 40 celsius?  Will the T_RT in accelerated again be set to 40 Celsius? and how do I validate in the lower limit?

And more challenging is how to validate in real time the entire range -10 to 40 celsius?

Also, I'd appreciate hearing some risk based consideration for setting storage condition with upper and lower limits.

Thanks,

Shimon 

Hi Shimon:

There is data supporting the use of accelerated aging by temperature for assessing long term integrity of a sterile barrier: ASTM F-1980, Arrhenius Equation et al. However this is often extended to the products contained within the pack, on an unsupported presumption that the sterile barrier seal is always the weakest part.

If you are thinking about a product validation, you need to consider the materials, manufacturing processes and sensitivities of the product. For example PVC welds can be more susceptible to radiation (including light), electronics to humidity etc, than the pack seal. You need to be clear if your study is merely to support the sterile barrier life or also the "fitness for purpose" of the product at that point.

ASTM F-1980 is tempting to use as a "one size fits all solution" and for many products it will give a good indication of realtime aging performance, but for others it won't - so my advice is to be very careful and precise in designing any accelerated time validation. 

Take care

Neil

Hi Everyone,

If I define the storage condition as room temperature, that seems easy. In accelerated aging (per ASM F1980) the T_RT will be set 25 Celsius, and in real time the devices will kept in a typical 20-25 celsius room temperature range.

But what to do if the storage condition has an upper and lower limits, say -10 to 40 celsius?  Will the T_RT in accelerated again be set to 40 Celsius? and how do I validate in the lower limit?

And more challenging is how to validate in real time the entire range -10 to 40 celsius?

Also, I'd appreciate hearing some risk based consideration for setting storage condition with upper and lower limits.

Thanks,

Shimon 

Hi Shimon:

There is data supporting the use of accelerated aging by temperature for assessing long term integrity of a sterile barrier: ASTM F-1980, Arrhenius Equation et al. However this is often extended to the products contained within the pack, on an unsupported presumption that the sterile barrier seal is always the weakest part.

If you are thinking about a product validation, you need to consider the materials, manufacturing processes and sensitivities of the product. For example PVC welds can be more susceptible to radiation (including light), electronics to humidity etc, than the pack seal. You need to be clear if your study is merely to support the sterile barrier life or also the "fitness for purpose" of the product at that point.

ASTM F-1980 is tempting to use as a "one size fits all solution" and for many products it will give a good indication of realtime aging performance, but for others it won't - so my advice is to be very careful and precise in designing any accelerated time validation. 

Take care

Neil

Hi Everyone,

If I define the storage condition as room temperature, that seems easy. In accelerated aging (per ASM F1980) the T_RT will be set 25 Celsius, and in real time the devices will kept in a typical 20-25 celsius room temperature range.

But what to do if the storage condition has an upper and lower limits, say -10 to 40 celsius?  Will the T_RT in accelerated again be set to 40 Celsius? and how do I validate in the lower limit?

And more challenging is how to validate in real time the entire range -10 to 40 celsius?

Also, I'd appreciate hearing some risk based consideration for setting storage condition with upper and lower limits.

Thanks,

Shimon 

Hi Everyone,

If I define the storage condition as room temperature, that seems easy. In accelerated aging (per ASM F1980) the T_RT will be set 25 Celsius, and in real time the devices will kept in a typical 20-25 celsius room temperature range.

But what to do if the storage condition has an upper and lower limits, say -10 to 40 celsius?  Will the T_RT in accelerated again be set to 40 Celsius? and how do I validate in the lower limit?

And more challenging is how to validate in real time the entire range -10 to 40 celsius?

Also, I'd appreciate hearing some risk based consideration for setting storage condition with upper and lower limits.

Thanks,

Shimon