Stability Data vs. USP 36 ...What's the safest path?

Dear Paul,

Our company stores finished sterile injectable product in a controlled room-temperature warehouse. The products are manufactured to USP requirements and our packaging requires the product to be stored at room temperature or less than 25 degrees C. The alarm limits for the warehouse are 15°C to 25°C. They do not calculate MKT for continuous temperature monitoring probes.

Questions:

Is this strategy sound, given that the USP states in Section 10.30.60 Controlled Room Temperature that primarily the warehouse temperature should be maintained between 20°C to 25°C with excursions allowed between 15°C and 30°C? Interestingly, the last sentence in USP 10.30.60 allows storage of products in a cool place unless otherwise specified in the individual monographs. This seems to indicate a temperature controlled environment of 8°C to 25°C may be acceptable... We are uncertain. Here are our questions:

• How should we interpret Section 10.30.60?
• What are you commonly seeing out in the field?

And, one last question: does this storage requirement apply to room temperature raw materials? Any guidance you can give is most appreciated!
Kind regards,
D

Answers:

Paul writes:

Dear D,

This topic is a great one for the varieties of interpretation, and for the changes currently underway in how our industry addresses GDP. Let’s imagine that the USP came up with these designations as a way to facilitate communication about the need for temperature control. I actually believe that is true, but we can't know the motivations behind the USP, so I won’t call it a fact just yet. It was a very important step to establish standards, which is what the USP is all about.

So if I say “Room Temperature” you would know I was talking about 15-25°C and not the temperature of whatever room I happened to be in. This is useful up to the point that we start having products that don’t match the general characteristics these categories were meant to capture. And that is exactly the point we are at.

Here are the storage requirements of a real product used by a friend: According to the label it should be stored at 2-8°C, but if it gets warmer than 20°C, then it should be maintained at Room Temperature (20 to 25°C) for up to 14 days. However, it must NOT be put back into a 2-8°C environment. You won’t find a definition for that in USP.

In short, USP definitions should just be treated as just that - definitions. We improve our communication if we clearly refer to USP’s standards as “USP Controlled Room Temperature”, and if we are clear about our own designations. The unfortunate side effect is that we lose some common words because we will always be in danger of being misinterpreted if we say “Room Temperature.” The only time we should refer to the USP’s definitions is when we use them on label claims, or have established policies that clearly refer to the USP categories. If we do our stability studies on a drug, we are not forced to choose a USP definition for storage; it is an option. But if we choose that option then we are locked into using it, the same as we are locked into any label claims.

USP Chapter <1079> says that you can use your stability data to justify other storage conditions than what is on the label, but this is not a claim that is agreed upon internationally. The safe path is to stick to the label no matter what. And that safe path includes referring only to the label conditions at all times, and not to convenient USP definitions. I spoke to a lady at a one of the larger biopharm companies who said that they don’t even use the term Controlled Room Temperature (CRT) just to avoid the issues you are dealing with.

Basically, your strategy is sound, imho. You are storing the products to the label requirements. The USP definition is appropriately concerned with high temperatures and allows temperatures to 15°C that are part of normal operation. Clearly temperatures to 15°C (or even to 8°C) aren’t going to raise MKT over the maximum 25°C. And the “cool place” statement gives you flexibility on the lower limit down to 8°C, but the USP does come out and say that the storage requirements on the product label will “trump” the “cool place” claim. So it sounds like you could do 8 to 25 as a policy, especially if you had a procedural check in place to make sure that all your products were not labeled against the 8 to 15°C range.

To your question on what's common in the field, there is a movement to consider (or even redefine) room temperature to mean 2°C to 25°C. This is driven mostly by the difficulties of the actual temperature-controlled distribution process in planes and trucks.

As for raw materials, I would again refer you to the label claim. In this case, the label would be the USP or NF monograph for the substance in question.

I hope this was helpful! Let me know if it wasn’t, or if I have only created more questions...

Best regards,

Paul Daniel

Stay Tuned!

Next week Paul replies to an email from a validation professional who watched our webinar on Sensor Placement. The question is on the maximum distance between sensors and how to justify that distance. Paul writes: "You are the one who must justify sensor placement as sufficient for the environment you are mapping. And (unfortunately) saying 'Paul told me to do it this way' just isn’t a viable rationale and not likely to impress an auditor/inspector... ;)"

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