-Taking a Shot at Interpreting the ´Temperature´ Issue-
Quality management requirements for transportation (EU) of Drug Products are mainly laid down in the Good Distribution Practice Guidance for Medicinal Products for Human Use Chapter 9 Transportation, and in EUDRALEX Volume 4 EU GMP Guide Annex 15, Section 6 Verification of Transportation.
The way both texts are worded has led to quite a spectrum of interpretation in the GxP regulated industry, with some companies trying to make reasonable sense of what is said, and some taking the freedoms of interpratation a bit far. My experience is, that this is especially true for the question of temperature during transport. A rather common understanding is:
„Assurance of adequate temperature conditions during transportation can be managed risk-based with the support of Drug Product stability data“.
This approach typically attempts to organize the transportation of Medicinal Products without or with very limited temperature controlled containers or vehicles. And the justification for this are stability data. In other words: Companies know that the way they transport their products may or certainly will(!) lead to temporary excursions of the permissible temperature conditions. But they still carry out such transportation, arguing that stability data allow for this practice. But is this true?
The first general question to be asked is: Can it really be aligned with Pharmaceutical Quality Assurance to put so much effort in qualified storages and temperature controlled warehousing of Drug Products, only to then dump all this overboard during transportation? Not really. Why should it? Because „…it is just transportation“? Transportation can take a very long time – several weeks actually, with many contributing parties, and it carries much higher risks than a product simply sitting in a manufacturer´s or distributors´s qualified warehouse. It does not make much sense to think a finished drug product could be treated in a riskier way during transportation than while being stored locally.
So why is it that in reality pharmaceutical companies allow for calculated temperature deviations during transport? One reason is a common interpretation of the EU GDP Guide for Medicinal Products (2013/C 343/01) Section 9.1:
Does not this text give me the perfect right to plan transportation based on stability data? At first glance yes. Yet an honest reading shows that the second highlighted section is actually not specifically referring to temperature conditions, but to anything that may impact product quality – and there are lots of other factors that can (Annex 15 talks about this more)! So a risk-based definition of alternative temperature conditions during transport (of all things really!) is likely not at all meant here.
More importantly, when it comes to the section before, the question is: Who has the right to say what are ´acceptable´ limits for temperature conditions and what limits are not acceptable any more? Most readers would think that the pharmaceutical company can make that decision. However, a statement from the EUROPEAN COMMISSION HEALTH AND CONSUMERS DIRECTORATE-GENERAL appears to most strongly contradict that. Upon a question on precisely this issue – apparently from a contract transportation service – the EC´s answer is quite clear (EU Ref. Ares(2014)968163 – 28/03/201):
From this it seems really obvious, that not even the product manfuacturer can assume the right to simply allow a transportation temperature other than the conditions for storage. An exception might be thinkable if separate limits for transportation are actually registered in the marketing authorisation. But other than that – probably not. There are other section in the GDP Guide and also in the Annex 15 text that present the reader with the same issue, for example GDP Guide 9.2:
Here again: This seems(!) to allow for freedom when it comes to temperature conditions during transport, because it uses words like ´risk assessment´ and ´temperature controls´, and talking about a determination the readers should make themselves. But the text really does in fact not(!) lift any expectation of keeping in line with registered storage conditions. I may see this in the text if I want to see it. That is reading into it, not taking out o fit. But the words and the context – in my opinion – do not carry such a meaning.
That means: A prospective planning of transportation (based on stability data), that calculates or basically allows for known to happen temperature deviations during transport, is not GMP- and not GDP-compliant. It is taking the risk-based approach too far.
Interesting to me when communicating with various companies on this over the years: Some try everything they can to deny this, and I respect that. Yet others have no problem, and live a different approach to comply with these texts. For sure there are forces wrestling with this in the industry. And of course some push for the easier solution. Time will tell how regulators and supervizing authorities will do with this.
What I personally would like to see in the future are GxP guidance texts that speak much more clearly to matters like this. Because the way especially the GDP Guide is written seems rather elusive on various details. If the law givers want compliance (and of course they do), they need to provide more clarity on what is expected.
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