Hi, Happy New Year and welcome back to my occasional blog on topics connected to extractable and leachables. If you have not come across the terms extractable or leachable then this may seem like a strange title for a blog to start 2022 with but perhaps you can bear with me, and I will explain a little as I go.
The world of E&L (Extractables and Leachables) has been part of pharmaceutical development for at least 25 years now and my experience began around the same time. Yes I am now very old.
As this topic area has matured there are terms which have come into use. The obvious ones to mention here are:
Leachable: (As defined in USP 1663) “foreign organic and inorganic chemical entities that are present in a packaged drug product because they have leached into the packaged drug product from a packaging/delivery system, packaging component, or packaging material of construction under normal conditions of storage and use or during accelerated drug product stability studies.”
There is also a definition found in ISO10993-18 which is relevant to medical devices which (in my opinion) a little easier to understand.
“Substance that is released from a medical device or material during its clinical use.”
Extractable: (As defined in USP 1663) is, “organic or inorganic chemical entities that are released from a pharmaceutical packaging/delivery system, packaging component or packaging material of construction and into an extraction solvent under laboratory conditions”
In essence, these two terms and their use have over that 25-year period are the subject of my prose today. Although these words have been defined above. I have to say I don’t think we have spent enough time in defining these words (only 25 years!). We still regularly confuse and misuse them.
This brings me to my main point and the link to the title. Because extractable is linked to a study which is conducted in the laboratory (the extractable study) there has been a proliferation in linked terms to describe what these studies are. In particular we now have the terms exaggerated extraction, exhaustive extraction, accelerated extraction and simulated extractable (sometimes leachable) studies.
The aims of these extractable studies are surprisingly opaque. But in general terms they attempt to provide a mechanism to predict what patient exposure to substances (impurities) which enter the drug product either from its packaging, its manufacturing environment (due to materials in use) or a delivery device used to deliver the drug product (for a combination product). In the case of a medical device, it in reality provides the only mechanism to do this. But for a drug product it is also possible to test the formulation itself for the presence of these substances (as leachables).
So, returning to the terms; exaggerated, exhaustive, accelerated and simulated, why have they come into use? It would seem to me (and this is an entirely personal opinion) that they are to a large degree an un-necessary complication of the term extractable study. But perhaps what it indicates is a lack of clarity on how extractable studies are both designed and how their results are then used.
Let’s look at the term exhaustive extraction (extractable study). The aim is direct extraction of a material with a solvent to the point where there is no further production of substances (extractable) to assess. However, in reality this point is highly variable because choosing a different solvent and extracting at different temperatures or with different sample preparation or methods of extraction will drive very different results. Additionally, you are left wondering how this study might relate to patient exposure too.
Moving to exaggerated extraction, this directs you to use solvents and conditions which “result in a greater number or amount of chemical constituents being released as compared to amount generated under clinical conditions of use” (ISO10993). Accelerated extraction are “whose duration is shorter than the duration of clinical use..” (ISO10993) but are expected to once again give useful information.
Finally, we have simulated extractions, since we have generated data above which is different to the expected clinical exposure we have now created an extraction that is expected do that. Are we really clear then what the purpose of the other kinds are? Too many choices.
I wonder why people are confused. I wonder what the regulators really want. Perhaps what we have here is a lack of something?
It would seem to me all these studies point to a lack of knowledge and understanding. If we truly had confidence that the correct experiments were being conducted then I think these terms would disappear. An experienced analytical chemist should be able to justify why the experiment conducted will predict patient exposure (this may require more than one experiment but perhaps not) but I see little benefit in naming extractable studies unless they help in that regard, especially if they add little or no benefit. So, when conducting extractable experiments in 2022, which one will you choose?
Happy 2022 everyone and I look forward to comments and questions on this or all thing E&L related. On a almost completely unrelated subject I have become mildly addicted to James Hoffman’s YouTube channel all about coffee (hence the picture above). He knows all about extractable experiments check him out here