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What would people most like to see in a future ICH document on E&L?

Updated: Dec 10, 2020

It's the New Year and with it comes New Year resolutions. So I wanted to write something forward looking and optimistic. Last year ICH decided to endorse a proposal for creation of a future guidance document on E&L. I was lucky enough to be part of the group involved in that and hope that this year it can be progressed further

So what could be more optimistic than seeing a clear consensus on a much needed guidance document for extractables and leachables. I thought I would list a few on my personal wish list for an ICH document. If you want you can add to the list and hopefully it might make it on to the list for consideration. Well that my New Year's resolution. Don't let a good idea go to waste, action it. If you want to leave a comment, please do.

Here is the action list (in no particular order):

  • Agreed list of extractable studies (with definitions)

Let's write down what needed from an extractable study, give it one name (not 3-4) then move on

  • Agreed design element for a good leachable study

Too many people are confused here, let's agree a minimum requirement (sure you can add more), let define or reference the storage time, temperatures, number of batches etc. People have managed this for stability testing let's do the same for leachable studies

  • Agree key terms

We have too many terms being created for the same activity - let's agree a list of major terms then try not to create any new ones

  • Let use the best of what is already out there

Like the key terms, I would like to see the minimum of changes in what has already already been published on how to conduct E&L studies. PQRI, USP, ICH, EP, and ISO all have created content. Let use that to harmonise and create one standard approach. Surely good scientific practice is universal?

  • Make sure that high quality risk assessment is at the heart of guidance

Risk Assessment can come in many forms (A fuller discussion in a future blog entry) but there are at least two major risk assessment which I believe should be part of an ICH Q3E guidance.

In no particular order these are:

  1. The technical risk assessment of container packaging or the manufacturing process materials

  2. the toxicological risk assessment of substances seen in studies

The technical risk assessment is a must to define the activities required and the activities not required (with justification) in any science-led risk based approach.

Equally, when the well constructed studies are completed, the toxicological risk assessment of the substances seen is a major step to determine drug product safety.

Now we are getting into some of the more difficult ones.

Let's agree a set of thresholds for safety risk assessment.

There are in place ICH thresholds for mutagenic impurities (M7), Solvent (Q3C), Metals(Q3D) and general pharmaceutical impurities (3A,3B). Together with processes for development of PDEs (See ICH Q3C, Appendix 1) so many of the potential leachables already have either PDEs or a threshold approach . If ICH M7 covers the mutagens, then we are left with non-mutagenic substances.

I have seen proposals to adopt Cramer classifications. Cramer classification (Cramer et al. in Food Cosm Toxicol 16:255-276, 1978) are based on work from Cramer then refinements from Kroes and Kozianowski (Toxicol Lett 127:43-46, 2002) and others. These a probalistimic (i.e. risk based) thresholds of toxicological concern based on structures of substances. Toxtree has been created to capture the approach, and can be seen here.

These and other in-silico predictions either of likelihood of toxic end-point or building thresholds are surely part of the solution here, rather than continuing to conduct rather meaningless small scale in-vivo tests more related to implantation than leachables in a drug product?

Whilst Cramer levels were developed from oral exposure data (which is quite common for most toxicological risk assessments) modifying factors are typical applied to account for added levels of uncertainty. It is interesting to compare and contrast this with level suggestions in ICH Q3A & 3B and the apparent disconnect which appears there for non-mutagenic process impurities in a drug API which frequently have higher thresholds than the Cramer based ones but as reactive intermediates of a synthetic process may be very similar in substances seen as leachables (or indeed the same substances). I hope ICH Q3E will attempt to resolve some of these disconnects and propose some pragmatic and science based thresholds for leachables of all kinds.

I am sure I am not going to solve all the potential issues which ICH Q3E might address here! But please comment and add to this dialogue to ensure your opinion is noted. Visit and leave a comment or two. You will also find my 2019 blogs there too.

Until next time....

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