Hi everyone, I thought for my Maven E&L blog this time I would touch on a subject which comes up regularly when we are discussing extractables & leachables and was a topic also heard recently mentioned at Smithers European conference on E&L too. That is the relationships between key contributors when we undertake extractable or leachable studies.
There is a phrase, “…it takes a village…”, and this sentiment is very much true when working in this topic area. Collaboration is at the heart of any extractable or leachable work undertaken. Indeed, it is the wide skillset required which makes this topic area so interesting (at least to me).
One of the most important collaborative efforts is between analytical chemist and toxicologist. I thought I would use this blog to share some of what I consider to be the key points in this relationship to make it a success. If you think I have miss an important point feel free to comment below or reach via my E&L forum at www.mavenEandL.com/forum or message me.
There are several points in development of a new drug product or during an existing products lifecycle, where analytical chemists and toxicologists might come together:
Screening of new or replace materials either for manufacturing equipment, packaging or delivery devices.
Support to the development process for a new product, either in clinical or final marketing application
As part of change control after product approval, to ensure safety of the manufactured product is maintained
In each of the examples, there is the possibility of a requirement for a safety evaluation of the potential for leachables and thus a need for analytical chemist and toxicologist to work in harmony to conduct an evaluation of substance (leachable) risk.
Below is a highly abbreviated process map of the requirement.
As you can see, I have created alongside the process as RACI, which for those who not come across one is just a term for who does what. It’s always good to be clear about this but in E&L especially important. As we move through an extractable or leachable study you can see that accountabilities and responsibilities change. As you might expect, analytical chemist taking the lead in creating an extract, analysing the extract and then processing the raw data into meaningful output.
I want to highlight two steps at this point, identification and quantitation. These are both highly important for the subsequent safety assessment so in these steps I believe the collaboration is at its most important.
Safety assessment by the toxicologist is reliant on knowing two things.
What something is
How much is the patient exposed to it
Therefore, the analytical chemist must be very mindful of this as the results of the analysis are produced and then reported. These two points seem simply but in reality, there are lots of decisions and choices wrapped up in these two points. Some of the more important ones are:
Decisions and choices on detection and quantitation limits
Choices made during design of the experiment can obviously effect these, so right from the beginning there needs to be a dialogue to agree how much will be extracted, what dilution or concentration of the extract will occur and how this will influence the outcome. That is what will be reported and what will not depend on these choices.
When the data is reported, how will you identify the substances. Will you use reference materials, if not will you be confident in the identity given? What criteria, are you going to use when you report a substances identity?
It is important to remember the toxicologist cannot provide a safety assessment of any kind without some kind of identity, however an incorrect or inappropriate identity can profoundly affect the conclusions which might be reached.
For example, Structure A and Structure B have the same molecular formula and therefore nominal mass and therefore its possible that one might be mistakenly reported for the other.
But Structure A is controlled substance MDMA and Structure B is not!
Both these have very similar EI Mass Spectra and retention times.
When thinking about quantitation, it might be possible to under or overestimate the amount present.
Generally, overestimation is less of a concern since the safety assessment would therefore be overestimating the risk. However, an underestimate of the amount could have serious consequences especially if this meant a substance not being reported for a toxicologist to safety assess.
Overestimation can be possible if an incorrect response factor is used to calculate amount so extra care and discussion is advisable to avoid that scenario. This is a complex area since response factors are not always available due to lack of a reference standard and relative response factors are sometimes used instead, utilising the response relative to an internal standard.
So in each case, it is vital that analytical chemist and toxicologist work in tandem and the analytical chemist when reporting the results makes clear of the potential limitations around the data that have been produced. Indeed if the toxicologist is to construct a adequate and compete assessment and more the analytical chemist can inform around what substances are and are not will allow the assessment to consider possibilities for data poor substances such as read across approaches.
Bringing this blog to a close, I hope you agree befriending a toxicologist shouldn’t be a chore but enlighten self-interest for all involved!
If you want to carry on the discussion, please join me at www.MavenEandL.com/forum