How Relevant is Stress Degradation to Real Life Pharmaceutical Stability?

so let’s look at some stress testing
data from 15 compounds so it because of the questions around I won’t tell you
all the background but the questions around Genotoxic mutagenic impurities
there there is interest to know how accurate we were in in our stress
testing where we going crazy in producing way too many degradation
products or were we reasonable. So we looked at stress testing results from 15
compounds that we had marketed formulations so that means it made it to
phase 3 or on to the market. So we looked at the API and the drug product stress
testing results that means we looked at the API and there all those acid-base
oxidative and we and we looked at the drug product under accelerated heating
humidity and I’ll show you those conditions in a slide, and we looked at
both the full accelerated and long-term stability results with and without
optimum packaging. So that’s a pretty complete data set around all these
compounds and here’s the stress conditions that over the years represent
essentially the way we get when I was at Lilly the way we settled in on and
conducted stress testing so for hydrolytic acid base we would look at P
at a minimum pH 1, 7 and 13 sometimes we would do it in increments of 2 to pH
units to give us more data, but one at a minimum 1, 7 and 13 up to 70 degrees C
for up to one week, that’s about as long as our experience would say you need to
go. The solid state we don’t advise 70 degrees C and 75 percent relative
humidity so you got a high and low humidity and wait 2 or 3 weeks 3 weeks
is probably as long as you need to go but both the drug product and the API.
For photolytic is the stress for photo stability is recommend two to five times
the ICH confirmatory guideline and we always use option 1 which is a little
bit more rigorous exposure it’s a simulating sun versus
indoor lighting which is a more complete exposure and we would do both the solid
state and in solution for the API and just the solid state unless it was a
parental, and for oxidative this is where most companies that I run into have
holes in their procedures. Most people do a peroxide stress and that’s you know
something like 0.3 percent hydrogen peroxide room temperature one to three
days we would only look at that for the API, but I recommend that you’re leaving
big holes in your study if you don’t use a radical initiator and if you don’t do
a transition metals, but the two most important ones are peroxides and radical
initiation. We conducted all of these studies was to stress it to the endpoint
regardless of whether there was degradation observed so if you didn’t
see any significant degradation at the end of those time points and conditions
it’s stable to acid or it’s stable to whatever and we would define major we
would focus in on the compounds that were produced as major so you can get a
lot of grass a lot of small peaks and if you focus in on all of those then you
really have an explosion, so you we really think it’s best to focus in on
the major ones and you can have an algorithm for defining them and we did
that by the 10% of more of the total degradation so that is if you have a API
that lost 20% 10% or more that would be 2% right and then you have to be you you
only focus in on the peaks that are at least 25% of the largest individuals. So
if you had 10% degradation and you had one peak at 8% and two peaks at 1% well
those 1% peaks are 10% of the total degradation 1% divided by 10 times
100 but they’re not 25% of 8 so you can kind of get rid of some of that’s
how you keep the stress studies from exploding and get you focused focusing
in on the ones that are most likely to be realistic and this has been
documented in a couple of publications and I include them here if you
look for more detail. So looking at those 15 compounds here’s what it looked like
from our knowledge space was a hundred and twenty four total compounds out of
15 products and so it’s not exorbitant its about 8.2 major degradents per drug
and drug product, so it’s not an excessive number some people would think all you must be looking at 30 well if you’re looking at the grass they’re very
small degradation products maybe so but if you focus in on the major it’s not
that many and if you look then so that’s our knowledge space our design space if
you want to call it would be what can form in that drug product under the
long-term storage condition or the accelerated storage condition, but not
really packaged as we’re finally going to have it and that that went from one
hundred and twenty four to forty five and then what does actually form in the
final drug product when you package it well it’s 39. Now it looks like 45 to 39
is not a very big decrease so it tells you that the accelerated is pretty
predictive but the levels of those 39 are coming down substantially so we
might not have had 39 had we not known there were 45 by that I mean they were
below maybe what we would have identified but now that we know that
that peak was there we can say oh yeah at point 0.06% there’s that peak at 0.03
percent there’s at peak so it but it gives you an idea that that kind of
stress procedure is pretty good now I’m not trying to claim that it always is
inclusive of everything like this this was it was a perfect subset but our
procedures at Lilly evolved I was responsible for stress testing for my
entire career so they evolved over the years because I
got caught with surprised surprises and that’s how we ended up developing these
procedures so that we wouldn’t anymore getting caught in late phase development
is very expensive and embarrassing and job threatening potentially.
So my assertion is that what we want is we want our stress testing studies to
have more degradation products than long-term we don’t want it to just
produce what’s going to happen because we want confidence that our method will
detect all all of the long-term deg we wanted to be a subset so that we know
that we’re comprehensive. Why do we want to reveal all of them it’s difficult to
anticipate which of those major degradation products that you observe in
stress testing are going to be the ones that are relevant and you need a method
that can detect it.

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