Good morning everyone and welcome to today's APS Choctaw sponsored by iff entitled how

to ensure pharmaceutical product ever it is my pleasure to introduce you to our two speakers
this morning the first is Katherine Katie hulet who is an application development and
Innovation scientist focus on pharmaceutical applications for iff where she is responsible for
educating and enabling customers on the performance enhancing benefits of performance
excipient in 2016 addition to a BNI from R&B where she was responsible for dancing
modified-release drug delivery platforms including application testing product launches our
areas of expertise includes and quality by Design Katie has a BS Material Sciences spider
from Stanford University and earned his PhD in Material Sciences and Engineering from
Northwestern University we also have Mohammed kedir degree in Pharmacy and
pharmaceutical analysis and a PhD in drug delivery and formulation design Mohammed has
over 12 years of experience in the pharmaceutical industry and Academia particularly and
formulation design and delivery of various business cards with enhanced knowledge and
expertise and controlled sustained delayed and pulsatile delivery he mostly worked in R&D
and possesses extensive experience in Prescott I can combine device development from
proof-of-concept clinical trials he previously published and presented in multiple conferences
across the globe it is my absolute pleasure to introduce you to wonderful speakers

Have a chance to speak to everyone about the I'd like to start off this without a brief
description and overview of our objectives for today are we in our past know that excipient
variability can find a very important role in determining the overall variability within final
pharmaceutical dosage forms standing at controlling this excipient impact up front when you
believe that I can save an enormous amount of time and effort on the behalf of our
customers and help prevent challenges. I'm and ultimately helped to develop robust
formulations in our talk today we'd like to give you a sneak peak on Ark ubb here quality by
Design efforts that we have internally we're working to try to understand how we can avoid
extreme variability within our excipient products in pharmaceutical products formulators start
with just a high-level overview of some of the key concepts for Quality by Design as as we
see that risk-based approach to product development efforts from conception through
commercialization and I would like to highlight and emphasize the word deliberate there and
this is not something that should just be done early or at random and if thrown in here and
there but really if it is involved in delivering corporated into your development process and
that really helps you to get the best results the ideas that you can design your process to
help consistently deliver the end product one of the key components of Peabody is really
understanding the impact of the starting materials and process parameters on product
quality if you look at the diagram on the left we know that are highlighted here these include
the variability within your starting materials such as I'm as well as the process the goal is
really to be able to understand the sources of variability and build in ways to tolerate it into
your process that you can improve robustness obviously has Mexican manufacturer our
focus is newly on the variability big stadiums but we do want to emphasize that all of these
sources are important so just to give you an example of the type of studies that we would do
with our materials the first. I'll talk about is looking at the critical material attributes of our
hydrogel forming of cell or hpmc we know that this material can play a very critical role and
particularly the formation of the gel is critical to regulating the release of a PI from The Matrix
look at the bottom of the triangle here but it is kind of our biggest chemistry by changing the
chemistry we can impact the solubility of the Palmer and the temperature at which the
hydrogel Swarms versus a 2019 or something along those lines The Next Step would be
viscosity of molecular maid service gosti is an indicator of molecular weight and we know
that as you have a higher viscosity or a larger molecular weight you're going to only have
longer chains as long as humans are more likely to get entangled and therefore are slower
to disentangle at the erosion front. Just you a doll that is a little bit stronger and more slowly
over time particle size is also something that can be quite critical or a scam see that will
enable you to have HCMC uniformly dispersed through your photos that says the percolation
fresh holes and really missed means that you have enough hpmc spread throughout your
tablet so that you have a contiguous swollen jowl with again will give you the most robust
performance and last but not least we also consider HP to be a Critic glass Butte for 8 p.m.
see because we know that I'd Roxy Pro Bowl content impacts the formation of that cell so
how do we look at these critical attributes internally we are constantly trying to understand
how they can impact modified-release performance and we typically look at model systems
in our lab we do have a sample Ivory that we're developing based on honor in several
studies for the best performance one example of this is shown in the Grass at bright of this is
looking at the map of felt safe around so this task is approximately 4,000 and a system using
a diaphragm I'd if we look at materials or Walmart with increasing HP values we do see a
step feeds our performance an HP round eight just showed us the way in which this
Ashtabula could have a significant impact on performance and it's not a formulation and
studies like this allow us to better understand how are materials might behave example of
how we go about to finding critical material attributes for one of our products I'd like to take a
little bit of a step back and talk more generally about the different ways in which we can
examine except and variability on the slide we get into more complex analyses they help
same time by better understanding variability we know that there are a lot of different
strategies that you can use to examine or variability of experience and other products and
we've based our work on discussions that we've had with customers and information that
we've gleaned from Whitaker and the talking to others in the industry. We'll start by looking at
some data so for example and this case we would take a few years worth of production data
and randomly select the wrestling 20 passes at 1 for amateur at a time but it doesn't
understand for the max Walmart internal studies as well as the development of our
community library The Next Step from there is not the bottom left so this would be a
multi-year analysis and this case is the visual way of examining out a few different variables
like compared to one another so in this case were typically looking at a critical material at 3
on on a graph this allows us to see where these values fall within our our specifications
ranges and also understand how these different attributes might correlate another Elvis was
a great visual message we can also apply some Advanced statistics to this the really help us
drive in and understands the variability in statistics would include something like principal
component analysis for a multivariate analysis does that sound I will turn it over to my
colleague Muhammad they're described more in-depth how these type of physical announce
these can be applied for our products take it away thanks Gucci and s*** to you have
described pipe to look into the statistics and how we can use this I would a tribute to your
porch and help you understand the visibility and looking for more analysis and the size of our
own data and make some internal devaluation based on income. What is techniques used
for this purpose for multivitamins is equal to use for the problem solving Elsa house to
display in the classification relationship control chart to a more agreeable at once I complain
Alice's like amox and computers or if you want to empty out more detail if there's any issues
here's an example on the corner where we can see an example of principal component
analysis show the dates I sell what you know if you have multiple variable data than you can
change into and screw and what was the scores be called them and sports you can put them
on the Facebook complete analysis graph as you can see on the left hand side Vision will
see you know how the data is spread and how the benches are actually spread within a
confined space and how far away is the average value to actually see if there's any group
can see that there are two distinct groups there now so we have some outside as well if you
want to work there get out into the daytime you can use emotes in which is on the right hand
side of the slide but I will discuss them little bit later as well so here is an example of a word
Masterson grade materials that we have or issues of the day here in this one and we can
see that it shows that the material has been produced a consistently for the last 8 years
Amazon data is included in the 95% of control and some of the moms because at 5% do you
know what kind of material do we have also it helps us to understand the Russian cycle or if
there are any outliers if he look at the next light we will see how we use this data and
augmented with the 3DS self in this particular case we have taken example of development
have six patches and when we compare them against the rest of the last eight or nine years
we can see that you know I was in the principal company is ready but evenly distributed and
go beyond and test it again the people who don't know about the directional selection and
the second and third and fourth time I've ever been observed that you know actors very nice
very nice profile I'm trying to say is definitely not all the time that we do samples to to test
your design space as well as we discussed there are other ways where we can let you know
when I'm leaving to the data is one of those examples where we can we can do and as an
outlier but this segment that particular batch and see where this appears different when we
tested it against us we have some of Pi do you know and some are pretty close to the
average value of any group other batches this kind of like these two houses to see whether
you know those parameters which are a different of the native to the functionality of the
material or something else and then it's house with to bring those permitted into the
foundation yourself to see whether it can pack it in long-term or not this is just a quick
overview of the presentation thanks Mohammad for that sad that overview I'd like to talk a
little bit about our process of digitalizing our manufacturing plants around even greater
control and consistency we can do this by taking many years of manufacturing data
variables in similar to the manufacturing process the information that our model improve
product quality and performance Christopher has resulted in a significant Improvement in
product and process stability what is this what is this look like the type of modeling so in the
past and we were we were lying very heavily on process variable so kind of your typical
control parameters that you might expect Engineering Process at which is a sample were
able to run analysis results and return that to the plant they could be a couple of hours which
is sometimes the run without knowing kind of how how things are going and if you're having
any sort of significance by incorporating the vibration of these models were really able to
have a much greater responsiveness and to what's happening in the plant so we've got a
synthetic variables as we call them similar to say the p c 1 PC to incorporate it is part of the
parameters that we're getting from our from our across the seas us they're running we can
see those it's the model and get this is enabled us to have an improvement that's over 10%
In First Class Prime increase in production the table at the bottom is an example of what's
playing at the planets so the red and yellow stones are highlighting areas for our buses
Engineers to focus on these don't necessarily mean that we are producing material out of
respect or have a significant deviation but they are areas where we have the potential put in
place as part of these models able to quickly addressed these during during the
manufacturing process and as a result these efforts or I can process in our goal is to
continually improve the quality of our products through looking at the the variability doing
statistical analysis and really trying to continually optimize the models that we have in our
overall production I thought I would just like to what better work with him and even as we
move forward into the future designing ones that are used to make them that helps I'm taking
all of that the knowledge that we are scams from our own internal Focus were able to to
better support our customers during their formulation development or any sort of trouble she
may have one of the things I do want to emphasize is that we acknowledge that this does
require discussion and a close partnership between excipient suppliers such as ourselves
and pharmaceutical manufacturers or formulation developers and we we think that that is a
very key component of that. I'm in a lot of time and effort we want to have those discussions
with customers to the most robust formulations possible if you have questions or concerns
around your formulation says well I think we have a few minutes for questions so I will turn it
back over to Stacy and me and her are contact information here thank you both so much
that was really very interesting and informative we have a couple of quick questions here
first question if my company is using his new to DVD how would you recommend we start
okay sure there's quite a few ways that you can you can start working in this space the
important things to have on your team who understand the mystics data out of work with it
right one of the variability so you need to make sure that you've got either Consultants or
people on your team who can help you to examine the variability within your own own
product and as I mentioned certainly we encourage you to reach out to the manufacturers of
your recipients your apis any of the products and equipment that you're working with John in
the morning that they have around their their process has to start a dialogue as you begin to
examine your own products great thank you this question would you recommend testing
samples that fall outside the 95% CI to understand the effect of extremes on a formulation
perform similar to testing specific range experience yeah and I think this is where that the
discussion is important so certainly you do you need to understand you're getting material at
the extremes and so how you define that depends on on you know who you're working with
her highest on that but certainly outside that confidence interval is a good place to try to
identify what material I want to also depends on the factors which met so that you know what
you're doing outside of confidence interval it could be something we know which is not very
significant development thank you Muhammad next question how do you identify the right
critical material attributes and ensure that you're tracking them are you sure this is where a
lot of the data analysis comes in handy man having having to work looking at a where there
is a possibility I'm discussing that again with with manufacturers and doing the type of of the
other statistical you're having people who are familiar with it and do those analysis is that is
very critical there people that came in if I have minitab software can this be used for
multivariable predictive modeling there is a specific you can use like a SIM card into a or
maybe a lower level you can use minitab to do some houses but if you really want to do like
VCA type analysis that was the last of our questions I want two of each half of a PS and all
of our ten days I want to thank our speakers today and we hope that you will join us again for
a future each how this child has been recorded and will be available on the aps website in
the inspection by this Friday of this week and you will have access to it in the next 90 days
so thank you all for participating we really appreciate it and hope to see you again soon you
can now disconnect from the webinar