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A custom designed sequential workflow
Kate Llewellyn, Product Development, GlaxoSmithKline
The Product Development Challenge
Integrated DoE and process understanding
Pre-term labour (prior to 37 weeks gestation) is the largest
single cause of infant morbidity and mortality and it is
frequently associated with long-term disability. GSK221149
(Retosiban) is an oxytocin receptor antagonist in development
for the treatment of pre-term labour.
A chemical stage consists of several unit operations that must be studied individually to identify potential
CPPs and then studied together in order to develop a design space. Each unit operation was investigated
using custom design technology in order to fully integrate prior process understanding in designing
experiments.
The product development challenge is to manufacture supply
of drug substance for Phase III clinical trials, commencing in
2015.
The final chemical stage (Stage 6) in the synthesis of the drug
substance is the coupling of GSK277221A with morpholine, in
a stereoselective reaction, which yields drug substance in
around 70% w/w yield.
–Reaction
–Washes
–Crystallisation
–Isolation
The team wished to explore the factors controlling stereoselectivity in Stage 6 and identify potential CPPs
controlling diastereoisomer formation under reaction conditions. Additionally, purging of critical impurities
across the washes and crystallisation unit operations was investigated. Each of the unit operations were
studied individually, with the initial focus on the reaction chemistry, in which a highly tailored custom design
was employed.
Reaction custom design
The starting point for any DoE is a review of the historical data, any prior DoE work and a brainstorm of
parameters to be studied. A 4 factor study had assessed the impact of 4 parameters in a fractional factorial
design, which had identified an important interaction and the
potential for curvature for some parameters.
At GSK, we use experimental design to generate the process
understanding that identifies critical process parameters
(CPPs) and safe operating conditions (design space) for the
manufacture of the drug substance. Using the example of
Stage 6, a range of custom designs are exemplified in
chemistry and engineering scenarios.
From this review and discussion, a set of 9 parameters were
identified for further investigation, including all of those previously
studied by DoE.
The custom design chosen to study the Stage 6 reaction is shown
here. This design incorporated prior knowledge on known
interactions and potential curvature.
An additional constraint that temperature 2 ≤ temperature 1 was
also included and the experimental study was conducted in 19 runs.
A custom designed sequential workflow
Kate Llewellyn, Product Development, GlaxoSmithKline
Custom design analysis
The data from this design was then analysed using several
platforms in JMP11. In most cases, simple models may be
identified using the screening platform.
However in some case, the screening
platform fails to identify a sensible model.
In these cases, multiple alternative
models can be assessed using “all
possible models” within the Stepwise
platform.
Models across multiple potentially
correlated responses are visualised
using the PCA platform. Impurities
that are formed by similar
mechanisms can be identified,
grouped and remodelled.
The prediction profiler is used
throughout to visualise the size and
direction of parameter effects.
Bespoke designs to solve
chemistry problems
Crystallisation
In order to meet the deadline for scale-up of the
chemistry, a fractional factorial design was initially
The remaining unit operations, the washing and
crystallisation were studied in smaller scale bespoke selected. The two most forcing sets of conditions in
designs, intended to quickly identify any interactions the design were run first. During processing, issues
across the unit operations and provide assurance of with performance of the
crystallisation were
robustness prior to scale-up.
observed. A change to
ranges was needed to
Washing
avoid problematic
A custom design was
conditions, producing
targeted at understanding
an unbalanced design
the impact of water in
which was also
washes on purging of
analysed in JMP.
key impurities in this unit
operation. The model was
Outcomes & next steps
specified so that the main effect of water, the
crossed term for water and a key interaction of
Following the completion of the sequence of
water with input were not aliased.
experiments across the three unit operations, the
manufacture of Phase III clinical supplies was
conducted in Singapore. Six batches at 2.9 kg each
Selection of
were manufactured in excellent yield and quality.
processing set
Next steps for Stage 6 will include revisiting the
points and ranges,
problematic crystallisation and exploring how the
is enabled by
established ranges perform as the specification of the
visualising multiple
input materials vary.
responses using
At each stage, we will be custom designing the
the prediction
experiments to solve the unique chemistry problems.
profiler.
Reaction custom design analysis
Back 1
Back 2
Defining the model
Rapid analysis in the
screening platform
Combining all data
in a PCA model
Modelling of key
responses
Exploring
alternative models
in “all possible
models”
Workup custom design analysis
Back
Assess colinearity using VIFs
Defining the model
Resolving conflicts through
visualising multiple responses
Visualising column
correlations
Crystallisation “edited” fractional factorial
Back
Inputting the
original model
Visualising correlations
when things go wrong!
Visualising model outputs