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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