(M1330-11-65) Compression Process Optimzation Using 2³ Full Factorial Design of Experiments

Purpose: Execute and analyze two 2³ full factorial design of experiments (DOE) + 3 center points to optimize the compression processes for two immediate-release tablet drug products using a Fette FE55 commercial scale rotary tablet press.  The study was performed to identify significant and reliable models relating turret speed, feeder speed, and main compression force settings to routine compression in-process controls/parameters for process development purposes.

Methods: Two dose-proportional strengths were evaluated using separate DOE studies. The formulation contained 30% drug substance. For each strength, eleven randomized runs with varying combinations of turret speed, feeder speed and main compression force were executed. The factors were turret speed (20-40 rpm), feeder speed (20-40 rpm), and main compression force (8-18 kN for the low strength and 15-25 kN for the high strength). The responses were weight, thickness, and hardness mean and relative standard deviation (RSD), friability (100 and 400 revolutions), mean disintegration, upper and lower punch stiffness, and main compression force relative standard deviation (srel). The DOE was executed with the tablet press in manual mode. After each combination of press speed, feeder speed, and main compression force parameters were entered into the press, the operator adjusted fill depth to achieve tablets within weight limits and let 30-60 seconds elapse before taking tablet sample. Weight, thickness, and hardness data were generated using a Sotax ST50 automated tablet tester. Friability and disintegration data were generated using a friabilator and Sotax DT2 tester, respectively. JMP 16 software was used for the DOE analysis.

Results: The analysis comprised four steps: Model significance, model fit, diagnostic check, and model interpretation. Model Significance - The models were optimized automatically using the stepwise personality, the minimum Akaike’s Information Criterion stopping rule, and the forward direction. From these optimized models, a p-value limit (alpha) of 0.10 was chosen for model term and overall model significance due to the moderate number of DOE runs. Terms with p-values not more than 0.10 remained in the model as well as main effects contained by significant two-way interactions. For the low strength, significant p-values were identified for hardness RSD, friability (100 rev), mean disintegration, and srel. For the high strength, significant p-values were identified for friability (400 rev) and both upper and lower punch stiffness. Model Fit - The model fit evaluation was performed next to identify reliable models that could be safely used to describe the relationship between the DOE inputs and outputs. For adequate model fit, a limit of NLT 0.70 was chosen for the adjusted R² term. This signified that the model must explain at least 70% of the variation in the data. Additionally, the difference between raw and adjusted R² values, as well as the difference between adjusted and predicted R² values, needed to be NMT 0.2. The lack-of-fit p-value was another measure of how well the model fits the data and needed to be NLT 0.10. For the low strength, the mean disintegration and srel models met these acceptance criteria. For the high strength, both punch stiffness models met these criteria. Meeting the acceptance criteria indicated adequate fit of the models to the data. Diagnostic Check - Adequately fitted models were checked to ensure the linear regression assumptions were satisfied for this study. This was done by examining the actual by predicted, residual by predicted, residual normal quantile, and residual by row plots. No red flags were observed for these models. Model Interpretation - Srel (main compression force relative standard deviation) increased as feeder speed increased and as turret speed decreased. The effect of turret speed was approximately twice that of feeder speed. Mean disintegration increased as main compression force increased which was expected from compression theory. Mean disintegration maximum was approximately 6.5 minutes at 16 kN main compression force for the low strength. Since all punch stiffness readings were below the alarm limit of 600 N, the full turret speed and main compression force ranges were suitable for that response for the high strength. See Figures 1, 2, 3, and 4 for the srel, mean disintegration, upper punch stiffness, and lower punch stiffness models, respectively.

Conclusion: The models generated adequately describe the relationship between main compression force, turret speed, feeder speed factors and srel, mean disintegration, and punch stiffness responses for the low and high strength formulations.  The knowledge gained was used in compression experiments in preparation for registration batch manufacturing.


Figure 1. Low Strength Srel Model


Figure 2. Low Strength Mean Disintegration Model


Figure 3. High Strength Lower Punch Stiffness Model