Control Strategy for Process Development of High-Shear Wet Granulation and Roller Compaction to Prepare a Combination Drug Using Integrated Quality by Design

In this study, we developed a control strategy for a drug product prepared by high-shear wet granulation and roller compaction using integrated quality by design (QbD). During the first and second stages, we optimized the process parameters through the design of experiments and identified the intermediate quality attributes (IQAs) and critical quality attributes (CQAs) relationship, respectively. In the first stage, we conducted an initial risk assessment by selecting critical process parameters with high impact on IQAs and CQAs and confirmed the correlation between control and response factors. Additionally, we performed Monte Carlo simulations by optimizing the process parameters to deriving and building a robust design space. In the second stage, we identified the IQAs and CQAs relationship for the control strategy, using multivariate analysis (MVA). Based on MVA, in the metformin layer, dissolution at 1 h was significantly correlated with intrinsic dissolution rate and granule size, and dissolution at 3 h was significantly correlated with bulk density and granule size. In dapagliflozin layer, dissolution at 10 min and 15 min was significantly correlated with granule size. Our results suggest that the desired drug quality may result through IQAs monitoring during the process and that the integrated QbD approach utilizing MVA can be used to develop a control strategy for producing high-quality drug products.

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Improved Understanding of the High Shear Wet Granulation Process under the Paradigm of Quality by Design Using Salvia miltiorrhiza Granules

Pharmaceutics ◽

10.3390/pharmaceutics11100519 ◽

2019 ◽

Vol 11 (10) ◽

pp. 519 ◽

Cited By ~ 3

Author(s):

Yi Zhang ◽

Brian Chi-Yan Cheng ◽

Wenjuan Zhou ◽

Bing Xu ◽

Xiaoyan Gao ◽

...

Keyword(s):

Experimental Design ◽

Quality By Design ◽

Salvia Miltiorrhiza ◽

Scale Up ◽

Granule Size ◽

Quadratic Polynomial ◽

Wet Granulation ◽

High Shear ◽

Validation Experiment ◽

High Shear Wet Granulation

Background: High shear wet granulation (HSWG) is a shaping process for granulation that has been enhanced for application in the pharmaceutical industry. However, study of HSWG is complex and challenging due to the relatively poor understanding of HSWG, especially for sticky powder-like herbal extracts. Aim: In this study, we used Salvia miltiorrhiza granules to investigate the HSWG process across different scales using quality by design (QbD) approaches. Methods: A Plackett–Burman experimental design was used to screen nine granulation factors in the HSWG process. Moreover, a quadratic polynomial regression model was established based on a Box–Behnken experimental design to optimize the granulation factors. In addition, the scale-up of HSWG was implemented based on a nucleation regime map approach. Results: According to the Plackett–Burman experimental design, it was found that three granulation factors, including salvia ratio, binder amount, and chopper speed, significantly affected the granule size (D50) of S. miltiorrhiza in HSWG. Furthermore, the results of the Box–Behnken experimental design and validation experiment showed that the model successfully captured the quadratic polynomial relationship between granule size and the two granulation factors of salvia ratio and binder amount. At the same experiment points, granules at all scales had similar size distribution, surface morphology, and flow properties. Conclusions: These results demonstrated that rational design, screening, optimization, and scale-up of HSWG are feasible using QbD approaches. This study provides a better understanding of HSWG process under the paradigm of QbD using S. miltiorrhiza granules.

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Mechanistic basis for the effects of process parameters on quality attributes in high shear wet granulation

International Journal of Pharmaceutics ◽

10.1016/j.ijpharm.2012.09.011 ◽

2012 ◽

Vol 439 (1-2) ◽

pp. 324-333 ◽

Cited By ~ 51

Author(s):

Sherif I.F. Badawy ◽

Ajit S. Narang ◽

Keirnan LaMarche ◽

Ganeshkumar Subramanian ◽

Sailesh A. Varia

Keyword(s):

Process Parameters ◽

Quality Attributes ◽

Wet Granulation ◽

High Shear ◽

Mechanistic Basis ◽

High Shear Wet Granulation

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Mechanistic Basis for the Effects of Process Parameters on Quality Attributes in High Shear Wet Granulation

Handbook of Pharmaceutical Wet Granulation ◽

10.1016/b978-0-12-810460-6.00026-9 ◽

2019 ◽

pp. 89-118

Author(s):

Sherif I.F. Badawy ◽

Ajit S. Narang ◽

Keirnan R. LaMarche ◽

Ganeshkumar A. Subramanian ◽

Sailesh A. Varia

Keyword(s):

Process Parameters ◽

Quality Attributes ◽

Wet Granulation ◽

High Shear ◽

Mechanistic Basis ◽

High Shear Wet Granulation

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Comprehensive Study of Intermediate and Critical Quality Attributes for Process Control of High-Shear Wet Granulation Using Multivariate Analysis and the Quality by Design Approach

Pharmaceutics ◽

10.3390/pharmaceutics11060252 ◽

2019 ◽

Vol 11 (6) ◽

pp. 252 ◽

Cited By ~ 5

Author(s):

Jong Kwon Han ◽

Beom Soo Shin ◽

Du Hyung Choi

Keyword(s):

Multivariate Analysis ◽

Process Parameters ◽

Scale Up ◽

Pilot Scale ◽

Quality Attributes ◽

Wet Granulation ◽

High Shear ◽

Critical Quality Attributes ◽

High Shear Wet Granulation ◽

The Relationship

A robust manufacturing process and the relationship between intermediate quality attributes (IQAs), critical quality attributes (CQAs), and critical process parameters (CPPs) for high-shear wet granulation was determined in this study. Based on quality by the design (QbD) approach, IQAs, CQAs, and CPPs of a telmisartan tablet prepared by high-shear wet granulation were determined and then analyzed with multivariate analysis (MVA) to evaluate mutual interactions between IQAs, CQAs, and CPPs. The effects of the CPPs on the IQAs and CQAs were quantitatively predicted with empirical models of best fit. The models were used to define operating space, and an evaluation of the risk of uncertainty in model prediction was performed using Monte Carlo simulation. MVA showed that granule size and granule hardness were significantly related to % dissolution. In addition, granule FE (Flow Energy) and Carr’s index had effects on tablet tensile strength. Using the manufacture of a clinical batch and robustness testing, a scale-up from lab to pilot scale was performed using geometric similarity, agitator torque profile, and agitator tip speed. The absolute biases and relative bias percentages of the IQAs and CQAs generated by the lab and pilot scale process exhibited small differences. Therefore, the results suggest that a risk reduction in the manufacturing process can be obtained with integrated process parameters as a result of the QbD approach, and the relationship between IQAs, CQAs, and CPPs can be used to predict CQAs for a control strategy and SUPAC (Scale-Up and Post-Approval Guidance).

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