Scale-Up Studies on High Shear Wet Granulation Process from Mini-Scale to Commercial Scale

Abstract

1431Recently the importance of QbD (Quality by design) in International Conference on Harmonisation (ICH) Q8 has been highlighted, 1) and scientific levels of formulation designing and manufacturing designing are more and more emphasized. In addition, there is pressure on the pharmaceutical industry in shortening the development time of new products. Further, considering current situation that there are cases where levels of formulation study and scale-up study, prerequisites of validation, are not sufficient, it is tended to be interpreted that conventional validation is not final verification of validity of acceptable manufacturing conditions, but one of processes of the cycle oriented to Continuous Improvement of quality through Product Life Cycle. 1,2) From the viewpoint of QbD, in the unit operations of formulation manufacturing, granulation process is a process which has a significant impact on quality of final products, and should be considered mostly to be studied. Therefore scale-up of high shear granulation has been approached in several ways.3-7) But in wet granulation, for example, there are numerous combinations of process parameters such as agitation speed, irrigation speed of binder solution, etc. and current situation is that generalized solution, covering from a small production scale to a commercial production scale, is not obtained.The concept of Design Space introduced in ICH Q8 defines the appropriate operation space of respective operation parameter in a commercial production scale, and vast experiments should be needed to establish multidimensional operation space of these variation factors. In the case of investigational drugs, however, there is a situation that ample drug substance can not be available, and this situation being considered, it is a critical requisite to establish experiment system of a small scale where by using small quantity of drug substance extrapolation to commercial production is intended as a means of realizing the concept of ICH Q8. But few studies report scale-up from a mini-scale to pilot scale. 5)In this study, experiments and analyses were performed by using a newly developed 0.2 L mini-scale high shear mixer where extremely small amount of drug substance is used, in order to seek possibilities to establish Design Space which can extrapolate manufacturing conditions from a small scale to pilot scale (investigational new drug production scale), finally to a commercial scale. ExperimentalMaterials Anhydrous caffeine (Shiratori Seiyaku Co., Ltd.) was used as model drug. The following inactive ingredients were purchased from commercial sources: D-mannitol (Toa Kaseikogyo Co., Ltd.) and dibasic calcium phosphate (Kyowa Kagaku Co., Ltd.) as fillers, pregelatinized starch (Matsutani Kagakukogyo Co., Ltd.) as a binder, corn starch (Nihonshokuhin-Kako Co., Ltd.) as a disintegrant, magnesium stearate (Taihei Kagaku Sangyo Co., Ltd.) as a lubricant for the preparation of the tablets. Purified water was used as the granulation liquid.Preparation of Granules All materials ...

Evaluating Scale-Up Rules of a High-Shear Wet Granulation Process

“…Scale‐up of high‐shear wet granulation (HSWG) process is of high relevance to the pharmaceutical and food industries. The topic has been a subject of extensive research over the years and many publications exist to date on different ways to scale up this process . The various scale‐up methodologies presented in literature can be broadly classified into two main categories: one that applies fixed mathematical rules to process parameters based on engineering principles from one scale to the other, and the other that empirically adjusts process parameters as needed to maintain the same granule attributes across scales.…”

Development and implementation of a hybrid scale up model for a batch high shear wet granulation operation

“…Aikawa et al 14 observed that the applicability of a scale up rule can be case specific. They saw that a constant impeller tip speed approach was valid for scaling up from a mini scale (0.2 L) to pilot scale (11 L), but not between the pilot and commercial scale (200 L).…”

Machine learning modelling of wet granulation scale-up using compressibility, compactibility and manufacturability parameters

“…Even when the equipment from the same manufacturer is used, with the same geometrical properties, the scale-up process of wet granulation can be a challenge [8]. Nevertheless, by developing a progressive design space with a QbD risk based approach, production of pharmaceutical products is robust enough to allow for scale-up adjustments of process parameters [9,10].…”

“…Furthermore, responses being observed are usually related to granule properties (particle size distribution [17], porosity [18], size and bulk density [19]). In studies conducted by Aikawa et al [10] and Badawy et al [20] the analyzed responses were tablet properties. Those studies, however, did not utilize machine learning techniques.…”