A scale-up approach for film coating process based on surface roughness. as the critical quality attribute

Transcription

1 Yoshino H. et al, Page AAPS PharmSciTech Original research papers A scale-up approach for film coating process based on surface roughness as the critical quality attribute Hiroyuki Yoshino a,b, Yuko Hara a, Masafumi Dohi a, Kazunari Yamashita a, Tadashi Hakomori a, Shin-ichiro Kimura b, Yasunori Iwao b, Shigeru Itai b,* a Pharmaceutical Research & Technology Laboratories, Astellas Pharma Inc., 180 Ozumi, Yaizu, Shizuoka , Japan b Department of Pharmaceutical Engineering, Graduate School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka , Japan *Address correspondence to: Shigeru Itai, Professor Department of Pharmaceutical Engineering, Graduate School pf Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka , Japan Tel.: , Fax: s-itai@u-shizuoka-ken.ac.jp (S. Itai). 23

2 Yoshino H. et al, Page ABSTRACT Scale-up approaches for film coating process have been established for each type of film coating equipment from thermodynamic and mechanical analyses for several decades. The objective of the present study was to establish a versatile scale-up approach for film coating process applicable to commercial production that is based on critical quality attribute (CQA) using the Quality by Design (QbD) approach and is independent of the equipment used. Experiments on a pilot scale using the Design of Experiment (DoE) approach were performed to find a suitable CQA from surface roughness, contact angle, color difference, and coating film properties by terahertz spectroscopy. Surface roughness was determined to be a suitable CQA from a quantitative appearance evaluation. When surface roughness was fixed as the CQA, the water content of the film-coated tablets was determined to be the critical material attribute (CMA), a parameter that does not depend on scale or equipment. Finally, to verify the scale-up approach determined from the pilot scale, experiments on a commercial scale were performed. The good correlation between the surface roughness (CQA) and the water content (CMA) identified at the pilot scale was also retained at the commercial scale, indicating that our proposed method should be useful as a scale-up approach for film coating process Keywords: film coating; scale-up; appearance; critical quality attribute; critical material attribute 44

3 Yoshino H. et al, Page INTRODUCTION The film coating of tablets is one of the general manufacturing pharmaceutical processes that are performed to improve the physical stability and distinguishability of formulations, and to mask any bitter taste and odor of the active pharmaceutical ingredients (APIs) (1, 2). The film coating process is, however, a complicated process that involves both mass transfer in spraying the coating agent to coat the tablet, and heat transfer in the dispersion of the coating agent to dry the solvent. As it is difficult to clarify the mechanism of the coating process properly, several scale-up theories for different film coating processes have been advocated; Agrawal (3) has classified broadly different scale-up approaches as macroscopic and microscopic one. There is also a specific approach which Tanabe (4) developed the model to predict exhaust temperature based on multivariate analysis using existing batch records. Most theories have been advocated usually in relation to a particular type of film coating equipment. Pandey (5) has developed a practical scale-up model for a solvent-based pan-coating process, based on a macroscopic evaluation of the coating process to determine the key parameters required to control the process. Andrew (6) used a thermodynamic film coating model and an atomization model to scale-up the film coating process from a Glatt GC 1250 coater (~ 115 kg pan load) and an IMA Perfima 200 coater (~ 160 kg pan load) to a Glatt GC 1500 coater (approx. 350 kg pan load). As can be seen from these reports, scale-up theories have been established for particular film coating equipment from thermodynamic and mechanical analysis. Therefore, although these models have been verified in practical use, their application and scope are limited. A thorough understanding of the film coating process is necessary to develop new methods that can be applied to a variety

4 Yoshino H. et al, Page of formulations, even when including recently developed APIs with various physicochemical properties. The systematic approach of Quality by Design (QbD) defined in the ICH Pharmaceutical Development Q8 Guideline (7), has been established and adopted in pharmaceutical development. The QbD approach was described in various literatures (8, 9) and generally proceeds with the following steps. Quality Target Product Profile (QTPP) related to the quality of drug product that guarantees quality, safety, and effectiveness is firstly defined. Next, critical quality attribute (CQA) of the drug product is identified so that the drug product characteristics affecting the QTPP can be managed. In addition, material attributes (MA) and process parameters (PP) that can affect the CQA of the product are identified based on knowledge, experiments, and risk assessments, and the functional relationship that associates MA and PP with the product CQA is determined. Application of the systematic approach of QbD to the development of film coating process has been reported (10-12); but most of these methods determined the relationship between a PP and a CQA on a similar experimental system and scale, and relationships that can be transferred between different experimental systems and scales have not been reported. A design space for guaranteeing CQA using critical material attribute (CMA) has been established in development studies for other processes, but not for film coating process because the CMA can be determined from experiments on a small scale as they do not depend on the model or production scale of the manufacturing equipment. For example, Alleso (13) has reported that the ribbon porosity as a CMA was found to be independent of the scale when comparing the average porosity of ribbon samples from small-scale to large-scale process. Nakagawa (14) has established a design space in the pharmaceutical development of a drug using only

5 Yoshino H. et al, Page CMAs during the process using Process Analytical Technology (PAT). Therefore, if a scaleup method using the relationship between a CQA and a CMA for film coating process could be established, a universal theory could be obtained for scale-up from small scale and pilot scale to production scale. Generally, dissolution and disintegration time of film-coated tablets are regarded to be one of film coating CQAs (10). However, film coating has been recently reported to rarely affect tablet disintegration and dissolution attributes (15, 16) due to recent high performance of film coating agent and equipment, and considerable experience and knowledge of pharmaceutical operators from the past. Therefore, other film coating CQAs should be set. Physical appearances, such as surface roughness and color difference in filmcoated tablets are regarded as film coating CQAs; however, these analyses are performed only by visual inspection, and quantitative evaluation methods had not been developed (Fig. 1A). Recently, we have reported an evaluation method that comprehensively enables quantitative appearance evaluation (17). Surface roughness, contact angle, color difference, and coating film properties determined by terahertz spectroscopy were used to quantitatively evaluate tablet appearance. Therefore, our quantitative evaluation method would be useful to find a CQA in film-coated tablets and consequently establish a new scale-up approach based on the relationship between a CQA and a CMA to achieve the desired QTPP (Fig. 1B). In this study, we first performed experiments to prepare film-coated tablets on a pilot scale using Design of Experiment (DoE) methods and attempted to determine a suitable CQA from surface roughness, contact angle, color difference, and coating film properties by terahertz spectroscopy. Then, we attempted to determine a CMA that does not depend on scale and to establish a scale-up approach to match the QTPP set as "film-coated tablet with

6 Yoshino H. et al, Page good appearance". Experiments on a commercial scale were performed to verify our proposed scale-up approach constructed from pilot-scale experiments MATERIALS AND METHODS Materials The tablet cores were prepared using D-mannitol (Roquette, Lestrem, France), microcrystalline cellulose (Asahi Kasei Chemicals, Tokyo, Japan), crospovidone (BASF, Ludwigshafen, Germany), and magnesium stearate (Merck KGaA, Darmstadt, Germany). The composition of each tablet core was as follows: D-mannitol 64% (wt/wt), microcrystalline cellulose 30 % (wt/wt), crospovidone 5% (wt/wt), and magnesium stearate 1% (wt/wt). D-mannitol, microcrystalline cellulose, and crospovidone were initially blended in a container mixer (PM200, Kotobuki Engineering & Manufacturing, Tokyo, Japan) before being blended with magnesium stearate in the same container. The blended powder was subsequently compressed with a tablet weight of 180 mg in a compression machine (HT- X20, Hata Iron Works, Kyoto, Japan) using 8 mm biconcave punches to form the core tablets. Opadry Yellow (Colorcon, Shizuoka, Japan) containing hypromellose, polyethylene glycol, titanium oxide, talc, and yellow ferric oxide was used as the film coating agent by dispersing in water at a concentration of 10% (wt/wt) Pilot scale experiments To clarify the relationship between the CQA, CMA, and PP, the film coating process was carried out on a pilot scale using a DoE approach. In the pilot scale DoE experiment, the film coating was performed with 33 kg of the core tablets charged into the

7 Yoshino H. et al, Page film coating system PRC-60 (Powrex, Hyogo, Japan) and Opadry Yellow dispersed in water were sprayed. Previously, Sheth (18) have tried to optimize rotating speed of pan and % solid content, in addition to spray rate, atomizing air pressure, and inlet air temperature among film coating parameters in a development small scale. However, the range of appropriate % solid content of film coating dispersion is determined almost for each film coating agent, and it would not be changed during product development. In addition, the pan speed which can be set is determined from the validation range for each device and the damage to the tablet is preferentially taken into consideration to determine the pan speed. Furthermore, the pan speed range that is realistically set on the production scale is numerically narrow. Taken together, rotating speed of pan and % solid content are found not to be important in actual production and scale up method. Therefore, the inlet air temperature, the inlet air volume, the spray rate, and the atomizing air volume were selected as the PP considered to affect the appearance of the film-coated tablets. These PP were allocated by the L8 orthogonal method containing one center point, and nine batches using the film coating process were produced (Table 1) Quantitative appearance evaluation All quantitative appearance evaluations were performed as described previously (17). The surface roughness of the film-coated tablets was measured using a VK-9700 laser microscope (Keyence, Osaka, Japan). The arithmetic average roughness (calculated as 157 R a N n 1 Z N n Z, where Z n is the individual height value of the measurement point by the

8 Yoshino H. et al, Page laser reflection measurement, Z is the mean value of all of the height data points, and N is the number of measurement points) was used as the standard roughness. Contact angle (A c ) measurements were recorded using a contact angle meter (Kyowa Interface Science, Saitama, Japan). The θ/2 method was used to measure the contact angles with 2 µl of purified water. The luminosity and chromaticity values were measured using a color difference meter (Konica Minolta, Tokyo, Japan). The specular component excluded method was used to evaluate colors in the near visual range. Differences in the color 165 ( E L 2 a 2 b 2 ) were calculated based on the average luminosity and chromaticity value of the center batch. The film-coated layers were visualized using a TAS7500 terahertz spectroscopic imaging system (Advantest, Tokyo, Japan). Details of element technologies have previously been reported (19). The thickness of the film-coated layer (FT) was obtained from the time lag between the reflected signal from the surface of the film-coated layer and core tablet. The reflectance of the reflected signal from the surface of the film-coated layer was obtained from the ratio of the amplitude of the reference signal and the measurement signal. The reflectance is known to change depending on the refractive index of the surface of the object to be measured (film-coated layer), which can be regarded as a parameter representing the density of the material. Therefore, the reflectance can be termed the film surface density (FSD) of the film-coated layer. The amplitude of the reflected signal from the boundary between the film-coated layer and the core tablet changes with the refractive index difference (density difference) at the boundary as suggested by Fresnel's formula. Then, the interface density difference (IDD) is defined as the ratio of the amplitude obtained from the reference signal and the measurement signal at the boundary. Definitions of these parameters have previously been reported (20), and the properties of the

9 Yoshino H. et al, Page film layer can be obtained using a non-destructive approach with terahertz pulsed imaging (21). The images were collected in the reflection measurement mode. A circular area with a radius of 2.1 mm was set as the measurement area at the center of the tablet. Fifty points were measured within the circular area in each sample. Based on the principles of terahertz spectroscopic measurement, we measured the average and relative standard deviation values of fifty points for the thickness of the film-coated layer (FT Ave and FT RSD ), the film surface density (FSD Ave and FT RSD ), and the difference between the interface density of the film layer and core tablet (IDD Ave and IDD RSD ) Materials and film coating for commercial scale experiments Formulation of core tablets for the pilot scale and Opadry Yellow dispersed in water at the same ratio as described before, were also used for the commercial scale experiments. To prepare the core tablets, materials were blended in a container mixer (PM1000, Kotobuki Engineering & Manufacturing, Tokyo, Japan) before being blended with magnesium stearate in the same container. The blended powder was compressed in a compression machine (AX45S, Hata Iron Works, Kyoto, Japan) using 8 mm biconcave punches. Film coating was carried out using PRC-600 (Powrex, Hyogo, Japan) as the film coating equipment and charging 330 kg, which is 10 times the pilot scale charging. Film coating conditions were determined within the range defined as the standard from results of previous manufacturing on a commercial scale; three batches of film coating were performed to change the water content as the CMA (Table 2) Statistical analysis

10 Yoshino H. et al, Page The effects of PP on the quantitative appearance evaluations for eight batches manufactured in the pilot scale experiments were evaluated using an analysis of variance (ANOVA) at the 5% level RESULTS AND DISCUSSION Results of manufacturing and quantitative appearance evaluation on a pilot scale Film-coated tablets were periodically sampled during spraying, and the results of the changes in the tablet weight gain and the water content measured by the loss on drying method are shown in Figs. 2 and 3. The changes in tablet weight gain and water content were different for each batch because of differences in the PP (Table 1). When the tablet weight was corrected by obtained water content with equation (1), almost the same behaviors to the tablet weight gain were confirmed (Fig. 4). The spraying was continued until the tablet weight gain calculated from the water-corrected tablet weight reached approximately 3% which is the specified weight of the core tablets (Table 3). (Water-corrected tablet weight) = (Measured tablet weight) (100-% water content) / 100 (1) The surface roughness, contact angle, color difference, and terahertz spectroscopic measurements of each film-coated tablet are shown in Tables 4 and 6. Various film-coated tablets with different quantitative appearances and physical properties could be produced by the L8 orthogonal method. The R a results were similar to that with laser profilometer reported before. (22, 23). According to the May s report (24), 40 μm was required as a minimum coating thickness to determine the coating thickness in terahertz measurements. From the literature reported by Lin (25), when the weight gain in film coating was about 3%

11 Yoshino H. et al, Page using a film-coated agent containing hypromellose, polyethylene glycol, titanium oxide, talc, yellow iron oxide like Opadry yellow used in this study, the film coating thickness was estimated around 50 μm. Since the film coating thickness by terahertz spectroscopy in this study was around 60 μm, the reliability of the terahertz measurement was considered guaranteed. From the ANOVA, two PPs, the inlet air temperature and the spray rate, significantly affect the surface roughness as shown in Table 6. This result was coincided with the reports from Sheth (18) and Patel JK (26), which revealed that spray rate and inlet air temperature had a major effect on film coating performance. A denser film was formed as the heat energy supplied during the film coating was increased or the drying efficiency increased, and consequently the film-coated tablet appearance improved, similar to the results from Ruosalainen s previous work (23). That is, as the inlet air temperature increased, the supplied heat energy increased, and as the spray rate decreased, the drying efficiency increased; so that the surface roughness was reduced (Fig. 5). Based on the above considerations, surface roughness can be regarded as the most quantitative appearance evaluation parameter that can express the effect of the PP, so surface roughness was set as the CQA. Page (27, 28) have developed a model for the prediction of the product water content during coating process and Suzuki (29) have mentioned that the surface state of coating layer is affected by the water content of drug product during coating process. The process variables affecting the weight gain were investigated by Pandey (30) and Dubey (11). Therefore, water content and the tablet weight gain calculated from the water-corrected tablet weight were investigated as candidates for the CMA for the relationship with surface

12 Yoshino H. et al, Page roughness as the CQA, as shown in Figs. 6 and 7. Plotting the CMA candidates against the surface roughness, water content showed a good linear correlation, compared with other parameters. Therefore, we set surface roughness as the CQA and the water content of the film-coated tablet as the CMA (Fig. 8) Manufacturing and quantitative appearance evaluations on a commercial scale To demonstrate the validity of the scale-up approach using the CMA to enable transfer between different scales of process, experiments were also carried out on a commercial scale to obtain film-coated tablets with a good QTPP. Similar to the pilot scale DoE approach, the film-coated tablets were periodically sampled during spraying, and the tablet weight gain and water content were measured during the commercial scale experiments (Figs. 9 and 10). As a result of changing the inlet air temperature, the spray rate, and the atomizing air volume, the changes in tablet weight gain and the water content varied from batch to batch. When the tablet weight was corrected by the obtained water content, similar behaviors to the tablet weight gain were confirmed (Fig. 11). The spraying was continued until the tablet weight gain calculated from the watercorrected tablet weight reached approximately 3% which is the specified weight of the core tablets (Table 7). The surface roughness of each batch is shown in Table 8. The results obtained from the commercial scale experiment were plotted on the graph of the correlation between surface roughness and water content from the pilot scale experiment, as shown in Fig. 12. The data from the commercial scale process also fitted on the correlation line of the data from the pilot scale experiments, indicating that the relationship between surface roughness

13 Yoshino H. et al, Page as the CQA and water content as the CMA did not depend on the scale of the process (Fig. 12). These data demonstrate that this strategy using the relationship between a CQA and a CMA might be useful to establish a scale-up theory for film coating process CONCLUSION In this study, a scale-up approach for a film coating process was investigated based on a quantitative appearance evaluation to find a suitable CQA. From the pilot scale DoE results, surface roughness and water content were found to have a good correlation. For a QTPP for a film-coated tablet with good appearance, surface roughness was set as the CQA and water content was set as the CMA. The correlation between surface roughness as the CQA and water content as the CMA, identified on the pilot scale, was retained on the commercial scale, showing the validity of this scale-up approach. As the water content can be monitored during the film coating process as the CMA, this scale-up approach may even be useful in a system to which PAT can be applied, and in continuous process manufacturing requiring no scale-up rule as a control tool to guarantee the product quality in real time Conflict of Interest The authors declare no conflict of interest. References (1) Maurer L, Leuenberger H. Terahertz pulsed imaging and near infrared imaging to monitor the coating process of pharmaceutical tablets. Int J Pharm. 2009;370:8-16. (2) Knop K, Kleinebudde P. PAT-tools for process control in pharmaceutical film coating applications. Int J Pharm. 2013;457:

14 Yoshino H. et al, Page (3) Agrawal AM, Pandey P. Scale up of pan coating process using quality by design principles. J Pharm Sci. 2015;104(11): (4) Tanabe S, Nakagawa H, Watanabe T, Minami H, Kano M, Urbanetz NA. Setting the process parameters for the coating process in order to assure tablet appearance based on multivariate analysis of prior data. Int J Pharm. 2016;511: (5) Pandey P, Turton R, Joshi N, Hammerman E, Ergun J. Scale-up of a pan-coating process. AAPS PharmSciTech. 2006;7(4):E125-E132. (6) Prpich A, Am Ende M, Katzschner T, Lubczyk V, Weyhers H, Bernhard G. Drug product modeling predictions for scale-up of tablet film coating A quality by design approach. Comp and Chem Eng. 2010;34: (7) International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. Pharmaceutical Development Q8 (R2) _R1/Step4/Q8_R2_Guideline.pdf (8) Yu LX. Pharmaceutical quality by design: product and process development, understanding, and control. Pharm Res 2008;25(4): (9) Mazumder S, Pavurala N, Manda P, Xu X, Cruz CN, Krishnaiah YSR. Quality by Design approach for studying the impact of formulation and process variables on product quality of oral disintegrating films. Int J Pharm. 2017;527: (10) Teckoe J, Mascaro T, Farrell TP, Rajabi-Siahboomi A R. Process optimization of a novel immediate release film coating system using QbD principles. AAPS PharmSciTech. 2013;14(2):

15 Yoshino H. et al, Page (11) Dubey A, Boukouvala F, Keyvan G, Hsia R, Saranteas K, Brone D, Misra T, Ierapetritou MG, Muzzio FJ. Improvement of tablet coating uniformity using a quality by design approach. AAPS PharamSciTech. 2012;13(1): (12) Nayak BK, Elchidana P, Sahu PK. A quality by design approach for coating process parameter optimization. Indian J Pharm Sci. 2017;79(3): (13) Alleso M, Holm R, Holm P. Roller compaction scale-up using roll width as scale factor and laser-based determined ribbon porosity as critical material attribute. Euro J Pharma Sci. 2016;87: (14) Nakagawa H, Kikkawa Y, Matsuura K, Tanabe S, Watanabe T. Implementation of Enhancesd QbD to drug product development. The Japan Society of Pharmaceutical Machinery and Engineering. 2015;24: (15) Zaid AN, Abualhasan M, Qaddumi A, Jodeh S. Development of film coated Atrovastatin calcium tablet using Opadry-OY. Int J Drug Deli. 2012;4: (16) Zaid AN, Natour S, Qaddomi A, Ghoush AA. Formulation and in vitro and in vivo evaluation of film-coated montelukast sodium tablets using Opadry yellow 20A82938 on an industrial scale. Drug Des Devel Ther. 2013;7: (17) Yoshino H, Yamashita K, Iwao Y, Noguchi S, Itai S. Quantitative appearance inspection for film coated tablets. Chem Pharm Bull. 2016;64(8): (18) Sheth N, Shan S, Potdar A, Shah A. Studies in optimization of aqueous film coating parameters. Int J Pharm Sci Nano. 2009;2(3): (19) Imamura M, Nishina S, Irisawa A, Yamashita T, Kato E. 3D imaging and analysis system Uuing terahertz waves. In: IEEE Int. Conf. IR. MMW. THz. Waves doi: /ICIMW

16 Yoshino H. et al, Page (20) Wataru M, Hiroyuki Y, Yoshifumi K, Kazunari Y, Keiji I, Kazuhiro S, Kato E, Akiyoshi I, Etsuo Y, Katsuhide T. Applying terahertz technology for nondestructive detection of crack initiation in a film-coated layer on a swelling tablet. Results Pharma. Sci. 2012;2: (21) Dohi M, Momose W, Yoshino H, Hara Y, Yamashita K, Hakomori T, Sato S, Terada K. Application of terahertz pulse imaging as PAT tool for non-destructive evaluation of film-coated tablets under different manufacturing conditions. J Pharm Biomed Anal. 2016;119: (22) Seitavuopio P, Heinämäki J, Rantanen J, Yliruusi J. Monitoring tablet surface roughness during the film coating process. AAPS PharmSciTech. 2006;7(2):E1-6. (23) Ruotsalainen M, Heinämäki J, Taipale K, Yliruusi J. Influence of the aqueous film coating process on the properties and stability of tablets containing a moisture-labile drug. Pharm Dev Technol. 2003;8(4): (24) May RK. Evans MJ, Zhong S, Warr I, Gladden LF, Shen Y, Zeitler JA. Terahertz inline sensor for direct coating thickness measurement of individual tablets during film coating in real-time. J Pharm Sci. 2011;100(4): (25) Lin H, Dong Y, Markl D, Zhang Z, Shen Y, Zeitler J A. Pharmaceutical film coating catalog for spectral domain optical coherence tomography. J Pharm Sci. 2017;106: (26) Patel JK, Shah AM, Sheth NR. Aqueous-based film coating of tablets: Study the effect of critical process parameters. Int J PharmTech Res. 2009;1(2):

17 Yoshino H. et al, Page (27) Page S, Baumann K H, Kleinebudde P. Mathematical modeling of an aqueous film coating process in a bohle lab-coater, Part 1: Development of the model. AAPS PharmSciTech. 2006;7(2):42. (28) Page S, Baumann K H, Kleinebudde P. Mathematical modeling of an aqueous film coating process in a bohle lab-coater, Part 2: Application of the model. AAPS PharmSciTech. 2006;7(2):43. (29) Suzuki Y, Suzuki T, Minami H, Terada K. A novel scale up model for prediction of pharmaceutical film coating process parameters. Chem. Pharm. Bull. 2016;64: (30) Pandey P, Katakdaunde M, Turton R. Modeling weight variability in a pan coating process using monte carlo simulations. AAPS PharmSciTech. 2006;7(4):

18 Yoshino H. et al, Page Tables Table 1. L8 orthogonal method for pilot scale experiments. Batch No. Inlet Air Temperature ( C) Inlet Air Volume (m 3 /min) Spray Rate (ml/min) Atomizing Air Volume (NL/min) P P P P P P P P Center Table 2. Film coating conditions for commercial scale experiments. Batch No. Inlet Air Temperature ( C) Inlet Air Volume (m 3 /min) Spray Rate (g/min) Atomizing Air Volume (L/min) C C C Table 3. Tablet weight gains in pilot scale experiment. Batch No. Final tablet weight gains calculated from tablet weight corrected by water content (%) P1 3.0 P2 3.0 P3 2.9 P4 3.0 P5 2.9 P6 3.0 P7 2.9 P8 2.9 Center

19 Yoshino H. et al, Page Table 4. Surface roughness, contact angle, and color difference measurements. Batch No. Surface Roughness Contact Angle Color Difference R a (μm) A C ( ) ΔE (-) P ± ± P ± ± P ± ± P ± ± P ± ± P ± ± P ± ± P ± ± Center 5.88 ± ± Table 5. Film thickness, film surface density, and interface density differences in the film-coated layers by terahertz spectroscopy. Batch No. Film Thickness (μm) Average RSD FT Ave FT RSD Film Surface Density (%) Average RSD FSD Ave FSD RSD Interface Density Difference (%) Average RSD IDD Ave IDD RSD P ± ± ± ± ± ± 8.1 P ± ± ± ± ± ± 7.7 P ± ± ± ± ± ± 6.6 P ± ± ± ± ± ± 13.2 P ± ± ± ± ± ± 9.9 P ± ± ± ± ± ± 10.9 P ± ± ± ± ± ± 12.2 P ± ± ± ± ± ± 9.4 Center 64.5 ± ± ± ± ± ±

20 Yoshino H. et al, Page Table 6. Analysis of variance results. Evaluation items Inlet Air Temperature ( C) Inlet Air Volume (m 3 /min) Spray Rate (ml/min) Atomizing Air Volume (NL/min) Surface Roughness R a (μm) Contact Angle A C ( ) Color Difference ΔE (-) Film FT Ave Thickness (μm) FT RSD Film Surface FSD Ave Density (%) FSD RSD Interface Density IDD Ave Difference (%) IDD RSD indicates statistically significantly differences (p < 0.05) Table 7. Tablet weight gains in commercial scale experiment. Batch No. Final tablet weight gains calculated from tablet weight corrected by water content (%) C1 3.0 C2 3.0 C Table 8. Surface roughness measurement of film-coated tablets on a commercial scale. Batch No. Surface Roughness R a (μm) C ± 0.28 C ± 0.22 C ± 0.13

21 Yoshino H. et al, Page Fig. 1. Flow diagram of pharmaceutical development applying the Quality by Design approach. (A) Development approach to the past. (B) Proposed scale-up method. The scale-up is to match the CMA which is a factor meeting CQA between scales.

22 Yoshino H. et al, Page Fig. 2. Tablet weight gain profiles of film-coated tablets during film coating in the pilot scale DoE experiment.

23 Yoshino H. et al, Page Fig. 3. Water content profiles of film-coated tablets during film coating in the pilot scale DoE experiment.

24 Yoshino H. et al, Page Fig. 4. Tablet weight gain calculated from the water-corrected tablet weight profiles of film-coated tablets during film coating in the pilot scale DoE experiment.

25 Yoshino H. et al, Page Fig. 5. Factorial effect of surface roughness in the pilot scale L8 DoE experiment.

26 Yoshino H. et al, Page Fig. 6. Relationship between surface roughness and water content of film-coated tablets. Water content shows a good correlation with the surface roughness as the CQA.

27 Yoshino H. et al, Page Fig. 7. Relationship between surface roughness and tablet weight gain calculated from the water-corrected tablet weight.

28 Yoshino H. et al, Page Fig. 8. Flow diagram of the scale-up method. Surface roughness was set as the CQA and the water content of film-coated tablet was set as the CMA.

29 Yoshino H. et al, Page Fig. 9. Tablet weight gain profiles of film-coated tablets during film coating in the commercial scale experiment.

30 Yoshino H. et al, Page Fig. 10. Water content profiles of film-coated tablets during film coating in the commercial scale experiment

31 Yoshino H. et al, Page Fig. 11. Tablet weight gain calculated from the water-corrected tablet weight profiles of film-coated tablet during film coating in the commercial scale experiment.

32 Yoshino H. et al, Page Fig. 12. Relationship between surface roughness and water content of film-coated tablets. (A) At the beginning of spray. (B) At the middle of spray. (C) At the end of spray. The correlation was maintained on a commercial scale, and it was shown that the relationship between the surface roughness set as the CQA and the water content of film-coated tablets set as the CMA does not depend on the scale.