(T1030-02-14) Quality Demonstration of Personalized Mini Tablet Manufacture Using Integrated Single-Dose Manufacturing System

Purpose: Personalized medicine, which involves manufacturing and providing medications tailored to individual patients, has gained increasing attention¹. To support this approach, authors have developed a compact, modular tablet manufacturing system which integrates powder dispensing, mixing, compression, near-infrared (NIR) spectroscopy-based quality assessment, and tablet ejection in a single unit² (Fig. 1(a)). If a wide range of formulations can be systematically investigated at the minimum single-tablet scale using the system, it could become a powerful tool for reducing time and cost associated with early-stage drug development. In addition, this compact system is attracting attention since it has the potential to be a tool to achieve decentralized manufacturing and point-of-care manufacturing³. Currently, there is only insufficient knowledge or the characteristics and quality of tablets manufactured using single-dose manufacturing system. Therefore, manufacturing demonstrations using various dosage forms and APIs are desired. In this study, mini tablets were prepared using this system and aspects regarding quality and manufacturing process were investigated.

Methods: The integrated single dose manufacturing system performs powder mixing, tableting and tablet ejection in a continuous manner (Fig. 1(b)). At the starting position, a compression die is placed on the stainless-steel table and fixed in position by a holding arm. The tableting process begins by sequentially loading pre-weighed materials into the die to a total of 10 mg. Once filled, the die will be automatically transported by the holding arm while maintaining contact between its bottom and the table surface to the mixing unit. Pulsed air from the mixing unit is introduced from the bottom of the table through the mesh and powders are mixing within the die. After mixing completed, the die is transported to the compression unit with the holding arm and the powder is compressed using a single-sided tablet press. Once compression is complete, the die proceeds to the tablet ejection unit and pushed out to an outlet hole on the table with upper punch since the tablet cannot be discharged by gravity alone. Tablets (internal diameter 2.0mm, weight 10mg) for this study were manufactured with different concentrations of API (acetaminophen, 10, 20, 40 and 50 wt%) and FujiTab (90, 80, 60 and 50wt%) (co-processed excipient, Fuji Chemical Industries Co., Ltd., Toyama, Japan) respectively. Mixing was performed in the following condition: air flow 30 L/min; air pressure 0.4MPa; air knocker supply air 0.4MPa, and samples with different mixing times (5, 10, and 30s) were prepared. The mixed sample was compressed at 3 kN. Tablet hardness (n=10) was measured using a tablet hardness tester (ERWEKA, Heusenstamm, Germany). Raman spectra (RS) were measured at room temperature using a confocal Raman microscope (XploRA PLUS, Horiba Ltd., Kyoto, Japan) equipped with a visible light detector. Dissolution studies (n=6) were undertaken using a dissolution test apparatus (Paddle method; NTR-6200; Toyama Sangyo Co., Ltd, Osaka, Japan).

Results: The picture of mini tablets prepared for this research are shown in Fig. 2. The experiment with 50wt% acetaminophen was terminated due to facing problems with tablet ejection, and maximum concentration of acetaminophen prepared in this study was 40wt%, which is a powder blend that is generally difficult to compress directly. The reason for preparation of tablets containing 40wt% acetaminophen without issues may be attributed from the slower compression speed of the pestle than that of a rotary tableting press. The tablet hardness of mini tablets shows decrease in hardness as the acetaminophen concentration increased (Fig. 3a), which the reason assumed to be from the overall effect of the higher acetaminophen concentration and a reduction in the concentration of forming aids such as binders contained in FujiTab. However, it should be considered as not a necessary point if the tablet is hard enough for dissolution measurement and intake since the system and pharmaceutics used in this study is intended for on-demand manufacturing. RS measurement of the cross section confirmed that as the acetaminophen concentration increased, the influence of air mixing efficiency tended to decrease but all formulation reached a stable mixture by mixing time of 30 seconds. In addition, tablets prepared by mixing time of 10 seconds for 20wt% (partially mixed) and 40wt% (completely mixed) were confirmed to have a similar dissolution profile. (Fig. 3b). These results suggest that complete mixing during integrated single-dose manufacturing is not always necessary for this purpose and formulation.

Conclusion: In the present work, we assessed the quality performance of the mini tablets produced by integrated single-dose manufacturing equipment and demonstrated the applicability of “minimum scale" manufacturing. The physicochemical properties of the mini tablets were satisfactory when compared with those of similar commercial ones. These findings can support the practical application of this system for providing personalized pharmaceutical tablets containing an API amount tailored to the patient and suggest that this system meets the basic requirements of a transportable pharmaceutical manufacturing plant.

References: 1. Cesario, A., Lohmeyer, F.M., D’Oria, M., Manto, A., Scambia, G., The personalized medicine discourse: archaeology and genealogy. Med. Health Care Philos. 24 (2021) 247–253.
2. Hayashi, Y., Okazaki, S., Tanabe, K., Nagato, T., and Sugiyama H., Development of concentration-prediction models in multiple manufacturing environments using NIR spectroscopy. J. Chem. Eng. Jpn. 58 (1) (2025).
3. Discussion paper; Distributed Manufacturing and Point-of-Care Manufacturing of Drugs (2022).

Acknowledgements: Hirokazu Sugiyama and Kohei Tahara report financial research support by Powrex Corporation. Kazuya Tanabe, Satoshi Kodama and Takuya Nagato reports a relationship with Powrex Corporation that includes: employment.


Fig. 1. Integrated single-dose tablet manufacturing system [1200 mm (length) × 600 mm (width) × 900 mm (height)]. (a) Machine appearance, (b) process scheme.


Fig. 2. Photograph of mini tablets (internal diameter 2mm, tablet weight 10mg) prepared by integrated single-dose tablet manufacturing system.


Fig. 3. (a) Tablet hardness of experimental tablet. Values are expressed as the mean ± standard deviation of the mean (n = 10). (b) Dissolution profile of acetaminophen mini tablets (n = 6).