(T0930-02-12) Real-Time Monitoring of Selective Laser Sintering 3D Printing Process For Lamivudine Content Quantification in the Printlets

Purpose: PAT tools can reduce the need for time-consuming and labor-intensive off-line testing, as they allow for in-line and on-line measurements (Kim et al., 2021). PAT contributes to more efficient manufacturing processes and faster production cycles (Food and Administration, 2004b). This is especially valuable in the point-of-care utilization of 3D printing, where conventional off-line testing may not be available. The ability to monitor and control 3D printing processes in real-time aligns with the FDA’s PAT framework, which emphasizes the importance of process understanding and control in ensuring product quality (Food and Administration, 2004a). The objective of the present work was to develop an in-line monitoring system for the selective laser sintering process while printing lamivudine (3TC) printlets and quantifying the drug content. The accuracy of the predicted drug content in the printlets was compared with off-line spectroscopic and HPLC methods.

Methods: Dissolution: Dissolution was performed using a USP-II apparatus (Model 708-DS with 850-DS autosampler, Agilent Technologies, Santa Clara, CA) equipped with a mini dissolution vessel (200 mL) and mini paddle. The printlets were placed in 200 mL of 0.1 N HCl solution. The paddle speed was fixed at 50 rpm, and dissolution tests were conducted at 37±0.5°C. A 1 mL sample was collected at 3, 6, 10, 15, 20, and 30 min. The percentage of 3TC dissolved from the printlets was determined by the validated HPLC method. Real-Time NIR Spectroscopy: NIR spectral data was collected using Antaris™ MX FT-NIR Process Analyzer (Thermo Fisher Scientific, Houston, TX) fitted with a scanning grating monochromator coupled with a diffuse reflectance rapid content analyzer. The measurement parameters were as follows: spectral range, 4000 to 10,000 cm−1, in 2 cm−1 increments, with a data resolution of 8 cm−1 for 32 scans. Near Infrared Hyperspectral Imaging: The spectral camera is capable of capturing images with a resolution of 384×288 pixels with a pixel size of 24×24 μm. The camera is a cryogenically cooled mercury-cadmium-telluride. The data were collected at an integration time of 2.865 ms, the frame rate of 226 MHz, and the scan-axis speed of 0.2 inches s−1. The data acquisition software used was Middleton Spectral Vision (Middleton Spectral Vision, Middleton, WI).

Results: Dissolution and Assay The total amount dissolved after 30 min was 95.7±6.2% and 99.3% for the Printlets A and C, respectively. This indicated a similarity in dissolution between two printlets differing in dimension. Real-time quantification of 3TC content in printlets Predicted 3TC amounts in each printed layer ranged from 114.9 to 95.8%, with an average 3TC concentration of all layers being 101.5% (Table 5). Near Infrared Hyperspectral Imaging The 3TC content in the Printlet C and the Printlet A was 98 and 105%, respectively.

Conclusion: A custom-made NIR probe was successfully installed into the selective laser sintering printer in order to collect real-time in-line NIR spectra of the printlets without interfering with the printing process. A chemometric model was developed to predict the drug loading from real-time NIR spectra. Predicted drug loading values were later compared with dissolution, assay, and another chemometric model built off-line. The real-time model proved to be accurate at predicting the drug concentrations at each printed layer. Overall, this study demonstrates the feasibility of adding a PAT element to the selective laser sintering process. This addition will aid the point-of-care performance and capability of selective laser sintering. The NIR probe is easy to operate and provides data equivalent to the gold standard quality control methods, such as HPLC, which is cumbersome, expensive, and time-consuming. With the addition of the NIR probe, the determination of content uniformity occurs as the printlets are being printed, which saves time and helps prevent costly mistakes.

References: Kim, E.J., Kim, J.H., Kim, M.-S., Jeong, S.H., Choi, D.H., 2021. Process analytical technology tools for monitoring pharmaceutical unit operations: a control strategy for continuous process verification. Pharmaceutics 13, 919. Food and Drug Administration, 2004a. Guidance for industry, PAT-A framework for innovative pharmaceutical development, manufacturing and quality assurance.Food and Drug Administration, 2004b. Pharmaceutical cGMPs for the 21st century—a risk-based approach, final report.

Dissolution vs time profile of Printlets

Content uniformity of 3TC in each of the printed layers collected in Real-time.

Total amount of 3TC in printlets Determined by Chemical Imaging.