Commercialization of the Xalkori Pediatric Multiparticulate Product Using Quality-by-Design Principles
<p>Process flow diagram of the melt spray congeal process. The red designates the heated path the melt follows from the extruder to the atomization disk. The cartoon depicts the droplets atomizing from the disk and cooling to the point of congealing, indicated by the color changing from yellow to blue, prior to impacting the collection bag.</p> "> Figure 2
<p>High-speed video footage of the crizotinib melt being dispensed onto the spinning disk and atomized on the rotary atomizer.</p> "> Figure 3
<p>Representative particle morphology for crizotinib lipid multiparticulates produced via MSC.</p> "> Figure 4
<p>Particle size (D[v,0.5] (µm)) (left) as a function of the two statistically significant process parameters. Potency (right) as a function of the one statistically significant process parameter (extruder screw speed). The black boxes in both figures denote the narrowed operating space to ensure consistent microsphere particle size. Note: <a href="#app1-pharmaceutics-16-01027" class="html-app">Supplement Table S1</a> reports the study design.</p> "> Figure 5
<p>Potency across three registrational stability batches of uncoated microspheres as a function of process time.</p> "> Figure 6
<p>Particle size distribution by laser diffraction for registrational stability lots of uncoated microspheres produced via melt spray congealing prior to screening.</p> "> Figure 7
<p>Mechanical scraper compared to air knife methods of removing the material cap.</p> "> Figure 8
<p>Left: Filled capsule weight RSD from the in-process control sampling for the (a) ICH campaign (mechanical scraper used) compared to (b) PPQ campaign (air knife used). Data are summarized for three batches of each campaign. Right: Capsule fill contents from extended uniformity of dosage units for the (a) ICH campaign (mechanical scraper used) compared to (b) PPQ campaign (air knife used).</p> "> Figure 9
<p>Volumetric dosing with a vacuum dosator. Process parameters are labeled and described in the text.</p> "> Figure 10
<p>Contour plots for filled capsule weight RSD (%) (shown as values on the contour lines; color spectrum from blue (0%) to red (2.5%) for the RSD values is shown at the bottom of the figure) for the statistically significant two-way interaction effects of (1) AC: air knife pressure and fill vacuum (left) and (2) AB: air knife pressure and infeed level (right) based on DoE Study 2. The stars denote additional process exploration, as explained below in <a href="#sec4dot3-pharmaceutics-16-01027" class="html-sec">Section 4.3</a>. Note: DoE Study 2 design and the results fitting and analysis are reported in <a href="#app1-pharmaceutics-16-01027" class="html-app">Supplement Tables S3 and S4</a>.</p> "> Figure 11
<p>Extended uniformity of dosage units across the demonstration batch among three different processing conditions.</p> "> Figure 12
<p>Capsule fill content uniformity for the ICH and PPQ campaigns, demonstrating the tight correlation between the fill content mass (X) and capsule assay (Y). Note that less than 2% of the capsules were less than 85 %LC and would be removed from the batch in the weight sorting process. Blue solid line: Y = 1.234 + 0.9921 × X (R<sup>2</sup> = 0.943); Black dashed line: Y = X for reference.</p> ">
Abstract
:1. Introduction
1.1. Product Background
1.2. Advantages of Multiparticulates
1.3. Problem Statement
2. Materials and Methods
2.1. Equipment
2.2. Materials
2.3. Design of Experiments
3. Multiparticulates Manufacturing
3.1. Manufacturing Process
3.2. Melt Spray Congeal
3.3. Fluid Bed Coating
4. Encapsulation
4.1. Equipment Upgrades
4.2. Process Space Determination through Statistical Design of Experiments
4.3. Process Demonstration
4.4. Process Validation
5. Uniformity Discussion
6. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Sample | D(v 0.1) µm | D(v 0.5) µm | D(v 0.9) µm | Span |
---|---|---|---|---|
ICH Lot 1 | 121.6 | 182.7 | 270.5 | 0.8 |
ICH Lot 2 | 122.7 | 184.8 | 273.5 | 0.8 |
ICH Lot 3 | 125.1 | 183.2 | 265.2 | 0.8 |
Sample | Average, %LC | Standard Deviation, %LC |
---|---|---|
PPQ Lot 1 | 100.3 | 0.5 |
PPQ Lot 2 | 99.6 | 0.3 |
PPQ Lot 3 | 99.6 | 0.5 |
Sample/Run Condition | Filled Capsule Weight RSD (n = 300, %) | Capsule Label Claim RSD (n = 20, %LC) by HPLC | Content Uniformity Acceptance Value by USP <905> |
---|---|---|---|
Centerline conditions | 1.42 | 1.9 | 4.4 |
Highest RSD condition | 1.86 | 2.6 | 7.7 |
Run Condition (Numbered in Figure 10) | Infeed Level (mm) | Fill Vacuum (mbar) | Air Knife Pressure (mbar) | Filled Capsule Weight RSD (%) |
---|---|---|---|---|
Condition 1 (target) | 10.0 | −170 | 450 | 1.9 |
Condition 2 (operating edge) | 9.0 | −190 | 375 | 1.9 |
Condition 3 (operating edge) | 11.0 | −150 | 525 | 2.0 |
Lot | Overall Mean (%LC) | Individual Potency Range (%LC) | Between Location Std. Dev (%LC) | Within Location Std. Dev (%LC) | Pass/Fail ASTM E2810 (95%/99%) |
---|---|---|---|---|---|
Process Demonstration | 101.2 | 95.8–107.2 | 2.0 | 2.9 | Pass |
Lot | Overall Mean (%LC) | Individual Potency Range (%LC) | Between Location Std. Dev (%LC) | Within Location Std. Dev (%LC) | Pass/Fail ASTM E2810 (95%/99%) |
---|---|---|---|---|---|
PPQ Lot 1 | 101.6 | 95.9–106.0 | 1.4 | 2.2 | Pass |
PPQ Lot 2 | 102.5 | 94.2–109.8 | 1.5 | 2.7 | Pass |
PPQ Lot 3 | 101.3 | 95.7–106.3 | 1.3 | 2.7 | Pass |
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Bartlett, J.; Culver, N.; Zhang, X.; Waybrant, B.; Sullivan, H.; Howell, L. Commercialization of the Xalkori Pediatric Multiparticulate Product Using Quality-by-Design Principles. Pharmaceutics 2024, 16, 1027. https://doi.org/10.3390/pharmaceutics16081027
Bartlett J, Culver N, Zhang X, Waybrant B, Sullivan H, Howell L. Commercialization of the Xalkori Pediatric Multiparticulate Product Using Quality-by-Design Principles. Pharmaceutics. 2024; 16(8):1027. https://doi.org/10.3390/pharmaceutics16081027
Chicago/Turabian StyleBartlett, Jeremy, Natalie Culver, Xiang Zhang, Brett Waybrant, Hannah Sullivan, and Logan Howell. 2024. "Commercialization of the Xalkori Pediatric Multiparticulate Product Using Quality-by-Design Principles" Pharmaceutics 16, no. 8: 1027. https://doi.org/10.3390/pharmaceutics16081027