(703d) Impact of Particles Needle Shape, a Critical Material Attributes (CMAs), on Miniaturized Pharmaceutical Units Operation

The US Food and Drug Administration (FDA) encourages the adoption of Quality by design (QbD) principles in drug product development and manufacturing¹. FDA emphasizes quality must be built into the product. QbD elements include the critical quality attributes (CQAs) of the drug product, identification of critical material attributes (CMAs) and critical process parameters (CPPs), and linking CMAs and CPPs to CQAs¹. A CMA is a physical, chemical, biological, or microbiological property or characteristic of an input material that should be within an appropriate limit, range, or distribution to ensure the desired quality of that drug substance, excipient, or in-process material. Typically materials move from one unit operations to another unit operations. CMAs can significantly impact on pharmaceutical unit operations, process consistency, and product quality attributes. Hence, material properties need to be tested and CMAs need to be defined and controlled. Drug substances physical properties such as particle morphology (shape) has a great impact when design and developing a robust drug product having intended CQAs.

At MIT we developed a miniaturized, portable, re-configurable and automated system to manufacture drug product from drug crystals^{2, 3}. The compact, portable system, roughly the size of a household oven, [72.4 cm (length) ×53.3 cm (width) ×134.6 cm (height)] is built to manufacture on-demand pharmaceutical direct compressible tablets on a scale of hundreds to thousands per day. Its design combines off-the-shelf devices with custom-designed automated mechanisms. The whole unit consists of: upper process streams start with powder feeding and end with blending and lower process streams include powder dispensing thru to making tablets. These two process streams operate independently under high-level software control, allowing for smooth integration between the two. Several commercial APIs having different dosage strength were manufactured and tested to meet U.S. Pharmacopeia standards. In the case of needle-shaped Ciprofloxacin HCl (CIPRO), processing difficulties were observed in different unit operations: feeding, dispensing even with the few grams of CIPRO.

Typically several strategies have been considered to handle needle shaped particles: alteration to crystallization process using crystal habit modifying agents, manipulation of solvents, and mechanical manipulation (e.g. milling). Each approach has its own drawbacks. Given the limitations, milling and micronization are still, at present, an attractive approach routinely used to obtain consistent particle size and shape modification during downstream formulation processing. However, the shape alteration of a few grams of materials by using conventional equipment is not typical.

In this research work, we emphasize on how particle shape, especially needle-shaped, a critical material attribute, impacted on different unit operations of the system even at a small scale and discussed different grinding options were attempted to improve the processability of needle-shaped particles. Finally, we showed the MIT team designed grinder performed well for small scale CIPRO powder, the powder can easily be processed through the system, and the manufactured oral dosage tablets showed a comparable performance of the commercially marketed CIPRO tablet.

References:

1. Lawrence XY, Amidon G, Khan MA, Hoag SW, Polli J, Raju G, et al. Understanding pharmaceutical quality by design. The AAPS journal. 2014;16(4):771-83.
2. Azad MA, Osorio JG, Brancazio D, Hammersmith G, Klee DM, Rapp K, et al. A compact, portable, re-configurable, and automated system for on-demand pharmaceutical tablet manufacturing. International journal of pharmaceutics. 2018;539(1-2):157-64.
3. Myerson A, Azad M, Hammersmith G, Brancazio D, Osorio Caicedo J. Systems and methods for the fabrication of tablets, including pharmaceutical tablets. U.S. Provisional Patent Application US 2018/0271791 A1, Published on September 27, 2018.