(507d) Pharmacy on Demand: On-Demand Drug Product Manufacturing in a Miniaturized and Portable System

Typically, in the pharmaceutical industry, drug substances (active pharmaceutical ingredients, APIs) are synthesized in one facility and formulated to finished dosage forms so-called drug products in another facility, which could be located anywhere else worldwide. Due to the complex nature of the pharmaceutical supply chain, the industry faces several major challenges when it comes to ensuring an adequate supply of quality drug products. These challenges are not only the causes of supply chain disruptions and financial loss, but can also prevent underserved and remote areas from receiving life-saving drugs. Another concern for orphan drugs that pharmaceutical company generates small sales in comparison to the development and manufacturing cost in a large footprint facility. To address all the above issues, at MIT we have developed a continuous manufacturing platform that combines both drug substance and final drug product development in a custom-built miniature system^1-3. In this work specifically, drug product as oral tablet manufacturing from drug crystals in the miniaturized, portable, re-configurable and automated system will be presented^1,2.

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 tablets on a scale of hundreds to thousands per day. Its design combines off-the-shelf devices with custom-designed automated mechanisms. A direct compression approach is considered for making tablets. The whole unit is divided into upper process streams and lower process streams. The upper process streams start with powder feeding and end with blending. The 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. As this is for on-demand pharmaceutical drug manufacturing, a simplified formulation approach is adopted by eliminating excipients required for stability. Hence, only filler, glidant, lubricant, and additional functional excipients, if necessary are considered for formulation.

Several APIs having different dosage strength were investigated. Here ibuprofen (200/340 mg) and diazepam (10/250 mg) were shown as the example. Assay, content uniformity, hardness and in-vitro testing of tablets were conducted to confirm it meets U.S. Pharmacopeia standards. Formulated blended powder is freely flowing (flow function coefficient (ffc)>10) and has a good bulk density (0.65-0.72 g/cm³) that are suitable for making tablets via direct compression. Assay of ibuprofen and diazepam tablets are found 98.8% and 103.7 % of the labeled amount, respectively. The acceptance value in content uniformity/weight variation test is 6.12 and 9.36, respectively for ibuprofen and diazepam tablets. The tensile strength of ibuprofen and diazepam tablets are 1.14 and 0.52 MPa, respectively. Tablets dissolution profiles for both of drugs meet USP standard criteria (85% dissolved in 30 minutes).

This custom-built miniature system has the potential to (1) help tackle regional drug shortages (a threatening global problem), (2) be advantageous for drugs with a short shelf life, (3) be put into immediate production of drugs based on demand, bypassing the need to stockpile drugs (e.g., for humanitarian needs), and (4) reduce formulation complexity relative to products needing yearlong stability. We envision that this system will enable the creation of small-scale, portable, fully integrated and closed loop pharmaceutical solids dosage manufacturing that can advance the treatment of human diseases at the point-of-care.

References:

1. Azad M, Osorio Caicedo J, Brancazio D, Hammersmith G, Klee D, Rapp K, Myerson A 2018. A compact, portable, re-configurable, and automated system for on-demand pharmaceutical tablet manufacturing. Int. J. Pharm. 539 (1-2):157-164.
2. Myerson A, Azad M, Hammersmith G, Brancazio D, Osorio Caicedo J. Systems and methods for the fabrication of Ttablets, including pharmaceutical tablets. U.S. Provisional Patent Application 62/621,429, Filed on January 24, 2018.
3. Adamo A, Beingessner RL, Behnam M, Chen J, Jamison TF, Jensen KF, Monbaliu J-CM, Myerson AS, Revalor EM, Snead DR 2016. On-demand continuous-flow production of pharmaceuticals in a compact, reconfigurable system. Science 352(6281):61-67.