Modular assembly line: a promising approach to reduce drug shortages, assure quality, and improve affordability.

The pharmaceutical industry faces multiple challenges (e.g., inefficient manufacturing techniques, quality control issues, and supply chain vulnerabilities) because of its current batch-wise approach to manufacturing. Recent regulatory support for continuous manufacturing and advances in continuous process technologies have caused an increase in interest from some drug manufacturers to modernize their production processes. However, many of these companies have focused on hybrid processes, where only certain steps are continuous, while others remain batch. Herein, the quality by design (QbD)-based design strategy and operation of an end-to-end integrated continuous manufacturing (ICM) pilot plant that produces both small-molecule active pharmaceutical ingredient (API) and oral solid dosages (OSDs) are discussed. Additionally, important quality and economic matters pertaining to scale-up and commercialization are addressed. ICM has significant benefits, including better quality control, increased supply chain flexibility, a lower capital investment (in the example provided, a ∼ 90% reduction), and lower operating costs (in the example provided, a 33.6% reduction for API and 29.4% reduction for tablets).

Much less waste was generated by the end-to-end Integrated Continuous Manufacturing (ICM) process compared to the batch process.

20Rheological characterization of ethylcellulose (EC)-based melts intended for the production, via 21 micro-injection moulding (μIM), of oral capsular devices for prolonged release was carried out. 22Neat EC, plasticized EC and plasticized EC containing solid particles of a release modifier (filler 23 volume content in the melt around 30%) were examined by capillary and rotational rheometry tests. 24Two release modifiers, differing in both chemical nature and particle geometry, were investigated. 25When studied by capillary rheometry, neat EC appeared at process temperatures as a highly viscous 26 melt with a shear-thinning characteristic that progressively diminished as the apparent shear rate 27 increased. Thus, EC as such could not successfully be processed via μIM. Plasticization, which 28 induces changes in the material microstructure, enhanced the shear-thinning characteristic of the 29 melt and reduced considerably its elastic properties. Marked wall slip effects were noticed in the 30 capillary flow of the plasticized EC-based melts, with or without release modifier particles. The 31 presence of these particles brought about an increase in viscosity, clearly highlighted by the 32 dynamic experiments at the rotational rheometer. However, it did not impair the material 33 processability. The thermal and rheological study undertaken would turn out a valid guideline for 34 the development of polymeric materials based on pharma-grade polymers with potential for new 35 pharmaceutical applications of μIM. 36 37 38

A new type of colon targeting system is presented, combining time-controlled and enzyme-triggered approaches. Empty capsule shells were prepared by injection molding of blends of a high-amylose starch and hydroxypropyl methylcellulose (HPMC) of different chain lengths. The dissolution/erosion of the HPMC network assures a time-controlled drug release, i.e., drug release starts upon sufficient shell swelling/dissolution/erosion. In addition, the presence of high-amylose starch ensures enzyme-triggered drug release. Once the colon is reached, the local highly concentrated bacterial enzymes effectively degrade this polysaccharide, resulting in accelerated drug release. Importantly, the concentration of bacterial enzymes is much lower in the upper gastrointestinal tract, thus enabling site-specific drug delivery. The proposed capsules were filled with acetaminophen and exposed to several aqueous media, simulating the contents of the gastrointestinal tract using different experimental setups. Importantly, drug release was pulsatile and occurred much faster in the presence of fecal samples from patients. The respective lag times were reduced and the release rates increased once the drug started to be released. It can be expected that variations in the device design (e.g., polymer blend ratio, capsule shell geometry and thickness) allow for a large variety of possible colon targeting release profiles.

The present work focuses on application of an investigational approach to assess the hot-processability of pharmaceutical-grade polymers with a potential for use in the manufacturing of reservoir drug delivery systems via micromolding, and the performance of resulting molded barriers. An inert thermoplastic polymer, ethylcellulose (EC), widely exploited for preparation of prolonged-release systems, was employed as a model component of the release-controlling barriers. Moldability studies were performed with plasticized EC, as such or in admixture with release modifiers, by the use of disk-shaped specimens ≥ 200 µm in thickness. The disks turned out to be a suitable tool for evaluation of the dimensional stability and diffusional barrier performance of the investigated materials after demolding. The effect of the amount of triethyl citrate, used as a plasticizer, on hot-processability of EC was assessed. The rate of a model drug diffusion across the polymeric barriers was shown to be influenced by the extent of porosity from the incorporated additives. The investigational approach proposed, of simple and rapid execution, holds potential for streamlining the development of prolonged-release systems produced by micromolding in the form of drug reservoirs, with no need for molds and molding processes to be set up on a case-by-case basis.

A predictive mathematical model for tablet dissolution was developed and implemented in an end‐to‐end integrated continuous manufacturing pilot plant. The tablets were produced for immediate release with a proprietary extrusion‐molding‐coating (EMC) unit operation. Besides the mass balance of API solute in the buffer solution, the model consisted of the dissolution, diffusion, and population balance of API particles in the swollen tablet, which was mainly controlled by the swelling and erosion of the polymeric excipient matrix. An equivalence study was investigated by comparing the model prediction to the experiments that were conducted according to USP42‐NF37 General Chapter <711> Dissolution, during which the drug dose level was varied in a range from 60 to 80 wt%. Consistent equivalence was demonstrated with the similarity factor f2 > 50 for all sampled tablets. Concluding remarks and industrial perspectives on model predictive in vitro dissolution testing are provided.

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