(496d) Production of Small-Batches of 3D Printed Multi-Compartment Capsular Devices for Oral Drug Delivery Using High-Throughput Robotic Manufacturing Technologies

In this talk, we present an automated production process enabling the manufacturing of multi-compartment capsular devices for oral drug delivery. This process includes i) the production of capsule parts and ii) filling the capsules with formulations containing active pharmaceutical ingredients. In this respect, our technology allows fast and efficient fabrication of fixed-dose combination products in small, personalized batches.

The capsular devices manufactured with this process have a structure that is different from the traditional capsules that are already on the market – generally made either of gelatin or hydroxypropyl methylcellulose. Our capsular devices have a modular structure that consists of multiple inner compartments, which are independent of one another. Each compartment can be filled with different active ingredients and with a range of doses, as well as formulations, of the same drug.

Moreover, these capsular devices transform the polymeric barriers of traditionally coated drug delivery systems into self-operating shells. Therefore, they represent a step forward in controlled release – separating the container (i.e. the capsule shell) from the content (i.e. the drug formulations contained in each compartment). The release performance of a compartment is determined by the composition and design features (i.e. morphology and thickness) of its walls. By varying the composition and thickness of each compartment, its release profile can be modified without affecting the properties of the other compartments. In other words, these multi-compartment capsules products yield multiple release kinetics in a single unit.

Multi-compartment capsular devices are especially advantageous for therapies involving multiple drugs that are mutually incompatible or interact in the gastrointestinal tract. Using multiple compartments simplifies the dosing schedule and has a positive impact on overall patient compliance. Moreover, these capsular devices enable the independent development of the drug formulation and the capsule shell, reducing time-to-market and development cost for new drug delivery systems.

The talk will present an example of this new class of capsular devices. The system consists of a two-compartment capsule shell composed of three parts: two hollow halves and a middle part, acting both as a joint and a partition. The joint allows the hollow parts to be assembled into a closed capsular device while dividing the internal cavity into two separate compartments. The hollow parts can have different shapes and thicknesses, resulting in compartments with different release properties and internal volume.

As a proof of concept, we will discuss the fabrication of capsule shells composed by 400 µm-thick and 800 µm-thick compartments using hydroxyl propyl cellulose (Klucel™ LF). We selected 3D printing by fused deposition modeling (FDM) as a suitable manufacturing technique for small-scale batches. This required the development of an industrial-grade FDM system able to realize pharmaceutical products. The talk will discuss in detail the development steps required to manufacture both the filament (through hot melt extrusion) and the capsule shells (through FDM 3D printing).

The FDM process requires as input material thermoplastic polymers supplied in the form of filaments – with suitable diameter and mechanical characteristics. We designed custom extrusion and 3D printing systems, and validated them to fulfill strict pharmaceutical quality requirements. In both cases, the study of the process was aimed at the identification of the critical operating parameters that affect the quality attributes of the final product. We assessed the stability of hydroxyl propyl cellulose after hot-processing and 3D printing, ruling out contamination and the formation of any hazardous degradation product. This led to the formation of an internal protocol for evaluation of by-products. These results demonstrate that the filaments and prototype capsule parts meet the target specifications – in terms of composition, absence of microbiological contamination, and absence of degradation by-products.

Once filled and assembled, the two-compartment capsular devices showed the expected two-pulse release behavior, in agreement with the swellable/erodible nature of the polymer. Furthermore, we compared the dimensional and release characteristics of multi-compartment capsules prepared by fused deposition modeling with those of analogous devices obtained by injection molding (IM). The real-time prototyping capabilities of 3D printing can significantly speed up the R&D process for IM. Both represent viable manufacturing techniques. 3D printing enables the rapid and inexpensive realization of small on-demand batches. Then, once the prototype capsules have been tested and refined, IM allows the large-scale production of capsule shells with the desired behavior.

After the capsule shells are produced, a proprietary robotic system fills each compartment with specific drug formulations. This part of the process relies on a set of automated filling modules working simultaneously, in parallel. The flexibility of this configuration is particularly suitable for the efficient production of small batches of fixed-dose combination products. The automated deposition stage allows the rapid and accurate adjustment of the combination and dosage strength of the active ingredients. Cross-contamination is avoided by enclosing each filling station in a dedicated clean room. A robotic arm (designed to safely collaborate with human operators) moves the capsular devices form one filling station to the next. The capsule filling systems were validated with preliminarily filling trials, which used powders with different particle size distribution and bulk density. We considered 25 batches of 50 capsule each for each powder formulation. In all cases, the amount of active ingredient deposited by the robots had an average coefficient of weight variation (i.e. the ratio between the standard deviation and the average value of the weight of the deposited powder) below 3%. These results demonstrate the accuracy and the flexibility of the powder deposition systems.

This robotic capsule filling system enables the realization of batches that are much smaller than the ones typical of traditional large-scale production processes. This level of personalization requires innovative in-process, non-destructive controls in order to guarantee the quality of the products in a cost-effective manner. We developed quality control machines that are able to check the thickness and weight of the capsule parts. Additionally, we use spectroscopic techniques to check the weight uniformity and identity of the pharmaceutical formulations.