Addressing Poorly Soluble APIs with Continuous Hot-Melt Extrusion

Continuous manufacturing has the potential to offer benefits in terms of reduced costs, footprint, raw material consumption, and byproduct and emission generation combined with increased process consistency and product quality. Regulatory submission timelines can also be advanced by more than 12 months and approval times by three months compared to products generated via batch manufacturing (1). Not surprisingly, the US Food and Drug Administration (FDA) encourages the development of continuous processes, and these processes are slowly becoming more prevalent in both small-molecule and biologics manufacturing. It is expected, in fact, that in the near future continuous operations will be the norm rather than the exception, according to Hibreniguss Terefe, director of research and development at Catalent. As such, outsourcing providers that develop continuous manufacturing expertise and leverage this technology can establish a differentiating competitive advantage.

Hot-melt extrusion (HME) by its nature is a continuous process, and its integration with other continuous manufacturing operations has the potential as an amorphous solid dispersion (ASD) solution to offer more benefits than just enhanced solubility and bioavailability for poorly soluble APIs. “Given that HME is one of the best tools for enhancing solubility, linking HME processes effectively with other unit operations such as tableting/capsule filling will reduce the number of unit operations, ease scale-up to commercial production, and ultimately help patients realize earlier access to products with positive economic impacts for sponsors as well,” states Purushottam Singnurkar, vice-president and head of formulation development at Syngene International Limited.

Many benefits of HME

Formulating drug substances into ASDs is a widely accepted approach to enhancing the solubility and bioavailability of poorly soluble molecules, according to Terefe. “The conversion of a crystalline API into an amorphous form by dispersing and immobilizing it in a polymeric carrier can be achieved through solvent- or fusion-based technologies. Spray drying is a solvent-based process, while HME is fusion-based technology,” he observes.

In addition to improved solubility, other benefits of using HME are good process control, scalability, and avoidance of solvents, notes Hannes Fuderer, technical operations manager with AbbVie Contract Manufacturing. “Good process control enables balancing of incoming variability into the extrusion process and reduces the variability of the extrudate itself to improve the performance of downstream processing. Good scalability provides the opportunity for faster development and transfer from
lab through pilot to commercial scale and affords flexibility to accommodate volume and extruder-scale changes during life-cycle management,” he explains.

“The ability to practically transfer material inputs continuously and have them transformed into output materials that are continuously removed leads to increased product quality assurance and enhanced product capability and control,” adds Singnurkar. He also comments that the fact that HME is a “green technology” that involves fewer processing steps than spray drying and freeze drying provides further advantages.

A naturally continuous operation

HME takes place in a twin-screw extruder, which is, according to Terefe, a continuous, versatile, and highly efficient self-wiping small mass mixer amenable to process analytical technology (PAT). That is why process parameters can be well controlled and HME processes can be readily scaled from R&D to commercial-scale equipment. “Once process parameters are established at a given equipment scale, the batch size is then a function of time and can be easily changed by running the process for a longer or shorter period without needing to change other process parameters,” he notes.

In addition, HME offers a high degree in flexibility and many use cases. “Based on the HME process design, there are many options to integrate an HME process into a fully continuous process or combine it with discontinuous up- and/or downstream processes if required, such as batch blending to feed the extruder or storage of extrudate intermediate prior to further (batch-wise) processing into final drug product,” Fuderer says. HME can also be used for potent compounds and due to the equipment design it typically results in high yields.

Integration with other continuous ops

An HME unit operation is usually performed as a continuous process through a sequentially assembled equipment system consisting of powder feeder(s), optional liquid pump(s), a twin-screw extruder, a conveyor, and a pelletizer (or a chill roll flaker) working in a harmonized and continuous manner, Terefe notes. The extrudate, however, is typically handled as an intermediate and further processed as a batch, limiting HME to a semi-continuous process.

On the upstream side, the material feed can be a mixed powder blend or individual streams of different ingredients (API and excipients) fed directly. Either approach can be performed continuously, according
to Fuderer.He also notes that, based on material properties or to increase the throughput, the blend can be densified prior to extrusion by a continuous roller compactor or side-stuffer.

The extrudate, meanwhile, can be shaped into nearly any form by the design of the extruder die in combination with several cutting and shaping technologies that are also all continuous processes, Fuderer says. Common shapes are flakes, pellets, and beads depending on the downstream unit operation. “It is possible rather than collecting and buffering the shaped and cooled extrudate in containers prior to further processing, it can be dosed immediately to the next unit operation as the mass flow is still controlled,” he adds.

Integrating the extrusion process with other upstream and downstream semi-continuous unit operations such as continuous blending, milling, tablet pressing (direct compression), and tablet coating would, Terefe says, create a fully end-to-end continuous solid-oral-dosage-form manufacturing process. “Combining a continuous HME process with continuous downstream operations could be envisioned as a viable means for taking full advantage of a continuous process to manufacture solubility- and bioavailability-enhanced products,” he concludes.

One example provided by Singnurkar involves transfer of the hot extrudate directly to dies of suitable sizes for the manufacture of 3D tablets. “Integration eliminates many process steps such as cooling and milling of the extrudate and mixing with excipients, among others,” he says. Any integration of continuous operations without a centralized computer system for control and the implementation of PAT tools for constant process monitoring will, however, reduce the likelihood of success, Singnurkar stresses.

Upstream process control essential

Understanding the critical material attributes (CMAs) of the API and polymer, such as the melting and glass-transition temperatures is also important for developing high-performing HME processes. “The machine settings, including the screw configuration, screw diameter-to-length-ratio, barrel-free volume, distribution of heating and cooling zones, die-orifice size and shape, and the cooling system are equality important. Critical process parameters include the barrel temperature, screw speed, residence time, and throughput,” Singnurkar from Syngene observes.

Controlling material inputs often presents the greatest challenge for HME process optimization, according to both Fuderer and Terefe. “Blend homogeneity, dosing accuracy, and risk of blend segregation during powder conveying are important issues that must be managed,” Fuderer stresses.

Inconsistent and inaccurate feeding of input material into the twin-screw extruder may be caused by poor flow properties of certain raw materials, or very low amounts of certain excipients such as plasticizers and surfactants, Terefe notes. “Feeding all of the components separately at an appropriate ratio of feed rates, as reflected in the formulation composition, would be ideal for a well-harmonized continuous
process, but this assumes that no additional pre-extrusion unit operations are necessary,” he says. Poorly flowing APIs may need to be preblended with a carrier polymer, and often, with additional flow-enhancing excipients, Terefe adds.

Fuderer does point out, though, that one advantage of the HME process is that variances in blend homogeneity and dosing are smoothened to a certain extent, and therefore, variances will not immediately impact extrudate quality.

Blend segregation, however, must be avoided during powder conveying into the extruder, according to Fuderer. This issue is particularly associated with discontinuous batch blending, as it poses higher risk for segregation at bin changes or if the upstream equipment runs empty.

In cases where the poor flow properties of the API or any excipient cannot be overcome by simple blending, Terefe observes that a pre-extrusion granulation step may be required. “Appropriate selection of the powder feeders with suitable feeder screw designs and the choice of liquid pumps for accurate liquid feeding without pulsation can help alleviate many of the input material feeding challenges,” he comments. Introducing a continuous blending process upstream of the extrusion step can also be beneficial for formulations for which simple blending cannot overcome these challenges, Terefe says.

Control of the HME process

Optimum HME processes generate extrudate with acceptable critical quality attributes (CQAs), such as amorphicity, content uniformity, and purity. Many CQAs impact downstream unit operations, according to Terefe, and thus it is crucial to have online monitoring capabilities (such as near-infrared spectroscopy for evaluating an extrudate’s crystallinity and content uniformity) to track these properties. Fortunately, says Fuderer, if HME processes are properly developed, they are robust and have good process control, and thus typically exhibit only minor variances in physical properties of extrudate intermediate that could impact downstream processing due to HME process performance.

Improper identification of critical material attributes and CQAs for HME processes can, believes Singnurkar, impact the uniformity, degradation profile, and dissolution behaviour of the final drug products. Misidentification of CPPs, meanwhile, can impact the milling of extrudates which can affect compressibility and thus make tabletting difficult. In addition, the API loading and miscibility of the API with the polymeric carrier can also, he says, significantly impact downstream processing.

It is the physical properties of the extrudate that are most important for downstream processing, Fuderer agrees. He adds, however, that they are mainly dependent on the product composition and less dependent on the HME process parameters such as the temperature profile. “As long as the product composition is controlled (e.g., blend homogeneity or ratio of solid and liquid feeds), no impact is expected on downstream processing,” he states.

In addition to product composition, Terefe emphasizes the importance of achieving consistent and controlled material throughput that is harmonized with downstream processes. For example, he points out that the material feed rate into a mill impacts particle size distribution, which may lead to inconsistency in the dissolution of the final product. Inconsistent material input into the continuous direct blending process downstream may also lead to poor blend uniformity, resulting in poor content uniformity of the final tablets.

Here again, the HME process benefits from good monitoring and control technologies. “Twin screw extruders typically have features for controlling and monitoring material throughput consistency, allowing the feed rate, extrusion load, and melt pressure to be continuously measured and monitored in real time,” Terefe explains. Any fluctuation in one of these parameters is a direct indication of material throughput inconsistency and the need to adjust the process.

A well-engineered HME process

Ultimately, the successful use of HME to enhance solubility and bioavailability of poorly soluble APIs manufactured in a fully continuous process, as is the case of any continuous manufacturing process, requires a well-engineered process design that can be controlled, Terefe contends. “When developing an HME process, there is a broad choice in polymers, equipment design, and development and scale-up approaches. It is important to involve appropriate subject matter experts at each stage to ensure the highest quality and most robust process for commercial manufacturing,” adds Fuderer.

The polymer and composition as well as the equipment and screw design are typically defined in early development at small extruder scale, according to Fuderer. At this stage, it is very important to understand how the material behaves in the extruder to prevent any issues to product quality or processability during scale-up because the opportunities to make changes to the composition later on are limited, he observes.

The processibility of the input material must be considered, says Terefe. For example, he highlights the need to understand the flow properties of the excipients in order to select appropriate feeders and determine pre-extrusion blending requirements.

“Investigating all possible variables that can impact product quality at the early stage can be challenging, however,” Fuderer comments. “Defining a design space that ensures product quality and processability, but also gives enough flexibility for post-development changes performed during lifecycle management (process and cost improvements, yield increases, supplier notifications for raw materials, etc.) is essential,” he concludes.

A well-planned process design that considers all technical and commercial perspectives and the company’s long-term strategy is fundamental, Terefe agrees. “The type of product(s) to be manufactured, the process flow, and unit operations need to be well understood, and the core equipment, along with necessary accessories, process control for each unit operation, and the CQAs of intermediate output material must be identified,” he states.

An effective means for achieving these goals is to use a quality-by-design (QbD) approach, according to Terefe. “A thorough risk assessment of CMAs and CPPs that impact CQAs for each unit operation must be conducted, along with identifying mitigation and control strategies,” he explains.

In addition, because continuous manufacturing aims to facilitate real-time batch release, a good understanding of each unit operation, both independently, and in combination with all other unit operations working in tandem, is essential, according to Terefe. In addition to PAT and real-time process analytics, he notes that model-based process optimization using relevant output data from sensors and processes is important.

It is also highly recommended, notes Fuderer, to keep process requirements for continuous processing in mind when developing HME processes to ensure that not only the HME process is developed to its optimum, but also that the interfaces to the up- and downstream unit operations guarantee final drug product meeting the desired quality.

Furthermore, well-organized and planned process integration into a computerized system that complies with GMP and good automated manufacturing process requirements needs to be established, as do proper IT structures and supervisory and control systems, Tenefe says. Such a centralized computer system that is integrated with various unit operations and PAT tools and provides real-time quality and process control is, in fact, essential for achieving consistent and optimum continuous HME processes, contends Singnurkar.

Reference

1. Mahesh R. An FDA Self-Audit of Continuous Manufacturing for Drug Products. FDA Podcast, FDA.gov. 28 June 2022. (Accessed March 30, 2023).

About the author

Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology Europe®.