Motivation
As a well-established process technology that has been developed and optimized over the past century, hot melt extrusion has become a staple of the plastics and food industries while continuing to gain prominence in the pharmaceutical industry. Melt extrusion has become a popular route for increasing the bioavailability of poorly soluble compounds owing to its role as a process technology used to manufacture solid solutions [1-3].
Twin-screw extruders are applied toward many complex pharmaceutical applications because of their inherent design and operating characteristics. Geometric similarities enable rapid process scale-up without compromising product quality. The potential for truly continuous drug product manufacture from individual raw materials to finished dosage form enables cost-effective production techniques. Moreover, the design characteristics of a twin-screw extruder facilitate the application of process analytical tools to measure product properties as straightforward as product temperature and as novel as real-time continuous composition monitoring [4]. It is significant to note that twin-screw extrusion in other industries is often associated with products having a much lower cost margin than pharmaceuticals, yet it proves its value as a “conventional” production technique.
The utilization of melt extrusion to manufacture products with tight specifications has been demonstrated regularly by other industries, but the challenge for the pharmaceutical industry is to reconcile the unique requirements placed on drug product quality. The combination of process understanding from other industries and a reliance on first principles enables a Quality by Design approach to pharmaceutical melt extrusion development. Armed with this systematic understanding of the process technology, Merck envisions increased regulatory flexibility.
Melt Extrusion: A Series of Unit Operations
Figure 1 - Schematic illustration of the unit operations occurring down the length of the extruder (image courtesy of C. Martin, Leistritz Corporation, used with permission)
Figure 1 illustrates some of the processes that may occur down the length of the extruder. Individual solid or liquid components are fed to the extruder, often using gravimetric feeders. Melting of the components is achieved through energy input from both barrel heat conduction and mechanical shear from the extruder screws. Mixing of the components ensures adequate compositional homogeneity and sufficient time, temperature, and diffusion area for production of a solid solution. Venting to the atmosphere or under vacuum may remove water or residual solvents in the API and other components. Finally, pumping may be critical depending on the downstream forming application.
Extruder size is described by the outer diameter of the screws, D, to which most other length-scales are normalized (length, tolerances, etc.). Extruders are typically geometrically similar upon scale up, making it possible to transfer an extrusion process to the next larger scale by keeping most input parameters the same and increasing the throughput by the ratio of the extruder free volumes [5]. Scaling in this manner typically conserves key dependent variables of interest including residence time, degree of fill, and maximum shear stress.
Process Design: An Alternate Approach to Scale Up
Increased equipment size is the conventional approach for increasing throughput for pharmaceutical processes, however continuous processes enable the user to redesign the process to increase throughput and maintain acceptable quality at the same scale [5]. The term “quality” is used here as a catch-all expression to encompass a wide variety of desired product attributes. A development plan based on extrusion process understanding enables effective scale-up using the same equipment.
Extruder screws are modular and can be assembled in many different configurations [6]. The manner in which the screw profile is designed generally causes changes to parameters such as mechanical shear and residence time [7]. Throughput, or the rate at which raw materials are fed into the extruder, affects the degree to which the extruder screws are filled. Consequently, throughput has implications for both thermal and mechanical energy input to the formulation. The feed methodology, whether the material is fed as one pre-blended stream or multiple feed streams, may also impact the product quality. Depending on their characteristic frequency, feed rate perturbations will result in compositional variations in the extrudate, thereby compromising product quality [8].
Screw speed and barrel temperature are well-known independent process variables that impact product quality, but it should be noted that barrel temperature may not have a strong impact on product quality, depending on equipment scale. The source of thermal energy input is the heated barrel surface, which scales with surface area. Conduction from the barrel and through the polymer will generally not be as effective at larger scales [9,10].
Process responses are measures of how the process reacts to a given input. They serve as useful “fingerprints” of a process as equipment size is increased. Torque is one of the most relevant practical responses. Available torque is often constrained in small extruders by the mechanical limit of the screw shafts. To a large extent, it is a function of the equipment design itself (brand, materials of construction, shaft diameter, etc.). Torque has historically been the critical parameter to product quality, since it was often the limit of throughput in the polymer industry. However, several polymers used in pharmaceutical extrusion are comparably lower in melt viscosity, so torque is less of a constraint. Residence time distribution plays a strong role in product quality. A perfectly conveying single-screw extruder exhibits very little mixing, so the addition of a delta function of a component to the feed results in a spike in the concentration of that component in the downstream product. However, twin-screw extruders are designed to mix so the residence time distribution broadens with an increasingly intense screw design [11]. The mean residence time within the extruder can be expected to decrease with increased throughput, but it can be varied considerably by changing screw design.
Specific energy describes the mechanical energy input to the material by the screws per unit mass. Whereas thermal energy input is a difficult parameter to accurately measure, the mechanical energy input can be assessed in a fairly straightforward manner. Melt temperature is often assumed to be the product temperature measured by the extruder die. At larger scales, where heat from the barrel is not significant, specific energy input is the strongest factor impacting melt temperature. Barrel temperature may significantly drive product temperature using smaller equipment, but this approach scales poorly [12].
The degree of fill of the extruder screws affects product quality. From a practical perspective, it sets the flood limit of the extruder. But the degree of fill has implications for shear as well. A given screw channel can be imagined to exhibit a shear profile, wherein the material closest to the back wall (trailing edge) experiences a greater shear rate than the material near the front wall (leading edge). So a formulation in a less-filled screw will experience greater average shear than a formulation in a more-filled screw.
Extrusion Design Space: Crafting a Control Strategy
Figure 2 - Conceptual representation of melt extrusion design space (image courtesy of L. Schenck, Merck & Co., Inc.)
Figure 2 provides a conceptual representation of process space. The vertical axis represents mechanical and thermal energy input to the formulation and the horizontal axis represents throughput or production capacity. The figure illustrates that a single-phase molecular dispersion will not be achieved if too little energy is supplied to mix the formulation, which increases in likelihood as throughput is maximized. Conversely, too much energy input risks material decomposition. The user is forced to scale up in a conventional way by purchasing larger equipment if a solid solution can only be achieved at low feed rates. If a solid solution can be achieved at a high throughput, the extruder may be unable to dampen disturbances in the feed at increased feed rates, leading to compositional heterogeneity.
The scale-up issue is approached with a set of technical requirements for the quality of the product, defined in terms of first principles and other practical constraints placed on the product. First principles suggest that the solid solution requires sufficient temperature, time, and surface area for diffusion between the components to occur. Further constraints include the desire for a stable process with no compositional drifting or spikes, no decomposition of the API or other components, and low moisture content in the extrudate.
The conventional method involves examination of the quality attributes in the context of the process independent parameters – determining how tuning each of the “knobs” on the extruder affects the product quality. The problem with this empirical approach is that it does not determine what drives product quality. The analysis would reveal how the inputs affect quality, but any change in equipment brand or location would require an entirely new set of experiments. For example, it was never really understood why setting the screw speed to 125 RPM was necessary to achieve adequate quality.
A bridge is sought for the gap between quality attributes and process independent parameters as we strive to link quality to process. Scaleindependent process responses are ideal for this purpose, including specific energy, residence time distribution, mixing cycles, maximum shear rate, melt temperature, cooling rate, and others. A set of studies to determine which process response parameters are critical to product quality, while another set of experiments to determine which process input parameters impact the process responses. The determined link between process responses and quality attributes of a drug product will remain, regardless of equipment scale or brand. Changes in equipment size, brand, or location only require a determination of the impact of process inputs on the critical process responses. A control strategy capable of evaluating which scale-independent parameters are critical to quality requires a single-phase solid solution, which can be fundamentally achieved through sufficient time, temperature, and interfacial area. These targets are then related to the extrusion process itself: seek effective energy input (temperature), residence time distribution (time), and mixing intensity (area). A multiple factor DOE aids in mapping key quality attributes to the process responses. Quality attributes may be sorted into several categories (bioperformance, phase state, chemical state, others) and measured by many characterization techniques (dissolution, DSC, XRPD, others).
Figure 3 - Hypothetical outcome of study to measure interplay between scale-independent parameters and critical quality attributes.
Each process response is impacted by multiple process independent parameters with complex interactions. The mapping of process responses is not routinely performed because of the inherent difficulty in tuning a particular process response. The scaleindependent parameters themselves cannot be directly set, but process independent parameters (screw speed, throughput, screw design, etc.) can be independently tuned to achieve a desired scaleindependent parameter. Figure 3 illustrates a hypothetical outcome of the study, which indicates a strong relationship between Parameter A and the desired quality response. According to this illustrative example, the formulation attributes require that the process response Parameter A must remain between 277 and 398 to maintain acceptable product quality. The formulator may ignore other parameters shown to be unrelated to quality upon scale up to production volumes. The formulator only studies how the new equipment’s process independent parameters (the “knobs” to be controlled) impact Parameter A (the new “quality fingerprint”). Process analytical tools facilitate continuous monitoring of product quality by measuring critical process responses during processing.
Flexibility in Development and Production
A systematic approach to melt extrusion based on an understanding of the interplay between process and product enables even more than rapid scale up. The International Conference on Harmonization (ICH) has described principles of Quality by Design, which recommend a “greater understanding of the product and its manufacturing process” to “create a basis for more flexible regulatory approaches.” [13]. The guidance bases the systematic understanding on a control strategy “derived from current product and process understanding that assures process performance and product quality.” [13]. The guideline affirms that “the degree of regulatory flexibility is predicated on the level of relevant scientific knowledge provided in the registration application. It is the knowledge gained and submitted to the authorities, and not the volume of data collected, that forms the basis for science- and risk-based submissions and regulatory evaluations.” [13]. An understanding of the interactions between process inputs, process responses, and quality attributes enables changes in site or capital during production to be systematically justified.
References
- Breitenbach J., “Melt Extrusion: from process to drug delivery technology”. Euro J. of Pharmaceutics and Biopharmaceutics, (2002) 54(2) 107-117.
- Dong et al, “Evaluation of Solid State Properties of Solid Dispersions Prepared by Hot-Melt Extrusion and Solvent Co-Precipitation”. Int. J. Pharm., (2008) 355(1-2):141-149.
- Patterson et al., “Melt Extrusion and Spray Drying of Carbamazepine and Dipyridamole with Polyvinylpurrolidone/vinyl Acetate Copolymers”. Drug Dev Ind Pharm, (2008) 34(1):95-106.
- V. S. Tumuluri, S. Prodduturi, M. C. Crowley, S. P. Stodghill, J. W. McGinity, M. A. Repka and B. A. Avery, The Use of Near-Infrared Spectroscopy for the Quantitation of a Drug in Hot-Melt Extruded Films, Drug Dev. Ind. Pharm., 30 (5), 505-511 (2004).
- Rauwendaal C., Polymer Extrusion, 4th Ed (2001) Hanser Gardner Publications, Inc.463-476.
- Lim S., White J. L., “Flow mechanisms, material distributions and phase morphology development in a modular intermeshing counter-rotating twin screw extruder of Leistritz design”. Int. Polymer Processing IX, (1994), 33-45.
- Potluri R., Todd D., Gogos C., “Mixing Immiscible Blends in an Intermeshing Counter-Rotating Twin Screw Extruder”. Adv. in Polymer Tech., (2006), Vol 25, no. 2, 81-89.
- Kim E. K., White J. L., “Transient Compositional Effects from Feeders in a Starved Flow Modular Co-Rotating Twin-Screw Extruder”. Polymer Engineering and Science, Nov (2002) 2084-2093.
- Todd D., “Melting of Plastics in Kneading Blocks”. Int. Polymer Processing (1993), 113-118.
- Jung J., White J. L., “Investigation of Melting Phenomena in Modular Co-Rotating Twin Screw Extrusion”. Intern. Polymer Processing, XVIII (2003) 127-132.
- Puaux J.P., Bozga G., Ainser A., “Residence time distribution in an corotating twin-screw extruder”. Chem. Eng. Sci, 55 (2000), 1641-1651.
- Tadmor Z., Klein I., Engineering Principles of Plasticating Extrusion, Van Nostrand Reinhold 1970.
- “Pharmaceutical Development Annex to Q8”, International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Step 2 Version, 01 November 2007.
Author Biographies
Michael Lowinger led a global cross-divisional extrusion technology development team, recently taking on the leadership of a similar team focused on spray drying technology development at Merck & Co., Inc., based in West Point, PA, USA. Mike has taken the role of formulator in Pharmaceutical Sciences, where he has overseen the development of fifteen poorly soluble compounds from early formulation screening through late-stage solid solution process development. Mike holds a B.S. in Chemical Engineering from the University of Delaware.