Most pharmaceutical granules and tablets are produced in batches, not only when preparing raw ingredients according to formulations but also when mixing excipients with powdered active ingredients. In other industries, such as food or chemicals, better process control and lower production costs enable the continuous application of similar powder mixing processes.

The U.S. Food and Drug Administration (FDA)'s “Continuous Manufacturing” initiative has spearheaded research into continuous pharmaceutical methods in the United States and Europe.

This initiative has driven equipment manufacturers to develop continuous modules and complete process solutions for solid production. This article focuses on one of the key foundations of continuous production: continuous feeding and mixing. Within a 2×2×2 m footprint, continuous feeding/mixing must handle 4 to 6 raw materials, far exceeding available space. This model can be applied to direct compression or continuous dry/wet processing. This paper reveals the principles and limitations of continuous feeding for excipients and active ingredients. Feed stability determines the residence time of formulation materials in continuous mixers, thereby defining their capacity. However, larger mixers require longer time to achieve stable operation once production commences. The same equipment can be used to produce initial clinical trial products for subsequent large-scale manufacturing, as this merely involves extending the continuous mixing duration from minutes to hours. This eliminates the need to validate different batch sizes, significantly accelerating the R&D process.

Particles, powders, and solids are generated across various industries and transformed into mixtures. The galactose sector—specifically the production of medical powders, capsules, tablets, and other forms—is formally classified as part of process engineering. Feeding, grinding, mixing, and granulation exemplify mechanical processing techniques, while fluid bed drying represents a thermal processing method.

Initially, all these processes were batch-based, including most mixing equipment. Most pharmaceutical mixers take the form of vessel mixers or double-cone mixers. Key process steps include formulation preparation, mixing, and mixer discharge, which are completed sequentially. Raw materials requiring mixing are manually pre-weighed in correct proportions according to the formulation before being fed into the mixer. Other industries facing intense competitive pressures have managed to reduce manufacturing costs by shifting to fully automated and continuous processing (e.g., continuous mixing processes).

Figure 1: Continuous Feeding/Mixing Module Flowchart (Source: R. Weinekötter - Gericke)

Table 1 provides several successful case studies of different types of continuous mixers used in the petrochemical, baby food, and pharmaceutical industries. Two data points in the table are particularly noteworthy: How many years have passed since the initial promotion of continuous mixing technology and the formal production deployment of continuous mixers? Continuous mixing has a history of over 50 years in the petrochemical industry. Advances in weighing technology have enabled continuous weighing, thereby making controlled and precise continuous feeding possible.

This development is driven by high cost pressures. By definition, continuous processing must be fully automated. Equipment dimensions are significantly smaller, occupying far less floor space; smaller equipment dimensions mean the production and processing of the product are more continuous and uniform overall. The defining characteristic of continuous processes is “process intensification.” To transfer continuous mixing technology from the petrochemical industry to pharmaceuticals, equipment downsizing is essential. In the galactose sector, production rates are typically linked to downstream processes like tableting, reaching up to 100 kg/h. For general pharmaceutical manufacturing, achieving process throughputs of 1,000 kg/h at industrial scale has proven feasible.

Traditional galactose production has long exhibited strong resistance to this “process intensification.” Limited investment has been made in developing continuous processing, despite established precedents for continuous mixing equipment in other industries. This reluctance stems from confusion surrounding the term “batch” in FDA guidance. J. Woodcock of the U.S. Food and Drug Administration (FDA) clarified in 2014 that CFR 210.3 imposes no regulatory restrictions on continuous production. In the context of continuous processing, “batch” (or “batch run”) refers to a specific production time or quantity, requiring the product to be manufactured continuously within defined process parameters.

Figure 2 Principle of Continuous Feeding/Mixing Module (Source: Weinekötter, R.; Reh, L.)

At the initiative of the U.S. FDA, several universities have begun investigating continuous processing in the pharmaceutical industry, including—particularly—the Massachusetts Institute of Technology and the Engineering Research Center (known as the Ethics Committee, comprising Rutgers University, Purdue University, New Jersey Institute of Technology, and the University of Puerto Rico). The latter decided to focus their research on the continuous processing of final formulation after converting active pharmaceutical ingredients (API) into powder. They are examining feeding and mixing processes, wet granulation and drying, as well as extrusion techniques. In Europe, research in this field is being conducted at institutions such as the RCPE in Graz, along with universities in Düsseldorf and Ghent. These studies rarely reference earlier findings from the broader field of general process engineering; however, pharmaceutical process engineering can still benefit significantly from its discoveries.

At the 2012 Achema conference, three pharmaceutical equipment manufacturers showcased continuous production modules for solid materials; by 2015, numerous manufacturers had joined their ranks. A key element of continuous production is the feeding/mixing module, applicable to direct compression requiring continuous processes as well as dry or wet granulation processes.

Continuous feeding/mixing modules comprise loss-in-weight feeders for precise ingredient dosing and compact downstream continuous mixers.

Process Concept: This approach replaces traditional volumetric feeders, dry/wet granulation equipment, and extruders used in tableting processes with “miniature” continuous feeders/mixers. The effective volume of the continuous mixer is only a few liters. The same continuous mixer can be used for clinical trial formulations as well as subsequent scale-up production (no equipment upgrade required). The throughput capacity (kg/h) of the continuous feeding/mixing module is aligned with downstream equipment. The continuous loss-in-weight feeder ensures formulation accuracy. Up to six raw material components can be fed into the continuous mixer simultaneously according to the formulation.

During continuous processing, raw materials are fed continuously into the mixer according to the formulation for blending, enabling continuous product production.

Whenever the equipment is at rest, the volume of raw materials inside remains constant. Continuous processes in the pharmaceutical industry include extrusion, (tablet) compression, dry granulation (roller compactors), and mixing. Raw material components undergo both radial and axial mixing within the continuous mixer.

Figure 3 Continuous Feeding/Mixing Module—Process Concept

The purpose of any mixing operation is to ensure uniformity—initially within the mixing chamber of the mixer, though what truly matters is the distribution characteristics of the powder in the retail packaging. In many cases, raw materials are blended in nearly equal proportions (e.g., a 50:50 ratio); however, from a process perspective, it becomes more challenging when trace elements (active ingredients) must be effectively and uniformly mixed with other raw materials present in higher proportions within the formulation. Determining whether these micro-components are optimally distributed involves more than just selecting the right solid mixer; in fact, the size of the raw material particles is often a more critical factor. Product quality heavily depends on the continuous weighing process upstream of the continuous mixer; any inaccuracies occurring during feeding will ultimately manifest in the final product, as the actual formulation will deviate from the desired target values. The uniformity of powder mixing is typically verified through trial measurements. Online measurement using PAT sensors and analyzers enables direct determination of mixing quality within the process. For instance, a near-infrared analyzer can be installed at the outlet of a continuous mixer to measure active ingredient concentration online, thereby assessing mixing uniformity.

The fluctuation range of actual mixing uniformity—such as the variance in active ingredient concentration across a sample set—determines the estimated mixing quality or uniformity. A smaller fluctuation range (correspondingly, lower variance) indicates superior mixing performance.

Assessing mixing uniformity depends on the number of samples tested and the sampling method employed. It is often overlooked that variance (as a measure of mixing quality or uniformity) decreases with increasing sample weight per unit. Even for identical mixtures, a 10 g sample exhibits significantly higher mixing variance than a 1 kg sample.

Random particle motion causes varying residence time distributions. For axial mixing, this positively attenuates time-limited feed fluctuations [3]. Mixer vessel and agitator designs ensure effective control of both axial and radial mixing, with residence time distribution also being controlled. Average mixing residence times range from 5 to 50 seconds. The average residence time of particles within the mixing chamber is influenced by several process variables [3]:

● Feed rate of raw materials into the continuous mixer, ranging from 10 to 500 kg/h. Higher flow rates result in shorter average residence times;

● Opening angle of the outlet baffle plate;

● Rotational frequency of the mixer;

● Shape and pitch angle of the mixing blades.

Following Danckwerts' design concept, the efficiency of continuous mixers is described using the variance reduction ratio [3]. A lower concentration variance indicates better mixing uniformity, which is why the variance of mixing uniformity—or the closely related concept of relative standard deviation—is frequently used as an indicator of mixing quality.

Weight-type feeders generally operate based on the “loss-in-weight” principle. Their purpose is to ensure a constant feed flow rate (mass flow). The unit commonly used for mass flow is kg/s. Feed flow can be described as the change in mass (∆m) over a given time interval (∆t), typically measured in kilograms, which may span seconds or hours. For continuous feeding, high-resolution weighing technology determines how much mass (∆m) the feeder loses (weight loss) during short time intervals (∆t). The rotational speed of the metering screw is regulated by a dedicated control unit. This approach enables the mechatronic system to achieve constant mass flow, incorporating weighing and control technologies. Loss-in-weight feeders require uninterrupted operation over extended periods without production stoppages due to raw material depletion; this is achieved through pneumatic feeding systems. In such cases, raw materials are pneumatically conveyed via fine tubes to vacuum feeders, thereby replenishing the loss-in-weight feeder. Fine active ingredients and excipients demand complex mechanical solutions and control systems. For instance, twin-screw loss-in-weight feeders deliver viscous materials into mixers with high precision and constant speed. Additionally, the pharmaceutical industry imposes stringent requirements for equipment safety and cleanliness. These demands are met through the consistent use of sealed, quick-release fasteners. Alternative solutions can isolate contaminated feed hoppers from gears and weighing devices, enabling their safe cleaning and processing through autoclaves. Loss-in-weight feeders should be integrated with continuous mixers. Safety and ease-of-cleaning requirements must be considered early in the design layout of feeding and mixing modules.

Compared to the large capacities required in other industries, mixers demanded by the pharmaceutical sector are typically considered miniature mixers due to their small volume, ranging from 1 to 15 liters. However, it is precisely this miniaturization that enables the equipment to be implemented in intriguing ways. The suspended mixing rotor serves as an excellent example. This bearing method allows the mixing chamber, rotor, and shaft seal to be separated from the fixed drive in seconds. Consequently, cleaning these micro-machine components requires minimal time, and sterilization is achieved by exposing them to high-pressure steam. The compact design facilitates easier integration of the micro-mixer or entire feed mixing module into a unified system.

The pharmaceutical industry currently faces the same cost pressures as other sectors, compelling it to devise new process approaches. Developing a new drug from conception to production can take up to 12 years. This timeframe demands substantial financial and human resources. Reducing these time-consuming processes would immediately enhance product profitability while creating a competitive advantage.

In traditional batch processing, the mixing process may require three separate validations to obtain approval for a new drug. This is because each scale-up stage must be validated:

Laboratory-scale validation during initial product manufacturing for clinical trials;

Pilot-scale production line validation;

Production-scale line validation.

Planning and implementing this three-stage mixing process demands considerable time and expense. In contrast, designing this process as continuous offers clear advantages through shortened pharmaceutical development timelines and more flexible manufacturing (see Table 2). Batch size is no longer dictated by mixer capacity but defined by production capability within a specified timeframe. Loss-in-weight feeders and mixers form compact continuous modules installed directly above tablet presses, granulators, or extruders.

本文作者系瑞士Gericke公司董事总经理。文/ Ralf Weinekötter 博士