John Yin is applications specialist, Freeman Technology, Tewkesbury, UK

John Yin

Bringing the benefits of continuous manufacture to tablet production is a significant goal within the pharmaceutical industry, and considerable investment is being made to ensure a successful outcome. One approach, which exploits existing processing strengths, is to use the same individual steps that are applied in batch manufacture but link and convert them into a continuous operation. This strategy relies on being able to closely control each of the processing steps and effectively integrate them with each other.

This article considers the potential benefits of continuous manufacturing and, focusing on the steps that constitute typical tablet production, reviews the challenges associated with implementing continuous processes as well as the associated analytical requirements. Experimental work on wet granulation is presented that demonstrates the use of dynamic powder characterization as a technique to support the development of continuous processes.

Shifts in the pharmaceutical manufacturing landscape


In response to increasing development costs, lengthening time to market and the increase in the production of generics, the past decade has seen significant investment in improving efficiency across the pharmaceutical lifecycle. The traditional manufacturing model is a clear target for these efforts. The adoption of smarter approaches to process development and operation, based on risk assessment, quality by design (QbD), and the effective use of process analytical technology (PAT) are driving substantial progress. As a result, new approaches such as continuous manufacture are gaining recognition.

Although widely employed in allied industries, such as the food and chemicals sectors, continuous processing may be viewed with caution by the pharmaceutical industry. Batch production dominates as it is well established and has some recognized benefits. Manufacturing discrete batches of product makes it relatively straightforward to isolate, trace, and resolve problems. In addition, stringent regulations have, arguably, tended to deter process development and the evolution of manufacturing practices.

However, even the best understood batch processes suffer certain inefficiencies, with batch-to-batch variability and the production of material outside of the defined specification being common in the pharmaceutical industry. These inefficiencies, which result in re-work and high levels of waste, are not conducive with the pharmaceutical industry’s objectives of increased efficiency. Continuous manufacture represents a possible solution. 

Compared to batch production, continuous processes are generally more easily managed and controlled, and provide benefits in the form of reduced labor requirements, lower capital investment and simplified scale-up (1). Implementing such processes can alleviate the problems associated with batch-to-batch variability and, provided that the process is tightly controlled, assures highly consistent output. The challenge is to successfully develop continuous processes—using the principles of QbD and appropriate PAT—that deliver these benefits. This is a complex undertaking that relies on comprehensive understanding and robust control of both the product and the process.

Continuous manufacture of oral solid dosage forms


Many unit operations within pharmaceutical manufacturing can already be thought of as semi-continuous. Considering the production of oral solid dosage forms, routine operations such as roller compaction, milling and tableting, are already continuously fed and run. However, the finished tablets are the end product of a number of sequential unit operations that together should combine APIs and excipients to deliver a finished tablet with the required critical quality attributes. 

 illustrates the stages in a typical tablet production process, which in batch manufacture are operated and controlled on a stand-alone, discrete basis. 

Typically, the first step in the tableting process is wet or dry granulation. This converts fine, but often dissimilarly sized, excipient and API particles into a homogeneous, granulated mass to avoid downstream component segregation and improve flowability through the process. In wet granulation, the exiting mass is dried to remove excess moisture prior to milling to ensure uniform, optimally sized granules that will perform well in the press. Flow additives, such as magnesium stearate, are often then added to the mixture in order to ease flow through the tablet press and lubricate interactions between the press and the blend during compaction and ejection of the finished tablet. Dry granulation is an alternative approach, especially for moisture-sensitive blends, and avoids the need for drying. 

The quality of the finished tablets relies on the output of each operation meeting the required specification to ensure success in the next stage of the process. Batch processes are heavily reliant on manual intervention and off-line analysis to support decision-making throughout an operation. The approach is to apply thoroughly defined processes, test the result, take any remedial action required, and then move material on to the next step. 

In contrast, continuous manufacture involves the successful integration of each of the process steps. It becomes essential to control each in real time to produce a suitable output that can then be fed to the following stage. The objective is to eliminate the need to intervene between each stage. Achieving this objective requires a comprehensive understanding of how materials and processes influence the output of each intermediate stage, and how to impose the necessary control. 

For example, in wet granulation, screw speed, feed rate, and water content all contribute to the physical properties of the granules. Successful integration of a continuous wet granulation process, therefore, relies on understanding how to manipulate these variables to produce granules that will reliably deliver high quality tablets. 

This need for more informed process design and operation requires a detailed understanding of powder behavior at every point of the manufacturing process. The diverse conditions that are applied during a tableting process subject the powder to a range of stresses and flow regimes, such as forced flow through an extruder, unconstrained flow into an empty tablet die, and compression. These different environments cause the powder blend or granules to behave in often unpredictable ways. The development of successful continuous processes is, therefore, supported by comprehensive powder characterization.


It is acknowledged that simple powder testing methods, such as angle of repose, flow through an orifice, and tapped density measurements, which are routinely used within the pharmaceutical industry, are relatively limited when it comes to developing efficient manufacturing practice (2). While the single number data these test methods generate give some insight into powder behavior, these techniques are often compromised by poor repeatability, reproducibility, and sensitivity. In addition, the test conditions do not represent the environment a powder is subjected to in a process. Consequently, the ability of these methods to deliver the relevant and reliable information needed to advance processing is limited. 

Dynamic powder testing is designed specifically to overcome these limitations and provide process relevant information. Dynamic flow parameters are generated by measuring properties of a powder in motion. Critical behavioral properties, such as flowability, can be measured under different conditions that more closely simulate the process environment and provide information that directly correlates with in-process behavior (3-4). 
Basic flowability energy (BFE) is a dynamic powder property that is determined from measurements of the axial and rotational forces acting on a rotating blade as it descends through a powder (see 

). BFE is a valuable parameter that reflects how a powder will flow under forced conditions, such as those that are applied by an extruder. Measuring the BFE of powders in different states enables quantification of the impact of different processing conditions, such as consolidation, aeration, and fluidization.

The experimental work detailed below explores how dynamic powder testing, and specifically measurements of BFE, supports the fast and efficient development of wet granulation via a design of experiments approach. 

As part of an on-going collaboration between Freeman Technology and GEA Pharma Systems, studies were undertaken to investigate whether dynamic powder properties could be usefully employed to quantify the quality of granules produced during wet granulation with respect to varying manufacturing conditions. The ultimate aim of the work was to establish a direct correlation between the BFE of granules and critical quality attributes of the tablets produced from them, such as hardness.

The trial focused on the performance of the ConsiGma 1 (GEA Pharma Systems), a lab-based, continuous high-shear wet granulation and drying system that can run samples from a few hundred grams up to 5 kg or more. The BFE of the granules produced using the ConsiGma 1 was measured at four different points: immediately upon exit from the wet granulator; after drying; after subsequent milling; and then after the milled granules were blended to form a feed for subsequent tableting. Experiments were carried out using two different trial blends: one based on paracetamol (APAP) the other on dicalcium phosphate (DCP) . All BFE measurements were made using an FT4 Powder Rheometer (Freeman Technology).

Impact of processing variables on the granule properties


The first set of experiments assessed the impact of the wet granulation operating conditions on the BFE of the resulting granules. The processing parameters that were varied were: amount of water added (15-25% water addition); powder feed rate (15-25 kg/hr); and granular screw rate (450 - 750 rpm). 

 shows how the BFE of the APAP granules produced at different screw speeds varies as a function of water content. 

Increasing water content, at constant screw speed, results in a higher BFE. Decreasing screw speed produces granules with a lower BFE, for a given water content. This trend is consistent with the observation that higher water content and lower screw speeds tend to produce larger, denser, and more cohesive granules that present substantial resistance to blade movements. Interestingly, the data indicates that granules produced at a water content of 11% and screw speed of 600 rpm have similar BFE values to those generated using a screw speed of 450 rpm and a water content of 8%. This suggests that it is possible to produce granules with similar properties using different operating conditions, an important finding when it comes to scoping the design space for a wet granulation process.

 shows the impact of varying the dry-powder feed rate. The BFE of granules produced with the DCP formulation was measured as a function of increasing feed rate with a fixed water content of 15% and screw speed held constant at 600 rpm. The BFE of the DCP granules was found to be indirectly proportional to feed rate, decreasing significantly with increasing feed rate.

To confirm the earlier finding that granules of similar properties can be formulated using different sets of operating conditions, additional research was carried out using the DCP formulations. Granules with 15% water content produced at a feed rate of approximately 18 kg/hr were found to have similar properties to granules containing 25% water made at a feed rate of 25 kg/hr. 

 shows the flowability measurements taken for two pairs of granules, each pair having similar BFE values produced using different process conditions. Conditions 1 and 2 result in granules with a BFE ≈ 2200 mJ, while 3 and 4 have a BFE ≈ 3200. The BFE of the granules was measured at each of four points in the process as outlined previously.

 shows how the flow properties of the granules change at each stage of the manufacturing process. The granules made using conditions 3 and 4 show an increase in BFE upon drying while the properties of those produced using conditions 1 and 2 stay relatively consistent as granule work up progresses. This increase can be attributed to the granule’s relatively large size, which in combination with increased density and hardness, results in increased mechanical interlocking in the dry sample, and greater resistance to forced flow. The granules produced using conditions 1 and 2 have a weaker structure, lower density, and relatively small size and are, therefore, less prone to mechanical interlocking. The BFE of these samples, therefore, remains comparable or slightly lower following drying. Following milling, particle sizes are more similar and flowability for the four batches converge--although difference in granule density, shape, and stiffness still exist--rationalizing the observed differences in BFE, which are retained following lubrication. 

Articles

Experimental work on wet granulation demonstrates the use of dynamic powder characterization to support continuous processing for tablet manufacturing.