Integrating Powder Characterization into Raw Material Selection and Process Optimization

October 1, 2019
Jamie Clayton

,
Todd Mollner

As tests at GSK have shown, integrating powder testing into overall operations can optimize process understanding, and with it, raw material selection, equipment design, and process development.

The past few decades have brought radical change to the pharmaceutical and healthcare industries. Generic pharmaceuticals now account for 90% of prescriptions in the United States, and manufacturers in the US and Europe continue to outsource more of their strategic operations to service providers. As a result, global pharmaceutical supply chains, even for widely used treatments, have become increasingly complex. Managing these supply chains is challenging but crucial, particularly in light of ongoing drug shortages (1). Maintaining product consistency and manufacturing re­lies on identifying multiple suppliers that can make active ingredients and excipients to required standards. Manufacturers must set a specification that defines those standards as a critical first step to ensuring and managing product quality. However, it is not unusual for an established speci­fication to fail to capture an aspect of behavior that results in poor performance during manufacturing. This article examines how powder testing can be integrated with manufacturing and quality operations and used to optimize raw material selection and process optimization, sharing results of some inhouse projects at GlaxoSmithKline (GSK). 

Establishing powder specifications 

Any supplier of a pharmaceutical raw material, excipient, or active ingredient must ensure that materials meet product specifications, which establish a basis for acceptance or rejection. For powders, however, materials may meet a product specifications, and yet go on to perform differently in the manufacturing process. This usually occurs because the specification failed to capture some aspect of powder behavior that is relevant to process performance. 

Pharmaceutical manufacturers could get around this issue by challenging suppliers to meet more demanding specifications. However, this would likely drive up both raw material and, by extension, finished pharmaceutical costs. A smarter approach would be to develop a better understand­ing of material performance requirements, based on what is actually needed for the product, and then choose suppliers whose products best meet those needs. 

Using powder characterization methods can provide better insight into material properties to help determine which of those properties are most critical to quality and which correlate most robustly with in-process behavior and manufacturing efficiency. 

 

 

 Coming to grips with powder testing

 

 

 

 

Techniques for powder testing vary considerably in terms of sophistication, ease-of-use, sensitivity, and process rel­evance. United States Pharmacopeia (USP) <1174> (2) specifies the following techniques: 

·     Angle of repose 

·     Compressibility index/Hausner ratio 

·     Flow through an orifice 

·     Shear cell methods. 

The first three techniques are simple methods that provide single number assessments of flow. Shear cell methods, devel­oped in the 1960s, represent the first attempt to bring a more scientific approach to powder characterization. These tests measure the force required to shear one consolidated powder plane relative to another. They were advanced to support a directly associated hopper design methodology and are widely used. Modern instrumentation has made the technique more accessible and reproducible via automated protocols and refined engineering design.

Shear cell testing is useful for assessing powders behavior under the moderate-to-high stress conditions typically found in a hopper. It can be challenging to implement, however, and is not intuitive with respect to data use or interpretation. Furthermore, the method is less relevant to process applications where the powder is in a low stress or dynamic state, particularly when aerated or fluidized. As a result, many companies consider pow­der testing to be an expert task that must be handled by external consultants. This may be a pragmatic approach, but it can result in one-off solutions, rather than integrating powder testing into improving understanding of process behavior for raw material selection and process optimization and troubleshooting. 

To facilitate an integrated approach, powder testing methods and instrumentation should: 

·     Be easy to use 

·     Offer relatively high productivity and deliver a good in­formational return on investment 

·     Provide data that correlate directly with process performance 

·     Measure with high sensitivity to provide effective differentiation. 

Dynamic methods 

Dynamic powder testing was developed specifically to meet industrial requirements for process relevant data.  Dynamic properties are determined by measuring the axial and rota­tional forces that act on an impeller as it is precisely rotated through a powder sample, which may be consolidated, mod­erately stressed, aerated, or fluidized depending on the pro­cess and conditions of interest (see Figure 1). Instruments for dynamic testing also have the capability for shear and bulk property measurement and can therefore be used to generate a database of powder properties to determine the precise charac­teristics that define optimal performance in any given process. GSK Consumer HealthCare has used dynamic testing methods to characterize powders that are routinely used in the production of a range of over-the-counter (OTC) pharmaceuticals. Results were incorporated into a database of specifications for all the materials used, enabling the evalu­ation of new suppliers and assessment of the consistency of established supplies. Data have also been used to establish correlations that define optimal processing parameters in processes such as tableting and roller compaction, and more generally in process optimization and troubleshooting.  

 

 

Choosing a raw material for roller compaction. 

One study of dynamic powder testing methods focused on the correlation between roller compaction and compressibil­ity. Roller compaction, which converts fine powder blends to stable, more freely flowing granules, is used routinely to produce OTC respiratory powders. In this case, previous in-house studies had identified compressibility as a critical parameter for roller compactor performance. Compressibil­ity quantifies change in bulk density (or volume) as a function of consolidation pressure (see Figure 2), with powders of higher compressibility requiring a greater compaction force to produce a stable ribbon in the compactor. Studies had been previously carried out to determine optimal processing parameters for feeds of varying compressibility. 

One of the active ingredients used in this process typically has a compressibility of approximately 5%. Alternative sup­plies, all of which met market specifications, were identified and tested to assess their suitability for use in the process. One material was found to have a compressibility of 10% and was easily accommodated by changing processing pa­rameters based on correlations and existing understanding. Another material was found to have a compressibility of 25%, which was somewhat surprising given all supplies had met the same specification. 

An attempt was made to process the high compressibility material to see whether granules could be produced. Given the need for a very high compaction force, it was hypoth­esized that any resulting granules would be very hard. It proved impossible, however, to produce any granules at all with the existing equipment, because sufficient compaction force could not be generated to produce a stable ribbon. 

As this example shows, measuring the right powder property (in this case, compressibility) allows manufacturers to differentiate between materials that are available on the market, even if they have all been manufactured to an existing specification, to determine which ingredients will and won’t work well in any given process. 

 

 

Robust process optimization 

In the previous example, powder testing allowed manufacturers to incorporate process requirements into the raw materials selection process, so that they could easily reject material that would be most likely to cause a process failure. Powder testing can also be used to solve a more common problem: the gradual decline in process performance that can often be traced to use of suboptimal raw materials.

Often optimal material characteristics are not well understood, so when powder testing is available and accessible to those with processing expertise, it can be used to optimize existing processes, as the next two examples show. In this case, powder testing was performed to troubleshoot a problem that occurred when product was discharged: at low levels, the active ingredient would separate from bulk materials, so, depending on its position in the hopper, the discharged product could contain more, or less, active ingredient than required.

A certain amount of product was therefore discarded with each batch to safeguard product consistency. The powder was tested, and results were processed through the instrument’s integral hopper design software (3). Based on results, a new hopper was specified with a 55% larger volume and different design parameters, a different half angle and outlet size, as shown in Figure 3.

Video footage from within both hoppers verified a change in flow and the new design’s superiority in delivering a better flow regime. The original hopper design induced funnel flow, a regime in which there is a central column of moving powder and static material at the hopper walls.

This flow pattern can result in rolling segregation and associated powder interactions with the hopper. The new design, in contrast, maintains a desirable ‘first-in,first-out’ flow pattern with no edge effect until the vessel is completely emptied. Though the new hopper is larger than the original, it empties faster and eliminates the product waste associated with the old design, saving 8% in material costs

De-bottlenecking

In this case, powder testing was carried out to define specifications for a legacy tableting process. The process had been running for many years, but, over time, throughput had been steadily eroding. Alternative raw material supplies were proving progressively more difficult to process, reducing tableting rates by almost 50% over a number of years. In-house studies identified both compressibility and flowability as key parameters for the tableting blends, allowing materials to be selected that could drive throughput back up to historical levels. In cases such as this, where throughput is increased by 50%, investment in inhouse testing equipment can return between 50 and 100 times its initial cost, delivering substantial return on investment.

References

1. S. Hoffmann, “Drug Shortages Pose a Public Health Crisis in the US,” theconversation. com, www.theconversation.com/drug-shortages-pose-a-publichealth-crisis-in-the-us-98295
2. USP, <1174> Powder Flow, USP-NF 28(2), March 2002,usp.org, www.usp.org/sites/default/files/usp/document/harmonization/gen-chapter/g05_pf_30_6_2004.pdf.
3. T. Freeman, “Modern Tools for Hopper Design,” freemantech.co.uk, www.freemantech.co.uk/literature/white%20papers/Modern_tools_for_hopper_design-LAF205-E.pdf

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