Improving Solid Dosage Forms With Dry Granulation

The pharma industry traditionally utilises batchbased manufacturing methods because of traceability requirements to ensure product safety. After several years of establishing new ways of analysing drug variability and quality in various manufacturing process stages (under the PAT initiative), the industry is moving away from conventional batch sampling and analysis to embrace more advanced techniques that analyse consistency in real time. The challenge now is for the industry to take this QbD concept and look at its manufacturing processes in lean terms to adapt for a more efficient future.

Continuous granulation processes

Tablet manufacture is traditionally a batch-based wet granulation process. Dry granulation, on the other hand, can be used as a semibatch process but could also emerge as one of the main continuous processing solutions due to its simplicity. There are other forms of dry granulation, but the most commonly used is roller compaction, which is a continuous technology by design that has been significantly further developed in recent years. In particular, a number of important changes have been made that differentiate novel technologies from conventional roller compactors (Sidebar 1).

Sidebar 1: Key advances made by new roller compaction systems

Combined with PAT techniques, roller compaction can help achieve a continuous granulation process. Depending on the objectives and site PAT strategy, measurements prior to the process can be taken to establish raw material consistency and blend uniformity. Essentially, this will enable a consistent processing window with established boundary limits to be achieved.

Sidebar 2 provides an example of PAT analysis data based on the measurement of terahertz wave forms, which are reflected from pharmaceutical roller compactions of various densities. The example demonstrates the potential for the technique as an in-line technology to analyse critical material attributes of compacted ribbons prior to milling to establish increased process understanding.

Sidebar 2: Terahertz pulsed imaging of pharmaceutical compacts

Wet granulation versus dry granulation

Wet granulation requires various quality stages, including materials quarantined, sampled and analysed prior to release. Because of this, equipment asset utilisation is inherently low; cleaning time and costs are substantial; and in-train material, capital equipment cost, building costs and energy consumption costs are all high.

Dry granulation also has its disadvantages, some of which are shared with direct compression to a degree. One of the main drawbacks is challenging formulation because of the physical characteristics of a particular API; for example, it may be cohesive with poor flowability, or have a low bulk density and be difficult to contain and feed, or it could be micronised and very fast flowing. Feeding dry powders and avoiding segregation is challenging, requiring helical feed screws called augers. If a product is considered cohesive or 'fluffy' because of its low bulk density then filling the auger is difficult. If it is not possible to fill the auger screw consistently, then compaction is not possible because of density variation at best, and no feed at worst.

At the other end of the scale, fast flowing materials can escape through the feed rollers, leading to a very high number of uncompacting fines that require re-compaction or a recycling system. It is sometimes possible to overcome these difficulties by adding specialist excipients or additives, but these can be costly.

Developing a suitable formulation that balances drug bioavailability with the ability to efficiently process on a realistic cost basis when additives are required has proven difficult with dry granulation. To overcome these issues, many formulation developers turned to wet granulation and fluid bed drying. Despite its initial drawbacks, dry granulation offers a number of benefits over wet granulation including:

• lower capital investment costs

• lower utility costs

• a simpler, shorter process with increased flexibility

• increased yields

• reduced quality assurance and validation costs

• simple scale up.

The details of some of these benefits are explained in more detail below.

The benefits of dry granulation

Costs and commissioning

A typical dry granulation process line consists of an IBC dry blending stage that would feed into the compactor. After the compactor, the granules would be collected into an IBC and be fed directly into the tablet press, or possibly re-blended in the IBC with a tabletting lubricant and then discharged into the tablet press.

A conventional wet granulation line typically requires more equipment and technology compared with a dry granulation roller compaction system. This additional equipment will probably include a liquid dispensary, wet granulator high shear mixer, wet mill and transfer system, fluid bed dryer, dry mill and transfer system, larger IBC handling system, automated IBC cleaning and an integrated computer control system.

Dry granulation also offers benefits when it comes to commissioning. Typically, a wet granulation suite will take 3–6 months to commission, validate and qualify. This is because there are many individual machines and control systems to qualify, or a large complex and bespoke integrated control system for the whole granulation suite. A roller compactor, however, will often fit into an existing standard process room as a self-contained machine with a standard control system. It can be operational in a week, and validated and qualified within three weeks.

Process flexibility and yield

Process plant designs and configurations for both roller compaction and wet granulation will depend on the process need (e.g., larger dedicated campaigns or multi-product, small flexible campaigns). A roller compaction installation can be adapted, so is flexible for future changes in demands. A wet granulation line is, however, invariably fixed as an integral part of the building, requiring significant safety considerations and almost always multilevel building structural integration making it inflexible.

Batch size flexibility is also challenging to achieve with a high shear mixer or a fluid bed dryer and the associated large IBC configuration. The working volumes are relatively fixed at the time of design and purchase, limiting flexibility to the number of batches that can be produced rather than a flexible batch size. Typically, a wet granulation line will produce 1–2 batches per shift, requiring cleaning after about six batches, depending on the product. Roller compaction systems are available that do not have filter cleaning requirements, potentially enabling them to run 24/7 for weeks on end.

The dispensing of raw materials and dry blending of powders prior to compaction for batchbased processing essentially remains unchanged for campaignbased dry granulation. Should true continuous processing be adopted, then further efficiency improvements can be achieved by automated dispensing and continuous blending, which eliminates more intermediate processing steps and product handling; however, this is subject to the development of a suitable quality and validation strategy to monitor the feeding system and blending technology to ensure blend uniformity.

Assuming that the dry blending process remains unchanged (i.e., an IBC dry blend is performed), the main process of feeding the roller compactor, from powders arriving at the infeed hopper until discharged as a finished granule, takes only a few minutes.

Wet granulation typically requires five or more process steps and can take 60–80 min. The process can also result in yield losses due to high shear granulation residue, fluid bed filter and bowl product retention, and vacuum transfer losses. Yield losses may also occur in continuous processing via roller compaction during process start up and close down; however, technologies are available that can mitigate this issue by creating an immediate stable, steady state process.

Establishing a stable and repeatable process with conventional wet granulation is often deemed more of an art than a science.² Although this is achievable in production, it requires a high degree of quality control, highly skilled and experienced operators, and a good control system because of the variability that can occur with large volumes of materials; for instance, variable air flow patterns, moisture content, particle sizes and agglomeration. With dry granulation, the volume of product being 'acted on' at any moment of time is constant and is in grams rather than hundreds of kilograms. The compaction process starts as the product is drawn into the compaction rollers — this is a precompression stage that continues to gradually increase the pressure on the product until it reaches the central point between the rollers, called the roller gap. At this point the product is compacted and has formed a ribbon. This is a very short process in terms of time and surface area with compression force only being applied to a small volume of material at any given moment in time, which is a significant QbD difference.

Quality assurance and control

A wet granulation line typically has 15 to 20 variable critical control parameters, creating a substantial amount of validation and critical control activities. With roller compaction, quality assurance only needs to focus on a single process, and there is a much smaller number of control parameters that are process critical.³

Being able to define and control the process is important because it enables developers to predict and establish the correct parameters for scaleup. Roller compactors also offer substantial cost and time savings for this transition because the process conditions that act on the product are exactly the same on both large production and small scale development machines. In fact, scaleup from the laboratory to production can take place the following day.

Environmental footprint

Sustainability is now a key focus of the industry, but most activity in this area is directed at the energy savings and carbon footprint of a new facility rather than internal manufacturing processes. According to our research, adopting dry granulation methods can reduce the size of GMP processing areas, from approximately 80 m² using wet granulation equipment to 10 m² with dry granulation. Typically, up to 70% of a pharma site's energy costs can be attributed to HVAC so process design footprint requirements have a direct impact on energy consumption.

Reducing the amount of required process equipment, process steps and product contact surfaces will also significantly reduce the cleaning burden in terms of water supply requirements, water supply capacity and purified water demand, as well as the use of detergents and surfactants. Some roller compactors also incorporate high-efficiency cleaning design and high-pressure lowflow water, which in most cases negates the need for detergents and minimises water effluent disposal.

Conclusion

Roller compaction technology has been used for many years, but up-to-date technology, good process understanding and user familiarity are key to successful process development. Moreover, roller compaction could be the key to achieving a continuous granulation process. Over the next decade, the industry will adopt continuous processing for many products at many production sites. The technology is already well suited to meet this shift; if a product can be tabletted it can usually be roller compacted, although sophisticated roller compaction systems will be required for more complex formulations and challenging APIs. Whereas the auger system may assist in homogenisation in some cases, it is essential that blend content uniformity is established prior to feeding the machine. Establishing a design space for the product is also important to optimise final granule density and particle size distribution⁴ for achieving optimum tablet press performance.

Acknowledgements

The authors acknowledge the support of Gerteis Maschinen & Process engineering AG (Switzerland), and Alex Well from De Montfort University (UK) for the TPI images of pharmaceutical compacts

Steve Boswell is Director at S3 Process Ltd.

Tel. +44 (0) 7891485368

sboswell@s3process.co.uk

Geoff Smith is Reader at Pharmaceutical Technologies Group, Leicester School of Pharmacy, De Montfort University (UK).

References

1. L.A. Wall et al., Journal of Pharmacy and Pharmacology, 62(10), 1485–1486 (2010).

2. D. Nhoomi, Pharma Times, 42(2), (2010).

3. G. Shlieout et al., Pharmaceutical Technology Europe, 14(9), 32–39 (2002).

4. S. Wiesweg, R.F. Lammens and K.J. Steffens, "Dry granulation: parameter influencing the particle size of rollercompacted flakes "at the University of Bonn. 6th world meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology (Barcelona, Spain; April 2008).