The pharmaceutical industry is changing. Under fire by political pressures to drive down the cost per tablet, compounded by new drug discovery becoming more challenging escalating research costs, the industry is looking to unleash its efficiency shackles of the past. Some existing process technologies are suited to the new era of solid dose pharmaceutical efficiency.
Is the pharmaceutical industry poised for the paradigm shift to continuous manufacturing or has dry granulation been waiting for the opportunity to do it for years?
We believe the industry will evolve over the next ten years into continuous manufacturing for many products. Some existing technologies are already well-suited to the change, and they present real opportunities. In particular, Gerteis® roller compaction technology offers an ideal interim solution as a semi-batch process but is also likely to be one of the primary final continuous solutions due to its process simplicity.
Roller compaction is a continuous technology by design but has developed significantly over recent years. Several significant changes have been made differentiating Gerteis® technologies from conventional roller compactors.
Some of the key advantages of Gerteis are:
- The advance feed system ensuring consistent and controllable feed from the infeed hopper through to the compacting rollers
- Special close loop control of compaction and the feed system to give consistent controllable product density
- Advanced roller design ensuring negligible process run up and run down, and no fines recirculation
- High tolerance granulator (milling and size reduction) integrated in the machine for consistent output of granules
- Low energy process input giving a negligible product heat gain
- Predictive processing software for rapid processing results
How does the business case stack up for a Gerteis® roller compactor?
Dry granulation offers some significant benefits both in-process and lean terms compared to existing wet granulation processes. These benefits are summarised below (also see table 1):
- Capital investment costs are substantially reduced
- Utility costs are substantially reduced, as is the GMP footprint
- Substantially simpler and shorter process and increased yield
- Reduced QA and validation costs
- Zero scale-up risk and cost
- Reduced processing times and increased flexibility
- Reduced labour costs
Capital investment comparison
We estimate that a conventional wet granulation line would typically require the following capital equipment and technology; this is in addition to a dry granulation roller compaction line:
Following is not required with Gerteis Roller Compaction:
- Liquid dispensary
- Wet granulator high shear mixer (fixed batch capacity)
- Wet mill and transfer system
- Fluid bed dryer (fixed batch capacity)
- Dry mill and transfer system
- IBC handling system
- Automated IBC cleaning
- Complex integrated computer control system
Commissioning complexity and its associated high costs for a wet granulation system offer more opportunities for substantial savings. Typically, a wet granulation suite will take anything from three to six months to commission. A roller compactor system will go into an existing standard process room, as a self-contained machine with a test standard control system and can be operational in less than a week, validated and easily qualified within three weeks, saving substantial time, cost and project risk.
Utility costs and GMP footprint requirements are reduced
As sustainability is now a primary focus of the industry, it is also essential to highlight the operational and environmental benefits, focusing on saving energy and reducing carbon footprints. It is possible to reduce the required processing areas by 50% by adopting roller compaction for manufacturing expansion.
Significantly reducing the amount of process equipment required, product transfers, process steps and product contact surfaces, will also significantly reduce the cleaning burden, for example, water supply requirements and water supply capacity.
The Gerteis® roller compactors incorporate high-efficiency cleaning design (CIP) and an optimised process using high-pressure low flow water. Moreover, with machines capable of achieving high levels of containment, this minimises external cleaning requirements for the process room, cross-contamination risks and costs while additionally benefiting operator safety.
GMP processing area and plant area requirements are also substantially smaller by comparison typically:
- GMP area of approximately 80m2 compared to Gerteis needing 10m2, potentially saving 70m2
- Technical area of approximately 50m2 compared to Gerteis needing 5m2, potentially saving 45m2
Substantially simpler and shorter process, and an increased yield
Assuming the dry blending process remains unchanged, for example, if an IBC dry blend is completed, the central process of feeding the roller compactor takes a few minutes from powders arriving at the infeed hopper until discharged as a finished granule ready for tabletting, capsule filling or sachets.
Furthermore, this will reduce yield losses that can be significant, for example, high shear granulation residues, fluid bed filter and bowl product retention and vacuum transfer losses typically up to 15% of accumulated batch losses. With the controlled slow start technology available from Gerteis®, a stable process ‘steady state’ is achieved in a few seconds avoiding product loss during process start-up and close down, losses of less than 1% by comparison.
Establishing a stable and repeatable process is simple and easy with Gerteis® dry granulation by comparison to wet granulation technologies, the volume of product being ‘acted on’ at any moment is constant and is in grams rather than 100s kilograms, a significant QbD difference. The process can be stopped and restarted at any point, immediately establishing a steady state.
Reduced quality assurance and validation
By nature, the process steps are shorter for Gerteis® roller compaction, and in-train product is significantly reduced, enabling quality assurance to focus on a single process controllable with less variable parameters and setpoints, also enabling real-time release testing for future continuous processing. By preparing larger batches by processing continuously this substantially reduces sampling and lab analysis costs. Gerteis® has a modest number of process-critical control parameters, and with the right equipment, are tightly defined and stable.
By achieving this tight and stable control of the process, developers can predict and establish the correct parameters for scale-up from R&D, Pilot-scale and manufacturing. Gerteis® roller compactors can offer a substantial cost and time saving for the transition from development to production. The machines range from a few grams to 25kg / hour, up to 100kg / hour, and up to 400kg / hour depending on equipment size, in effect, very small scale-up is required with Gerteis® technology.
This means that conventional scale-up of wet granulation parameters not linear or easily predictable must be developed, and establish leading to extensive validation time and cost. With a Gerteis® roller compactor, the product process parameters are established efficiently at lab scale and can be applied to large production machines rapidly, representing a significant saving in time and cost.
Reduced processing times and increased flexibility
Process plant designs and configurations will depend on the process need, for example, larger dedicated campaigns or multi-product small flexible campaigns. A Gerteis® roller compactor can be simply picked up and relocated, so is flexible for the future changes in demands.
The Gerteis® roller compaction system does not have filter cleaning requirements as a wet granulation system and has the capability of running 24/7, potentially for weeks on end, for larger campaigns. More realistically, running the Gerteis® roller compactor for an extra hour or 30 mins gives the ultimate product output flexibility, essentially time-based to meet any variable production requirements.
There are some further points to be considered when selecting roller compaction technology. The technology has been used for many years, yet more process understanding and user familiarity are key to successful process development. Essentially, with the right Gerteis® equipment, if a product can be tableted, it can be roller compacted. Therefore, for the versatility of R&D or more complex formulations and challenging APIs, Gerteis® has the solution and knowhow to succeed.
Your particular cost savings comparing wet granulation to Gerteis® dry granulation can easily be calculated simply by evaluating the table below:
Table 1. Cost comparison indication in Euro
In conclusion, there is a powerful business case to reduce the ‘cost per table’ for pharmaceutical and healthcare granulated products in capital, operational, strategic and environmental terms to consider Gerteis® roller compaction technology for development and use in a modern pharmaceutical solid dose manufacturing facility.
Gerteis technology has the essential process control and functionality built-in and proven, ideally suited for the transition to continuous manufacturing, yet provides the flexibility for batch and semi batch-based operations.