The project team at a major pharmaceutical manufacturing company initiated an in-depth feasibility study to assess the capabilities and constraints of ConsiGma™’s technology and process characteristics.

The Rise of Continuous Manufacturing

Traditionally, the pharmaceutical industry has relied on batch manufacturing processes to produce drugs wherein materials are charged before the start of the process and discharged at the end. Ironically, most other, less regulated industries transitioned to continuous manufacturing (CM) at the time of the industrial revolution. CM, during which material is simultaneously charged and discharged from the process, is generally considered to be more efficient as it consistently delivers a higher quality product.

In a recent GEA case study (Envisioning the Factory of the Future), the authors noted: “It’s perhaps not surprising to hear that the pharmaceutical industry is under pressure. Many countries are cutting their healthcare budget, resulting in reduced prices and reimbursement rates. This evolution negatively affects gross profits and sales volumes. Increased competition from generic companies aggressively seeking to extend their market share is a constant threat, the R&D success rate of ethical pharmaceutical companies is substantially decreasing while the patent protection of blockbusters is slowly but surely fading away.”

All these factors have led to declining company revenues. And, whereas increased R&D budgets are required to maintain pipelines and profitability, this means that every department and function in the drug production supply chain has to drastically increase its efficiency. Product development needs to be faster: reduced costs, improved production economics and increased manufacturing flexibility are key — and CM technologies can play an important role in achieving these challenging objectives.

As well as cost efficiencies, the other hurdle encountered when implementing new techniques is regulation. However, since the introduction of quality by design (QbD) in the International Conference on Harmonisation (ICH) guidelines (Q8/9/10), and the adoption of the US Food and Drug Administration’s (FDA) Pharmaceutical Quality for the 21st Century: A Risk-Based Approach initiative, CM has been actively encouraged.

Continuous Granulation

Wet granulation is a widely used process in the pharmaceutical industry as it plays a significant role in improving the flow properties, homogeneity and compressibility of the solid dosage powder mix. Fluidized bed granulators and high shear mixers are typically used in traditional batch wet granulation processes; these two techniques differ from each other in terms of the technique used for solid agitation and on the mode of granule growth, but both have a long history of application in both drug development and manufacturing. In recent years, however, quasi-continuous and continuous granulation techniques have been investigated as a means to reduce time-to-market and to increase the cost-effectiveness of production.

Traditional batch granulation is both time-consuming and expensive. In addition, many of the scale-up problems associated with batch granulation processes can be avoided by applying a continuous granulation process; the same equipment using similar process parameters can be used for the lab-scale and large-scale production.

As the industry’s interest in CM started to emerge, some of the world's leading research-based pharmaceutical companies became early adopters of the technology and investigated its potential. In their attempt to evaluate the market for oral solid dosage (OSD) CM technology, a project team from one such company was put in place to assess a science- and risk-based strategic decision in favor of this innovative manufacturing technology and to select the most appropriate equipment and vendor. They focused on the continuous high shear wet granulation and drying technology of GEA.

ConsiGma™

The ConsiGma™ is a multipurpose platform that has been designed to transfer powder into coated tablets in development, pilot, clinical and production volumes in a single compact unit. The system can perform dosing and mixing of raw materials, wet or dry granulation, drying, tableting and quality control, all in one line. By producing granules continuously, batch sizes are determined by how long you run the machine; and, because of ConsiGma™’s innovative design, the amount of waste produced during start-up and shut down is significantly reduced compared with conventional methods. Quality is measured throughout the process and, as such, drastically reduces the cost per tablet.

ConsiGma™ was developed in compliance with the FDA’s QbD initiative. It satisfies the industry’s need for reduced risk and higher quality while avoiding lengthy and costly validation and scale-up to bring products to market faster and cheaper. The inherent flexibility enables manufacturers to meet demand, keep expensive cleanroom space to a minimum and reduce inventory costs.

Optionally integrated advanced process control and PAT tools enable monitoring during production, so quality can be designed into products from the start. ConsiGma™ provides the maximum output in an energy efficient way, has been tested using more than 100 different formulations and is already being used by several large pharmaceutical companies, and ethical and generic research and manufacturing centres worldwide.

Case Study

The project team at a major pharmaceutical manufacturing company initiated an in-depth feasibility study to assess the capabilities and constraints of ConsiGma™’s technology and process characteristics. To support the business case, they selected a representative formulation from their conventional fluid bed granulation batch process portfolio and focused on four key areas: time, quality, cost and agility. Production parameters were defined using a Design of Experiment (DoE) approach in a relatively short period of time, a small amount of product and only a few trials. Process stability and repeatability was established during a number of long runs using online measurement techniques.

When the process and tablet quality control (QC) data derived from the long runs were thoroughly analyzed, the project team was able to confirm the stability of the process and to evaluate any process sensitivity fluctuations caused by minor changes in environmental conditions. The excellent correlation between the process data and the tablet QC data enabled the team to confirm the process parameter settings and ranges and satisfactorily demonstrate process robustness.

When using CM, process development is much faster (as a result of more efficient DoE). Tech transfer is also much faster, as scale-up and process transfer is reduced or eliminated and cycle times are also shorter owing to the elimination of intermediate storage steps between unit operations. With the ConsiGma™ 25, for example, scale-up is eliminated: direct transfer of the granulation parameters to production is possible as the granulator has the same design as the ConsiGma™ 1.

From a quality perspective, much more intensive process monitoring and control allows operators to proactively address deviations from normal operating parameters and, as a result, run a more stable and consistent process. The operator interface is very user-friendly, using touchscreen technology and logical user graphics.

Cost reductions are paramount in today’s industry, particularly in development, investment, production cost and energy consumption, QC and inventory. The faster development and reduced scale-up efforts will naturally impact the cost of development, whereas the small footprint of the equipment will reduce investment costs and those related to energy consumption for HVAC. Online monitoring and real-time release testing will reduce QC costs and, again, eliminate intermediate storage costs by linking the different unit operations together. Finally, the ConsiGma™-1 is designed for easy deployment. It will fit into the most compact of laboratories and can be transported easily to wherever it's needed. Requiring only electricity and standard utilities such as water and compressed air, the system is practically "Plug-and-Play" and can also be configured for hot melt granulation.

Conclusion

The study showed that, using ConsiGma™ technology, process development could be done much faster and more robustly, using a minimum amount of API. Assuming development and commercial manufacturing is done on the ConsiGma™-25 line, technology transfer is redundant, resulting in a substantial time-to-market reduction and decreased costs. The agility of the system, thanks to the flexible process technology, has been proven during process development, resulting in effective and efficient DoE. Process stability and robustness have been proven during the long runs and real-time, in-line measurements have shown their ability to monitor the process based on predetermined intermediate and finished product attributes (and to detect minor changes in these attributes).

Benefits of Continuous Manufacturing

  • continuous quality verification
  • real-time product release
  • reduced costs
  • improved energy efficiency
  • reduced carbon footprint
  • faster time to market
  • improved flexibility throughout the product lifecycle
    • batch size depends on time of production, not machine size
    • the same equipment can be used for R&D and production
    • different technologies can be combined in the same platform
  • improved quality
    • PAT tools
    • steady state, better production control.

Using the example cited in this article, it can be concluded that CM is ideally suited to the QbD development and manufacture of high quality medicines with reduced development timelines. As noted recently in AAPS Newsmagazine, this will ultimately benefit patients. CM should result in smaller, operationally more efficient and environmentally friendly commercial manufacturing plants. In addition, incorporating extensive PAT to allow for real-time release (RTR) provides enhanced efficiency and significantly reduces QC work.

ConsiGma™ 1 Continuous High Shear Granulator

ConsiGma 1 web

Continuous high shear granulation for more efficient R&D. The ConsiGma™ 1 is a mobile laboratory continuous granulator with an optional fluid bed dryer for early R&D work, offering

  • flexible process capacity
  • no scale-up
  • minimized losses
  • fast changeover
  • advanced user-friendly controls
  • "out of the box, ready to use."

The test set-up in the GEA Process Development Center houses a complete ConsiGma™ tableting line consisting of a continuous high shear granulator and dryer combined with a MODUL™ P rotary tablet press and a continuous coater. A special in-line blender mixes in the external phase between granulation and tableting. 

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