Large volumes only! How continuous manufacturing can benefit pharma
Despite its popularity in the food and chemical industries, continuous manufacturing in pharmaceutical tablet production has not been well adopted. However, there are diverse advantages of this method of production, especially for large volume products. Here, GEA assess the specific benefits of continuous manufacturing for pharma.
Despite the fact that less well-regulated food and chemical production has long been dominated by continuous manufacturing (CM), pharmaceutical tablet production — until relatively recently — was solely a batch-based process.
To add some context, the aforementioned food and chemical lines are typically used to manufacturing a single, large-volume item and, as such, require very little cleaning and rarely undergo product changeovers.
Advantages of continuous manufacturing
The benefits of continuous manufacturing are diverse and many, ranging from smaller installation footprints, greater levels of efficiency, higher quality, lower staffing requirements and shorter cycle times, all of which contribute to more cost-effective production — especially for large volume products.
So why was big pharma hesitant to adopt CM? Conventional wisdom suggested that only large volume products (more than 1 billion tablets per year) justified dedicated production lines. And, although some over-the-counter (OTC) products are manufactured in volumes of more than 10 billion tablets per year, the vast majority of pharmaceutical solid dosage forms are produced in much smaller quantities that don’t warrant a dedicated line.
Furthermore, the CM lines in the food industry are extremely complex. Should extensive cleaning be required during a product changeover, for example, the potential downtime could extend to several weeks, which would eliminate any cost advantages gained as a result of the increased productivity.
The right time for pharma CM?
During the last decade, the pharmaceutical industry has become increasingly interested in CM for a number of reasons. In batch mode, the finished product (as well as intermediate products) is tested by quality control (QC) personnel and either the entire lot is accepted or the entire lot is rejected.
As this procedure has, in several cases, actually resulted in drug shortages, the authorities have put considerable pressure on pharmaceutical companies to implement a much higher level of process control and understanding to minimise the risk of out-of-specification (OOS) batches and consequent product losses.
By contrast, tablet compression has always been a continuous operation, including an inline weight check of every tablet. Compared with end-product testing, only a limited number of tablets are rejected should weight variations occur.
In terms of product volumes, as opposed to product values, the blockbuster era is over! Now, several bestselling products are priced in the $100 per tablet range. When the pharmaceutical industry started to develop these products, they identified three further CM benefits.
Pharmaceutical development: When working with rare and/or expensive active pharmaceutical ingredients (APIs), development can be done with significantly smaller amounts of material. You don’t need to process an entire (small) batch to generate a design of experiment (DoE) data point, just run a continuous line for a short while until stable conditions have been reached (typically about two minutes). Then, the next data point can be assessed. This not only saves huge amounts of API, it speeds up development as well.
Eliminate scale-up: As products for clinical trials and commercial supply are made using the same line, there’s no need for scale-up. It’s simply a matter of how long you run the machinery.
Reduced losses for IPC and QC: Modern analytical techniques allow the inline determination of (nearly) all critical quality attributes (CQAs) without the need to extract material for destructive testing. This massively increases the yield, particularly when working with small volume/high value products. Real-time release (RTR) capitalises on this concept: if the in-process controls (IPCs) are within specification, no final QC testing is required. Just ask Vertex!
The direct compression trend
For large-volume products, economics often dictate the use of ingredients with suboptimal physical properties (such as flowability). During wet granulation, these materials are converted to a form that’s easier to process using a high-speed tablet press. This process also reduces the risk of segregation. For small-volume products, however, the situation is different.
Here, it is more economical to use more expensive raw materials with optimised physical properties and eliminate the wet granulation step. CM also removes the risk of segregation. In batch mode, hundreds of kilograms of granules sit above the tablet press and are exposed to all kinds of mechanical forces; during continuous processing, the formulation is blended and compressed immediately.
Conclusion
Whereas the food and chemical industries are chiefly interested in the throughput benefits of using dedicated large-scale systems, the advantages of CM for big pharma manifest themselves in massively reduced OOS product, huge API savings during development and the elimination of scale-up.