To be continued: 5 ways continuous manufacturing adds value for pharma

Stephen Closs, VP, Global Technical Operations, Patheon explains continuous manufacturing as an enabling technology for quality by design – and highlights five ways it adds value for the pharmaceutical industry.

Continuous manufacturing holds great promise for the pharmaceutical industry, enabling much faster pharmaceutical production and more reliable products via an uninterrupted process. In some cases, manufacturing that takes a month by batch technology might only take a day using continuous manufacturing techniques, according to a recent FDA blog. Similar approaches are already widely used by industries such as steel, petroleum, automobile and food, where they have lowered processing costs, improved quality and consistency, and boosted productivity.

In the pharmaceutical industry, all continuous manufacturing processes – where material is allowed to flow from one unit operation to the next, not pausing to complete any one step – share two key attributes:

• The definition of the batch size required to have consistent quality is not set by the scale of the manufacturing equipment
• It is possible to devise real-time control strategies, which span across separate unit operations utilising data taken from the process in real time.

Continuous manufacturing can improve reliability, while reducing waste and costs compared with the batch method. A feeder array dispenses materials into steady-state unit operations such as blending and compaction, making it much simpler to characterise a process, since these do not vary over time. This makes it easier to relate material attributes to process conditions and product attributes. As a consequence, Quality by Design (QbD) process understanding can be built on a scale more typically associated with pilot scale quantities than with manufacturing-scale production, requiring smaller investments in time and money.

Continuous manufacturing offers value to the pharmaceutical industry in five major ways.

First, there are monetary benefits. In traditional manufacturing, very large and expensive pieces of equipment – such as blenders and tablet presses – operate in batch mode. The standard approach to drug manufacture starts by producing batches in the 1kg to 10kg range, and then scales up by a factor of 10 for pilot scale experimentation, and another factor of 10 for commercial scale production, which typically involves 150kg to 800kg. At each step up the scale, multiple batches are manufactured over a relatively short period when compared to the full production lifecycle, often using active pharmaceutical ingredient (API) material that is still undergoing process changes. The product must be tested extensively at each step to ensure that it remains consistent. In contrast, the cost of development is much less for an API made using a continuous manufacturing process. In continuous manufacturing, an assembly line approach is used, with raw materials going in at one end, and product coming out at the other end, and no holding of intermediates. Unique sets of materials and process conditions can be tested in the time it takes for a change to move through the line. On current production scale manufacturing processes this consumes between 10kg and 60kg, which is on the same scale as batch pilot studies. It is not unrealistic for a company to save millions of dollars with continuous manufacturing based on the reduction in material costs from not needing to run multiple manufacturing-scale development batches during process development. The timeline to develop a continuously manufactured product is also shorter, driven by the fact that most development activities and preliminary process trials are carried out with the commercial manufacturing train. Under the traditional approval process, this may or may not affect the overall timeline. However, it does become critical in the event of a breakthrough therapy.  Since the commercial scale process can be interrogated with pilot scale quantities, there is no need for additional costly scale-up. Overall API usage can be reduced by as much as a factor of 10. Efficiencies are gained by collocating all processes for a particular product in one area and not having to stop production. The resulting cost-of-goods savings bring benefits to both the patient and the manufacturer.

Second, the time to market is accelerated due to the reduced development time, with no scale-up or pre-validation required for continuous manufacturing. Traditionally, clinical programs were dependent on the state of the development process, which often delayed filings. With continuous manufacturing, as soon as regulatory clinical trials are complete and in vivo data has been created, the company can move ahead with the filing. This has potential to improve pharmaceutical company revenues and alleviate drug shortages.

Third, assurance of product quality is increased, a vital attribute for all healthcare stakeholders, including regulators, physicians and patients. Compared with batch production, continuous manufacturing involves a smaller operation, a unified assembly line, and a higher level of instrumentation, which generates large amounts of data on the process. Feedback and feed-forward control loops within this data-rich environment help ensure that the product meets quality targets at each step in the continuous process. This continually verifies the product based on quality markers at each process step, making alterations if needed to maintain the product quality within a defined range, and greatly reducing or even eliminating events where products fall out of spec (OOS). This ensures that product can be shipped directly without further testing once it comes off the line. Continuous manufacturing is the technological realisation of QbD – with quality built in rather than tested at the end – allowing true QbD programs to be executed from development through to commercialisation.

Fourth, pharmaceutical engineers can do more with less, fitting five to 10-times higher capacity within a given manufacturing footprint, since continuous manufacturing uses smaller equipment for assembly-line production. In addition, compared with batch processing, continuous manufacturing operates more efficiently, resulting in a smaller carbon footprint due to reduced electricity and water requirements, and reduced waste production.

Fifth, flexibility and supply chain optimisation is offered by construction of modular manufacturing trains, made possible by the smaller size of equipment and ability to integrate processes to make a continuous line. Today’s drug manufacturing landscape is filled with factories designed to produce blockbusters of the past. This model does not meet current requirements for flexible manufacturing, which often require multiple supply solutions designed to fit a broad range of product volumes and patient populations. Tomorrow’s manufacturing operations will need to involve smaller, more flexible production plants, with more distributed local-to-market manufacturing options that can produce cost-effective and affordable treatments.⁵A warehouse-like pharmaceutical workspace can be constructed that meets GMP requirements, and continuous manufacturing modules can be linked to manufacture a drug substance or drug product. These can then be taken apart, cleaned, and reassembled into different configurations, or combined with additional modules, to make a variety of products. Within a single workspace, manufacturing ‘pods’ can be created and integrated using advanced control systems to create novel manufacturing platforms or process trains to create virtually all products and dosage forms. These modular trains can also be transferred to other geographic locations. This offers more flexibility than many original equipment manufacturer (OEM) offerings, which are often permanently fixed within a plant.

Looking ahead, in order to benefit from the many advantages of continuous manufacturing, drug companies will need to take responsibility for the whole manufacturing process, including process design. Continuous manufacturing can save substantial amounts of money, and enables companies to gather knowledge at each stage of the product lifecycle, from development to production, and feed this back into a single, risk-based control strategy. Through ongoing process improvements, manufacturers can reduce the need for testing of end-products – and even eliminate it over time – as the process becomes increasingly well understood, and controlled. On the rare occasions when a product falls OOS, adjustments can be made quickly, in real time, to minimise the amount of OOS product, saving time and money, and moving ever closer to the ideal quality standard.