Over the last two centuries, medicines have evolved from crude herbal and botanical preparations into more complex manufacturing of sophisticated drug products and dosage forms. Along with the evolution of medicines, the manufacturing practices for their production have advanced from small-scale manual processing with simple tools to large-scale production with sophisticate equipment as part of a trillion-dollar pharmaceutical industry.
Today’s pharmaceutical manufacturing technologies continue to evolve as the internet of things, artificial intelligence, robotics, and advanced computing begin to challenge the traditional approaches, practices, and business models for the manufacture of pharmaceuticals. The application of these technologies has the potential to dramatically increase the agility, efficiency, flexibility, and consistency in the quality of the industrial production of medicines. How these technologies are deployed on the journey from data collection to the hallmark digital maturity of Industry 4.0 will define the next generation of pharmaceutical manufacturing.
Industry 4.0 is characterised by integrated, continuous, autonomous, and self-organizing production systems. For adopting Industry 4.0 in pharmaceuticals, new thinking will be required to overcome the inertia of current manufacturing infrastructure, operations, and regulation. While implementing, many of the advanced technologies and manufacturing approaches needed to enable Industry 4.0 may not be that easy, it may well be worthwhile as they bring the potential for higher output, increased manufacturing safety, improved quality, better value, increased agility, additional flexibility, and reduced waste.
Industry 1.0 is the starting point of the modern pharmaceutical industry. The application of herbal or botanical preparations as medicines has spanned the history of civilization. Industry 1.0 saw the manual processing of botanical, mineral, and animal derived materials transition from simple hand-operated tools to commercial-scale machinery able to crush, mill, blend, and press larger quantities of medicines (Anderson, 2005). In the 19th century, larger-scale production of drugs utilising non-electrical power-driven machinery emerged from two sources – individual pharmacies or the dye and chemicals industry.
The second industrial revolution was enabled by electricity and early electronic machines and assembly lines with pre-set controls that incorporated basic automation and process controls which provided manufacturers the ability to set basic process parameters. Electronic machine-based crushing, milling, blending and tablet pressing allowing for larger-scale production and – importantly – more monitoring of processes and quality. Industry 2.0 developments led directly to machines such as modern tablet presses that can reliably produce over one million tablets per hour. Some industries are now well into Industry 3.0, but in many ways the pharmaceutical industry is still very much transitioning into it. For example, continuous manufacturing is a technology that sends materials produced during each process step directly and continuously to the next step for further processing; it has been widely adopted in other industries. For various reasons and due to legacy of operating in batch process, the pharmaceutical industry has been slower to adopt continuous manufacturing.
The third industrial revolution brought pharmaceutical manufacturing advanced process analytical technology (PAT), which aims to provide process and product quality data in near real time. Industry 3.0 also advanced model-based or Quality by Design (QbD) processes, which aim to control target product quality profiles within a defined set of quality parameters from it synthesis stage to piloting to manufacturing till it’s end use. However, to achieve the full potential of PAT and QbD, more technology advancements are needed to attain deeper process knowledge and real-time analytics to more widely enable real-time release testing with high levels of product quality assurance – especially for biotechnology products.
The experience gained in the automated and digital environment of Industry 3.0 empowers the widespread transformation into Industry 4.0 in pharmaceutical manufacturing. Whereas Industry 3.0 saw rapid advancements of individual operations and tools, Industry 4.0 promises advancements of entire manufacturing systems and infrastructures. In such an environment, performance data can be analysed by algorithms and used for critical real-time business and operational decisions that directly impact production outputs. The stages of data transformation on the path to realizing Industry 4.0. In these stages, data are transformed from raw signals captured from a system to full digital maturity. Data are initially collected from a manufacturing process, then organized by data digitization and analysis as Big Data into information, then synthesized into knowledge by the meaning discerned via artificial intelligence, and finally to actionable wisdom attained through the combined insights of digital maturity.
Multiple data sources can integrate to connect both external and internal information. In pharmaceutical manufacturing, external information – including variables such as patient experience, market demand, supplier inventories, and public health emergencies – could fuse with internal information such as energy and resource management, modelling and simulation outcomes, and laboratory data. Integrating internal and external data sources enables unprecedented real-time responsiveness, monitoring, control, and prediction.
A key to implementing Industry 4.0 is the digitisation of multiple complex pieces of the pharmaceutical value chain with embedded cyber security. A critical concept in developing the so-called “smart factory” is the industrial internet of things (IoT), which is a type of cyber-physical system comprising interconnected computing devices, sensors, instruments, and equipment integrated online into a cohesive network.
The Pharma industry has started implementing industry 4.0 technologies in the recent years only and it has been using batch manufacturing for more than 50 years. However, the traditional batch manufacturing has proved lengthy one and after each step in the process the production is typically stop and tested for the quality attributes which consume time. Sometime during this hold time, the material has been stored in the container and ship to the other unit for further processing. Each break increases the lead-time and may increase the possibility of the defects and error. Today we are entering in to the era of precision (Personalised) medicine where drug must be made with unique features and provided more quickly to the patient need. In order to provide the personalised need pharma factories are no longer needed to manufacture in big batches but in small lot in suitable time manner for example HIV drugs.
In pharma industries, continuous manufacturing is all about moving the substance nonstop with in the same facility thus eliminating the hold times between the different steps in the process. Continuous manufacturing save time, eliminate the errors, increase process stability, improve process performance, accelerate the process development, optimise the maintenance and most important consistent in the quality.
The Rising generic drugs enter the market the demand for the high drug quality, prolonging the shorted drug life cycle and the need to reduce the high cost of batch manufacturing is only possible with continuous manufacturing.
The pharma industry is heading towards adopting more and more Industry 4.0 technologies and continuous manufacturing. With FDA’s encouragement, the pharma industry is now on the track of catching up with other industries such as petrochemical or semi-conductor.
A few of the companies have already entered in to the industry 4.0 and are enjoying the fruits (example-Johnson & Johnson, Novartis, GSK, Pfizer) while many have still not started the journey.
(Hiren Shah is the Senior Vice President, Operations at Cadila Pharmaceuticals)