Pharma 4.0: Digital Manufacturing and the Facility of the Future
The Way Forward: APIs and Automation
The COVID-19 pandemic revealed critical weaknesses across global supply chains, highlighting shortages of various kinds. This became highly evident with the resulting short supply of pharmaceutical products which most often rely on active pharmaceutical ingredients (APIs) manufactured in Asia, or more specifically, in China and India.
Unsurprisingly, the regionalization of supply is currently seen as one potential solution to increase the resilience of pharmaceutical supply chains. As we rapidly enter the digital age, current manufacturing setups in the pharmaceutical industry should be put under rigorous scrutiny.
What would the manufacturing plant of the future look like in order to offer new solutions to the challenges mentioned above?
An array of supply chain components can be delineated. First, the manufacturing plant needs to comply with the many regulatory requirements of the pharmaceutical development process. For example, manufacturers would need to enable material supply for toxicology and clinical processes as well as adhere to the requirements of global regulatory approval processes. Additional requirements would need to be considered:
- Scalability to support the ramp-up process and enable the fulfillment of individual product demand following the introduction of new pharmaceutical products in global markets.
- Flexibility to respond to demand variations in markets without compromising process stability or product quality.
- Fulfillment of individual country requirements for packaging as well as being compliant with the serialization requirements of pharmaceutical products.
- Cost competitiveness over the product life-cycle and the ability to adapt to cost constraints in global aging societies.
Where APIs and pharmaceutical product manufacturing are concerned, both scenarios need to be protected against human and environmental contamination. Individual elements (each API manufacturing unit and pharmaceutical manufacturing unit) need to seamlessly integrate into a continuous end-to-end design for the entire supply chain.
The Plant of the Future: APIs as an Enabler
Protecting the product against human contamination and influence (e.g. process variation) requires a high degree of automation across all manufacturing processes.
Deploying automated design processes will have a positive impact on manufacturing costs and process stability. Process stability and degrees of repeatability will ensure continuous high-quality products with little-to-no process variations.
For many pharmaceutical manufacturers, it’s often difficult to imagine the actual application of these elements in today’s multi-purpose plant setups because it requires higher degrees of asset dedication in contrast with what is already in place. Before the backdrop of increasing efficacies (e.g. highly potent products), manufacturers will be required to increase smaller product quantities. As a result, this will render current large vessel volumes based on a multi-purpose setup to be less economically attractive. Thus, smaller product quantities in combination with a higher degree of dedicated assets will enforce the introduction of smaller-scale manufacturing entities.
The solution centers around decoupling points in API production. The manufacturing of early intermediates based on forecasting supply scenarios in large, centralized manufacturing units will be combined with decentralized dedicated manufacturing units. This will be true at least for the final steps from pharma intermediates to an individual API. Connected, flexible operations in manufacturing can increase efficiencies, support smaller batches, and bring novel therapeutics to the market more rapidly. This highlights a greater paradigm shift that is underway from large, global manufacturing facilities to smaller, more localized operations. This brings API production to more cost-effective locations, allowing pharmaceutical companies to create personalized medicines closer to those who need them.
Units focusing on early intermediates will rely on lean oriented manufacturing principles with a special focus on flexible product changes and cleaning validation concepts. Dedicated assets will follow a demand-driven – perhaps even a daily lot size – to create a robust production schedule with short throughput times. This will have two major implications. On the one hand, standardization of equipment will become increasingly important to keep engineering costs low during the design phase. On the other hand, standardization of assets will be a key enabler to ensure demand flexibility – for example – rising product demand will lead to the multiplication of manufacturing assets.
Standardization of assets and process stability work hand in hand to ensure uncompromised high product quality. Adherence to critical process parameters identified during process development will be supervised by a combination of process analytical technologies (PAT) and the continuous supervision, analysis, and visualization of system parameters. This concept will become increasingly important as the current manufacturing approach to analyze each API batch has significant costs attached to it, owing to the high costs incurred by quality control measures. Going forward, parametric release without routine analysis will require a deep understanding of process parameters that need to be generated during the process development phase. This will include the continuous monitoring of process parameters to reconcile cost competitiveness and product quality in the long run.
The Value of Digital Manufacturing
With the modern manufacturing plant of the future, pharmaceutical companies will unlock new levels of efficiency through data acquisition, data analysis, and data visualization. The plant of the future will be built upon the core principles of data handling, real-time visualizations of an asset’s current status, and degrees of automation combined with a level of self-regulation comparable to autonomous driving – this will be necessary for the long-term success of a more regionalized API manufacturing landscape. The flow and impact of data will extend across the entire value chain. Real-time insights and data management systems enable pharma manufacturers to take advantage of a variety of new capabilities made possible through the application of new technologies. These capabilities include optimizing the manufacturing process with predictive maintenance, remote monitoring, digital twin technology, inventory management, and process automation. However, as the supply chain becomes more connected, pharma manufacturers need to focus on cybersecurity as a solution where sensitive information is protected and secured.
Automated systems and networked machines will detect any anomalies that arise during production and will alert manufacturers with sufficient time to respond in case the asset needs maintenance. Digital twins are adding another layer of process optimization whereby a virtual model is created using computer-aided engineering and integrated with IoT, machine learning, and big data analytics that merge real-time data from its physical counterpart onto an interactive visual interface. The pharmaceutical plant of the future will be based upon the idea of an entirely new supply chain concept, where the synchronization of all interacting parts in the supply chain (from raw material supply to product delivery schedules) will be a key enabler. Each counterpart will have the ability to communicate with one another via machine-to-machine communication, rapidly speeding up operations.
Pharma manufacturers can take advantage of new technologies such as IoT, machine learning, and robotics by digitizing downstream activities such as batch review, batch release, and advanced process analytics.Beyond the manufacturing process, we can expect to see a significant shift in the future of work for people employed in such factories with modern requirements regarding core competencies and educational training.
The Future will be Agile
The manufacturing plant of the future is built on the core principle of an agile supply chain. As the world continues to evolve and increasingly complex demands arise, there is an urgent need for a more agile and connected approach to production — to create products with shorter lifecycles using data to make operations more efficient. With this new, robust supply chain, we will find a mix of highly flexible multipurpose plants for early intermediates and dedicated highly standardized small-scale assets for advanced intermediates up to the API.
Rigorous supervision of process and system parameters combined with artificial intelligence in highly automated assets will result in a high degree of self-regulation and optimal batch conditions — to produce what is known as the ‘golden-batch’. Multiplying assets will offer a solution to flexible demand scenarios in an environment with increasing product efficacies that require fewer APIs and pharmaceutical products in the long-run. Next-generation manufacturing processes are under development to help eliminate inefficiencies in the pharmaceutical supply chain so that products can reach the market rapidly, reliably, and at a reduced cost. The pharmaceutical plant of the future is reimagining the nature of production to create a competitive edge that will simultaneously deploy the supply chain of the future – one that is agile, responsive, and personalized.
Dr. Christian Ewers
Managing Director, Pure Biooroganics SIA, Latvia