Cognitive process solutions in a highly regulated industry environment: The Pharma Perspective

Continuous manufacturing and its on-line control offer unique opportunities and may minimise or even eliminate process steps. The global economic importance was highlighted in 2019, when Janet Woodcock, then-director of the FDA’s Center for Drug Evaluation and Research (CDER) now Acting Commissioner of the FDA, in a hearing with the subcommittee on health, committee on energy and commerce, with the U.S. house of representatives presented that just 28% of manufacturers producing drug ingredients for the U.S. market were based in the U.S. [i] She concluded, local manufacturers using batch-based production “could never offset the labor and other cost advantages” enjoyed by contractors in China and India but continuous processing could be the way to go.[ii]

A simple capacity evaluation shows that a continuous manufacturing plant running constantly 24/7 for 50 weeks/year, with no significant downtime for major, has a capacity of 1 billion tablets per annum. This translates to 110,000 tablets per hour, a throughput that is very typical of a single pilot scale line using conventional technologies.

While there is continued interest harvesting the full potential from advanced manufacturing techniques, it is a challenge and requires investment in time and resources to develop the scientific basis and implement the technologies and in particular the respective control tools, preferably based on cognitive solutions, to steer the continuous processes in-line. This is an essential task in the CAPRI project as we intend to move away from batch wise to continuous processing.

However, a suitable quality system in the pharmaceutical environment is mandatory and key to the success of the approach in general. This is even more important when cognitive solutions take action in a manufacturing process and have a ruling over quality in general.

Therefore, it is important to take a closer look at the regulatory framework which has developed and needs to be followed when cognitive solutions are implemented: Already in September 2004, the FDA published the guidance “A framework for Innovative Pharmaceutical Development Manufacturing and Quality Assurance,” which discusses using the approach of building quality into products and the necessity for process understanding and opportunities for improving manufacturing efficiencies through innovation.

The International Council for Harmonisation (ICH) recently published Q13 draft guidelines on continuous manufacturing “Quality Considerations for Continuous Manufacturing” to advance the ability to obtain approvals for products manufactured using continuous manufacturing processes. This guidance discusses the advantages of embracing the concept of continuous manufacturing, in particular and relevant to the CAPRI project control strategies and approaches to process validation as well as scale-up. Also, bridging existing batch manufacturing process to a continuous manufacturing process is discussed which is exactly the intend of the pharma consortium of RCPE and AMS in CAPRI.

In detail, ICH Q13 presents a regulatory framework for more flexibility and, at the same time, reliability in manufacturing processes. The guideline provides clarification on continuous manufacturing concepts, describes scientific approaches, and presents regulatory considerations specific to continuous manufacturing of drug products. It is important and relevant to the CAPRI project that different models can be applied a manufacturing process:

Combination of approaches with some unit operations operate in a batch mode while others operate in a continuous mode
All unit operations of a drug product manufacturing processes are integrated and operate in a continuous mode as presented in the CAPRI project framework and,
Last but not least, an approach where the API and drug product unit operations may be integrated, and drug substance and drug product form a single continuous process.

Generally, the size of a batch produced by continuous manufacturing can be defined by either the quantity of the output materials, the quantity of the input materials, or the run time at a defined mass flow rate.[iii]

The progress from an industry perspective has been steady and examples of marketed products with continuous processing exist: In 2015 Vertex’s Orkambi (lumacaftor/ivacaftor) to treat cystic fibrosis was the first product approved applying continuous manufacturing. Vertex’s Symdeko, one of Orkambi's sister drugs, also uses the approach. Janssen’s Prezista (darunavir) to treat HIV was the first drug that FDA allowed to be switched from batch processing to continuous manufacturing.

By 2019 FDA gave approval for six products using continuous manufacturing. Following the CDER’s 2020 annual quality report three additional applications using continuous manufacturing processes have emerged. For the first time, continuous manufacturing for an API and the first continuous biomanufacturing process was approved in 2020. Eli Lilly’s breast cancer product, an ovular, off-white, tablet is manufactured by feeding powdered raw materials into a continuous system where the materials are continuously fed, blended and compressed into tablets.[iv]

Also, clinical supplies of Pfizer’s acute myeloid leukemia drug Daurismo, were pivoted to development on Pfizer’s Portable, Continuous, Miniature and Modular (PCMM) oral solid-dose technology. PCMM embeds the continuous process in a portable, autonomous area, Pfizer calls POD. Up to 70% smaller than a traditional manufacturing line, Pfizer’s modular system is compact enough to fit on the back of a truck and can be set up in about a year. Normally for a stationary plant this takes two to three years. Three other clinical candidates are being manufactured on the PCMM platform in Groton, Connecticut, and Freiburg, Germany. Pfizer estimates that 70% of its small molecule, solid oral dose portfolio will be manufactured on PCMM projected to yield shorter cycle times, faster technology transfers and reduced process variability.[v]

One major advantage of continuous pharmaceutical manufacturing over traditional batch manufacturing is the possibility of enhanced in-process control, reducing out-of-specification and waste material by appropriate discharge strategies. The decision on material discharge can be based on the measurement via process analytic technology (PAT) and represents a significant step to true continuous manufacturing. [vi]
Process analytical technology has been defined by the European Medicines Agency as a system of controlling manufacturing through timely measurements of critical quality attributes (CQAs) of raw and in-process materials. Critical Process Parameters (CPP) affect Critical Quality Attributes (CQA).[vii]

This highlights the importance of the development of adequate sensor systems and their incorporation into the continuous manufacturing streams.[viii]

Critical Process Parameters and Critical Quality Attributes (CQA) in a pharmaceutical environment are part of the risk management principles.[ix] The importance of quality risk management as a valuable component of an effective quality system is evident.

It is commonly understood that risk is defined as the combination of the probability of occurrence of harm and the severity of that harm. However, achieving a shared understanding of the application of risk management among diverse stakeholders is difficult as each stakeholder might perceive different potential harms, place a different probability on each harm occurring and attribute different severities to each harm.

In relation to pharmaceuticals, the protection of the patient by managing the risk to quality is of utmost importance.[x]

In the manufacturing of a medicinal product, it is important to understand that product quality should be maintained throughout the product lifecycle such that the attributes that are important to the quality of the medicinal product remain consistent with those in development e.g., in the clinical studies.

In essence, the desire to establish continuous manufacturing applying cognitive solutions is therefore linked to the development of suitable sensors securing the control of CPPs and CQAs which in turn is linked to a quality risk management system.

Because of in-line process analytical technology tied to the control system, the ultimate goal of real time release (RTR) may become reality if the before mentioned aspects are in place.