Continuous Manufacturing - Redefining Drug Production

Introduction

Continuous Manufacturing (CM) has been embedded in many Industries such as automotive, petrochemical, water treatment plants, as well as food and beverage for many years now. By comparison, CM is still regarded as an emerging technology in the pharmaceutical space, with the trend beginning to gain momentum in more recent years. Increased interest is likely due to factors such as the Covid-19 pandemic which highlighted global supply chain issues and the need for more manufacturing resilience and production onshoring [1]. And more recently, by global economic downturn which has resulted in rising energy and raw materials costs, driving the need for more cost-effective ways to manufacture medicines that are high quality, safe and effective. As the climate crisis becomes more evident day to day, the need for greater sustainability and waste reduction will no doubt also contribute as a key driving force.

In 2015, pharmaceutical company Vertex was the first to receive approval by the FDA for its’ cystic fibrosis combination drug ORKAMBI produced on a CM production line. Since then, 20 applications have been approved by the FDA which employ CM / advanced manufacturing methods [2].

So what is Continuous Manufacturing (CM) and what’s all the hype about?

CM can apply to some or all unit operations in a manufacturing process. The technique involves the continual feed of materials into a process, while in-process materials are transformed and finished product removed simultaneously without any pauses.

Traditionally for the past 50+ years, batch manufacturing has been commonly used in pharma involving numerous separate processing steps where production is stopped in between, and products tested to ensure they meet stringent quality assurance criteria. This can result in lengthy hold times, where products must be stored, and may even need to be shipped between a number of manufacturing sites within a region or throughout the globe, to complete the next stage in the production cycle [3].

CM line uses continuous in-line process verification to ensure a higher level of quality assurance, maintaining product flow and removing delays

By comparison, a CM line uses continuous in-line process verification to ensure a higher level of quality assurance, maintaining product flow and removing delays. In-line process analytical technologies (PAT) and sensors continually monitor material critical quality attributes (CQAs) and critical process parameters (CPPs). This data is used for active control of the process, to ensure it remains within predefined control limits. Where deviations do occur, non-conforming material is detected and immediately diverted from the process stream without risking the entire process. This, combined with better traceability and automation methods can translate to significant reductions in waste and savings in resources for a company, especially where expensive active pharmaceutical ingredients (API) are involved.

CM operates on a reduced footprint where smaller-scale equipment is run for longer e.g., 24 / 7 to expand production, avoiding the need to scale to larger equipment. This can lower capital / manufacturing costs, while avoiding a host of scale-up and tech-transfer challenges, which can also help speed-up time to market. CM offers agility to respond to shifting market needs, where for example modular CM equipment can be quickly switched in and out as needed.

R&D activities and clinical development also benefit from CM. Design of experiments (DOE), the precursor to any process development stage is iterative by nature and can have a reputation to be labour intensive when executed manually, particularly where more complex factors are involved. The ability to run automated DOEs associated with CM can really streamline this investigative process, saving valuable resources such as time and expensive materials, while accelerating process understanding and development timelines. CM also offers flexibility in support of clinical studies as investigational medicines may be produced on demand.

Problems & Barriers

As drug shortages become increasingly common, this presents a big problem for governments, manufacturers, doctors, and patients alike. Manufacturing delays, unexpected increase in demand, quality issues and API unavailability are some of the reasons cited for short or no supply, which supports the need for more resilience [4]. CM has the potential to address some of these key issues and is considered by the World Economic Forum (WEF) and regulators alike as having real potential to revolutionize drug manufacturing and accelerate drug product development, getting medicines to the patient faster.

Although companies may recognize the need to innovate, barriers can and do exist. It can be difficult, especially for smaller manufacturers to justify the significant costs associated with implementation of CM lines and the new / advanced technologies which go hand in hand in the execution, particularly where companies have already made big investments in state-of-the-art batch facilities and may not yet have seen the returns. In situations where therapeutic products have already won regulatory approval with finely tuned manufacturing processes, the prospect of transitioning from batch to continuous may be a daunting prospect in terms of regulatory risk, uncertainty, and not to mention the potential for delays.

Regulators must familiarize themselves with emerging technologies, as they must be assessed within the current regulatory frameworks, which have been designed with the batch process in mind. The Emerging Tech Programme (ETP) was established in 2014 by The Centre for Drug Evaluation and Research (CDER) which operates as part of the FDA in regulating medicines. The ETP brings together industry representatives and ETP members to address technical and regulatory challenges around novel technologies before a submission. This is one example of some of the ongoing and encouraging work being done to help resolve uncertainty, and to bridge the gap between technology advancements and the slow adoption by industry [5].

Recent and significant progress has also been made in addressing regulatory concerns around implementation of CM by harmonizing approaches among different regulatory bodies such as the FDA and EMA. The International Council for Harmonization recently released the final version of ICH Q13 guidance on continuous manufacturing, which aims to assist drug manufacturers in their journey towards CM by laying out the scientific and regulatory expectations. Building in Quality by design (QbD), robust control strategies, advanced process control and being able to demonstrate a state of control, are some of the key takeaways [6].

Other barriers may include lacking the specific skillsets and expertise needed to implement CM and associated advanced technologies. CM is built on automation, connected devices, real-time / advanced process control so having skilled automation engineers that also acutely understand the process and material dynamics is essential. CM also embodies digital transformation, abolishing the paper trail in favour of data driven digital systems.

For manufacturing plants which rely on older legacy equipment, unconnected systems and siloed data, can impede the ability to innovate, automate and efficiently track materials and process information throughout the value chain.

Where companies don’t have budget for large scale investment for CM, one option is to work with what they have i.e. to retrofit or upgrade older legacy / existing batch equipment transforming it into an interconnected smart manufacturing system, capable of advanced control and automation, supplying data in a seamless way and making it accessible to those who need it most.

Small Steps for Big Gains

An example of one such technology from InnoGlobal Technology (formally known as Innopharma Technology), that can help bridge this gap is the SmartX process automation and digitization platform which can be readily integrated on any standalone / legacy equipment, enabling real-time data capture from any 3rd party connected sensors, PAT as well as from the process equipment itself. Data is aggregated, time aligned and stored, where it can be used by the system in real-time to implement advanced process control. Automation is implemented through a low-code / no-code control interface that allows the process scientist / engineer to implement process automation without the need for complex programming skills.

The SmartX system was used to integrate a Pharma 11 twin screw granulator and all its’ associated ancillary equipment i.e. loss-in-weight feeder, peristaltic pump, chiller and PAT (Particle Size Analyzer) into a unified and connected smart manufacturing system perfectly amenable to CM. Prior to this transformation, each piece of equipment was operated and controlled both manually and discretely, whereas now once configured within the SmartX system, the equipment is controllable via a single point of interaction through the systems’ dashboard / HMI (human machine interface).

To demonstrate utility, the system was used to execute an automated DOE for twin screw wet granulation, which included a total of 14 experimental runs and more involved factors (barrel fill level % and liquid to solid ratio %). If executed manually, complex on the fly calculations would have been required before each factor setting change, due to an interdependent relationship thereby increasing the risks of calculation and handling errors. As all calculations were predefined in the DOE automation / control logic, the DOE was executed by the touch of a button, leaving space for the process scientist to focus on monitoring the process and real-time data. This approach significantly reduced the risk of errors and wasted resources, while accelerating process understanding by facilitating easy access to key process and material data. This is one example of how a relatively small change can result in big gains.

Final Thoughts

CM perfectly mirrors the overall objectives of smart manufacturing, an approach which incorporates technologies such as process automation, Industrial Internet of Things (IIoT), big data / analytics for improved process robustness, efficiency, improved product quality as well as data control and insights. Implementation of innovative approaches such as CM modernize existing drug manufacturing methods, delivering more robust processes and therapeutic products, while simultaneously reducing the occurrence of process interruptions and failures. This in turn drives down product recalls and helps to tackle the ever-growing global problem of drug shortages. CM can help build a more resilient future.

References

1.????? Zamecnik, A. (2022) Continuous Manufacturing Builds on Hype but Adoption Remains Gradual. Available at: https://www.pharmaceutical-technology.com/features/continuous-manufacturing-builds-on-hype-but-adoption-remains-gradual/?cf-view (Accessed 25 October 2023)

2.????? Eglovitch, J.S. (2023). Industry Expert Details Advantages of Continuous Manufacturing. Available at: https://www.raps.org/News-and-Articles/News-Articles/2023/7/Industry-expert-details-advantages-of-continuous-m (Accessed 25 October 2023)

3.????? Lee, S (L). (2017) Modernizing the Way Drugs Are Made: A Transition to Continuous Manufacturing. Available at: https://www.fda.gov/drugs/news-events-human-drugs/modernizing-way-drugs-are-made-transition-continuous-manufacturing (Accessed 26 October 2023)

4.????? Health Products Regulatory Authority. (2023) About Medicine Shortages. Available at: https://www.hpra.ie/homepage/medicines/medicines-information/medicines-shortages/about-medicines-shortages (Accessed 26 October 2023)

5.????? U.S. Food & Drug Administration. (2023) Emerging Technology Program. Available at: https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/emerging-technology-program (Accessed 26 October 2023)

6.????? The International Conference for Harmonization (ICH) (2023) Q13 Continuous Manufacturing of Drug Substances and Drug Products Guidance for Industry. Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/q13-continuous-manufacturing-drug-substances-and-drug-products (Accessed 26 October 2023)

About the Author:

Caroline McCormack is a Process Scientist at InnoGlobal Technology with 7+ years’ experience, with sometime in medical device manufacturing. Her academic background includes Biochemistry, Pharmaceutical and Medical Device Manufacturing, and Industrial Biopharmaceutical Analysis. Caroline is responsible for experimentation around our process analytical technologies and advanced process control techniques currently under development, across the oral solid dose manufacturing space.

Contact us today to learn how InnoGlobal Technology can transform your manufacturing operations. [email protected]