QbD for Small-Molecule Continuous Process Development

FDA, as well as other regulatory agencies around the world, have for many years been encouraging drug makers to switch from batch to continuous processing due to the many benefits this manufacturing technology offers. FDA has approved several small-molecule drugs, including novel products that were initially developed leveraging continuous processing and existing products for which some part of their production was switched from batch to continuous operation. The COVID-19 pandemic highlighted the need for such manufacturing solutions that can afford higher quality products more reliably and efficiently. Continuous manufacturing is attractive because it provides both cost and quality benefits, and is in fact in alignment with FDA’s initiatives focused on designing quality into processes from the outset, rather than relying predominantly on confirmational testing at the end of a production run.

Many advantages of continuous manufacturing

Continuous processing offers many advantages over batch production, including improved quality, lower costs, greater sustainability, more flexibility, and the ability to produce novel chemicals not accessible in batch mode (1–3). Higher drug-substance and/or drug-product quality results because continuous processes operate at an optimal steady state with minimal byproduct formation or processing failures, respectively. That results in fewer lost “batches,” greater confidence in product performance, improved manufacturing efficiency, and assurance of supply for patients.

For drug substances, flow chemistry performed in microreactors enables the implementation of highly exothermic reactions and the use of hazardous materials that might not be possible in batch mode. Higher purities and yields mean reduced purification needs for greater efficiency and lower cost.

For both drug substances and drug products, shorter processes with fewer steps are often possible, leading to shorter processing times. Smaller footprints and elimination of the need for intermediate hold and storage tanks also contribute to reduced costs. Continuous processing also affords the flexibility to increase or decrease production to meet changing market demands, increasing supply-chain security. Scale-up (or scale-down) can be achieved by running the process for a longer (shorter) time on the same equipment, eliminating any need
for additional process optimization in larger bioreactors.

Continuous manufacturing also supports a quality-by-design (QbD) approach to process development and leverages process analytical technology (PAT) for real-time quality monitoring.

As of late 2021, FDA had approved 10 continuous manufacturing applications, most for small-molecule drug products. The first approval was made in 2015. In 2020, however, the agency approved the first application for continuous production of an API and the first continuous process for a biologic (2).

Process development understanding and control at the heart of QbD and continuous manufacturing

Successful development and implementation of a continuous manufacturing process requires deep understanding of the process, most notably how changing process conditions impact product quality. Establishing the optimal steady state at which a continuous process should be run cannot be achieved without in-depth process knowledge. Real-time monitoring is then essential to ensure the optimal process conditions are maintained.

The QbD approach similarly requires deep process and product understanding (4,5). This knowledge is used to first establish a quality target product profile (QTPP) that will ensure safety and efficacy for the final drug product. Critical quality attributes (CQAs), or specific characteristics of the drug product and drug substance that impact product quality, are then identified during process development. Design-of-experiment (DoE) studies and process modeling can then be leveraged to determine which specific critical process parameters (CPPs) impact the CQAs. A control strategy is then established to ensure
those CPPs remain within acceptable limits, leading to the development of a highly robust process.

The reliance on process understanding links the QbD approach closely with continuous manufacturing (6). One is a quality strategy, the other a manufacturing method. When pursued simultaneously, continuous manufacturing, in fact, can lead to greater process understanding and ultimately process control, and thus more robust processes. It has been suggested that continuous manufacturing “can be seen as a practical application of the QbD principles, providing a mechanism to achieve the QbD goal of consistently producing high-quality products” (6).

Control strategies for continuous drug substance and drug product manufacturing

One of the challenges with continuous processing approaches in which multiple operations are linked together, such as flow chemistry for API synthesis with purification via filtration and crystallization and then continuous tableting, is the fact that any changes in process conditions in upstream unit operations may impact the performance of linked downstream unit operations.

That is one reason a QbD approach to process development can be highly beneficial. It enables the development of robust processes with well-defined design spaces that account for potential feed characteristics from upstream and potential impacts downstream combined with carefully established control strategies that ensure appropriate CPPs are maintained (4). The greatest benefits of such a process development strategy can be gained by using feedforward and feedback controls based on real-time data collected using PAT tools. Furthermore, because the same equipment can be used from early development to commercial production, typically once a control strategy based on CPPs is implemented and shown to be effective, it can be leveraged across all development stages.

During process development, the specific control strategy to be implemented should be determined by conducting a risk assessment (4). Strategies can be based on manual collection of process data all the way through automatic adjustment of feeds based on real-time data gathered using PAT tools. It is also possible for continuous processes to include the ability to divert material for a given time in the event it is found using real-time analysis to be nonconforming.

Verification of control is realized by testing the developed process with varied feeds and confirming process behavior (4). Proper performance of in-process analytics and control methods must also be demonstrated. Control ranges should be justified. Once a process has reached commercial stage, it is then necessary to perform periodic assessments to confirm continued effectiveness of the control strategy despite any variations in process equipment, raw materials, or environmental factors (7).

Regulatory support for emerging technologies

FDA has been a leader in championing the modernization of pharmaceutical manufacturing to enhance efficiency, quality, and safety. Its efforts began back in 2002 with launch of its Pharmaceutical cGMPs for the 21st Century: A Risk Based Approach initiative (8). The European Medicines Agency (EMA) and Japan Agency for Medical Research and
Development (AMED) have joined in more recently, also encouraging the use of emerging technologies.

To further encourage adoption of new manufacturing technologies, FDA in 2004 published PAT–A framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance, guidance encouraging the use of a QbD approach and PAT (9). In its 2011 Strategic Plan for Regulatory Science, FDA called for research to identify better technologies that enable continuous manufacturing (10).

In 2017, the agency reiterated its support for continuous processing in Advancement of Emerging Technology Applications to Modernize Pharmaceutical Manufacturing Base, guidance issued by FDA’s Emerging Technology Team (ETT) (11). FDA then addressed quality issues for continuous manufacturing in the 2019 draft guidance, Quality Considerations for Continuous Manufacturing (12).

Overall, FDA consistently stresses the alignment of QbD with continuous manufacturing and emphasizes the fact that continuous processes can be developed and implemented with the existing regulatory framework (7) and using a data-driven approach (12). In addition, success can be best assured by leveraging well-established data models constructed using multivariate data analysis and real-time process monitoring technologies during process development and when implementing continuous processes to aid with process control, reduce variability, and improve product quality and consistency (13).

The concept of quality by control (QbC) has been proposed in recent years as a means for taking QbD even further (3). In this approach, active feedback control is used for process design and development, which can for certain processes accelerate identification of optimal CPPs using much less expensive materials.

2023 Final ICH Q13 guidance on small- and large-molecule continuous processing

The most recent regulatory guidance for continuous drug manufacturing was finalized in March 2023. International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Q13 Continuous Manufacturing of Drug Substances and Drug Products (14) “describes scientific and regulatory considerations for the development, implementation, operation, and lifecycle management of continuous manufacturing” for both small- and large-molecule drugs and builds on existing ICH quality guidances (15).

The document was developed through collaboration of FDA, EMA, and other international regulatory bodies with pharmaceutical companies and industry trade groups. In the section of pharmaceutical development, the ICH Q13 guidance specifically refers to the need for application of QbD principles and the importance of establishing deep process understanding and effective process control strategies and the appropriate use of mathematical modeling (6). The importance of effective control strategies is reiterated in sections on manufacturing and control strategy implementation, which also emphasize the need to use a science- and risk-based approach for the development and implementation of continuous processes.

The ICH Q13 guidance can, according to some, be viewed as a “comprehensive framework for the implementation of continuous manufacturing processes” that not only provides regulatory clarity on the subject, but also emphasizes the adoption of a lifecycle approach to process validation; integrates QbD and risk-management approaches for improved quality and consistency; highlights the potential for increased sustainability; encourages innovation and modernization; and creates opportunities for increased manufacturing flexibility and efficiency (6).

Integrated continuous manufacturing

To date, approved products that are manufactured using continuous processes leverage hybrid approaches in which one or two unit operations have been implemented in a continuous fashion. The ultimate goal will be to achieve fully integrated continuous manufacturing solutions in which, for small molecules, raw materials undergo conversion via flow chemistry into APIs that are then directly purified (e.g., continuous crystallization) in a continuous fashion, with the purified material then directly fed into a continuous drug-product production process, possibly involving blending with excipients, traditional extrusion, tableting, and coating, as well as hot-melt extrusion, spray-drying, and electrospinning for the formation of amorphous solid dispersions (3).

Such an end-to-end (E2E) or fully integrated continuous manufacturing process would provide even more benefits that have been observed with the continuous processes approved to date (3,7). The Novartis-MIT Center for Continuous Manufacturing (CCM) demonstrated the first end-to-end continuous process for production of aliskiren hemifumarate starting from advanced synthetic intermediates through tableting in 2012 (16). Compared to the traditional process, this solution took approximately one-sixth the time. A much smaller version of the reconfigurable flow chemistry unit was then developed and used to produce diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride, which were purified in batch mode to generate liquid dosage forms (17,18).

The success of this academic-commercial relationship recently spurred follow-on activity by this involving exploration of continuous manufacturing for mRNA products (19), which is heavily encourged by Peter Marks at FDA.

Based on this initial work, the company Continuus Pharmaceuticals was spun out of the CCM in 2012 to commercialize ICM solutions. The company has collaborated with Italian pharmaceutical equipment maker IMA to develop practical solutions. The first true end-to-end integrated continuous manufacturing system for production of small-molecule oral solid dosage forms was introduced by the company in 2019 (20). Today it offers a pilot-scale E2E system (21) for late-stage process development and early clinical manufacturing. In 2021, Continuus Pharmaceuticals won a $69-million grant from the US government to produce in the United States using a good manufacturing practice-certified, E2E continuous manufacturing facility three small-molecule drugs considered to be essential medicines (22).

References

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About the author

Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology®.

Article details

Pharmaceutical Technology
Vol. 48, No. 2
February 2024
Pages: 14-17

Citation

When referring to this article, please cite it as Challener, C.A. QbD for Small-Molecule Continuous Process Development. Pharmaceutical Technology 2024 48 (2).