Addressing barriers in implementing pharmaceutical continuous manufacturing – Key concepts & challenges in pharmaceutical continuous manufacturing

As its name suggests, pharmaceutical continuous manufacturing (PCM) aims to connect discrete steps into a single operational unit so that, in theory, there is no disruption between the start and end of drug production. (1) This goal exists in contrast to the traditional approach to drug manufacturing, or batch manufacturing, which requires discrete steps where samples of an intermediate product are taken to multiple laboratories for different aspects of quality control before sending the entire batch to the next step in manufacturing, which may also be in a different location. All these additional steps increase demands on working capital, strain the supply chain, and require more time and personnel. The batch manufacturing of pharmaceutical drugs can have between 10-20 steps, resulting in an overall production time of at least 12-24 months. Any interruptions in the supply chain, such as those caused by pandemics or geopolitical events, can delay the process. These delays can manifest as a shortage of essential medicines during increased demand. (2) Batch manufacturing can pose critical constraints for the overall product cycle because there are large amounts of intermediate chemical waste between drug manufacturing processes that are toxic to the environment and the manufacturing process itself (2).

While traditional batch manufacturing has been and will likely remain the mainstay pillar for pharmaceutical manufacturing, PCM has been touted to have several advantages over batch approaches. Potential PCM benefits include shortened production times and increased throughput, especially in the active pharmaceutical ingredient (API) manufacturing phase. If fully realized, implementing the concept of fully integrated PCM can ensure that a pill is synthesized, purified, isolated, formulated, and packaged in the same geographical location in a continuous manner without having to go through and wait for multiple intermediary batches to complete to get the final product. These benefits may allow better control over the supply chain and logistic efforts while also allowing improved quality control through real-time monitoring of manufacturing processes and reduced environmental footprints (1). Decreased development cycles, access to new chemistries not practical in batch, improved safety, flexible manufacturing platforms, and improved product quality assurance. The transformation from batch to continuous manufacturing processing is the focus of this review. The review is limited to small, chemically synthesized organic molecules and encompasses the manufacture of both active pharmaceutical ingredients (APIs) (3, 4)  Potentially, drugs can be manufactured in weeks to even days to meet market needs with minimum waste, while significantly reducing production costs (5). This could be especially beneficial for drugs needed on small scales for targeted supplies or selective patient populations. While there is evidence that PCM can provide certain benefits over traditional batch manufacturing, there is also agreement that PCM is not right for every product or organization (6, 7).

The need to sustainably modernize and diversify pharmaceutical manufacturing, by leveraging the cost, quality, and environmental benefits of PCM and other advanced manufacturing technologies (8), has never been greater, and has been recognized and supported by U.S. National Academies’ study reports, (9-12)  government legislation and executive orders, (13-15),  and U.S. FDA initiatives such as the Emerging Technology Program (ETP). (3, 16-17) Over the past decade, there has been a significant increase in the number of academic publications, advanced manufacturing- and PCM-specific conferences, and formation of multidisciplined industry-academia consortia that have laid the scientific foundation of advanced manufacturing technologies, including PCM. (1, 18) Some of the most prominent industry-academia consortia include the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS, U.S.), the Alliance for Building Better Medicines (U.S.), the Continuous Manufacturing and Advanced Crystallization Hub (CMAC, U.K.), and the Research Center for Pharmaceutical Engineering (RCPE, Austria). Many global players have already invested significantly in PCM over the past decade. Some examples include large pharma organizations such as Lilly, Vertex, Pfizer, Novartis, Johnson & Johnson, Amgen, and GSK, as well as contract research and manufacturing service (CRAMS) providers like AMPAC, Cambrex, WuXi, and Asymchem. (1, 19)

The advances in PCM have resulted in U.S. FDA approval of 13 oral solid drug products (DP) manufactured through continuous tableting. (8, 20-22). In contrast, far fewer APIs (small molecules and biologics) manufactured through continuous processing have received regulatory approvals; however, this is despite PCM being accepted as a production modality across global regulatory authorities in the U.S., EU, Canada, Australia, and New Zealand. (1, 20) It is important to consider that the pathway to regulatory approval for any drug is long, even without implementing newer manufacturing methods. (23) Hence, innovative manufacturing processes like PCM need adequate time to prove themselves under regulatory scrutiny and build trust with potential adoptees. To help speed this process along, it is first necessary to identify and reduce the barriers to facilitate adoption.

Financial Investment & Transformation: Although PCM has many potential benefits, it still represents a drastic change in the manufacturing model. The first challenge comes in terms of the initial justification any organization needs to provide for a transition from an existing batch manufacturing plant with installed (possibly fully depreciated) base technology and established business and regulatory processes (in multiple countries) to an entirely new paradigm. C-level executives need an understanding of the processes and related risks to support this transformation financially. The supply chain for current batch manufacturing might be diversely scattered across geographies, and a complete paradigm shift would be a daunting task for the company, including hiring manpower, sorting out logistics, diagnostics, and technology integration to make provision for seamless PCM. The business case for significant investments is challenging in the current landscape, where medicine production is moving to a smaller volume paradigm. Hence, a milieu of investment and transformational challenges make a paradigm shift from batch to continuous manufacturing increasingly difficult (24, 25). Additional costs are accrued during regulatory submissions as they are different from usual batch-related submissions.

Technology Implementation on Scale: To implement PCM commercially, thorough process control for every step is critical. Process analytical technologies (PAT) are tools to conduct a real-time analysis of the process to ensure final product quality. PAT consists of two components: a set of scientific principles and tools to analyze the critical process parameters (CPPs) and critical quality attributes (CQA), and a strategy for regulatory implementation that will accommodate innovation. (26, 27) In order to effectively implement PAT tools to analyze variations in real time at any stage, without the usual intermediate batch isolates, comprehensive knowledge of various factors is required. This includes the need to understand required equipment, design spaces, material attributes such as homogeneity, segregation, and traceability, as well as thermodynamic and hydrodynamic properties, along with the chemical properties of raw materials, intermediates, and finished products. Once the necessary data at the starting point is acquired, there is a need to ensure optimal performance throughout the process through understanding and implementation of feedback and feed-forward steering controls, continuous data acquisition, multivariate analysis, monitoring tools, process-flow characterization and residence time distribution (RTD) measurement tools, start-up and shut-down timing, interruption procedures, impurity controls, and flow chemistry analysis. The sheer volume of data that needs to be analyzed within a given regulatory framework can make the entire process error-prone if the correct tools and techniques are not implemented (28).

Quality Control & Regulatory: Quality regulation is very important in ensuring that drugs are safe and effective, and both quality by design (QbD) and PAT play a key role. QbD is defined as a systematic, risk-based, proactive approach to pharmaceutical development that begins with identifying predefined objectives, emphasizing product and process understanding and control based on sound science and quality risk management, as per the  International Conference on Harmonization (ICH) Q8 guideline (29). It takes into account parameters like the quality attributes of the target product profile (QTPP), CPPs, CQAs, and critical material attributes (CMA), and then uses these to design experiments based on inter-relationships between these parameters. This allows an understanding of the sources of variations in these attributes for both the materials and the equipment as well as continuous monitoring of the process. The most common challenges in this regard include the ever-changing landscape of products, lack of specialized trained personnel, misaligned values within organizations (especially between R&D and manufacturing teams), lack of proper equipment for bench and pilot-scale experiments, lack of experience in selection and development of flow-chemistry transformations or performing risk-assessments. Adding to these is a lack of harmonized guidelines for regulatory submissions (30). The existing regulatory norms are better established for batch manufacturing processes, but not for PCM, as they are still evolving. Examples of such guidelines include ICH Q8, Q9, Q10, Q11. Guidelines to keep in mind while designing PCM are FDA PCM (ICH Q13) and process validation guidelines, and ASTM E2968 and E2537 (31). Shifting from an already existing regulatory submission framework for existing batch manufacturing processes to new submissions for continuous processes remains a challenging task.

Though all challenges cannot be solved by implementing PCM alone, ensuring the right practices and regulations will optimize the process and minimize these challenges. A few useful interventions in this regard would be an increased acceptance rate among industry leaders, more R&D facilities supporting PCM, education and training regarding all critical PCM technical and regulatory parameters, capacity building exercises with established industry-academia consortia, more insights on risk-mitigation and step-wise but steady implementation strategies. One can start with a batch model and then transition towards a hybrid or continuous model, much like Pfizer’s oncology drug Daurismo (glasdegib), which was initially approved with a batch production process and then transitioned to PCM later (30). Going forward, artificial intelligence, big data analytics, and cloud computing could enable improved data analysis, better process understanding, and enhanced quality control. This would in turn propel more sectors to undertake PCM-specific actions and develop a more resilient supply chain.

Organizations need trusted partners in undertaking the PCM implementation challenge. The U.S. Pharmacopeia (USP) is one organization that has been working towards lowering the barriers to build trust and support implementation for those companies interested in pursuing PCM. Partnering with multiple stakeholders in the public and private sector and appropriately addressing quality and regulatory needs can help build trust and speed up adoption (5, 32). The power of a community-mediated effort should not be underestimated – sharing past experiences, current advances, and financial issues from the pioneers of PCM implementation, and forming discussion boards and communities, would be of immense assistance in facilitating exploration of where PCM may be most impactful and how best to implement the technology. One way USP is working towards this goal is through creation of a Continuous Manufacturing Knowledge Center digital platform (33, 34). Creating more opportunities by conducting end-to-end translational workforce training, and through development and educational courses from certified institutes, also can help alleviate the workforce issues. Additionally, fostering PCM R&D in cutting-edge laboratories, providing services, and incubating more start-ups could help enable more PCM-related drug production (35, 36).

Mr. Dennis Hall and Dr. Mark Verdecia for reviewing the manuscript and Sreetama Dutt for assistance with preparing the manuscript.