Continuous Tableting and the Road to Global Adoption
1. Introduction
Continuous Tableting (CT) is defined as continuous manufacturing of oral dose drugs, specifically tablets. As per ICH's Q13 definition1, a continuous manufacturing process in the pharmaceutical industry comprises at least two unit operations integrated from a mechanical and software perspective. There is a wide combination of possible CT process configurations that are dependent on the needs of the intended product formulation and each of the individual unit operations that constitute the process train can be continuous, semi-continuous, or batch processes. The typical manufacturing processes for tablet formulation are direct compression (DC), dry granulation (DG) and wet granulation (WG)2 - details on these manufacturing processes are beyond the scope of this article, so the interested reader is directed to relevant literature. The actual implementation of CT technology in a facility can broadly vary depending on the level of desired integration and automation. Process trains can be designed to be flexible and converted between multiple configurations (e.g. continuous DC, DG and WG), controlled by the end user from one single software and within a single clean room. The other possibility would be for subsections of the CT process to be divided into multiple clean rooms where inprocess materials are transferred between suites via a bin-to-bin approach (e.g. a granulation suite to prepare granules from raw materials followed by continuous DC (CDC) to blend the granules and produce tablets). The level of automation and instrumentation designed into the CT process (typically involving Process Analytical Technologies, PAT) can open the possibility to implement sophisticated control strategies. Key components of a control strategy that need to be considered for CT are material tracking and genealogy, knowledge of the residence time distribution (RTD), and in-process controls (spectroscopic and/or soft sensors based on process parameters). Holistically, these control strategy elements enable the implementation of a material diversion strategy to automatically divert out of specification material from the process. In their most advanced form, control strategies may also enable real time release testing (RTRt) of the final tablet drug product and reduce the off-line analytical burden and the number of operators needed to manage the process.
The evolution of the technology has led to a growing interest from the industry and an explosion of CT line varieties, specifically more modular lines with various levels of integration using different software standards. Throughout this evolution, health authorities, industry, and academics have had a continuous discussion on how best to converge towards meaningful standards and assure appropriate equipment harmonization. Some key initiatives that have been central to this are:
- ASTM E2968 - The Standard guide for application of Continuous Processing in the Pharmaceutical Industry3
- ISPE (International Society for Pharmaceutical Engineering) Good Practice Guide for Continuous Manufacturing of Oral Solid Dosage Forms4).
- ICH (International Council for Harmonization) Q13 in 20231
In addition to several other standards and countless peer reviewed articles and textbooks on the topic of CT, each of these guides have been a sequential steppingstone in the establishment of CT as a dependable manufacturing technology for the pharmaceutical industry. The Food and Drug Authority (FDA) in the USA especially has been highly active in supporting and influencing the adoption of CT by the industry through their own laws (e.g. FDORA5) and peer reviewed publications6, 7, 8. The most recent article demonstrated that CT can enable a remarkable reduction in time to regulatory approval and market entry8.
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2. Highlights of the industry
Continuous manufacturing is not necessarily new for the pharmaceutical industry, as many of the unit operations for pharmaceutical processing such as spray dryers, roller compactors, and tablet presses are intrinsically continuous, i.e. acceptable product is removed simultaneously as the raw materials are fed4. However, continuous tableting is novel in the sense that the continuous unit operations are integrated from a mechanical and a software perspective, where raw material and product are entering and leaving each of the integrated unit operations all at once. Relative to the batch-based framework of pharmaceutical manufacturing that has been the status quo for decades, continuous tableting requires a more modern orchestration of quality assurance that does not rely on manual management of operations, spurs innovation through new applications of automation and leverages a deeper process understanding of the process dynamics, i.e. the propagation and impact of upstream variability on the downstream product. Therefore, to fully convert a pharmaceutical company's strategy from batch to continuous manufacturing there will initially be differing levels of disruption to the existing day-to-day routines as the company culture learns to embrace the new way of working - as with the implementation of any novel technology. This unknown impact on the day-to-day routines has, naturally, resulted in a high perception of risk to the drug approval process and a conservative posture for innovative change. Prior to the early 2000's, indeed this environment in the pharmaceutical industry was a barrier to even considering the switch from batch to continuous. In 2004, the FDA issued the Report on their Pharmaceutical GMPs for the 21st century9, which acknowledged that new tools are needed such as science and risk-based assessments, process analytical technology, and a systematic approach to quality management. It was the eventual implementation of these tools in the late 2000's through FDA and ICH guidance's for harmonization that opened the doors for the consideration that implementing continuous manufacturing could provide the boost the industry was seeking for the 21st century.
The first adopters of CT were pharmaceutical firms such as Eli Lilly, Janssen, Pfizer and Vertex Pharmaceuticals10. They partnered with academia and equipment suppliers to develop their own pilot plants and explore the technical and quality system boundaries11, 12, 13 for implementing continuous manufacturing in a GMP environment. Gradually, an ecosystem built around continuous tableting started to take shape in the form of precompetitive consortia such as the Center for Structured Organic Particulate Systems (C-SOPS) and Innovation and Quality (IQ), to name a few. Beside technical development of CT, a main objective of these consortia was to influence standard setting organizations (e.g. ISPE, ASTM, USP) to adapt current standards to include guidance on CT and author new guidance where there were unique gaps for implementing CT. As the first CT lines began to come online and generate data for the consortia, so too did the FDA's Emerging Technology Program (ETP) which had the objective to reduce the regulatory uncertainty for the adoption of new technologies within a highly regulated industry.
Continuous manufacturing has been the leading requested technology for review by the ETP as of 202314. Through the experience of the ETP reviewing CT based products, continuous direct compression (CDC) has graduated as a mature technology. Graduation of a technology within the ETP framework means that the FDA feels it has gained enough experience to feel confident that industry will submit successful future applications14. In the case of CDC, only certain types of experience "bands" are considered to be graduated, namely: any BCS class I-IV, immediate release products, greater than 5% drug loading, and RTD process models that are used for diversion only (i.e., RTD for blend uniformity prediction may be considered novel and still meet the criteria for ETP discussion).
The value proposition for making the paradigm shift from batch to CT operation has been somewhat unique for each company. Speed to market, manufacturing flexibility, and improved quality and robustness were all recognized as key rewards for making the switch, but each driver requires a slightly different equipment design, integration, and control strategy. For example, to enable speed to market, early process development will benefit from highly flexible machines to evaluate multiple process configurations, whereas flexibility in late-stage manufacture of a product can result in complex maintenance and operations. By virtue of the integrated nature of CT processes and the many in-process data streams that arise from monitoring, process quality assurance and process robustness are considered to be superior to batch manufacturing. This leads to the additional considerations around what the appropriate control strategy might be for a CT process. Since in CT processes, product quality typically relies on real time quality assurance due to the fast process dynamics, new tools, such as real time process models, or in-line Raman spectroscopy for monitoring the process have been gradually introduced. To date, there has not been a blueprint in place for when and how much monitoring is needed and therefore an opportunity still exists to harmonize on the appropriate level and type of in-process monitoring to ensure a robust CT process.
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Given the novelty of CT and the need for monitoring of transient events that may impact quality, there has been an expectation from regulatory agencies for manufacturers to have the means for robust in-process monitoring at the time of filing a new CT process as described in the ICH Q13 guideline1. The industry had recognized that the application of process analytical technology (PAT) seemed to be a functional tool to monitor for blend uniformity, assay, and many of the other potential critical quality attributes, usually in the form of near infrared (NIR) spectroscopy. NIR was highlighted in the GMPs for the 21st century initiative and is9 therefore an acceptable approach by the more forward-thinking regulatory agencies on the adoption of CT, such as the FDA, EMEA, PMDA and others. It is true that spectroscopic PAT was arguably considered the "hammer for all nails" when monitoring for in-process quality. However, being an empirically derived model, its robustness is derived from being calibrated to representative process conditions and expected product variability. This can be challenging in early development, or when demand is low, especially for highly potent compounds that result in very low drug load to measure a signal. Therefore, first adopters of PAT for CT overcame steep learning curves during development and GMP implementation of CT. Building on the experience of the first adopters, today NIR continues to be the standard approach for developing the knowledge around RTDs and process dynamics knowledge. However, deployment of NIR for CT processes needs to be commensurate with the level of risk when registering CT processes, as it requires robust lifecycle and maintenance program management.
Today's CT lines look different from the lines 10 years ago, as the first lines were multi-story processes, often custom-built lines with equipment from multiple vendors of individual unit operations controlled by a SCADA (supervisory control and data acquisition) that was integrated by a third party (e.g., Janssen with Prezista15) or built directly by the manufacturer in house, as in the case of Eli Lilly16. Pfizer and Vertex took a slightly different approach, in that they erected custom built lines from a single equipment supplier11,13. These CT lines were typically very flexible with the possibility to have different CT configurations (i.e., continuous direct compression, roller compaction, or twin screw granulation), however, they were also highly complex with many parts to maintain and clean, resulting in multiple weeks to change over a line between products. These lines, typically, also incorporated many options for PAT to accommodate different control strategy needs. Today's CT lines have evolved from the first generation to be simpler, more compact, have fewer parts, and equipment vendors are offering turnkey solutions where the PAT is already integrated, and control strategies options are a la carte. One of the biggest evolutions is the development of semi-continuous manufacturing in the form of mini batches, but also in the cultural realization that not all CT lines need to be integrated end-to-end in order to take the benefits. In fact, the benefits from CT often originate more from fit for purpose integration and automation of routine manufacturing shop floor tasks rather than inherently implementing continuous manufacturing.
3. Key Learnings from commercialization of CT
Regardless of the configuration of the process (line) along with integrated PAT, there are some factors to consider when designing, installing, qualifying and operating continuous processes.
A lot of attention, and deservedly so, has been paid to the appropriate hardware configuration of continuous processes. However, the development, deployment and qualification of the control system that runs the hardware is equally, if not more, important. The complexity of the control system that runs the process can often be underappreciated in the early stages of the design and installation of continuous processes. It originates from integration of the control architecture of hardware components, combined with development and integration of the control logic of the transition elements (for example, pneumatic transfer elements, rotary valves, transfer chutes, etc). The classical hardware integration subsequently needs to be married to a material tracking and segregation system along with the PAT Management System (PMS). For bespoke configurations, this complexity can be amplified, therefore it is important that qualification routines reflect robust performance of the control system per the design specification requirements.
The broad range of features of the control architecture translates to more intricate system interfaces and sufficient attention must be paid to ensure that training plans take into consideration operator skill sets and aptitude. Unlike batch process, where operators run single unit operations typically via a local HMI, the integrated nature of continuous processes results in an automation interface that controls multiple unit operations and the transition units between these unit operations. The frequency of operator prompts, process warnings, and alarms that an operator typically must address in a continuous process is also found to be higher by virtue of multiple unit operations running in concert. All of these factors have required the operations teams to have targeted training plans for CT. Naturally, as the technology evolves and becomes simpler, the learning curve will become less steep. A creative approach to tackle the longer and more intense training regimen in such processes is to enable the same operations team to be responsible for operations from the commissioning stage through the completion of qualification, and subsequent operation of the program lifecycle. The commissioning and qualification stages provides ample opportunities for "tinkering" and often proves to be fertile ground for training. The same principles apply for PAT-focused and quality assurance (QA) personnel.
An interesting opportunity that CT brings is to have the quality assurance (QA) unit closer to the shop floor operations, to ensure fit for purpose adoption of quality systems to the continuous paradigm. Early, proactive and structured integration of the quality assurance unit into the program is critical to the overall success of the program. This can be as early as the installation of the equipment, and subsequent installation qualification stage of the unit. Hand-inhand with the integration of the QA unit is the adoption of the continuous paradigm in existing quality systems. Although there are multiple approaches to driving towards this end goal, this process can begin with a gap analysis of existing procedures and systems, followed by the necessary updates and creation of new procedures.
And lastly, as a continuous tableting program matures to commercial manufacturing, process efficiency and overall equipment effectiveness (OEE) take on added importance. OEE is a widely accepted measure of equipment utilization for productive manufacturing. It's not unexpected for a mature product manufactured on a CDC process that is properly staffed and trained to have an OEE that exceeds the OEE of a comparable batch-based process. The criticality of process efficiency and equipment utilization increases as a continuous process transitions to commercial manufacturing. A key factor that does, however, impact efficiency in the continuous paradigm is equipment downtime. Downtime in a single unit process impacts the entire operation by virtue of its integrated nature. Sufficient attention must thus be paid to the creation of a robust calibration and preventive maintenance program in conjunction with a risk-oriented equipment reliability and spare-part management program.
Similar to equipment downtime, the utilization of the equipment also depends on the efficiency of the change-over or the change of line (cleaning) operation. The integrated nature of the hardware brings significant benefits to the operation, including a reduction of the opportunities for operator exposure, but results in additional parts, which adds to the overall cleaning effort - the magnitude being a function of the equipment configuration. Moreover, unlike batch processes, cleaning and operation cannot be staggered between unit operations - cleaning of a continuous process results in the entirety of the process being stopped for cleaning. It is thus important to pay sufficient attention to the efficiency of the cleaning process. Automated cleaning mechanisms such as clean-inplace (CIP) systems, parts washers or replacement plug-and-play assemblies should be considered to reduce the overall cleaning cycle time. Sufficient attention must also be paid to the design of the facility and flow of parts and people in the context of an efficient cleaning operation.
4. Outlook
There is no question that like other industries, the pharmaceutical industry will naturally evolve its manufacturing processes towards greater adoption of continuous manufacturing. It is clear that the technology has several benefits such as enabling accelerated product launch and improved manufacturing efficiency, facilitating higher scrutiny of the process that assures improved product quality among others. The end users of the CT technology, and especially the CDMOs, have a key role in pushing for the promotion of technology adoption. Nevertheless, there are some hurdles, real and perceived, that still need to be overcome. Thankfully, amazing progress is being made across multiple fronts: manufacturing floor operations are being streamlined as companies gain more experience to enable operation with reduced workforces; control strategies are being simplified by increasing the reliance on more robust sensing technology; and process development and technology transfer methodologies are being further improved to decrease the reliance on extensive analytical testing of intermediate materials and finished product. The expectation is that as the industry further simplifies CT, the technology economics will naturally become more competitive, and ultimately, help CT turn into a mainstream industrial platform.
5. List of abbreviations
BCS Biopharmaceutical Classification System
CDC Continuous Direct Compression
CIP Cleaning in Place
CT Continuous Tableting
CM Continuous Manufacturing
DC Direct Compression
DG Dry Granulation
ETP FDA’s Emerging Technology Program (ETP)
HMI Human Machine Interface
PAT Process Analytical Technology
PMS PAT Management System
OEE Overall Equipment Effectiveness
RTD Residence Time Distribution
RTRt Real Time Release testing (RTRt)
WG Wet Granulation
About the Authors
Dr José Luís Santos is Director of Technology Intensification at Hovione and leads key projects that aim to position Hovione among the leading spray drying and continuous tableting service providers.
Dr Anthony Tantuccio is a Fellow of Continuous Tableting (CT) driving collaboration and innovation across functional groups to develop workflows, build efficient CMC practices, and foster manufacturing excellence of CT.
Dr Sarang Oka is a Fellow Scientist at Hovione and is tasked with intensifying the implementation of continuous tableting within the organization.
Notes:
1 ICH Q13 Continuous Manufacturing of Drug Substances and Drug Products, Guidance for Industry, March 2023
2 Leane M, Pitt K, Reynolds G; Manufacturing Classification System (MCS) Working Group. A proposal for a drug product Manufacturing Classification System (MCS) for oral solid dosage forms. Pharm Dev Technol. 2015 Jan;20(1):12-21. Doi: 10.3109/10837450.2014.954728. Epub 2014 Aug 27. PMID: 25162770.
3 ASTM Standard E55, E29648–14 Standard Guide for Application of Continuous Pro- cessing in the Pharmaceutical Industry, ASTM international, West Conshohocken, PA, 2014.
4 ISPE Good Practice Guide: Continuous Manufacturing of Oral Solid Dosage Forms, March 2022
5 Text – H.R.2617 – 117th Congress (2021-2022): Consolidated Appropriations Act, 2023. (2022, December 29). https://www.congress.gov/bill/117th-congress/house-bill/2617/text
6 Lee, S.L., O’Connor, T.F., Yang, X. et al. Modernizing Pharmaceutical Manufacturing: from Batch to Continuous Production. J Pharm Innov 10, 191–199 (2015). https://doi.org/10.1007/s12247-015-9215-8
7 Tian, G., Koolivand, A., Gu, Z. et al. Development of an RTD-Based Flowsheet Modeling Framework for the Assessment of In Process Control Strategies. AAPS PharmSciTech 22, 25 (2021). https://doi.org/10.1208/s12249-020-01913-8
8 A.C. Fisher, W. Liu, A. Schick, M. Ramanadham, S. Chatterjee, R. Brykman, S.L. Lee, S. Kozlowski, A.B. Boam, S. Tsinontides, M. Kopcha, An Audit of Pharmaceutical Continuous Manufacturing Regulatory Submissions and Outcomes in the US, International Journal of Pharmaceutics (2022), doi: https:// doi.org/10.1016/j.ijpharm.2022.121778
9 FDA, Pharmaceutical Quality for the 21st Century – A Risk-Based Approach Final Report, September 2004
10 Wahlich J. Review: Continuous Manufacturing of Small Molecule Solid Oral Dosage Forms. Pharmaceutics. 2021; 13(8):1311. https://doi.org/10.3390/pharmaceutics13081311
11 PRWEB. (2013, September 24). GEA Process Engineering and G-CON Manufacturing Announce PCMM Collaboration with Pfizer. Retrieved November 21, 2023, from https://www.prweb.com/releases/gea_process_engineering_and_g_con_manufacturing_announce_pcmm_collaboration_with_pfizer/prweb11155867.htm
12 Janssen Expands Partnership with Rutgers for Continuous Manufacturing Research. PharmTech, (2015). https://www.pharmtech.com/view/janssen-expands-partnership-rutgers-continuous-manufacturingresearch.
13 Manufacturing medicines for today and the future. GEA (2016). https://www.gea.com/en/stories/continuous_manufacturing_technologies.jsp
14 O’Conner, T. (2023, November 1).CDER’s Emerging Technology Program. [Pharmaceutical Quality Symposium]. Webinar. https://youtu.be/dz5izu8caDM
15 Cassetti. J&J experience: CM from equipment qualification to regulatory submission. [European GMP Online Conference. Continuous Manufacturing form Development to Operation]
16 Industry Application: Gravimetric Feeders Support Eli Lilly’s Advancements in Continuous Direct-Compression Tableting (2020, July 9). Tablets & Capsules. https://www.tabletscapsules.com/3641-Technical-Articles/585757-Industry-Application-Gravimetric-feeders-support-Eli-Lilly-s-advancements-in-continuous-direct-compression-tableting/
