José L. Toro, PhD, Lachman Consultants09.16.19
Batch manufacturing (BM) of solid oral dosage forms has been around for well over half a century and will very likely continue to be around for a long time to come. BM is based on a sequence of start-and-stop individualized manufacturing steps. At each stop of an individualized manufacturing step, generally there are numerous quality inspections, quality control (QC) analysis, or both. The industry has proven without a doubt that this approach to manufacturing solid oral dosage forms has been tried and true.
So, what is the buzz about continuous manufacturing (CM)? What benefits does it bring to the manufacturer and what regulatory challenges are there to overcome? This article discusses the current thinking on the benefits of CM and the regulatory hurdles a manufacturer has to overcome.
Batch vs. continuous processes
In a BM process, the manufacturer develops a multi-step and multi- vessel or container process pending the next step in the process. After each discrete step, the intermediate is held, pending the quality testing results. After successfully completing this discrete intermediate step, the manufacturer then proceeds to either charge a new vessel or re-activate the current vessel the intermediate was held in to start the next processing step.
The effect of continuously stopping, waiting for results, and reinitiating the process can be extremely time consuming, creates manufacturing equipment idle time and could also create unwanted quality attributes of the intermediate, such as powder segregation. Cost and quality are only two factors mentioned here but there others that make BM somewhat antiquated.
What is CM? CM is not novel and has been used by many industries for numerous years. These uses and industries include petrochemical, single-unit flow reactor operations in active pharmaceutical ingredient (API) processes and more notably the biomanufacturing operations that use bioreactors for biological compounds, to name a few.
Pharmaceutical products manufactured using CM move through their respective manufacturing steps non-stop within a specific facility or location within a facility. CM is a process where raw materials are moved through an assembly of vessels or reactors that are fully integrated components. CM is a highly automated process which utilizes automated production steps that successfully integrate either chemical or formulation steps to work together to provide an end-to-end product with minimal intervention and stoppage of the process.
To enable CM end-to-end processes with minimal or no intervention, the manufacturer and the corresponding manufacturing process has to have the right technology to measure, in real time, the optimum endpoint of a specific step in the process before moving on to the next step in its journey to the end. Sensor technology, automation and in-line process analytical technology to measure the critical process parameters and critical quality attributes are instrumental in designing a CM process. Newer versions of Delta V technology that have embedded advanced control applications are making CM less complicated to provide information from multiple sources and carry out a closed-loop control system in a single self-contained vessel.1 Two proven process analytical technologies (PAT) are non-spectroscopic determination of active substance concentration during feeding and the other is a spectroscopic measurement of content uniformity during the process.2
When manufacturing steps are carried out in a continuous manner, fully characterizing the properties of each raw material used is of greater significance than in BM. Each raw material’s ability to be processed continuously needs to be characterized.2 The ultimate goal of CM is to take all the raw materials in a single production line starting from one end and finishing with a final dosage form (tablet or capsule) out the other.
Who are some of the early adopters of CM? From 2015 to date, at least four solid oral dosage drugs (OSD) manufactured using CM have been approved by the U.S. Food and Drug Administration (FDA). Three out of the four approved OSDs were new molecular entities and the fourth one was a conversion from BM to CM. Table 1 illustrates the FDA approvals of OSDs produced by continuous manufacturing.
Table 1. FDA Approved Oral Solid Dosage Drugs Manufactured by Continuous Manufacturing3
Regulatory challenges
An FDA statement published in February 2019 made, by then FDA Commissioner Scott Gottlieb, MD, and Janet Woodcock, MD, Director of the FDA’s Center for Drug Evaluation and Research (CDER) made it clear what direction the FDA is taking toward CM. The statement read:
“We’re encouraged to see a growing number of companies embracing CM. It’s a key step towards promoting drug quality and improving the efficiency of pharmaceutical manufacturing. We’ve worked hard to help industry develop the tools to start advancing these goals. The FDA is committed to helping more companies advance these CM platforms owing the public health benefits of these more modern approaches. We support the early adopters that are embracing this innovative technology, and we look forward to working with other interested companies.”4
What are these expressed benefits that the FDA Commissioner and the Director of CDER are emphasizing? One of the anticipated benefits of CM is the ability to match supply with demand by customizing your lot size to your client’s requirements. Another benefit in using uninterrupted production processes is the elimination or potential significant reduction of the dreadful “hold times” which are established during BM and require analytical and/or microbiological testing and validation before proceeding to the next discrete step. This extends your production cycle time.
Other benefits of CM are:
In 2017, the FDA issued a new guidance to support and stimulate industry to consider new emerging technologies entitled, “Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization.” This guidance provides the platform for industry to seek: “the development of pharmaceutical innovation and modernization, such as a more robust drug product design and improved manufacturing with better process control, thereby leading to improved product quality and availability throughout a product’s lifecycle.”8 The program offers the manufacturer to have early engagement and additional meeting opportunities with the FDA. During these meetings the manufacturer can discuss: “(1) product or manufacturing design and development issues and (2) submission content related to the emerging technology.”7
In 2019, the FDA issued a new draft guidance entitled “Quality Considerations for Continuous Manufacturing,” which provides FDA’s current thinking on quality considerations for CM of small molecules, solid oral drug products that are regulated by CDER.9 In this draft guidance, the FDA “focuses on scientific and regulatory considerations that are specific or unique to continuous manufacturing. These considerations include process dynamics, batch definition, control strategy, pharmaceutical quality system, scale-up and bridging of existing manufacturing to continuous manufacturing.”8
The FDA strongly encourages the manufacturer to understand its process dynamics as a function of the attributes of the input materials (material flow and potency properties), process conditions, equipment design elements, the ability to enable material traceability (how to preserve and access the identity and attribute of a material throughout the system) during the manufacturing process and establishing a sound risk assessment of the continuous manufacturing process. Hence, a comprehensive QbD process.9
One common approach to characterizing material flows throughout the process is the characterization of residence time distribution (RTD) for individual equipment trains and the fully integrated system.10 RTD models are vital to better understand the process dynamics and adequately support process monitoring throughout the continuous manufacturing process. The RTD models can be used to monitor the traceability of raw material, intermediates and even finished goods when the desired specifications are not met.9
In summary, CM can provide quicker response to demand, potential reductions in manufacturing cost and facilities investments. Also, reduction in Work in Progress inventories are conceivable, the ability to reduce production cycle times, and improved quality of the finished product can be achieved by reducing the manipulation of intermediates. The FDA is open to emerging technologies and has issued recent guidance documents that provide those of us interested in the industry to consider and implement this technology in our operations. Automation, understanding your process by using a comprehensive QbD approach, and the patience to potentially expect prolonged approval cycles can ultimately give a better product to the patient and provide potential/significant manufacturing cost saving.
References
José L. Toro, PhD
Lachman Consultants
José L. Toro, PhD, is a Director in the Compliance Practice at Lachman Consultants who has extensive R&D Quality, and Quality Operations experience in the pharmaceutical industry. Dr. Toro specializes in the transformation of Quality and Technical Services organizations including Quality Systems, global implementations, corporate auditing, technology transfer and plant operations. He has a broad knowledge of regulatory compliance and quality control. Dr. Toro is well versed in FDA, MHRA, IMB, ANVISA; Japan and Korean inspections. He is highly experienced in manufacturing technologies for multiple dosage forms and associated processes; aseptic operations, complex prefilled syringes, extended-release solids, liquids, semi-solids, parenterals, medical devices, combination products, as well as bulk operations. Dr. Toro co-authored the PDA Technical Report (TR 60-2) on Solid and Semi-Solid Process Validation.
So, what is the buzz about continuous manufacturing (CM)? What benefits does it bring to the manufacturer and what regulatory challenges are there to overcome? This article discusses the current thinking on the benefits of CM and the regulatory hurdles a manufacturer has to overcome.
Batch vs. continuous processes
In a BM process, the manufacturer develops a multi-step and multi- vessel or container process pending the next step in the process. After each discrete step, the intermediate is held, pending the quality testing results. After successfully completing this discrete intermediate step, the manufacturer then proceeds to either charge a new vessel or re-activate the current vessel the intermediate was held in to start the next processing step.
The effect of continuously stopping, waiting for results, and reinitiating the process can be extremely time consuming, creates manufacturing equipment idle time and could also create unwanted quality attributes of the intermediate, such as powder segregation. Cost and quality are only two factors mentioned here but there others that make BM somewhat antiquated.
What is CM? CM is not novel and has been used by many industries for numerous years. These uses and industries include petrochemical, single-unit flow reactor operations in active pharmaceutical ingredient (API) processes and more notably the biomanufacturing operations that use bioreactors for biological compounds, to name a few.
Pharmaceutical products manufactured using CM move through their respective manufacturing steps non-stop within a specific facility or location within a facility. CM is a process where raw materials are moved through an assembly of vessels or reactors that are fully integrated components. CM is a highly automated process which utilizes automated production steps that successfully integrate either chemical or formulation steps to work together to provide an end-to-end product with minimal intervention and stoppage of the process.
To enable CM end-to-end processes with minimal or no intervention, the manufacturer and the corresponding manufacturing process has to have the right technology to measure, in real time, the optimum endpoint of a specific step in the process before moving on to the next step in its journey to the end. Sensor technology, automation and in-line process analytical technology to measure the critical process parameters and critical quality attributes are instrumental in designing a CM process. Newer versions of Delta V technology that have embedded advanced control applications are making CM less complicated to provide information from multiple sources and carry out a closed-loop control system in a single self-contained vessel.1 Two proven process analytical technologies (PAT) are non-spectroscopic determination of active substance concentration during feeding and the other is a spectroscopic measurement of content uniformity during the process.2
When manufacturing steps are carried out in a continuous manner, fully characterizing the properties of each raw material used is of greater significance than in BM. Each raw material’s ability to be processed continuously needs to be characterized.2 The ultimate goal of CM is to take all the raw materials in a single production line starting from one end and finishing with a final dosage form (tablet or capsule) out the other.
Who are some of the early adopters of CM? From 2015 to date, at least four solid oral dosage drugs (OSD) manufactured using CM have been approved by the U.S. Food and Drug Administration (FDA). Three out of the four approved OSDs were new molecular entities and the fourth one was a conversion from BM to CM. Table 1 illustrates the FDA approvals of OSDs produced by continuous manufacturing.
Table 1. FDA Approved Oral Solid Dosage Drugs Manufactured by Continuous Manufacturing3
Regulatory challenges
An FDA statement published in February 2019 made, by then FDA Commissioner Scott Gottlieb, MD, and Janet Woodcock, MD, Director of the FDA’s Center for Drug Evaluation and Research (CDER) made it clear what direction the FDA is taking toward CM. The statement read:
“We’re encouraged to see a growing number of companies embracing CM. It’s a key step towards promoting drug quality and improving the efficiency of pharmaceutical manufacturing. We’ve worked hard to help industry develop the tools to start advancing these goals. The FDA is committed to helping more companies advance these CM platforms owing the public health benefits of these more modern approaches. We support the early adopters that are embracing this innovative technology, and we look forward to working with other interested companies.”4
What are these expressed benefits that the FDA Commissioner and the Director of CDER are emphasizing? One of the anticipated benefits of CM is the ability to match supply with demand by customizing your lot size to your client’s requirements. Another benefit in using uninterrupted production processes is the elimination or potential significant reduction of the dreadful “hold times” which are established during BM and require analytical and/or microbiological testing and validation before proceeding to the next discrete step. This extends your production cycle time.
Other benefits of CM are:
- the potential to increase speed and agility for developing new products/processes5
- CM could offer a safer process, eliminating the transition steps where the intermediate is discharged, held, recharged into another vessel6
- CM can be an advantage in developing and providing new drugs for clinical development by shortening formulation development5
- CM can provide the manufacturer a reduced risk of human error. CM may involve fewer manufacturing personnel in the production process from beginning to end8
- CM can offer a significant production cycle time reduction. The FDA estimates that some drugs can take over a month to produce using BM processes which if made by CM could be completed in a few days.8
- CM can offer the manufacturer added assurance to respond to market demands by using a “just in time” approach instead of the conventional method of keeping large finished goods or Works in Progress in the warehouse just in the event of demand surges5
- CM could represent a smaller footprint in the manufacturing facility which, in turn, could free up valuable qualified manufacturing rooms for other products.6
- for existing approved products, the current production lines/trains are tied to the regulatory approvals that were defined in the original submission and moving to CM requires a new submission.
- not having a global harmonized regulatory approval process for CM makes it more difficult when addressing country specific vs global launches of a product.
- not having global harmonized regulatory approval process could lead to prolonged approval times for medically necessary drugs and could drive the manufacturer to choose the more conventional batch process to get approval of the new drug.
- the selection and development of flow chemistry transformations, difficulties processing dry solids, and solid-laden fluids present a challenge in CM.6
- the lack of appropriate bench and pilot scale equipment, and development of control strategies are significant hurdles a manufacturer needs to overcome.6
- developing a comprehensive QbD process requires experienced professionals within the organization to achieve the desired CM process.
In 2017, the FDA issued a new guidance to support and stimulate industry to consider new emerging technologies entitled, “Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization.” This guidance provides the platform for industry to seek: “the development of pharmaceutical innovation and modernization, such as a more robust drug product design and improved manufacturing with better process control, thereby leading to improved product quality and availability throughout a product’s lifecycle.”8 The program offers the manufacturer to have early engagement and additional meeting opportunities with the FDA. During these meetings the manufacturer can discuss: “(1) product or manufacturing design and development issues and (2) submission content related to the emerging technology.”7
In 2019, the FDA issued a new draft guidance entitled “Quality Considerations for Continuous Manufacturing,” which provides FDA’s current thinking on quality considerations for CM of small molecules, solid oral drug products that are regulated by CDER.9 In this draft guidance, the FDA “focuses on scientific and regulatory considerations that are specific or unique to continuous manufacturing. These considerations include process dynamics, batch definition, control strategy, pharmaceutical quality system, scale-up and bridging of existing manufacturing to continuous manufacturing.”8
The FDA strongly encourages the manufacturer to understand its process dynamics as a function of the attributes of the input materials (material flow and potency properties), process conditions, equipment design elements, the ability to enable material traceability (how to preserve and access the identity and attribute of a material throughout the system) during the manufacturing process and establishing a sound risk assessment of the continuous manufacturing process. Hence, a comprehensive QbD process.9
One common approach to characterizing material flows throughout the process is the characterization of residence time distribution (RTD) for individual equipment trains and the fully integrated system.10 RTD models are vital to better understand the process dynamics and adequately support process monitoring throughout the continuous manufacturing process. The RTD models can be used to monitor the traceability of raw material, intermediates and even finished goods when the desired specifications are not met.9
In summary, CM can provide quicker response to demand, potential reductions in manufacturing cost and facilities investments. Also, reduction in Work in Progress inventories are conceivable, the ability to reduce production cycle times, and improved quality of the finished product can be achieved by reducing the manipulation of intermediates. The FDA is open to emerging technologies and has issued recent guidance documents that provide those of us interested in the industry to consider and implement this technology in our operations. Automation, understanding your process by using a comprehensive QbD approach, and the patience to potentially expect prolonged approval cycles can ultimately give a better product to the patient and provide potential/significant manufacturing cost saving.
References
- Neil, S., “Pharma Catches on to Continuous Manufacturing”, Automation World, December 6, 2017, http://www.automationworld.com/article/technologies/dcs/pharma-catches-continuous-manufacturing
- ECA Academy, “USP article on pharmaceutical continuous manufacturing”, – November 14, 2018, https://www.gmp-compliance.org/gmp-news/usp-article-on-pharmaceutical-continuous-manufacturing
- Douglas B. Hausner,PhD, Christine M.V. Moore, PhD, “Continuous Manufacturing Current Status”, Pharmaceutical Engineering, May/June 2018, http://ispe.rog/pharmaceutical-engineering/many-june-2018/continuous-manufacturing-current-status
- FDA, “FDA statement on FDA’s modern approach to advanced pharmaceutical manufacturing,” February 26, 2019, https://www.fda.gov/news-events/press-announcements/fda-statement-fdas-modern-approach-advanced-pharmaceutical-manufacturing.
- Pagliarulo, N., “Pharma’s slow embrace of continuous manufacturing”, BioPharma Dive, September 24, 2018, http://www.biopharmadive.com/news/pharmas-slow-embrace-of continuous-manufacturing/532811/ (quoting David Pappa, Head of Technical Services and Manufacturing Sciences, Eli Lilly and Company)
- Mascia, S., et.al., “End-to-End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation”,Angewandte Chemie International Edition, 52(47):12359-12363, November 2013.
- Pagliarulo, N., “Pharma’s slow embrace of continuous manufacturing”, BioPharma Dive, September 24, 2018, http://www.biopharmadive.com/news/pharmas-slow-embrace-of continuous-manufacturing/532811/ (quoting Markus Hayek, Managing Director at Accenture Strategy)
- FDA, “Advancement of Emerging Technology Applications for Pharmaceutical Innovation and Modernization: Guidance for Industry”, September 2017, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/advancement-emerging-technology-applications-pharmaceutical-innovation-and-modernization-guidance
- FDA, “Quality Considerations for Continuous Manufacturing: Guidance for Industry”, Draft, February 2019, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/quality-considerations-continuous-manufacturing
- Escotet-Espinoza, M. Sebastian, et. al., “Effects of tracer material properties on the residence time distribution (RTD) of continuous powder blending operations. Part I of II: Experimental evaluation”, Powder Technology, 342: 744 – 763, January 2019.
José L. Toro, PhD
Lachman Consultants
José L. Toro, PhD, is a Director in the Compliance Practice at Lachman Consultants who has extensive R&D Quality, and Quality Operations experience in the pharmaceutical industry. Dr. Toro specializes in the transformation of Quality and Technical Services organizations including Quality Systems, global implementations, corporate auditing, technology transfer and plant operations. He has a broad knowledge of regulatory compliance and quality control. Dr. Toro is well versed in FDA, MHRA, IMB, ANVISA; Japan and Korean inspections. He is highly experienced in manufacturing technologies for multiple dosage forms and associated processes; aseptic operations, complex prefilled syringes, extended-release solids, liquids, semi-solids, parenterals, medical devices, combination products, as well as bulk operations. Dr. Toro co-authored the PDA Technical Report (TR 60-2) on Solid and Semi-Solid Process Validation.
