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Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations (2021)

Chapter: 5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks

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Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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5

Innovations in Integrated, Flexible, and Distributed Manufacturing Networks

In the next 5–10 years, the U.S. Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) is likely to see substantial innovations in integrated, flexible, and distributed manufacturing. Those advances are in many ways the culmination of the innovations that have been discussed in the preceding chapters and provide a fully integrated approach to the manufacture of drug substances and drug products and enable new, distributed manufacturing systems. In this chapter, the committee discusses projected innovations and technical and regulatory hurdles that might stand in the way of implementation of end-to-end manufacturing systems, modular approaches to streamline development and production, and deployment and use of highly portable manufacturing units. Those integrated systems are largely interrelated, so technical and regulatory challenges related to them and committee recommendations for addressing them are discussed together at the conclusion of the chapter.

END-TO-END SYSTEMS

System Description

End-to-end manufacturing involves the effective integration of all the necessary components in manufacturing systems from raw materials through final drug products. In end-to-end manufacturing, raw materials flow through a continuous series or small incremental series of unit operations with intermediate transfers in a closed system, which ideally includes final drug-product release. It differs substantially from typical pharmaceutical manufacturing in which unit operations are largely independent and material in one operation can be held pending in-process testing before the next one. Where standard manufacturing processes separate raw-material inputs, drug substance, and drug product, end-to-end systems seek a single, inclusive, integrated production process that can lead to important departures from the status quo. For example, legacy processes often consider the drug substance as a raw material, but end-to-end innovations in material and process assessment and handling and in process control and reliability will increasingly integrate the production of drug substance and drug product. Furthermore, the ability to trace mass balance through the material flow streams is critical for end-to-end processes and is foundational for monitoring stability in these systems; thus, application of innovative in-line measurements to enable fast feedback is fundamental to their control.

The emergence of commercial end-to-end systems started with a hybrid of small-batch and continuous flows and has occurred primarily in small-molecule manufacturing. An example is a commercially available granulation system that uses continuous powder and binder feeds to a continuous twin-screw mixer–granulator and then transitions to a segmented fluid-bed dryer in which each segment operates essentially as a batch before materials are blended together for downstream continuous processing (Vercruysse et al. 2013). Although such hybrid approaches offer important process advantages, the transition points (continuous to batch and vice versa) can make it difficult to manage the stability of the process flow. FDA is increasingly likely to see the evolution of hybrid systems that focus on minimizing uncertainties related to batch–continuous transition points by using mass-balance sensing and control. Furthermore, small-batch processing might be increasingly implemented as a means of providing fast feedback, especially where end-point control offers an inherent advantage for process stability. Overall, end-to-end integration will simplify handling and reduce the overall cycle time for production, and it is increasingly likely to be seen in regulatory filings.

In large-molecule manufacturing, end-to-end integration of bioreactors with downstream processing is still in its early days, and continuing innovation in end-to-end systems in bioprocessing applications is expected (Smart 2013). Because of the length of upstream processes in the production of many biologics, much of the growth in end-to-end processing has centered on downstream puri-

Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
×

fication and formulation and fill–finish activities. In the future, integration of upstream fed-batch processes with downstream continuous processes might enable a truly end-to-end processing capability for production of biologics and appears increasingly likely to be presented to FDA within 5–10 years.

Integral to and critical for an effective end-to-end system is the matched adaptation of in-process testing to enable quality assessment and process control. In-line sensing is the ideal approach; it requires no mass removal and avoids handling delays and analytic process queues associated with conventional testing. Associated data analytics, including multivariate analysis, are expected to be an important enabler within the next several years, and it is anticipated that increased integration of plantwide data analytics throughout manufacturing processes will greatly facilitate process validation, quality assessment, and root-cause analysis of product-quality issues. Increased use of data analytics might further advance end-to-end processes through better fault prediction, detection, and recovery. As was described in Chapter 4, sensing and statistical modeling enable process stability, which is essential for effective end-to-end systems.

Drivers of Development

The development of end-to-end approaches is being driven primarily by economic factors because the systems are designed for efficiency and can scale to meet market demand and reduce inventory. The end-to-end approach leads to efficiencies in the use of resources relative to output and reduced cycle times in development, production, and distribution. The approach is contrary to that in today’s pharmaceutical industry, in which production is based on available capital equipment and is geared to large batches so as to reduce needed regulatory compliance testing. The resulting substantial work-in-progress1 and product inventories contribute to the characterization of the pharmaceutical industry as having undesirably low inventory turnover—a key manufacturing performance metric defined as the ratio of product sales to materials in inventory in a given period (Spector 2018). End-to-end processes and agile supply strategies can rectify that problem by decreasing both raw materials and work-in-progress inventories.

Although there clearly are opportunities to “rightsize” production scales, in a way that is consistent with continuous and small-batch processing, adoption of scaled-down end-to-end systems has been impeded by the existence of legacy capital equipment and processes. Specifically, when companies try to create end-to-end facilities by including existing batch equipment, which is typically designed for large-batch production, they lose some of the benefits of an end-to-end approach. Several speakers during the committee workshops commented that use of right-sized, continuous end-to-end systems will most likely come with products that can be made, distributed, and administered in no other way (NASEM 2020a,b). That said, there is a growing sense of acceptance for end-to-end thinking, driven partly by reinterpretation of a regulatory batch in the context of FDA’s guidance for continuous manufacturing with process analytic technology (PAT). In biologic processing for which much longer batch-cycle times are required in bioreactors, there is a trend toward right-sizing through the use of small single-use process vessels, especially in the early growth stage of a product’s market introduction (Jensen 2016).

Applications

To be successful, innovations in end-to-end systems need to meet several criteria beyond technologic invention (Griffin et al. 2012). Successful innovations address important problems, are based on deep technical understanding, are implemented effectively, and gain market acceptance. Market acceptance can be a substantial challenge for regulated products for which the solutions in question might be outside the bounds of current regulatory thinking, at least as perceived by industry. Successful pharmaceutical innovation requires a drug product that solves an important problem for a cohort of patients, has an actionable means of drug delivery and treatment, and has a price structure that can cover development and manufacturing costs while being competitive in controlling factors in the marketplace, including health-care insurance and reimbursement. In the post-blockbuster-drug era and with the greater emergence of personalized medicine, the drivers described appear to favor the application of end-to-end approaches, and the aging of large-batch infrastructure likely will provide further incentives to use end-to-end manufacturing systems.

End-to-end systems are enabling some highly innovative and relevant approaches to drug manufacturing described later in this chapter, including modular and distributed manufacturing. Elements common to those systems include continuous flow and implementation of advanced assay methods, data analytics, and process controls that can reduce or eliminate conventional in-process testing.

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1 “Work-in-progress” inventory refers to unfinished goods in the production process.

Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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MODULAR SYSTEMS

System Description

Modular systems are composed of interconnected unit-operation “modules” that are often in a fully closed end-to-end system. The component modules can be arranged and adapted to enable a single facility to manufacture a large array of drugs and biologics (Rogers et al. 2020). The approach is in marked contrast with standard facility designs and manufacturing operations that tend to be “fit for purpose” to produce large batches of a single product or class of products and are not as easily adapted to changing requirements in manufacturing breadth and scale.

Modular approaches are emerging primarily in small-molecule manufacturing. Small-molecule production facilities can be designed in such a way that each module occupies a predictable space and has defined inputs from and outputs to other modules. Processes can then be developed and adapted by using existing modules within the facility with greatly reduced need for design of unique hardware and processes. Because new processes are based largely on existing modules, facilities can be more easily reconfigured, and new manufacturing campaigns started more rapidly. Such newfound agility supports production scales that enable precision and personalized medicine, reconfigurable facilities that are responsive to surge requirements, and even distributed manufacturing concepts.

In large-molecule manufacturing, production is often based on unit-operation modules. The reuse of modules (such as chromatography and tangential flow-filtration units) is well accepted, and process development is often geared toward use of broadly applicable technologies. Single-use systems have greatly increased the ability to turn over unit operations rapidly in an agile facility format, and there is an increasing push toward fully closed systems and continuous-manufacturing approaches facilitated by modular operations. The use of fully closed systems of modules has important implications for in-process testing and design of control systems in complex biologics manufacturing campaigns.

Drivers of Development

The introduction of modularity into manufacturing systems has been driven by the desire to reduce drug costs, address drug-shortages, and provide increased manufacturing flexibility for multiproduct-facility concepts. Modular systems might reduce or eliminate the separation of drug-substance and final drug-product manufacture. In addition to reducing the manufacturing-facility capital costs and the timeline to facility availability, the use of standardized unit operations throughout a product portfolio can reduce equipment lead time and process development time and can improve process predictability and quality. Such adaptable systems might enable deployment at the point of care in some cases and potentially meet the needs of personalized-medicine approaches more cost-effectively. The use of standardized modules might also simplify technology transfer of processes by enabling addition of manufacturing trains or sites and a more streamlined process to demonstrate site equivalence. Regulatory familiarity with specific modular approaches has the potential to streamline regulatory approval, as discussed below.

Applications

In both small- and large-molecule production systems, modular approaches potentially can enable rapid changes in manufacturing processes to accommodate a wide array of products and increase production by duplicating identical module trains. Such approaches, when combined with continuous-production methods, can decrease the manufacturing footprint to far less than that of a typical pharmaceutical-manufacturing facility. In addition to the potential to increase efficiency and throughput in traditional facilities, a set of potential uses emerges wherein the modular facility has a small footprint (for example, shipping-container size) and is capable of fully end-to-end production. That capability could be used to serve remote locations and underserved parts of the world or as part of a disaster response to provide an array of critical drugs until normal supply chains can be re-established. The ability to produce a wide array of products could have important national-security implications by enabling an “on-demand” nationally distributed production capability for critical drugs in short supply and enabling increased domestic capabilities for drug manufacture.

The ability to reconfigure module-based processes rapidly could enable a more efficient means of addressing rare diseases and precision and personalized medicine (Siiskonen et al. 2020). In such cases when only a few doses are needed, modular manufacturing units might emerge as a routine modality up to and including highly portable modular systems, as described in the following section. It is important to note that the use of modular systems, even within a facility compliant with current good manufacturing practices (cGMP) and especially for the unique applications described here has substantial quality and regulatory implications, which are discussed in detail below.

Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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HIGHLY PORTABLE SYSTEMS

System Description

Highly portable systems are composed of interconnected unit-operation modules, often in a fully closed end-to-end system, that are packaged in the smallest footprint possible to enable portability. Being extremely small is what sets highly portable systems apart from the modular systems described above. They have designs that typically compress all operations into a single box that can fit on the back of a truck (in the near term) or in a suitcase (in the midterm). A key facet of small, portable systems is their enabling chemical reactions that occur as reactants flow through relatively small tubes and chambers; this is in stark contrast with the large vats that are used to carry out most large-scale drug production. These miniaturized versions, like the larger modular systems, maintain a degree of process flexibility by swapping in different module components. That flexibility theoretically enables them to be reconfigured so that a single system can be used to produce multiple drugs or biologics with turnover time reduced to only a few hours. The portability and relative simplicity of these small-scale systems creates unique opportunities for automated production that requires little human oversight. There is a potential for decentralized and even point-of-care production that can be deployed on time scales that are not currently possible and to regions of the world that lack sufficient drug-manufacturing capabilities.

Highly portable systems are emerging in both small- and large-molecule manufacturing. Portable systems for small-molecule production are based on continuous-flow synthesis, a strategy that exploits microfluidics, that is, involves pumping reagents through a series of microchamber modules that are interconnected by thin, flexible tubes. The result is an uninterrupted assembly line of chemical reactions and processes required to synthesize and then purify a drug. Although they are small, such systems can handle reaction conditions of up to 250℃ and pressures reaching 17 atmospheres. Incorporation of various in-line sensors enables process monitoring and analytic testing of the product, and the resulting data can be used in process-control strategies to maintain optimal conditions within different microchambers by altering reaction conditions and reagent loading. The systems are still largely in development in academic laboratories and industry but are demonstrating substantial promise in breadth of capabilities and product quality. For example, continuous end-to-end synthesis has been achieved in a refrigerator-size (about 1.25-m3) unit that yielded sufficient quantities of diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride per day to supply hundreds to thousands of oral or topical liquid doses that conformed to U.S. Pharmacopeia standards (Adamo et al. 2016). More recently, smaller systems (about 0.5 m3) that can manufacture final oral solid doses as tablets from drug substances have been reported (Azad et al. 2018; Zhang et al. 2018). The portable, flexible, and modular nature of these emerging systems have wide applicability for drug manufacturing, as discussed in greater detail below.

In large-molecule manufacturing, portable production can also be achieved by using small-footprint manufacturing systems that comprise modular unit operations that include a biosynthesis module for producing the biologic, a purification module for separating the protein drug from the producing host cell and host-cell proteins by using chromatography, and a formulation module for suspending the purified protein drug in a buffer that preserves it until it is administered to a patient. Although the overall operating principles are similar to those described above for portable manufacturing of small molecules, the biosynthesis module constitutes a key differentiator and is one of the most challenging components to develop. In systems that have been described to date, this module has consisted of either living yeast cells (for example, Pichia pastoris) that can be engineered to secrete large amounts human-like proteins or cell-free extracts from reconstituted lyophilized Chinese hamster ovary (CHO) cells, which are shelf-stable for up to 2 years and thus have advantages over systems based on even fast-growing cells like yeast (Adiga et al. 2018; Crowell et al. 2018). Future systems are likely to explore alternative expression hosts or cell-free extracts as discussed below. It is important to note that portable systems described to date are remarkably small, fitting on a benchtop or in a suitcase, and can produce various clinical-quality recombinant therapeutic proteins in a liquid dosage form by using integrated production, purification, and formulation in a single control architecture.

Drivers of Development

The drivers of the development of highly portable manufacturing systems are largely independent of the financial drivers typical of pharmaceutical manufacturing. The drivers center on provision of drugs or biologics to populations that would otherwise be unable to acquire them because of cost, logistics, or specificity of the drug. Many of the drivers would be expected to originate in government agencies or philanthropic groups and to include the manufacture of critical drugs in austere envi-

Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
×

ronments and in response to humanitarian crises. More in line with typical financial drivers are the needs for emerging precision and personalized medicine, which might require dose-tailored, patient-specific, or rare-disease–specific batches of a drug. In addition, because many drugs could be produced on demand at the point of care, highly portable systems could eliminate the need for centralized manufacturing and long-term storage and thereby address many of the supply-chain challenges in the United States and around the world, especially in regions that lack large-scale drug-manufacturing and storage facilities. Small-batch portable manufacturing could also bring down production costs and improve patient access to drugs whenever and wherever they are needed.

Applications

The potential applications of highly portable manufacturing systems are aligned with the drivers of their development and include the following:

  • The manufacture of small amounts of drugs that are prohibitively expensive to produce in large-scale plants, such as “orphan drugs” that are needed by few patients or precision and personalized medicines that are tailored to the genetic or molecular profiles of specific patient populations.
  • Response to drug shortages or surges in demand for specific drugs with speed and logistical flexibility.
  • The supply of medicines to austere environments, such as developing countries or battlefields in remote locations.
  • The supply of much-needed drugs to people affected by disease outbreaks, natural or man-made disasters, or wars.

Many of the applications are shared with larger, deployable modular systems, but the highly portable systems can enable rapidly deployable and highly specific applications that stem from the ability to deliver medicine at point-of-care settings, including a patient’s bedside, a doctor’s office, a local pharmacy, a battlefield, a disaster area, underserved parts of the world, and remote locations. As with modular systems, highly portable systems introduce a host of quality and regulatory implications and challenges, which are discussed in detail below.

KEY TECHNICAL CHALLENGES FOR INNOVATIONS

Most key technical challenges in integrated, flexible, and distributed manufacturing networks are broadly applicable to end-to-end, modular, and highly portable systems. There are three main types of challenges: (1) process challenges are specific technologic challenges in manufacturing that could have substantial effects on the future adoption of the technologies, (2) assay challenges concern the specific methods that enable these manufacturing concepts, and (3) control challenges are critical for all the manufacturing approaches, but most critical for highly portable systems.

Process Challenges

Precursor and Supply Chain

A critical consideration for all the manufacturing processes, but especially those in systems intended for deployment outside a standard cGMP facility environment, is the supply chain of raw materials, including drug-substance precursors, media and buffer components, assay reagents, lyophilized cells, and DNA plasmids. The development of a manageable and robust logistical supply chain and the ability to track, test, and ensure the quality of the supplies can present a highly complex set of problems, especially in deployable systems. Although logistical concerns are outside the scope of this report, critical issues regarding quality aspects of the supply chain remain. Typical inbound material in a cGMP facility will undergo a specific set of tests that include validated methods to prove the identity and purity of the material. Additional measures might be needed to ensure the stability of the precursor if it is labile and the environmental conditions to which it is exposed as it progresses through the stages of the supply chain are not well controlled. As these novel manufacturing approaches become further separated from a typical cGMP environment, challenges regarding supply-chain quality assessment will increase, and innovative methods might be required to ensure the quality and acceptability of inbound raw materials and supplies to enable the use of these systems.

Expression Systems for Biologics

As noted earlier, implementation of end-to-end systems in biologics production is less mature than in small-molecule production largely because of the complexity and longer duration of upstream biologics production that can cause a mismatch between upstream production and downstream purification throughputs (IAVI 2020). Continuous upstream processes are in development but are not widely used in a fully end-to-end manufacturing approach. The most common cell line for biologics production that is relevant to CDER is the mammalian CHO line.

Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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CHO cells have become the preferred host for making complex protein products, such as monoclonal antibodies because they are known to express production-relevant quantities of fully functional proteins into the culture supernatant, and this simplifies downstream purification. CHO-produced proteins are expressed with human-like post-translational modifications, in particular disulfide bond formation and glycosylation patterns, and thus are generally well tolerated by humans. Because CHO cells require long production times and have high material costs, much activity is focused on the development of alternative hosts and expression systems that might be more adaptable to end-to-end biologics production (IAVI 2020). See Chapter 2 for a more detailed discussion.

Low Production Volumes

As discussed above, one primary driver for the efficiencies in modular and deployable systems is the ability to manufacture small lots of drugs targeted specifically to small populations and potentially even to individuals. During normal production, drug-substance and drug-product doses are retained both for quality assessment and for ongoing stability programs. Although the number of doses retained is relatively minor in comparison with normal full-scale production lots, as lot size decreases, these standard approaches could result in a situation in which the amount of retained material exceeds the material intended for patient use. The full implementation of the small production runs enabled by modular and deployable systems depends on development of innovative approaches to assessment of product quality and stability that match the lot size and intended product use. The technical approaches to process control and in-line testing described primarily in Chapter 4 might be effective in decreasing the amount of material needed for quality assessment to address this challenge.

Highly Complex Molecules

The use of end-to-end and modular systems has the theoretical benefit of being able to be reconfigured to produce many drugs. Drugs that have simple structures might be amenable to production with a standardized set of production modules. Similarly, the ability of a set of modules to produce one member of a class of drug increases the probability that other drugs in the class will be producible. Increased drug complexity might increase the need for unique modules or require drug-substance precursors that are more difficult to source. That need or requirement presents a big challenge when the systems are deployed to more austere environments. Development of manufacturing processes that rely less on complex precursors or unique processes is therefore a key technical challenge for the full realization of these systems, particularly highly portable systems.

Assay Challenges

The use of integrated, flexible, and distributed manufacturing systems will depend largely on the ability to maintain quality and prove that it is acceptable and equivalent to that of existing processes. The complexity and quality risk associated with an innovative manufacturing process might depend on the degree to which it differs from accepted or licensed processes. When an end-to-end process aligns closely with established processes, adaptation of existing assay methods to end-to-end systems might be relatively straightforward. As the process is increasingly innovative with respect to unit operations and continuous processing, opportunities to leverage standard assays might decrease, and innovative methods and use of models might be needed to monitor product quality throughout the process. An extreme example is a highly portable system in which all in-process testing, process control, and release testing are necessarily embedded within the system and requires extreme robustness and validation.

Challenges can also occur in the manufacture of increasingly novel drugs. Systems might be designed to manufacture drugs that have been approved and have critical quality attributes and metrics that are well known and accepted. In such a case, it should be possible to adapt assays to measure the known attributes and thus simplify quality assessment. As a product is increasingly specialized—for example, as required for precision medicine—the ability to use standardized assays decreases, and specific quality attributes might require innovative assessment approaches. The full realization of the agility of end-to-end and modular manufacturing processes is based not only on the increased capabilities of the manufacturing processes but on the ability to assess product quality during and after production in a way that matches the efficiencies of traditional manufacturing.

Chapter 4 describes the use of novel in-line sensing approaches to monitor many process variables to assess quality attributes. In-line sensors allow in situ measurements, eliminate sampling preparation, and enable real-time monitoring. The challenge in implementation of the current sensors is that they are more expensive and less rugged than traditional sensors and require labor-intensive and sophisticated calibration. All those factors are at odds with more agile and flexible manufacturing approaches

Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
×

defined in this chapter. The expansion of large-scale data analytics, including machine learning, to support process validation throughout the entire manufacturing process has the potential to reduce final product testing in the next 5–10 years and is seen as a key enabler of the systems described in this chapter.

Control Challenges

Process Controls for End-to-End Systems

One of the technical challenges associated with module-based and end-to-end systems is the potential complexity of process controls. Models designed for standard process controls theoretically can be applied to end-to-end systems, including flowsheet models that describe the integration and interaction of processes within the manufacturing system. It is important to note that end-to-end systems are not necessarily synonymous with fully continuous processing. In fact, hybrid approaches that use both batch and continuous processes can have important control advantages, although it is important to reduce complexity by minimizing the number of transitions between batch and continuous processes. The advantages stem from the fact that control instabilities that might be difficult to manage in a fully continuous process can be corrected at batch processing steps. A full discussion of control strategies in hybrid end-to-end processes was presented in Chapter 4.

Software and Hardware Development and Integration

Addressing control challenges in integrated, flexible, and distributed manufacturing processes will require innovations in software and hardware. According to the workshop on advanced manufacturing technologies held at the International Conference on Accelerating Biopharmaceutical Development in 2019 (Lee and Mantle 2020), improved automation and robotics could be a factor in realizing the vision of rapid and flexible manufacturing of biopharmaceuticals. During that workshop, robotics was touted as a key enabling technology to improve compliance with quality and safety standards. As discussed in Chapter 4, the adaptive plant in the digital-plant maturity model supports multiple manufacturing modes, such as modular and continuous; however, there is substantial reliance on automation and information-technology support.

The digital twin is another enabling technology for integrated, flexible, and distributed manufacturing processes. Using digital-twin technology increases flexibility of manufacturing by allowing virtual modifications of manufacturing configurations and testing of all processes before the optimal configuration is determined. Combining the digital twin with real-time data and data-processing allows tracking of health indicators and detection and diagnosis of faults. That approach leads to greater resiliency in end-to-end systems. Digital-twin technology, however, relies on large-scale data collection and data integrity. Chapter 4 provides more information on how digital-twin technology can address control challenges in integrated systems.

Designing control strategies for highly adaptable and reconfigurable modular systems is complex. The modularity of the manufacturing process lends itself to modular software design, implementation, and testing, and that is consistent with modern software engineering that relies on modular design to facilitate implementation and testing.2 Standardization of software and hardware interfaces allows greater interoperability without the need to redesign or reimplement solutions. Futran (2020) stated that modular design of software and hardware and standardization of their interfaces enable transition to a high-throughput line, if needed, and provide an approach to lowering costs by enabling lower production when high throughput is unnecessary. Although extensible software solutions are more expensive in the original implementation and testing of a single product, the incremental cost of adding new products can be reduced, and the overall quality is improved (Bockle et al. 2004).

The testing of well-designed modular software is widespread in many industries. Risk-based methods and testing at various levels of integration of the software and hardware can be used.3 The committee recommends that regulators become knowledgeable about these methods so that they can assess the level of rigor that should be and is used for various systems.

Safety and Security

The high degree of automation that is required especially as systems progress from modular to portable will require not only highly innovative control approaches but unprecedented levels of safety and security built into the hardware and software. Control technologies that can trigger actions in real time and without human intervention require robust failure detection and fault tolerance. As manufacturing moves toward the adaptive plant, automation progresses from predominantly manual process-

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2 See http://aosd.net/importance-of-modularity-in-programming/.

3 See https://www.atlassian.com/continuous-delivery/software-testing/types-of-software-testing.

Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
×

ing to predictive behavior to adaptive behavior in which controls adapt on the basis of detected states. Such advancement requires increased reliance on sensors and modeling. The PAT initiative encourages the use of that type of technology to increase innovation through the phases of development, manufacturing, and quality assurance of pharmaceuticals within the scope of current regulations. Nonetheless, there is a need to identify where current regulations need to be updated to handle the level of automation that is being explored with integrated, flexible, and distributed manufacturing networks.

Data, multivariate data acquisition, and analytic tools are crucial in the design, analysis, and control of manufacturing processes. Speakers at the committee’s workshops discussed the potential to incorporate data lakes (centralized data repositories) to advance data analytics (NASEM 2020a,b). Unlike traditional data-warehousing approaches, data lakes allow capture of data from multiple sources and storing of data that are not yet completely understood. The data-lake approach makes it possible to advance analytics without the need to rerun processes to capture and store data that were not previously understood or known to be useful. It also makes it possible to find new behavior in the manufacturing process, such as correlations of conditions with faults, that might not have been expected. The reliance on data, however, requires advanced security measures to ensure that the data have not been compromised. At the committee’s first workshop, the ability both to trust the data and to act on them were identified as barriers to leveraging of process data (NASEM 2020a). Stored data can lose their credibility in many ways, such as hardware faults and malicious behavior. Hardware faults can include sensor faults, in which data collected are invalid or a data-storage device becomes corrupted. The Pharma 4.0 Special Interest Group aims to address those issues.4

KEY REGULATORY CHALLENGES TO INNOVATIONS

Regulatory approval focuses primarily on the product, but the associated innovative approaches to manufacturing also must be approved. Although standard end-to-end approaches might not face substantial challenge or disincentive, the regulatory challenges to modular systems that reuse modules and systems that are deployed in mobile cGMP environments are far greater. The most innovative manufacturing systems are portable ones that operate outside typical cGMP controls with minimal operator oversight and full on-board drug-release capability. Those systems encounter several obvious regulatory challenges, but they are becoming mature and robust enough to push the regulatory envelope within 5–10 years. The challenges described below include overarching challenges and more specific ones related to the definition of a manufacturing facility and approaches to quality management.

Challenges in the Regulatory Approach

The regulatory framework is based on approval of individual products, so there is no way to evaluate a manufacturing approach outside that framework, and this presents substantial problems in transitioning manufacturing processes to innovative systems. It is particularly evident when viewed from a product-specific perspective. Retroactively developing processes to enable marketed drugs to transition to new systems would likely be financially untenable. In the current regulatory system, if a pharmaceutical company wanted to manufacture a set of critical drugs, for example, in a highly portable system, each drug would need to be approved separately for manufacturing in that system. That burden creates a situation in which modular and portable systems—which are designed for broad applicability and agile changeover—are difficult to implement to their full potential. That regulatory hurdle exists for approved products, which would require further regulatory approval to enable manufacture in a new system, and for new products that are not yet approved. The product-centric approach to regulatory approval, although justified and necessary, can present important impediments to the maximal use of end-to-end, modular, and highly portable systems because neither the process, a component module, nor the portable system has a mechanism by which it can be approved outside the product approval process.

Challenges in Defining a Manufacturing Facility

The FDA approach to licensing manufacturing facilities is well understood by industry and follows cGMP guidelines that provide predictable requirements (for example, for process-performance qualification runs and preapproval inspections) for products that are in the approval process. The use of modular systems, for example, to duplicate a process in a separate facility would typically require that facility also to be licensed, so there is no defined mechanism by which the modular approach offers a regulatory advantage. Facility definition becomes more difficult if a facility is contained within a transportable POD that can be relocated, and more difficult still is the highly portable system in which the “facility” is a

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4 See https://ispe.org/initiatives/pharma-4.0#.

Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
×

suitcase. Potential use of the systems internationally adds yet another layer of complexity. To enable implementation, an innovative and flexible regulatory approach will need to take into account unique quality-management approaches and facility definitions. Some examples of questions about this type of system are provided below; the list is not exhaustive, nor does it reflect the full complexity of implementation and regulatory acceptance of these systems.

  • How are facilities that do not have a physical address regulated?
  • Can processes within identical modular facilities be duplicated efficiently to support surge manufacturing?
  • How will in-process and release testing be handled without a standard onsite quality-control and quality-assurance unit?
  • How will data be managed in this new manufacturing-facility construct? How will data be collected and shared? How well connected do the facilities need to be? How will data be protected?
  • How does an event in one area of a distributed manufacturing network affect the rest of the network? How are control systems integrated?

The committee concludes that the full implementation of these systems will not occur without easing the regulatory burden and a proactive approach by FDA to enable their use.

Challenges Related to Quality Management

Closely related to defining a manufacturing facility are potential differences in the standard expected cGMP infrastructure and quality systems. The differences are most apparent in the case of a highly portable system; there are questions as to whether the system is equipment or is itself a manufacturing facility. However, all modular and end-to-end processes deviate to some degree from standard cGMP processes. Any of the differences can present a substantial regulatory hurdle to be overcome, but when a given system has multiple differences, the regulatory challenges can pose an insurmountable challenge for timely and cost-effective drug approvals and manufacture. Several examples are provided in Table 5-1. If there is a requirement to address each difference in a manner that proves at least equivalence to accepted processes, that requirement could present a substantial finan-

TABLE 5-1 Examples of Questions Related to Product Quality for Innovative Manufacturing Formats

Topic Example Questions
Manufacturing environment
  • Are cGMP-compliant environmental conditions relevant in fully closed end-to-end systems?
  • How can cGMP environmental compliance be maintained, or even sampled, in highly portable systems?
  • Are there unique operator qualifications, especially in highly automated systems?
System portability
  • Will a deployable process (for example, one that can be moved to another location within a manufacturing POD or truck) require full installation and operational qualification of all systems at each redeployment?
  • Will facility inspections be required after each redeployment?
  • How will process repeatability be assessed when the system’s address changes or when identical systems are used for the same production process?
Oversight of quality assurance and quality control
  • How will in-process testing be viewed in fully end-to-end systems?
  • How are drug substance and product-quality assessments handled in a fully end-to-end process, especially a fully closed process? Is the lack of a drug-substance stability program an issue?
  • Can product release be based on analysis of quality throughout the process?
  • How will release of parenteral dosage forms be managed in highly portable systems?
  • Will full supportive product data or a subset (such as stability or bioequivalence data) be required for replicated portable modules? What would be the data requirements for a network of identical systems?
Low production volumes
  • How will lots be defined if only a few doses are produced at a time? How will lots be defined in fully end-to-end or continuous systems?
  • How will analytic standards be defined in systems that produce low volumes of special products and dosage forms, for example, in personalized medicine?
  • Are there acceptable approaches to enable nondestructive release testing for low-volume production runs?
  • What is the acceptable approach to stability in low-volume production runs?
Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
×

cial and time burden. The committee finds that adoption of increasingly innovative manufacturing technologies will require equally innovative regulatory approaches.

OVERCOMING REGULATORY CHALLENGES

Guidance

One mechanism that facilitates adoption of novel approaches is the publication of FDA guidance documents. They provide a framework for an approach to implementation and are authoritative descriptions of FDA’s expectations. The innovative approaches described in this chapter constitute a gradation of innovation from end-to-end manufacturing in the context of cGMP facilities to reconfigurable manufacturing modules that enable repeatable processes and agile changeover to highly portable systems that at first glance are antithetical to accepted cGMP approaches. Thus, there will likely need to be a graded approach to guidance documents as each approach matures and is implemented. FDA draft guidance—such as “Advancement of Emerging Technology to Modernize the Pharmaceutical Manufacturing Base” and “Quality Considerations for Continuous Manufacturing”—and the still-in-development ICH Q13 “Continuous Manufacturing of Drug Substances and Drug Products” can serve as examples. Those documents illustrate the type of industry guidance needed to provide a framework of process definitions and quality-related strategies to help to advance innovative approaches through regulatory acceptance in the United States and internationally.

For end-to-end manufacturing, the primary regulatory guidance will need to describe approaches to quality for systems that do not have typical in-process and release testing and that might have specialized, highly advanced control systems that are based on innovative inline testing methods. The typical differentiation between drug substance and final drug product might also present regulatory challenges in end-to-end systems, in which process intermediates are not as easily defined. The ultimate realization of a fully automated end-to-end process is the ability to rely on control using well-defined process parameters to enable immediate product release.

The next level of complexity comes with the introduction of reconfigurable modules. The full implementation of a modular system is expected to involve module-based unit operations in a number of manufacturing processes and for various product lines. Modular approaches will be most effective and create the greatest efficiencies when manufacturers can be assured that there is a regulatory advantage to using particular modules—that is, a decreased scrutiny of the module-based manufacturing process. That regulatory accommodation is predicated on a degree of consistency within the modules that can be defined in guidance documents and that still enable the desired system configurability and agility.

The most ambitious approach is to divorce production from a classical cGMP environment and support structure. Although that is clearly applicable to more standard cGMP systems contained in a portable cleanroom, the concept is best exemplified in fully portable systems that make only a few doses. The utility of those systems will likely depend on their ability to produce a moderately sized set of desired drugs. At the moment, that would mean that each drug would need to be approved for manufacture in that specialized system. Apart from the monumental task of maintaining and proving product quality in the systems, the financial and regulatory burden of enabling each manufacturable drug makes implementation difficult to envision. In addition, proving the reliability of what would almost necessarily be a fully automated control system presents its own regulatory challenges and costs. There is a need for a highly innovative regulatory approach that could enable manufacture and release of a drug on the basis of nonstandard in-line quality checks and release tests, probably with few onboard process controls. Almost by definition, that would require substantial relief from standard regulatory requirements and a rethinking of approaches to measure product quality. Guidance on adoption of innovative quality-assessment approaches could facilitate implementation by removing some degree of regulatory risk.

Regulatory Science and Agency Involvement in Phased Approaches

Although guidance documents described above could greatly facilitate implementation of novel manufacturing technologies, it is clear that direct FDA involvement with implementation could provide important advantages and accelerate the use of innovative systems. For example, FDA has been involved with companies that have developed continuous processes and modular approaches. That interaction between companies and regulators has proved to be powerful and has in some cases facilitated adoption of technologies. The highly innovative technologies and approaches envisioned in this chapter will likely not advance, or at best will not advance quickly, in the absence of a major shift in drivers or incentives or without direct participation by FDA in their development and maturation.

The FDA Emerging Technology Team is an important mechanism for the agency to understand what is on the

Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
×

horizon; however, advances in regulatory science could be greatly accelerated by an increased emphasis on hands-on research and testing by FDA. For example, development of a useful approach to regulation of modules could be accelerated if FDA scientists actually used the modules, aided in their development, and formulated guidance rather than waiting for a regulatory filing and only then providing expectations. Innovative regulatory approaches to decrease or eliminate subsets of cGMP controls could benefit from hands-on analysis of early systems by FDA, with evaluation and early guidance for developers independently of product-specific filing. FDA could also assist in outlining phased approaches to implementation of advanced manufacturing systems. For example, the first implementation of a highly portable system could occur in a cGMP facility that has the appropriate facility and quality support structures. FDA could then work closely with developers to outline an acceptable path to maintain product quality control and assurance outside the normal cGMP environment and provide a set of acceptable success criteria for continuing development and a path toward implementation. The fundamental recommendation is that FDA needs to be an active participant in removing barriers to innovative approaches. In some cases, given the drivers described in this chapter, the costs to private industry might be too high, despite the benefits that could eventually be realized by their implementation.

A related mechanism that FDA could leverage to accomplish hands-on research on and testing of new technology is the creation of specific testing laboratories that are designed to facilitate collaboration between the developers of novel manufacturing systems, the end users of the systems, and FDA. Such collaboration could produce use cases, systems to implement the use cases, and FDA regulation best practices or modifications to accelerate the process of technology transfer. That approach could lead to a pragmatic reduction in regulatory barriers or perceived barriers. The start-up cost of the partnership would be high, but all parties would benefit from it. End users of the manufacturing systems (the pharmaceutical companies) would have a large incentive because they would be influencing system development and receiving direct feedback from FDA that will help them bring their products to market. The approach has proved effective in the co-design of high-performance computing systems for the Department of Energy (DOE); small proxies for large-application software are used to allow hardware vendors and application developers to make many iterations before the product is delivered, and this makes final acceptance of the whole product much more efficient.5 It allows all parties to become more agile and flexible through the entire process of deploying innovative technology. In the context of this report, pharmaceutical companies can provide use cases that represent the core characteristics of their overall processes, similar to proxy applications, and the developers of the technology can apply their solutions to the specific use cases. FDA can use the approach to foresee innovations, understand how current regulations apply to them, and use its knowledge of the technology to evolve regulations to meet the needs of future technologies.

For the distant future of manufacturing innovation, the committee recommends strong collaboration with developers of novel manufacturing systems, end users of manufacturing systems, and academia. The committee recognizes that, as systems become more continuous and rely on sensors, data analytics, and automation, the breadth of expertise in the workforce greatly expands. Working with academia and with public-private partnerships, such as the National Institute for Innovation in Manufacturing Biopharmaceuticals, to develop multidisciplinary programs that are forward-looking can help to address future workforce shortfalls, address long-term research issues, and create a pipeline for future innovation. The committee recommends evaluating the Predictive Science Academic Alliance Program6 in DOE as an example. That program supports multi-institution centers to address key research areas and provides opportunities for students to work directly with DOE laboratory personnel.

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6 See https://psaap.llnl.gov.

Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
×
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Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
×
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Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
×
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Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
×
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Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
×
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Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
×
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Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
×
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Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
×
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Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
×
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Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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Suggested Citation:"5 Innovations in Integrated, Flexible, and Distributed Manufacturing Networks." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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In 2002, the U.S. Food and Drug Administration (FDA) launched the Pharmaceutical Quality for the 21st Century Initiative to encourage adoption of innovative technologies that would lead to an agile, flexible pharmaceutical manufacturing sector. The goal was to encourage a transition to manufacturing processes and approaches that could produce high-quality drugs reliably without extensive regulatory oversight. Much progress has been made toward that goal as the industry has developed and advanced new technologies, but more progress is required as recent natural disasters and the coronavirus pandemic have revealed vulnerabilities in supply chains and highlighted the need to modernize pharmaceutical manufacturing further.

At the request of the FDA Center for Drug Evaluation and Research (CDER), Innovations in Pharmaceutical Manufacturing on the Horizon identifies emerging technologies - such as product technologies, manufacturing processes, control and testing strategies, and platform technologies - that have the potential to advance pharmaceutical quality and modernize pharmaceutical manufacturing for products regulated by CDER. This report describes many innovations to modernize the manufacture of drug substances and drug products, to advance new control approaches, and to develop integrated, flexible, and distributed manufacturing networks within 5-10 years.

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