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Integrated Continuous Pharmaceutical Technologies—A Review

  • András Domokos
    András Domokos
    Budapest University of Technology and Economics, Organic Chemistry and Technology Department, H-1111 Budapest, Hungary
  • Brigitta Nagy
    Brigitta Nagy
    Budapest University of Technology and Economics, Organic Chemistry and Technology Department, H-1111 Budapest, Hungary
  • Botond Szilágyi
    Botond Szilágyi
    Budapest University of Technology and Economics, Faculty of Chemical Technology and Biotechnology, H-1111 Budapest, Hungary
  • György Marosi
    György Marosi
    Budapest University of Technology and Economics, Organic Chemistry and Technology Department, H-1111 Budapest, Hungary
  • , and 
  • Zsombor Kristóf Nagy*
    Zsombor Kristóf Nagy
    Budapest University of Technology and Economics, Organic Chemistry and Technology Department, H-1111 Budapest, Hungary
    *Telephone: +36-1-463-4129. Email: [email protected]. Postal address: 3 Műegyetem rkp., H-1111 Budapest, Hungary.
Cite this: Org. Process Res. Dev. 2021, 25, 4, 721–739
Publication Date (Web):March 2, 2021
https://doi.org/10.1021/acs.oprd.0c00504
Copyright © 2021 The Authors. Published by American Chemical Society
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Abstract

Innovation in the pharmaceutical industry has been limited for a long time to the research and development of new active compounds; meanwhile, the structure of the production, dominated by batchwise technologies, has not changed to date. As has already been demonstrated in several other industrial sectors, continuous manufacturing (CM) has many advantages over batch processes. Faster, cheaper, and more flexible production can be developed with a significantly higher level of quality assurance. In the recent years the main regulatory agencies recognized the need for a change in drug production and started to promote continuous technologies and encourage pharmaceutical companies to develop and adapt such processes. As a result, by today extensive research was conducted in the various fields of pharmaceutical technologies from drug substance to drug product manufacturing. Many publications deal with synthetic steps carried out in flow reactors and crystallizations implemented in a continuous manner, and on the formulation side continuous filtration, drying, granulation, and blending have all been studied to a lesser or greater extent. Moreover, besides the modification of these traditional processes to continuous operation, novel, intrinsically continuous technologies are being studied as well. In order to entirely exploit the advantages of CM, the mainly separately developed processes need to be integrated to form end-to-end systems from the raw materials to the final dosage forms. However, even the integration of two technological steps is a challenging task. The development of end-to-end systems requires deep process understanding and a holistic approach toward process development and optimization. The aim of this work is to give insight into the state-of-the-art and new directions in integrated continuous pharmaceutical technologies by critically reviewing the recent literature of the broad field.

1. Introduction—Challenges of 21st Century Pharmaceutical Manufacturing

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By the end of the 20th century, most of the largest industrial sectors built production lines based on assembly line, continuous technologies. (1) This could be observed in the electronic, automobile, food, and petrochemical industries as well. In contrast, the pharmaceutical production traditionally relies on batch processes. The facilities are designed for the large-scale batch production of “blockbuster” drugs using large volume centralized batch manufacturing plants. (2)
This approach divides the manufacturing process into many separate steps which are clearly isolated in space and time. (3) The two major parts of drug production, i.e. synthesis, isolation, and purification (drug substance manufacturing) and formulation (drug product manufacturing), are often located in different geographical regions, including different countries. (4) This elongates the supply chains drastically and increases transportation times on the order of weeks. (2,5,6) During the batch manufacturing process, samples are taken from each produced batch, which are carried to separate laboratories to conduct in-process-control measurements before moving the material to the next operation. (7) Since the production of a pharmaceutical product can take up to 10–20 steps, this cumbersome procedure together with the long supply chains could result in 12–24 months of overall production. (1,2,5) Moreover, these long supply chains have modest resilience against sudden regulation changes and lockdowns, which was generated by the recent SARS-COV-2 outbreak. This situation made governments of many countries consider self-sufficiency in the supply chain. (8)
Pharmaceuticals are manufactured in a “campaign-like” manner, meaning that a given intermediate is prepared in successive batches, collecting a certain amount of material together before moving to the next step. (2,9) This manufacturing practice requires substantial storage capacity, which inherently raises the production and thus the product cost. (2,5) Additionally, storing large amounts of hazardous active pharmaceutical intermediates contributes to the safety issues of the manufacturing process. (10)
Scale-up is always a great challenge during the development of batch technologies, as the process behavior can show strong scale-dependence, which is often associated with hydrodynamic effects. Thus, the processes optimized on laboratory scale sometimes require thorough reoptimization, which might be challenging, since ensuring adequate supply for the clinical trials is the priority. (11) Hence, usually the first operating procedure is accepted for industrial-scale operation and submitted to regulatory approval. After reaching the market, any modifications aiming at the improvement of production efficiency must go through the time- and money-consuming approval procedure again. (12)
The greatest drawback of the batch-based structure of pharmaceutical manufacturing is presumably the currently common practice of quality assurance. In the case of drug products, ensuring consistent quality is of utmost importance, which is intended to be achieved by strict regulatory control. (4) The applied practice is the Quality by Testing (QbT) method, which consists of the analysis of samples taken from the raw materials, the intermediates after each step, and the final products. (13,14) If any of the parameters is out of the regulatory-approved specifications, the entire batch must be reprocessed or discarded causing significant delays and extra costs. (7) The fluctuations are intended to be minimized by the tightly controlled process parameters. (4)
The presented structure of the drug production makes the pharmaceutical industry slow and highly inflexible and thus unable to give quick answers to the changes in demand. (15) This poses a potential public health threat as the root causes of numerous reported drug shortages can be traced back to the problems of the current manufacturing strategy of the industry. (16,17) Furthermore, recent trends in drug product development show that fewer and fewer blockbusters can be brought to the market, and the cost of new pharmaceutical research and development outpaced market growth. (3,5,10,18) There is an increasing need for a more agile, robust, and efficient manufacturing structures in order to keep up with changes in market demand, to reduce costs, and to produce pharmaceuticals more reliably with improved quality. (15)

2. Advantages of Continuous Manufacturing

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As has already been shown in other industrial sectors, significant improvements can be accomplished in the production by replacing the batch processes with continuous technologies. (1) Unlike batchwise manufacturing, in the case of continuous processes, the raw materials and the product are continuously fed into and discharged from the equipment. All the materials are continuously flowing through the system, eliminating the idle time between the different technological steps. (15) After a start-up period, continuous processes converge into a steady state, during which the process parameters remain constant in time. (4) Monitoring and maintaining these variables on the fixed set point is much easier than handling the dynamic nature of batch operations. Therefore, by the development of appropriate analytical methods even constant product quality can be attained. (4) In the case of an error, the deficient product section can be traced back accurately; hence, discarding the entire amount of material is no longer necessary. (19)
Continuous technologies are usually developed as a whole, integrating the consecutive steps into one system. (20) Such a system in the pharmaceutical industry would result in a drastically different and improved production strategy. (10) By connecting the currently separated manufacturing sections, such as the drug substance and drug product manufacturing, the elongated supply chains could be cut down. (3,6) As materials could flow directly to the next step, the huge and expensive inventory capacity maintained for storing the intermediates becomes unnecessary, and the factory footprint can be reduced as well. (15) Because of the high-level automation and the lack of termination between the technological steps, human intervention and exposure can be minimized, reducing the toxicity- and safety-related issues of traditional batch manufacturing (e.g., the production of anticancer drugs and hormones is safe only in severe protective equipment). (21) Due to the typically lower material holdup of a continuous system compared to the batch counterpart, the hazards and safety issues of the reagents, solvents, or other involved materials are inherently reduced.
The productivity can be increased simply by operating the system for a longer time, facilitating provision of a rapid response for sudden changes in demand. (10,22) There is no need for a classical scale-up procedure, since it is enough to utilize parallel processing lines of the equipment used in laboratory, which accelerates the whole drug development process and reduces the time to market. (10) In the case of continuous technologies, process optimization is usually faster and easier, which means that a more understood and optimized process can be submitted for regulatory approval. Additionally, the investment and operating costs of continuous technologies are lower, and the expenses can be reduced even by 40%. (23,24)

3. First Steps toward Continuous Pharmaceutical Manufacturing

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The necessity to improve the efficiency of current batch-based drug manufacturing processes drew the attention of the industry, the academia, and the regulatory agencies to continuous technologies. The vision of a faster, cheaper, more flexible, and more robust production initiated the paradigm shift of the frozen-in pharmaceutical industry. (25,26)
In 2005 the American Chemical Society (ACS) Green Chemistry Institute (GCI) and several global pharmaceutical corporations, such as Novartis, Pfizer, Roche, Sanofi, Eli Lilly, Johnson & Johnson, and others founded the ACS GCI Roundtable. (27) This roundtable defined “continuous processing” as one of its research priorities. (28,29) The U.S. Food and Drug Administration (FDA) issued the first framework about promoting the application of Process Analytical Technologies (PAT) in 2004. (30) PAT includes real-time process monitoring and control supported by advanced data processing, with which better process understanding and improved product quality can be accomplished. (31) In the following years, several further guidelines were launched by the FDA, (32) the International Council for Harmonization (ICH), (33−37) and also the European Medicines Agency (EMA) (38) in the topic of quality improvement through the development and adaption of continuous technologies. Recently the FDA declared continuous manufacturing (CM) as one of the most important tools in the modernization of the pharmaceutical industry. (39)
According to the guidelines, quality should be designed into the product; thus, the Quality by Design (QbD) approach is preferred for quality assurance instead of QbT. (7,40) Pharmaceutical QbD means a systematic approach toward development, starting with defining the critical quality attributes (CQAs) of the product, identifying the critical material attributes (CMAs) of the starting materials and the critical process parameters (CPPs) as well. By linking CMAs and CPPs to the CQAs, it is possible to understand how the product quality is affected by changing the process parameters and the material attributes. As a result, an operating space of parameters can be defined, and within this processing region (design space) the desired product quality can be reached. As another step forward, the concept of Quality-by-Control (QbC) has been proposed in the recent years. (41) The QbC paradigm takes the QbD approaches to a higher level by applying active feedback control for process design. (14) Thus, in some cases the suitable operating conditions can be found much faster, and significantly less material is required. (42)
By today nearly all the major innovator pharmaceutical companies are working on continuous technologies. (19) As a result, a handful of drug products were released on the market which are produced at least partially using regulatory-approved continuous technologies by Vertex (lumacaftor, ivacaftor, tezacaftor), by Johnson & Johnson (darunavir), by Eli Lilly (abemaciclib), and by Pfizer (glasdegib). (9,14,43,44) These examples show that changing from batch to continuous technologies is truly advantageous economically as well: Johnson & Johnson achieved significant reduction in manufacturing cycle time, footprint, and testing duration. (45,46) Much effort was required to achieve this progress; however, there is clearly much room for improvement. Obviously, the movement toward CM is a long and costly journey, which requires extensive research. (47) It is necessary to evaluate the applicability of existing technologies in a continuous manner and to develop novel continuous processes not yet utilized. (19) Moreover, changing the current mind set and training of CM experts also takes a long time.
There is a growing body of literature of continuous pharmaceutical manufacturing, covering the entire production line. Considerable research has been conducted for example in the field of flow chemistry, (48) continuous crystallization, or continuous blending and tableting. (20) Moreover, the possible real-time monitoring strategies of the continuous processes using in-line PAT tools have been studied extensively. (31,49) However, besides examining the different continuous processes, connecting the individual steps is a much greater challenge. (50) In order to fully exploit the promise of CM, the separated technological processes must be integrated, forming end-to-end systems from the raw materials to the final dosage forms. According to the literature, significantly fewer publications deal with continuous technologies in which at least two consecutive steps are coupled in any way. Moreover, the development of end-to-end continuous systems from the raw materials to the end products is presented only by a handful of papers. This also might be the result of the currently separated synthetic and formulation section, as scientists and experts usually do not have expertise in both fields. It is clearly visible that a complete change in mind set is required for a more integrated development approach toward continuous technologies. (4,9)

4. Recent Progress in Continuous Pharmaceutical Technologies

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The following sections aim to present the progress accomplished to date in the most important areas of continuous pharmaceutical manufacturing. First, the flow chemical transformations and multistep syntheses of active pharmaceutical ingredients (APIs) will be discussed, followed by continuous crystallization and filtration. After these, the continuous blending and tableting of pharmaceuticals will be presented. Emphasis will be put on publications dealing with more than one consecutive technological step, integrated in a continuous manner to show the progress accomplished toward end-to-end pharmaceutical manufacturing. A few techniques from a usual pharmaceutical manufacturing line, such as granulation, milling, and drying are left out of this review, as several well-organized and up-to-date studies focus on these research areas. (51−55)

4.1. Multistep Flow Synthesis of Pharmaceuticals

4.1.1. Principles of Flow Chemistry

The multistep synthesis of complex organic molecules from simple precursors represents a significant achievement but is also one of the greatest challenges of the synthetic organic chemistry. (56) The traditional batchwise synthetic route consists of a series of batch reactions with workup procedures, purification, and isolation after each step (Figure 1a). Although this approach is the basis of all modern syntheses, such a procedure is usually time-consuming and wasteful compared to the single-cell multistep biosynthetic pathways known in nature. (56)

Figure 1

Figure 1. (a) Traditional batchwise multistep synthesis and (b) continuous flow approach for the telescoped synthesis of complex molecules (adapted from ref (56)).

Continuous flow chemistry offers several options for the implementation of organic syntheses. (57) In flow systems the materials are flowing in tubes with small diameter (usually between 50 and 1000 μm), and the reactions take place in these so-called microreactors (Figure 2). (58) The starting materials are fed by pumps, and mixer elements provide the sufficient mixing of the liquid streams (which is often an issue due to the low Reynolds numbers in these systems). Back-pressure regulators (BPRs) can be applied at the end of the tubes to pressurize the system, allowing increase of the boiling point. Directly connectable devices are available for the purification of the reaction mixtures, i.e. liquid–liquid extractors. Besides homogeneous systems, solid–liquid or gas–liquid reactions are also accessible with packed bed reactors or tube-in-tube reactors. (59−62) Furthermore, microwave flow reactors can be applied to compare the effect of microwave conditions to conventional heating. (63−65) The in-line monitoring of the flow reactions is possible by applying e.g. flow-through spectroscopic analytical techniques including UV–visible, (66) fluorescence, (67) Raman, (68) and infrared spectroscopy. (69)

Figure 2

Figure 2. General structure of a typical continuous flow systems.

These systems have a number of advantages over traditional batchwise reactors. The small cross-section of the tubes means that the heat transfer area to reactor volume ratio is about 50–60 times bigger (calculating with the same kg per a day throughout). (21) The small channel dimensions of the reactors allow precise control over process parameters: quick heat transfer or efficient and accurate illumination during photochemical reactions. (70,71) In the pressurized system significantly elevated temperatures can be applied, thus accelerating the reactions and making new pathways possible that are otherwise not accessible. (72) Reduced reaction time, excellent yield and selectivity, enhanced safety, and good reproducibility were reported in the literature numerous times. (73−75) Naturally, new challenges have arisen with the new technology, for example dealing with solid materials and the issue of clogging, the integration with in-line purification techniques, or the cost of flow equipment, which all must be handled during the development of a flow chemistry process.
Owing to the advantages of flow chemistry, the number of publications focusing on synthetic organic flow systems has increased significantly in recent years. The International Union of Pure and Applied Chemistry (IUPAC) organization named flow chemistry among the top ten emerging technologies in chemistry. (76) The majority of publications deal with different chemical transformations implemented in flow reactors and comparing them to the batch result. Many excellent review papers have been published summarizing the progress in this area, highlighting the barriers of this new technique, and providing a guide for researchers whether it can be advantageous to develop a flow system for a certain process. (57−59,72,73,77−82)

4.1.2. Flow Synthesis of Pharmaceuticals

By connecting several flow reactors, multistep syntheses can be carried out in an uninterrupted system. (56,83) The great benefit of this approach is that the isolation of intermediates can be eliminated, simplifying and accelerating this process (Figure 1b). Without transportation and off-line quality testing after each step, the footprint of the production facility can be reduced, improving flexibility at the same time. This is especially true for the synthesis of APIs, as these complex compounds often require 6–10 synthetic steps from the starting materials. (78) Usually some compromises are inevitable and the synthetic route is split up to shorter sequences for intermediate purification of the reaction mixtures or for solvent switch. (84) Integrating the operation steps, including in-line purification, workup, and real-time analysis requires holistic optimization and deep process understanding. Nevertheless, the telescoped synthesis of APIs under flow conditions has a growing body of literature (70,72,80,83,85,86) and due to the challenge of the integration of in-line purification into a flow system, this topic is also gaining more and more attention. (59,87,88) In Table 1 APIs with reported continuous flow total synthesis are summarized. Regarding the industrial application of flow chemistry, in 2018 Hughes collected seven examples from the patent literature for API synthesis, during which at least one reaction step is carried out under flow conditions. (89) However, in these cases it was not public whether these routes are used for commercial manufacturing or not.
Table 1. Examples for Published Multistep API Flow Syntheses
APIYear of publicationRef
Ibuprofen2009 (90)
Nabumetone2011 (91)
Fluoxetine2011 (92)
Artemisinin2012 (93)
Imatinib2013 (94)
Tamoxifen2013 (95)
Diphenhydramine HCl2013 (96)
Amitriptyline2013 (97)
Olanzapine2013 (98)
Rufinamide2014 (99)
LY28867212014 (100)
Aliskiren hemifumarate2014 (101)
Efavirenz2015 (102)
Rolipram + phenibut2015 (103)
Telmisartan2015 (104)
Ibuprofen2015 (105)
Ribociclib2016 (106)
Diphenhydramine HCl2016 (1)
Lidocaine HCl2016 (1)
Diazepam2016 (1)
Fluoxetine HCl2016 (1)
Pregabalin2017 (107)
Flucytosine2017 (108)
Captopril2017 (109)
Prexasertib2017 (110)
Clozapine2018 (111)
Hydroxychloroquine2018 (112)
Dolutegravir2018 (113)
16-DPA2018 (114)
Nicardipine HCl2018 (115)
Ciprofloxacin HCl2018 (115)
Neostigmine HCl2018 (115)
Rufinamide2018 (115)
Acetylsalicylic acid2018 (116)
Hymexazol2019 (117)
Vortioxetine2019 (118)
Flibanserin2019 (119)
Imatinib2019 (120)
Treprostinil2019 (121)
Ibuprofen2019 (122)
Lomustine2019 (123)
Linezolid2019 (124)
Lesinurad2020 (125)

4.1.3. API Flow Syntheses Integrated with Downstream Processes

In order to build end-to-end systems, the developed multistep flow synthesis of the APIs must be connectable to the subsequent technological steps. The final reaction is usually followed by the purification of the synthesized API, which can be carried out by numerous methods, including liquid–liquid extraction, chromatography, etc., but the compound must be brought to solid form with a continuous crystallization step. This is usually carried out in mixed suspension mixed product removal (MSMPR) crystallizers of plug flow reactors (PFRs) (for more details see section 4.2.1).
Only a handful of studies describe synthetic routes with emphasis on the connectability to the subsequent continuous workup processes. In a publication by Snead et al., in-line purification was integrated with the flow synthesis of diphenhydramine hydrochloride, followed by semibatch crystallization. (96) Ingham et al. presented a system in 2015 for the integration of three connected chemical steps coupled with liquid–liquid extraction, solvent exchange, and continuous filtration as well. (126) Similarly, the two-step synthesis of ribociclib—published by Pellegatti et al. in 2016—was followed by an in-house built in-line liquid–liquid extraction and a semibatch crystallization. (106) Although not synthesizing an API, Lichtenegger et al. developed a system in which flow chemical transformations were truly connected to continuous crystallization in PFRs. (127) With the incorporated in-line analysis and process control strategies, 6-h long operations were carried out without human intervention. In 2018, Balogh et al. developed and published the flow synthesis of acetylsalicylic acid (ASA). (116) The final reaction mixture was suitable for directly coupled formulation by electrospinning (see later in section 4.5). Tacsi et al. studied the continuous crystallization of ASA in an MSMPR crystallizer, in which the starting solution was the final reaction mixture of the flow synthesis of the API. (128) Thus, after the scale-up of the flow synthesis to relevant flow rates for continuous crystallization, the two developed processes could be run in an integrated fashion. In 2019, Rimez et al. published a two-step continuous tubular system incorporating a synthetic step and plug flow crystallization for the production of ASA crystals in 2019. (129) They further examined the crystallization step in a subsequent study, which might be ready for the connection to other flow chemical processes. (130)
In the research area of flow syntheses coupled to continuous workup procedures, a great work was accomplished by Ely Lilly and Company. (131) They conducted extensive research in the area of flow chemistry and the integration of the synthetic steps. Johnson et al. published a scaled-up system with flow synthesis, continuous crystallization, and filtration. (132) They carried out a high-pressure continuous asymmetric hydrogenation reaction in a PFR and then continuous liquid–liquid extraction for purification. Following this step, a semibatch solvent exchange distillation process, a two-stage MSMPR crystallization, and batch filtration were executed. The entire system was integrated, and stable operation was achieved on a kilogram per a week production scale. In the next paper they developed the synthesis of a drug candidate, LY2886721. (100) The system consisted of a flow chemical step and continuous reactive crystallization. In this study the authors presented the optimization of the processes, the scale-up and development of the equipment, and longer operational tests as well. In a follow-up study, Cole et al. developed the fully integrated continuous synthesis of prexasertib under cGMP conditions at a throughput of roughly 3 kg/day. (110) Eight reaction steps were incorporated in one system, and the previously described continuous liquid–liquid extractor, semibatch solvent exchange device, MSMPR crystallization, and batch filtration were all utilized during operation. The developed equipment and the knowledge of this study were transferred to the CM center of Ely Lilly and Company in Kinsale, Ireland.

4.2. Continuous Crystallization and Filtration

Crystallization is a key purification and separation technique in the pharmaceutical industry, and it is a critical step in connecting synthesis and formulation. (133) More than 90% of the currently marketed APIs are going through at least one crystallization step during their production. (134) The crystal size and shape have a strong impact not only on the downstream operations through bulk density or flowability but also on the dissolution rate and bioavailability of the final drug product. The importance of the process drew attention to continuous crystallization in the recent years. (135−138) In the technological line crystallization is followed by filtration for the isolation of the solid product. (139) This technique is usually assessed by the filterability of the crystals, the moisture content of the filter cake, and the recovered mass. Also, the process might affect the crystal size through agglomeration. (140) Continuous filtration is a relatively new area of study in the pharmaceutical industry, and only a handful of papers were published. In the following sections, continuous crystallization and filtration will be discussed focusing on connected and integrated continuous crystallization–filtration systems.

4.2.1. Continuous Crystallization

Currently, the vast majority of crystallizations in the pharmaceutical industry is carried out in stirred batch reactors. (138) These systems have been used for decades, and the processes are thoroughly optimized and reasonably well-understood. (136) However, there are still significant issues with batch-to-batch variability, which can lead to substantial difficulties in the downstream processing of the crystal product. (133) The root cause of batch-to-batch variability is the highly nonlinear crystallization kinetics, as well as the high sensitivity of secondary nucleation (primary nucleation is virtually eliminated by seeding) on the process parameters and seed quality, which, in practice, cannot be fully eliminated.
The implementation of novel continuous processes can provide a number of advantages in the area of crystallization. Continuous technologies naturally require smaller and thus cheaper equipment, reducing the production footprint. (135) As an example, for a given crystallization process to reach the same annual productivity a 250 L continuous reactor would be sufficient, while in batch mode a 5000 L reactor could provide the appropriate amount of crystalline product. (133) From an engineering perspective, the steady-state operation eliminates the inherent dynamic nature of the batch systems. By this, the continuous systems offer improved control and reproducibility over the physical characteristics of the product. By setting the appropriate operating conditions, the key parameters such as particle size and shape can be accurately controlled. (135) Additionally, certain downstream processes might be eliminated which are usually applied as particle size correction steps, e.g. granulation or milling. However, in the steady state of continuous crystallizations—unlike with batch systems—the equilibrium cannot be reached, decreasing the maximum attainable yield of the process. This can be overcome by the application of optimized recycle loops. Fouling of transfer lines and blockages are new challenges that arose with the new technology, which have to be addressed during process development. (135)
In the case of continuous crystallization, the API solution (and the antisolvent, if necessary) is continuously fed into the equipment, while the product slurry is continuously withdrawn. Numerous different systems have been published for the implementation of such a process. (136) The two most widespread technologies are the MSMPR crystallizers and the PFRs (Figure 3). (138)

Figure 3

Figure 3. Schematic drawing of (a) a mixed suspension mixed product removal crystallizer and (b) a plug flow reactor.

The MSMPR crystallizers are conventional jacketed stirred tank reactors, with continuous input of starting material and continuous product removal. The practical advantage of these systems is that the existing stirred tank equipment can be further utilized and can help to convert the existing batch crystallization processes to continuous operation. (135) By connecting several MSMPR reactors into a multistage cascade system, flexible temperature profiles can be used resulting in better control over crystallization mechanisms, (141) and the final stage concentration can be adjusted close to equilibrium for yield considerations. (134,142) On the challenges side, the continuous tank systems have broad residence time distributions, and the scale-up difficulties of the original batch processes cannot be overcome easily. MSMPR crystallization of APIs is a frequently studied topic in the literature. (135,137) The effects of process parameters, (143) different setups, (142,144) strategies, (141,145) and novel slurry transfer systems (146−148) are all examined in detail.
In tubular crystallizers the API solution is continuously flowing through a tube with constant flow rate. (135) The great benefit of these systems is the excellent process control due to the relatively small tube diameter being often on the order of centimeters, easy scale-up (similarly as described at flow reactors, in section 4.1), and the narrow residence time distribution, which can provide improved product uniformity. The steady state of tubular systems is comparable with the batch operation (with degenerate residence time distribution, a basic assumption of PFRs, is identical), which is a useful property when it comes to the batch to continuous transition. The literature of PFRs includes a substantial number of papers about the continuous crystallization of APIs. (130,149−153) An important variant of PFRs is the continuous oscillatory baffled crystallizer (COBC), where a piston provides an oscillatory flow which, in combination with and the internal orifices (baffles), can greatly reduce the sedimentation and clogging even at low net flow rates, i.e. long residence times. COBCs are applied for the processing of pharmaceuticals more and more frequently, mainly among academic researchers. (154−158) Nevertheless, the fouling in tubular crystallizers, PFRs or COBCs, is a significantly greater issue than in the case of MSMPR crystallizers. (159) Several strategies can be found in the literature to overcome this challenge, e.g. model-based antifouling control via temperature cycling, adding extra additive or solvent, increasing the conveying intensity, and applying new internal features to enhance mixing. (135,137,160)

4.2.2. Continuous Filtration

The produced crystals are separated from the mother liquor in the filtration step. (139) This is a technique often developed by practical and empirical understanding due to the complex nature of cake growth and properties and to the interacting process parameters. (161) Therefore, it is necessary to carry out experiments with the actual slurry on the required scale since predicting filtration performance is cumbersome. (162) In the pharmaceutical industry filtration is generally carried out in batch mode, but there are already a few examples for continuous filtration devices. (161,163) The low number of publications dealing with pharmaceutical-related continuous filtration is probably due to the fact that it is a complex technical challenge and involves the use of less established technologies. (25)
The few examples that can be found in the field of pharmaceutical-related continuous filtration are discussed in this section. Cross flow filtration is a well-known continuous filtration technique, mainly utilized during the processing of biological products to concentrate slurries. (164,165) Gursch et al. and Kossik et al. reported studies related to this technique for API suspensions with a membrane-based device (166,167) and a rotary drum filter. (168,169) Researchers at MIT designed, built, and tested the prototype of a small-scale continuous pharmaceutical filtration instrument using linear motion. (170) Pfizer developed a semicontinuous filter-drier with a 3-way valve, which filtered small amounts of slurry (15–30 mL) every cycle, yielding a kg per a day productivity. (171) In 2015, BHS Sonthofen marketed a manufacturing scale (up to 85 kg/h) continuous indexing belt filter with pressing and steam-drying capabilities. (172) This apparatus was tested in a study by Hohmann et al., in which they investigated the performance of a modular miniplant during the continuous downstream processing of an amino acid, l-alanine. The system comprised a wiped-film evaporator, a tubular crystallizer, and a vacuum belt continuous filter. (173) A continuous filter dryer prototype unit, CFD20 (Alconbury Weston Ltd.) was tested by Ottoboni et al. (Figure 4a). (140) Compared to standard batch filtration, similar results were obtained with the CFD20, but significantly less manual intervention was required due to the higher degree of automation.

Figure 4

Figure 4. (a) Picture of the CFD20 device applied by Ottoboni et al. (140) and (b) design of the hybrid filtration-drying-dissolution unit developed by Wong et al. (174) Reproduced with permission from refs (140) and (174). Copyright 2013 American Chemical Society and Copyright 2019 Elsevier.

4.2.3. Integrated Continuous Crystallization and Filtration

A few publications were found from the research area of continuous crystallization, in which the filtration step was addressed in any way. In 2012, Wong et al. presented a study about a single-stage MSMPR crystallizer with a recycle system. (175) In this system standard batch filtration was directly connected after crystallization using a coarse glass filter disk with a filter paper having 1 μm thickness. In 2014, Ferguson et al. built a similar single-stage MSMPR system with a filtration step connected directly to the outlet. (176) After the filtration of crystals, the mother liquor was subjected to an organic solvent nanofiltration method in order to eliminate the impurities and increase the concentration of the remaining dissolved API, deferasirox. Acevedo et al. connected a single-stage MSMPR reactor to a continuous filtration carousel (CFC) device (similar to the one used by Ottoboni et al. (140)). (177) A buffer tank was applied between the two steps, and after the optimization of filtration parameters, stable operation was achieved with this two-step system. In 2019, Liu et al. further examined the connectability of the CFC with continuous crystallization in a novel oscillatory baffle reactor (OBR). (178) In this study, paracetamol and benzoic acid were crystallized, and the filtration performance showed significant dependence on crystal size and shape. Wong et al. designed and built a compact system of a continuous MSMPR crystallizer (with novel scraped surface impeller design) coupled with a hybrid filtration-drying-dissolution unit (Figure 4b). (174) Three APIs with different shape attributes were used as model compounds: fluoxetine hydrochloride, ibuprofen, and diphenhydramine hydrochloride. By applying scraped wall crystallization, improvements were accomplished in terms of better kinetics and reduced aggregation, and the semibatch application of the hybrid device saved a considerable amount of time and material, while appropriate performance was achieved with each step. Capellades et al. designed and investigated a similar device, in which filtration, drying, and mechanical processing were integrated. (179) A unique impeller was applied to enhance the processability of needle-like crystals of ciprofloxacin hydrochloride, and this way they successfully reduced the amount of lumps in the material following filtration and drying. Nagy et al. developed the model of an integrated continuous crystallization-filtration system in 2020. (180) In this publication the effect of slurry properties on filtration performance was studied, and simulations were carried out with the integrated system which showed good correspondence with experimental data.

4.3. Continuous Powder Blending and Tableting

Blending of powders is an essential step in many industrial sectors such as the manufacture of chemicals, construction materials, foods, and drugs. (181) Ensuring the homogeneity of the produced powder blend is pivotal, and it is especially true for drug products. (182) The appropriate distribution of the API in the excipients is the key to produce final dosage forms, i.e. tablets with acceptable drug content uniformity. Continuous blending has long been known in the mentioned industries; (183) however, in the pharmaceutical industry, batch mixers are applied in the vast majority of cases to date. (184) The rising of continuous pharmaceutical manufacturing in recent years gave a new push to continuous blending as well.
Continuous blending has a number of advantages over the traditional batchwise method, similar to the case of the earlier described technologies in previous sections. (182) Steady state operation can be reached within a few minutes, in which process control is much more accurate, improving quality. (184) The equipment used for process development can be used for production, eliminating the difficulty of scale-up and reducing the footprint. The continuous operation makes the integration possible with the following continuous tableting step. Thus, the overall efficiency and final product quality can be increased. These advantages can significantly reduce costs during development and manufacturing of pharmaceuticals. (185)
The main body of most continuous blenders is a cylindrical chamber with an average diameter of 3.5–20 cm and an average length of 25–75 cm (Figure 5a). At one end of the cylindrical chamber there is a vertical inlet (hopper) for feeding the materials into the blender. (9) At the other end, the chamber is open allowing the produced powder mixture to leave the device. Motor-driven rotating impellers can be found in the chamber, which mix the components. Bladed, ribbon or ribbon-bladed impellers can be applied, which direct the flow in axial direction (Figure 5). (184)

Figure 5

Figure 5. (a) Schematic drawing and (b) photograph of a twin-screw continuous blender; and photographs of a (c) paddle and (d) a ribbon blender.

Vanarase et al. published a study about an experimental investigation of the mixing performance and flow behavior in a continuous blender using a pharmaceutical mixture. (186) The impeller rotation rate was found to be the most important process parameter affecting the mixing performance, and the blade configuration also had an effect on powder homogeneity. A similar study was conducted by Osorio et al. in 2016 using a novel continuous blender. (187)
Different strategies can be applied to reach a final dosage form after the blending step. (188) The most common and widespread tablet formulation is produced mostly in high-throughput rotary tableting machines. (189) The simplest way is the so-called “direct compression” technology, during which the blend of the API and the excipients is directly sent to tableting (Figure 6a). Otherwise granulation can be applied to improve powder characteristics and to reduce the risk of segregation after blending (Figure 6c). In this field, either wet or dry granulation can be applied, followed by drying, milling, and another blending step before tableting. Roller compaction is another way to modify the particle size (Figure 6b). Moreover, the powder mixture can directly be filled into capsules. (190)

Figure 6

Figure 6. Different strategies for the production of final dosage forms after blending: (a) direct compression, (b) roller compaction followed by milling and another blending step, and (c) granulation, drying, milling, and blending again (adapted from ref (188)).

As interest in CM is growing in the pharmaceutical industry, more and more research is performed on integrated powder-to-tablet manufacturing lines. (26) This approach is much more beneficial than using single unit operations, since interactions between the individual steps might affect the quality of the final product. Direct compression is the easiest way to develop such an integrated system. (191) In this case controlling the flowability and compressibility of the components is paramount to obtain tablets of good quality. Järvinen et al. studied the effects of the rotation rate of the mixing impeller, the total feed rate, and the drug content on tablet properties and drug release in an integrated continuous blending-direct compression line. (189) All results showed good drug release, while process parameters affected tablet uniformity. Ervasti et al. produced HPMC-ibuprofen extended release tablets on a similar continuous blending-direct compression manufacturing line. (192) The importance of good flowability was also underlined, as the best results were obtained with the good-flowing samples with large particle size. Researchers at the University of Eastern Finland constructed a modular CM line. (193) This system was tested in a study by Simonaho et al. during the continuous production of tablets with three different system configurations. Van Snick et al. conducted a study for the production of sustained release tablets with a continuous direct compression system. (194) Azad et al. designed and built a compact, portable, reconfigurable, and automated tableting machine at MIT. On-demand flexible tablet manufacturing was feasible with this device, which was demonstrated in two studies with several compounds. (195,196)
In order to ensure the uniformity of the powder product of the continuous blending, real-time analytical techniques have to be applied. Several measurement methods are known, such as spectroscopy (NIR, Raman), image analysis, acoustic techniques, and many others, which are carefully collected in reviews. (197−200) These analytical methods were applied successfully in numerous cases. Nagy et al. used Raman spectroscopy for the monitoring and feedback control of a continuous blending and tableting process. (201) Successful experiments were carried out with the model system of caffeine, glucose, and magnesium stearate, introducing the Process Analytical Controlled Technology (PACT) method. In a recent paper published by Palmer et al., the performance of a direct compression system was tested for a wide range of process parameters and material attributes. (202) The API content in the powder blend was monitored by a NIR probe. The DoE framework was applied to find the relationship between process parameters, material properties, and the quality of the produced tablets. Numerous further examples can be found for the development of continuous blending processes, for the investigation of the connectability with continuous tableting, and for the implementation of in-line analysis in a complex continuous blending-tableting system. (203−210)

4.4. Novel Continuous Formulation Techniques

On the way moving from batch production toward CM, besides evaluating the applicability of the traditional production steps for continuous operation, novel methods should be evaluated as well. Many technologies exist which are inherently continuous, and the spread of CM in the pharmaceutical industry can bring the breakthrough for these processes. Such techniques are for example electrospinning (ES) and hot-melt extrusion (HME), allowing the preparation of amorphous solid dispersions (ASDs). (211) ASDs are innovative drug delivery systems designed to enhance the bioavailability of poorly soluble drugs. Since a substantial amount of recently discovered APIs have very low water solubility, the importance of such innovative drug delivery systems is increasing. (212)

4.4.1. Hot-Melt Extrusion and Dropwise Additive Manufacturing

Among the formulation methods of ASDs, HME is probably the most popular technique. HME was originally adapted from the plastic industry. (213) During the process, a drug-polymer mixture is fed into the heated equipment, where usually corotating screws transport the melted material toward the end of the extruder. After cooling, the product is forwarded to cutting or grinding. This technique is intrinsically continuous, having as the main advantage over ES the solvent-free operation. As a limitation, HME is suitable exclusively for thermostable APIs.
HME has been applied several times for the continuous formulation of pharmaceutical products. Drug-loaded pellets, granules, or tablets were produced by HME in the studies of Kalivoda et al. and Gryczke et al. (214,215) In a publication by Baronsky-Probst et al., the continuous production of pharmaceutical tamper-resistant tablets was carried out by HME. In their work a DoE approach was applied to investigate the relationship between CPPs and CQAs of the product. NIR spectroscopy was used as a PAT tool for real-time analysis, which greatly facilitated the rapid product quality evaluation. (216) HME has industrial applications, too: melt granulation was used in the formulation of a Novartis product comprising metformin and vildagliptin. (217,218)
Dropwise additive manufacturing is another innovative method for the production of final drug products. (219) The principle of the process is the predictable and controllable deposition of a droplet containing an API onto an edible substrate, such as a polymeric film or a placebo tablet. Solvent-, melt-, and suspension-based processes can be developed, and continuous operation is easily attainable. (220) Among several applications, Radcliffe et al. utilized the method using nonideal particulate suspensions for the production of high-dose drug products. (221) Içten et al. presented a supervisory control system for the reproducible production of a melt-based solid oral formulation by drop-on-demand manufacturing. (219)
Dropwise techniques like injection molding and 3D printing have been coupled to HME as well, (222) allowing the production of either sustained- or immediate-release matrix tablets. (223) Zhang et al. investigated the differences between tablets produced by HME and 3D printing and direct compression of milled extrudates and tablets prepared from physical mixtures of the ingredients. (224) In another publication, carvedilol-loaded 3D-printed floating tablets were produced. (225) It was found that the integration of HME and printing techniques is advantageous for both bioavailability improvement and production efficiency. This is a promising approach for personized medicine; albeit, its throughput is significantly lower than e.g. in tableting. (213)

4.4.2. Electrospinning

ES is a well-known technique for the production of ASDs by applying high voltage on a solution containing an API and a polymer excipient (Figure 7). (226−228) The pharmaceutical utilization of the technique is reported in a vast amount of literature, since the versatility of the available polymers allows the formation of ASDs with sustained, controlled, and ultrafast release. (229−236)

Figure 7

Figure 7. Schematic representation of a single-needle electrospinning process, with the scanning electron microscopic picture of the electrospun material on the right.

The applicability of electrospinning for the continuous production of orally dissolving web (ODW) formulations containing a poorly soluble API (carvedilol) was presented in 2019. (237) As regards the industrial applicability of ES, scaling the laboratory-size ES process up to industrially relevant volumes has recently been presented. (238,239) The downstream processing of the electrospun material, enabling the direct integration of ES into the CM line, has also been published. (213,240) Despite the promising studies, the high potential shown in laboratory systems, and its intrinsically continuous manner, ES has not become a widely applied industrial technique yet.

4.5. End-to-End Continuous Production of Final Dosage Forms

Although significant progress has been made in the field of continuous pharmaceutical manufacturing covering the entire production line from drug substance to drug product manufacturing, the majority of published research works treats the operations separately. Only a few examples refer to processes that were developed with connectability to other technological steps in mind, and even fewer publications were found in which two or more continuous processes have been truly integrated. However, in order to fully exploit the advantages of continuous technologies, the connection of more and more technological steps must be pursued. The final aim would be the development of end-to-end systems, in which the materials are flowing through from raw materials to the final dosage forms in one complete, continuous system (Figure 8). In the following part the published examples for such systems will be presented.

Figure 8

Figure 8. Concept of end-to-end continuous pharmaceutical manufacturing from raw materials to final products with real-time quality control (adapted from ref (227)).

The Novartis-MIT Center for Continuous Manufacturing was one of the first locations where intensive and thorough continuous process research was conducted. The model API was aliskiren hemifumarate, which was synthesized starting from an advanced intermediate. The first example for the end-to-end production of heat-mold tablets of the API was designed and built, in which all technological steps, including flow synthesis, continuous crystallizations, filtrations, and extractions, were integrated and automated (Figure 9a). (10,101,241) In a follow-up work the previous, container-sized continuous production unit was reduced to the size of a typical refrigerator. (1,242) This was designed in a reconfigurable manner, and four different APIs (diphenhydramine hydrochloride, lidocaine hydrochloride, diazepam, and fluoxetine hydrochloride) could be synthesized. The flow synthesis was followed by batch downstream steps of crystallization, filtration, and redissolution to obtain liquid dosage forms. This platform was further improved by incorporating continuous crystallization, semicontinuous filtration, washing, dispensing, and drying (Figure 9b). (115) In this second-generation system nicardipine hydrochloride, ciprofloxacin hydrochloride, neostigmine hydrochloride, and rufinamide were synthesized, purified, and formulated into the previously mentioned liquid oral dosage form. The first fully automated end-to-end commercial ready CM pilot plant was developed by Continuus Pharmaceuticals, a spinoff company of the Novartis-MIT collaboration, and presented by Hu et al. in 2019. (243) This system consisted of a dissolution unit for the raw materials, a five-stage reactive MSMPR crystallization cascade, a continuous filter followed by resuspension, a novel continuous drum dryer, and hot melt extrusion for the preparation of the final heat-mold tablets. PAT probes were applied for real-time analysis, e.g. in the reactive crystallization and for the monitoring of particle size after filtration. The E-factor analysis of the system in another publication revealed substantial improvements compared to batch manufacturing. (244) The same group published the design and commercialization of a pilot-scale end-to-end CM system, where the significantly lower capital and operating costs were highlighted. (245)

Figure 9

Figure 9. Examples for published continuous end-to-end manufacturing systems for the production of (a) heat-mold tablets of aliskiren hemifumarate (10) and (b) liquid dosage forms of nicardipine hydrochloride, ciprofloxacin hydrochloride, neostigmine hydrochloride, and rufinamide. (115) Reproduced with permissions from refs (10) and (115). Copyright 2013 John Wiley and Sons and Copyright 2018 John Wiley and Sons.

The end-to-end production of an ODW final dosage form containing ASA was published by Balogh et al. in 2018, presenting the development and optimization of the two-step flow synthesis of the API. (116) High voltage was applied on the reaction mixture leaving the second microreactor; thus, the synthesized API was processed directly by ES to form a nanofibrous product (Figure 10). The ASA-loaded nanofibers produced from the flow reaction mixture were collected on the surface of a continuously moving carrier film, and the formed double-layered strip was cut it into smaller pieces ready for patient administration.

Figure 10

Figure 10. End-to-end production of acetylsalicylic acid-loaded electrospun orally dissolving web dosage forms. The API was synthesized in a 2-step process in flow microreactors and formulated into nanofibers by applying high voltage on the reaction mixture. Reproduced with permission from ref (116). Copyright 2018 Elsevier.

The first example for the end-to-end production of conventional compressed tablets was presented in 2020 on a proof of concept level. (246) In this study the MSMPR crystallization of the flow reaction mixture of ASA was directly connected to continuous filtration in a CFC device (the same used by Acevedo et al. and Liu et al. in earlier studies (177,178)). The continuously filtered product was moved to a continuous blending step with the tableting excipient microcrystalline cellulose (Figure 11). The materials were fed into a continuous twin-screw blender, and a conveyor belt carried the produced blend to an eccentric tablet press, which pressed it into 500 mg tablets of 100 mg dose strength. The continuous production of ASA-loaded tablets was accomplished with a throughput of 300 g/h, which could provide 14400 dosage units per day. The in-line analysis of the powder blend showed very low fluctuation in ASA concentration, which was in good agreement with the at-line and off-line analysis of the produced tablets.

Figure 11

Figure 11. Feeding of MCC and ASA into the hopper of the continuous blender (left); NIR probe mounted above the belt conveyor after blending (middle); continuous blender, belt conveyor, and tableting machine integrated in one CM line (right) (adapted from ref (246)).

Although technically not an end-to-end solution, it is noteworthy to mention the study of Hadiwinoto et al., where the production of a final dosage form in an integrated continuous system was accomplished. (247) Spray drying was connected directly to process the slurry produced by a tubular crystallizer, which was demonstrated for two APIs (rifapentine and beclomethasone dipropionate). Process performance was evaluated, and the continuous operation was optimized to produce a dosage form applicable for pulmonary delivery.

5. Conclusions

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Reviewing the recent literature of the continuous pharmaceutical technologies revealed that significant progress has been made to achieve CM in pharmaceutical manufacturing. In the case of flow synthesis, it is clear that although the total synthesis of a few dozen APIs has already been published, more research is necessary to build continuous end-to-end systems. The multistep synthesis of pharmaceuticals must be developed in a way to be connectable with the following technological steps for the workup of the reaction mixture. A couple of publications were presented, which are excellent examples of how continuous crystallization and (semi-) continuous filtration could be coupled in a continuous manner for pharmaceutical purposes and how it could be built in multistep processes. Although numerous examples exist for integrated continuous blending–tableting systems, connection with the upstream manufacturing was made only in a handful of studies. The majority of continuous technologies are developed separately by examining the individual steps alone. The true integration of the processes is often full of challenges, related to the throughput at which the individual operations are being developed, the effect of impurities, and the propagation of disturbances through the continuous system. The development of true end-to-end CM systems for the production of any type of final dosage form is an important scientific topic, while only a very small number of publications can be found in the literature dealing with it. Therefore, it would be of great interest and high techno-economic impact to develop further end-to-end systems to produce either novel drug delivery systems or conventional tablets. The integration of separate technological steps and unit operations allow leveraging the advantages and promises of CM from every perspective, starting from process safety improvements, through the economic and ecological advantages, to the realization of shorter supply chains and production times. Clearly, developing true end-to-end integrated CM technologies requires wide interdisciplinary efforts, ranging from fundamental chemistry aspects to advanced process monitoring and plant-wide control, and recently, machine learning and artificial intelligence are also involved.

Author Information

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  • Corresponding Author
  • Authors
    • András Domokos - Budapest University of Technology and Economics, Organic Chemistry and Technology Department, H-1111 Budapest, HungaryOrcidhttp://orcid.org/0000-0003-1968-4679
    • Brigitta Nagy - Budapest University of Technology and Economics, Organic Chemistry and Technology Department, H-1111 Budapest, Hungary
    • Botond Szilágyi - Budapest University of Technology and Economics, Faculty of Chemical Technology and Biotechnology, H-1111 Budapest, Hungary
    • György Marosi - Budapest University of Technology and Economics, Organic Chemistry and Technology Department, H-1111 Budapest, Hungary
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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This work was supported from grants by National Research, Development and Innovation Office of Hungary (grant numbers: KH-129584, FK-132133, PD-121143). This work was also performed in the frame of FIEK_16-1-2016-0007 project, implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the FIEK_16 funding scheme. The research reported in this paper and carried out at BME has been supported by the NRDI Fund (TKP2020 IES, Grant No. TKP2020 BME-IKA-VIZ) based on the charter of bolster issued by the NRDI Office under the auspices of the Ministry for Innovation and Technology, supported by the ÚNKP-20-3 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund.

References

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