The pharmaceutical industry has relied on batch processing to manufacture medicinal products for decades.
A typical production campaign takes 4-8 weeks, and is labour and chemical intensive. Batch-to-batch variations often cause quality concerns. As a result, regulatory agencies are increasingly auditing batch production records focusing on any observable variations. Facing increasing pressure on quality and costs, the industry is gradually embracing the concept of continuous manufacturing. The pivotal technology to achieve more e(icient, reliable and economic pharmaceutical production lies in flow chemistry.
Flow Chemistry and Microreactor Technology
Flow chemistry provides a novel approach to conduct chemical synthesis in a continuous flowing stream instead of traditional batch stationary reactors. In a flow system, a given chemical reaction occurs in a microreactor — a microfabricated system hosting multiple sub-millimeter microchannels.1 Reactants are continuously pumped into the microreactor, where they mix and react, and the product is continuously collected. The inner volume of the microreactor is usually less than a millilitre.2 Additionally, individual microreactors can be tethered and sequenced so that a virtual microfluidic chemical plant is obtained. The small size of the microreactor o(ers high surface-to-volume ratio which translates into more e(icient mixing, heat and mass transfer than traditional batch reactor, ultimately leading to higher yields and better product profile with fewer impurities. This feature is especially useful in handling reactions that are highly exothermic (e.g. hydrogenation, oxidation, nitration), or require hazardous or unstable materials (e.g. halogens, cyanides, carbon monoxide). Moreover, important process parameters such as mixing, temperature, pressure, flow rate, reaction residence time are under rigorous control, allowing fast parameter screening and process optimization.3 Due to the tiny volume and high controllability, microreactor technology opens the door to develop new chemical reactions under conditions that are considered di(icult or even impossible in batch reactors (e.g. flash chemistry, high temperature/pressure). Many of these new routes lead to new types of molecules. Exciting research is underway to develop new methodologies for the selective synthesis of complex chiral drugs under continuous flow organocatalysis.4 Another benefit o(ered by flow chemistry is fast and simple scale-up strategies. The production capacity of a microreactor can be increased in three ways:  Increasing the capacity/size of the microreactor (scaling up).  Increasing the number of reactors running in parallel (numbering up). This method is common in the industry, particularly for biopharmaceutical production.  Run the reaction for longer (scaling out) reactor will improve yields. Therefore, for flow chemistry, scale-up from microgram to kilogram quantities o'en require minimal chemistry modifications or reactor engineering.
Flow Processing for Continuous API Manufacturing
Flow technology was introduced to the pharmaceutical manufacturing in the early 2000s, when academic scientists started to develop a flow system for active pharmaceutical ingredients (APIs) and intermediate synthesis. Scientists from the industry (mainly from large pharmaceutical companies) joined the endeavour to apply flow chemistry around the mid-2000s. They focused more on applying flow technology to solve industrial problems, such as scale-up, as well as understanding the benefits of continuous manufacturing over conventional batch processing. Through comparison, flow processing has been demonstrated to be safer, cleaner, more e(icient and cost-e(ective. In general, continuous flow systems can be divided into four types: type I, II, III and IV (Table 1). Both type I and type II systems are designed for catalyst-free reactions, while types III and IV require the presence of a catalyst. All reagents in type I and type III systems are flowed through the reactor. For type III, a separation step is required to remove the catalyst from the product. The type II system constitutes a solid reactant that is confined into the reactor. In the type IV system, the catalyst is immobilized onto the reactor while the reactants are flowed through, in which separation is unnecessary. Additionally, type IV is the preferred system to conduct multistep synthesis under continuous flow stream.4 Multiple synthesis is extremely important for complex API preparations. A trend in microreactor technology is to develop modular flow reactors based on various reaction types and physicochemical characteristics. Depending on the specific requirements for the reaction and process, the appropriate microreactor is selected and assembled with other integrated components, including heating and cooling zones, micro-mixers, residence tubing coils, separators, and diagnostic/analysis units.5 This customized microreactor configuration is expected to expand flow-based applications and promote industry-wide adoption.
Integration of In-line Analytical Technologies
Under the quality by design (QbD) paradigm, there is a strong focus on process understanding of the impact of process parameters and material attributes on product quality. Implementing process analytical technology (PAT) gains such process knowledge and develops riskbased quality control. In flow process development, integrating in-line analytical technologies provides a valuable tool to understand and monitor the system in real time. Based on this analytical information, process conditions can be optimized and maintained through the operation; variations or problems can be identified and responded to immediately without affecting downstream processes.6 In addition, advances in sensor technology and process sampling can greatly enhance the capability of in-line monitoring and control. In recent years, Fourier transform infrared spectroscopy (FTIR) has gained ground as a novel analytical technique for in situ, real-time monitoring of continuous flow chemistry. FTIR is designed to simultaneously detect a wide range of the infrared spectrum of absorption or emission of a solid, liquid or gas. In the flow process, it is useful to determine the chemical structure and product concentration as well as identifying unstable species. FTIR can be integrated into the flow system by adding a capping layer of IR transparent materials to the microchannel or installing an off-chip FTIR detector to the microreactor.1 For gas-phase reactions, a challenging area for FTIR, photoacoustic spectroscopy (PAS) is a potential alternative analytical method for reaction monitoring.
End-to-End Pharmaceutical Manufacturing
Over almost two-decades of development, flow chemistry has evolved from a novel synthesis concept to a powerful and versatile platform for continuous manufacturing of APIs with high productivity, a small manufacturing footprint, and reduced cost and waste. A new ambitious goal is now centred on integrating the entire pharmaceutical manufacturing process, from raw materials to final dosage forms, into a continuous flow process. Scientists form Massachusetts Institute of Technology (MIT) are leading this e(ort. In 2013, a research team at MIT (sponsored by Novartis) showcased the proof of concept by synthesizing aliskiren from advanced intermediates to final tablets in a continuous flow process. The manufacturing process was performed in a compact plant module (2.4m×7.3m2) where flow synthesis, purification, formulation and tableting were fully integrated.7 In 2016, the same team developed a refrigerator-sized (1.0m×0.7m×1.8m, [W×L×H]), reconfigurable manufacturing platform that can perform multistep synthesis, work-up, purification (e.g. crystallization), formulation and real-time monitoring. Four drugs were tested on the platform from commercially available starting materials to finished forms at a rate of hundreds to thousands oral or topical liquid doses per day. Moreover, the final products met US Pharmacopeia standards.8
Two remarkable FDA approvals have heralded a manufacturing paradigm shi' towards continuous manufacturing. The first was for Vertex’s Orkambi (lumaca'or/ivaca'or for cystic fibrosis) in 2015 as the first New Drug Application (NDA) approval for using a continuous manufacturing technology for production. A 4,000-square-foot continuous manufacturing facility was built in Boston for this purpose. The second FDA approval was for Johnson & Johnson’s Prezista (darunavir for HIV) in 2016 as the first NDA supplement approval for switching from batch manufacturing to continuous manufacturing.6 The company plans to produce 70% of its highest-volume products through continuous manufacturing within 8 years. The FDA has been a strong advocate for continuous manufacturing since the launch of the Pharmaceutical cGMP initiative in 2002. According to the agency, there are no regulatory hurdles for implementing continuous manufacturing. However, there is a lack of experience. Early and frequent discussion with FDA before implementation is highly recommended. The aforementioned FDA approvals paved regulatory pathways are essential for continuous manufacturing.
Due to its risk-averse nature, the pharmaceutical industry has been slow to adopt continuous processing technology. It is exciting to see that most large pharmaceutical companies are at the forefront of early adoption. GlaxoSmithKline and Eli Lilly have announced plans to build continuous manufacturing plants in Singapore and Ireland, respectively. Other large companies like Novartis, Merck, Bayer, and AstraZeneca have been working on continuous manufacturing for many years. A small number of contract manufacturing organizations (CMO) have also specialized in continuous manufacturing. The industry is likely to witness a growing trend in continuous manufacturing of APIs, as well as tableted products. Developing robust continuous flow processes requires great levels of chemical, analytical, and engineering expertise and sophistication. Behind the success of Vertex and Johnson & Johnson’s FDA approvals are years of collaborations between industry and academia. Communications between these two groups are quite important in order to develop novel practical continuous flow approaches that meet industrial needs. In addition, developing customized microreactors requires collaboration between pharmaceutical companies and equipment manufacturers, so that microreactors can be tailored to meet the requirement for production scales.
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