Continuous flow technology vs. the batch-by-batch approach to produce pharmaceutical compounds

Introduction: For the manufacture of small molecule drugs, many pharmaceutical innovator companies have recently invested in continuous processing, which can offer significant technical and economic advantages over traditional batch methodology. This Expert Review will describe the reasons for this interest as well as many considerations and challenges that exist today concerning continuous manufacturing.

Areas covered: Continuous processing is defined and many reasons for its adoption are described. The current state of continuous drug substance manufacturing within the pharmaceutical industry is summarized. Current key challenges to implementation of continuous manufacturing are highlighted, and an outlook provided regarding the prospects for continuous within the industry.

Expert commentary: Continuous processing at Lilly has been a journey that started with the need for increased safety and capability. Over twelve years the original small, dedicated group has grown to more than 100 Lilly employees in discovery, development, quality, manufacturing, and regulatory designing in continuous drug substance processing. Recently we have focused on linked continuous unit operations for the purpose of all-at-once pharmaceutical manufacturing, but the technical and business drivers that existed in the very beginning for stand-alone continuous unit operations in hybrid processes have persisted, which merits investment in both approaches.     

Development of a Novel Continuous Filtration Unit for Pharmaceutical Process Development and Manufacturing

The lack of a commercial laboratory, pilot and small manufacturing scale dead end continuous filtration and drying unit it is a significant gap in the development of continuous pharmaceutical manufacturing processes for new active pharmaceutical ingredients (APIs). To move small-scale pharmaceutical isolation forward from traditional batch Nutsche filtration to continuous processing a continuous filter dryer prototype unit (CFD20) was developed in collaboration with Alconbury Weston Ltd. The performance of the prototype was evaluated by comparison with manual best practice exemplified using a modified Biotage VacMaster unit to gather data and process understanding for API filtration and washing. The ultimate objective was to link the chemical and physical attributes of an API slurry with equipment and processing parameters to improve API isolation processes. Filtration performance was characterized by assessing filtrate flow rate by application of Darcy's law, the impact on product crystal size distribution and product purity were investigated using classical analytical methods. The overall performance of the 2 units was similar, showing that the prototype CFD20 can match best manual lab practice for filtration and washing while allowing continuous processing and real-time data logging. This result is encouraging and the data gathered provides further insight to inform the development of CFD20.     

Small-Scale Continuous Drug Product Manufacturing using Dropwise Additive Manufacturing and Three Phase Settling for Integration with Upstream Drug Substance Production

The pharmaceutical industry has traditionally relied on mass manufacturing to make its products. This has created multiple problems in the drug supply network, including long production times, inflexible and sluggish manufacturing and lack of personalized dosing. The industry is gradually adapting to these challenges and is developing novel technologies to address them. Continuous manufacturing and 3D printing are two promising techniques that can revolutionize pharmaceutical manufacturing. However, most research studies into these methods tend to treat them separately. This study seeks to develop a new processing route to continuously integrate a 3D printing platform (Drop-on-Demand, DoD, printing) with crystallization that is generally the final step of the active ingredient manufacturing. Accomplishing this integration would enable harnessing the benefits of each method- personalized dosing of 3D printing and flexibility and speed of continuous manufacturing.A novel unit operation, three-phase settling (TPS), is developed to integrate DoD with the upstream crystallizer. To ensure on-spec production of each printed dosage, two process analytical technology tools are incorporated in the printer to monitor drug loading in manufactured drug products in real time. Experimental demonstration of this system is carried out via two case studies: the first study uses an active ingredient celecoxib to test the standalone operation of TPS; the second study demonstrates the operation of the integrated system (crystallizer – TPS – DoD) to continuously make drug products for the active ingredient- lomustine. A dissolution test is also performed on the manufactured and commercial lomustine drug products to compare their dissolution behavior.     

Using Compartment Modeling to Investigate Mixing Behavior of a Continuous Mixer

In this paper, the development of a compartment model to simulate mixing within a continuous blender is reported. The main benefit of the method is that it can generate extensive modeling predictions in very short computational time. The model can also be used to explore the effect of sampling parameters on estimated mixing performance, a topic that has been central to pharmaceutical manufacturing for the past 15 years and that remains a central issue in the PAT initiative. However, this method requires more input than conventional particle dynamics methods. Thus, we investigate the effects of modeling parameters on mixing performance to develop general guidance needed to adapt this modeling framework to any continuous process. An experimental technique based on longitudinal sampling is used to examine the content uniformity of the blend along the continuous mixer. The model compares favorably with continuous mixing experiments, capture the effects of feeding rate variability, active product ingredient concentration, and blender processing angle, while effectively capturing and making explicit the effect of sampling parameters such as number of samples and sample size. The modeling approach provides a convenient tool for process design.     

The reality of in-line tablet coating

The possibility of continuous processing in pharmaceutical tablet manufacturing is hampered by the viscoelastic recovery of tablets post-compaction. Compacted tablets are typically aged before coating to allow complete viscoelastic recovery so as to avoid subsequent coating defects. There has been little attempt to overcome tablet recovery in order to enable continuous processing and improve manufacturing efficiency. However, with the introduction of improved or newly developed types of tablet-coating equipment, there is renewed interest in the coating of tablets in-line. In-line tablet coating is defined as the coating of tablets immediately after compaction. It is a one-step highly integrated system that circumvents the delay in processing time typically given to allow viscoelastic recovery of tablets. This review aims to summarize the requirements of an in-line tablet-coating system. The possibility of carrying out in-line tablet coating in the near future will also be discussed.     

A proposal for a drug product Manufacturing Classification System (MCS) for oral solid dosage forms

Abstract

This paper proposes the development of a drug product Manufacturing Classification System (MCS) based on processing route. It summarizes conclusions from a dedicated APS conference and subsequent discussion within APS focus groups and the MCS working party. The MCS is intended as a tool for pharmaceutical scientists to rank the feasibility of different processing routes for the manufacture of oral solid dosage forms, based on selected properties of the API and the needs of the formulation. It has many applications in pharmaceutical development, in particular, it will provide a common understanding of risk by defining what the “right particles” are, enable the selection of the best process, and aid subsequent transfer to manufacturing. The ultimate aim is one of prediction of product developability and processability based upon previous experience.

This paper is intended to stimulate contribution from a broad range of stakeholders to develop the MCS concept further and apply it to practice. In particular, opinions are sought on what API properties are important when selecting or modifying materials to enable an efficient and robust pharmaceutical manufacturing process. Feedback can be given by replying to our dedicated e-mail address (mcs@apsgb.org); completing the survey on our LinkedIn site; or by attending one of our planned conference roundtable sessions.     

Continuous Twin Screw Wet Granulation and Drying—Control Strategy for Drug Product Manufacturing

The use of continuous manufacturing has been increasing within the pharmaceutical industry over the last few years. Continuous direct compression has been the focus of publications on the topic to date. The use of wet granulation can improve segregation resistance, uniformity, enhance density, and flow properties for improved tabletability, or improve stability of products that cannot be manufactured by using a direction compression process. This article focuses on development of appropriate control strategies for continuous wet granulation (especially twin screw wet granulation) through equipment design, material properties and manufacturing process along with areas where additional understanding is required. The article also discusses the use of process analytical technologies as part of the control and automation approach to ensure a higher assurance of product quality. Increased understanding of continuous wet granulation should result in increased utilization of the technique, thereby allowing for an increase in diversity of products manufactured by continuous manufacturing and the benefits that comes with a more complex process such as wet granulation compared with direct compression process.     

Simulation-Based Design of an Efficient Control System for the Continuous Purification and Processing of Active Pharmaceutical Ingredients

In this study, an efficient system-wide controlsystem has been designed for the integrated continuous purification and processing of the active pharmaceutical ingredient (API). The control strategy is based on the regulatory PID controller which is most widely used in the manufacturing industry because of its simplicity and robustness. The designed control system consists of single and cascade (nested) control loops. The control system has been simulated in gPROMS ^TM (Process System Enterprise). The ability of the control system to track the specified set point changes as well as to reject disturbances has been evaluated. Results demonstrate that the model shows an enhanced performance in the presence of random disturbances under closed-loop control compared to an open-loop operation. The control system is also able to track the set point changes effectively. This proves that closed-loop feedback control can be used in improving pharmaceutical manufacturing operations based on the Quality by Design (QbD) paradigm.     

药品连续制造全球监管发展现状与思考

目的：在连续制造技术越来越多地应用在药品领域这一背景下,综述相关法规指南从概念探索、 正式发起至发布的发展历程,介绍全球多个采用连续制造技术生产药品获批上市的概况,探讨促进我国业界和监管机构借鉴全球药品连续制造发展经验。方法：通过对比传统的批量制造技术以分析连续制造具有的优势和面临的挑战,结合对全球监管指南制定过程中各监管机构对策的梳理,研究相关共识的发展考量和意义。结果：药品连续制造监管发展已经进入了新的时代,我国相关法规指南的制定和产业技术水平提升需要借鉴全球发展的经验,特别是国际人用药品注册技术协调会及美、欧、日等国家药品监督管理机构或国际组织的现有指南在批定义、工艺验证、稳定性等方面的监管对策,为该新兴技术的监管科学研究提供理论基础。结论：通过对药品连续制造全球监管发展现状的综述和思考,为我国相关法规、技术指南和标准的制定提供参考,并希望为产业发展发挥促进作用。     

Model-based analysis of high shear wet granulation from batch to continuous processes in pharmaceutical production – A critical review

The manufacturing of pharmaceutical dosage forms, which has traditionally been a batch-wise process, is now also transformed into a series of continuous operations. Some operations such as tabletting and milling are already performed in continuous mode, while the adaptation towards a complete continuous production line is still hampered by complex steps such as granulation and drying which are considered to be too inflexible to handle potential product change-overs. Granulation is necessary in order to achieve good flowability properties and better control of drug content uniformity. This paper reviews modelling and supporting measurement tools for the high shear wet granulation (HSWG) process, which is an important granulation technique due to the inherent benefits and the suitability of this unit operation for the desired switch to continuous mode. For gaining improved insight into the complete system, particle-level mechanisms are required to be better understood, and linked with an appropriate meso- or macro-scale model. A brief review has been provided to understand the mechanisms of the granulation process at micro- or particle-level such as those involving wetting and nucleation, aggregation, breakage and consolidation. Further, population balance modelling (PBM) and the discrete element method (DEM), which are the current state-of-the-art methods for granulation modelling at micro- to meso-scale, are discussed. The DEM approach has a major role to play in future research as it bridges the gap between micro- and meso-scales. Furthermore, interesting developments in the measurement technologies are discussed with a focus towards inline measurements of the granulation process to obtain experimental data which are required for developing good models. Based on the current state of the developments, the review focuses on the twin-screw granulator as a device for continuous HSWG and attempts to critically evaluate the current process. As a result, a set of open research questions are identified. These questions need to be answered in the future in order to fill the knowledge gap that currently exists both at micro- and macro-scale, and which is currently limiting the further development of the process to its full potential in pharmaceutical applications.     

Challenges for the oral delivery of macromolecules

The rapid integration of new technologies by the pharmaceutical industry has resulted in numerous breakthroughs in the discovery, development and manufacturing of pharmaceutical products. In particular, the commercial-scale production of high-purity recombinant proteins has resulted in important additions to treatment options for many large therapeutic areas. In addition to proteins, other macromolecules, such as the animal-derived mucopolysaccharide heparins, have also seen dramatic growth as injectable pharmaceutical products. To date, macromolecules have been limited as therapeutics by the fact that they cannot be orally delivered. This article will address the current status and future possibilities of oral macromolecular drug delivery.     

Modeling of Semicontinuous Fluid Bed Drying of Pharmaceutical Granules With Respect to Granule Size

In the transition of the pharmaceutical industry from batchwise to continuous drug product manufacturing, the drying process has proven challenging to control and understand. In a semicontinuous fluid bed dryer, part of the ConsiGma? wet granulation line, the aforementioned production methods converge. Previous research has shown that the evolution of moisture content of the material in this system shows strong variation in function of the granule size, making the accurate prediction of this pharmaceutical critical quality attribute a complex case. In this work, the evolution of moisture content of the material in the system is modeled by a bottom-up approach. A single granule drying kinetics model is used to predict the moisture content evolution of a batch of material of a heterogeneous particle size, where it is the first time that the single granule drying mechanism is validated for different granule sizes. The batch approach was validated when the continuous material inflow rate and filling time of the dryer cell are constant. The original single granule drying kinetics model has been extended to capture the granules’ equilibrium moisture content. Finally, the influence of drying air temperature is captured well with a droplet energy balance for the granules.     

Combining Isolation-Free and Co-Processing Manufacturing Approaches to Access Room Temperature Ionic Liquid Forms of APIs

The addition of non-active components at the point of active pharmaceutical ingredient (API) isolation by means of co-processing is an attractive approach for improving the material properties of APIs. Simultaneously, there is increased interest in the pharmaceutical industry in continuous manufacturing processes. These often consist of liquid feeds which maintain materials in solution and mean that solids handling is avoided until the final step. Such techniques enable new forms of APIs to be used in final dosage forms which have been overlooked due to unfavourable material properties. API-based ionic liquids (API-ILs) are an example of a class of compounds that exhibit exceptional solubility and stability qualities at the cost of their physical characteristics. API-ILs could benefit from isolation-free manufacturing in combination with co-processing approaches to circumvent handling issues and make them viable routes to formulating poorly soluble APIs. However, API-ILs are most commonly synthesised via a batch reaction that produces an insoluble solid by-product. To avoid this, an ion exchange resin protocol was developed to enable the API-IL to be synthesised and purified in a single step, and also produce it in a liquid effluent that can be integrated with other unit operations. Confined agitated bed crystallisation and spray drying are examples of processes that have been adapted to produce or consume liquid feeds and were combined with the ion exchange process to incorporate the API-IL synthesis into isolation-free frameworks and continuous manufacturing streams. This combination of isolation-free and co-processing techniques paves the way towards end-to-end continuous manufacturing of API-IL drug products.     

Orodispersible films: Product transfer from lab-scale to continuous manufacturing

Orodispersible films have been described as new beneficial dosage forms for special patient populations. Due to various production settings, different requirements on film formulations are required for non- continuous and continuous manufacturing. In this study, a continuous coating machine was qualified in regards of the process conditions for film compositions and their effects on the formed films. To investigate differences between both manufacturing processes, various film formulations of hydrochlorothiazide and hydroxypropylcellulose (HPC) or hydroxypropylmethycellulose (HPMC) as film formers were produced and the resulting films were characterized.The qualification of the continuously operating coating machine reveals no uniform heat distribution during drying. Coating solutions for continuous manufacturing should provide at least a dynamic viscosity of 1?Pa*s (wet film thickness of 500?μm, velocity of 15.9?cm/min). HPC films contain higher residuals of ethanol or acetone in bench-scale than in continuous production mode. Continuous production lead to lower drug content of the films. All continuously produced films disintegrate within less than 30?s. There are observed significant effects of the production process on the film characteristics. When transferring film manufacturing from lab-scale to continuous mode, film compositions, processing conditions and suitable characterization methods have to be carefully selected and adopted.     

A Training on: Continuous Manufacturing (Direct Compaction) of Solid Dose Pharmaceutical Products

As the pharmaceutical industry increasingly adopts continuous manufacturing technology, significant attention must be paid to process analytical technology (PAT), process integration, and process control. Published information is no substitute for hands-on comprehensive training, which is critical to implementing and operating continuous pharmaceutical manufacturing systems effectively and efficiently. In this article, an intensive hands-on training course has been developed and implemented at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS) based on 15 years of experience and several implemented systems. Here, we brought the details of the four integral components in a continuous direct compression manufacturing process: (1) unit operations, (2) PAT, (3) modeling and process controls, and (4) material characterization. Each section built-in classroom lectures with a brief overview on the theoretical aspects of each topic, followed by a hands-on session covering the classroom theory. The training program is described here in sufficient detail to enable creation of similar programs at other institutions.     

Crystal and Particle Engineering Strategies for Improving Powder Compression and Flow Properties to Enable Continuous Tablet Manufacturing by Direct Compression

Continuous manufacturing of tablets has many advantages, including batch size flexibility, demand-adaptive scale up or scale down, consistent product quality, small operational foot print, and increased manufacturing efficiency. Simplicity makes direct compression the most suitable process for continuous tablet manufacturing. However, deficiencies in powder flow and compression of active pharmaceutical ingredients (APIs) limit the range of drug loading that can routinely be considered for direct compression. For the widespread adoption of continuous direct compression, effective API engineering strategies to address power flow and compression problems are needed. Appropriate implementation of these strategies would facilitate the design of high-quality robust drug products, as stipulated by the Quality-by-Design framework. Here, several crystal and particle engineering strategies for improving powder flow and compression properties are summarized. The focus is on the underlying materials science, which is the foundation for effective API engineering to enable successful continuous manufacturing by the direct compression process.     

Engineering of pharmaceutical materials: an industrial perspective

Crystal engineering provides a rational approach to solving formulation, processing and product performance problems. This review discusses how the concept of crystal engineering can be judiciously utilized to manipulate the solid-state properties of drugs and excipients for successful pharmaceutical formulation and process development. Existing and emerging manufacturing as well as co-processing technologies being applied in the pharmaceutical industry are also presented together with selected examples of crystal form design, crystal form selection and crystal modifications for illustration purposes.     

Batch and continuous processing in the production of pharmaceutical granules

A quasicontinuous granulation and drying process to avoid scale-up problems is introduced in this work. Consistent and reproducible granule quality is a key factor in robust dosage form design and fits ideally the prerequisites of a drug quality system for the twenty-first century and the Food and Drug Administration's Process Analytical Technology (PAT) initiative. In scale-up, factors that simulate or reproduce the laboratory scale must be considered. This system provides a new possibility for industrial manufacturing and galenical development of pharmaceutical solids. The quasicontinuous method described in the present work, and the laboratory and production batches and the granulating equipment used to produce them, are the same. Once a robust process has been defined in the laboratory, it is merely repeated as many times as necessary to achieve the desired final batch size. The quasicontinuous process gives new possibilities to simplify manufacturing procedures and to validate them faster. The quality of the resulting granules and tablets compared with classical methods is equal until better. In many cases, existing products have been transferred to the multicell process without formulation changes. The quasicontinuous production concept for high-shear granulation and fluid-bed drying offers many advantages over the classical methods used to produce pharmaceutical granules. The wet massing process may be monitored by the power consumption of the mixer motor for each subunit, as in classical high-shear granulation processes. The air volume, temperature, and humidity of each of the drying cells may be controlled individually to avoid overheating of temperature-sensitive materials. All processing variables must be precisely controlled by a computer, and the data must be collected for documentation. As such, product quality and reproducibility for each subunit is assured.     

Continuous processes for the production of pharmaceutical intermediates and active pharmaceutical ingredients

Continuous processing can be applied to the production of pharmaceutical intermediates and active pharmaceutical ingredients. Relatively small, well-designed continuous reactors offer enhanced heat and mass transfer rates, shorter inventories of hazardous materials and precise control of reaction and quench times compared with batch processing. These factors have a significant impact on the safety, quality and economics of a process. Continuous processing, a mainstay of the chemical industry, remains a novelty within the pharmaceutical industry; however, there has been renewed interest in the application of continuous processing to organic synthesis in the pharmaceutical industry in recent years, and this review discusses the opportunities for reaction engineering of low-molecular-weight compounds.