Scale-up in the 4th dimension in the field of granulation and drying or how to avoid classical scale-up

In the pharmaceutical industry, the production of granules is based on a batch concept. This concept offers many advantages, as a batch can be accepted or rejected. However, the scale-up of the batch size may lead to problems. The variety of the equipment involved does not facilitate the scale-up process and the capital invested in space and equipment is high. An alternative approach is the use of a continuous process. However, continuous processes have the disadvantage among others that the batch size is not well defined. Thus, a special quasi-continuous production concept was developed, taking into account the advantages of a batch type and a continuous process. This concept was developed in cooperation with the Institute of Pharmaceutical Technology of the University of Basel, Glatt CH-4133 Pratteln and F. Hoffmann-La Roche, CH-4070 Basel. The equipment allows to implement a “Just in Time Production Concept” as a large batch B consists of n subunit (SU) batches b, i.e. B=nb. The subunit batch b corresponds to, e.g. 7-kg material for the production of pharmaceutical granules for further processing such as tabletting. At the Roche production site, this novel process equipment was used to manufacture batch sizes B with n=10, n=100 and so far up to n=600 subunits. This leads to an optimal use of capital invested in GMP space and equipment. The difference to the classical scale-up is the following: with classical scale-up, the dimensions of the equipment x, y, z is enlarged and the process time is more or less kept constant. With this novel concept, the dimension x, y, z of the equipment is kept constant and the process is repeated in the 4th dimension “n times”. Thus, for the scale-up in the 4th dimension, i.e. in the time, the equipment needs to show a “self-cleaning” property and appropriate formulations. The novel concept is of special interest, as the quality of the product is not changed during scale-up.     

Aspects of granulation in the chemical industry

In general, the intention of granulation processes in chemical industry is to achieve certain product properties. The requirements are specific for each product and cover application properties, process and handling properties, safety characteristics and marketing features. However, selection of an agglomeration process and equipment to be used for production is usually influenced by other factors than product properties: Options are often limited, because equipment which was used for another product is available, or the granulation process has to fit in the total production process.In granulation, only few information about scientifically based differentiation between alternative granulation processes such as mixer agglomeration, compaction or fluidized bed granulation and classification of different apparatus can be found in literature.Therefore, one focus of industrial investigations in granulation is on comparison of different processes and assessment of different types of apparatus. Here, an example for a comparison of different granulation processes with respect to product properties will be shown.     

Investigation and scale-up of hot-melt coating of pharmaceuticals in fluidized beds

This study was performed to investigate and scale-up the hot-melt coating process in fluidized beds. A series of well-designed experiments was carried out in a pilot scale unit with 20 kg product capacity to investigate the effects of process variables on the efficiency of the coating of Cefuroxime Axetil with stearic acid. Results showed that the efficiency is at the highest when the fluidization air flow rate is adjusted by considering the changes in the amount of materials present in the unit as well as the changes in the terminal velocities of particles during the process.With the objective to scale-up the hot-melt coating process from pilot to production scale, a dynamic thermodynamic model based on conservation equations of mass and energy was developed. Predictive accuracy of the model was assessed by applying it to the pilot scale unit and comparing its predictions with the online measurements taken on the same unit. Results showed that the predictions of the model agree well with the measurements. Utilizing this model and taking several experiments performed in the pilot scale unit as a basis, scaling up of the hot-melt coating process was carried out. Comparisons of the model predictions with the measurements taken on the production scale unit (200 kg product capacity) revealed that the model is able to reproduce the product attributes and the outlet air temperatures across scales. Therefore, it proves to be a promising tool that can be used in the scale-up of the hot-melt coating processes in fluidized beds.     

Profitability as a criterion of batch process control design

Batch processes have in some cases many advantages in comparison with continuous processes even though continuous processes are becoming common.

The main disadvantages of batch processes are the discontinuous usage of raw materials and energy as well as the discontinuous production thus causing difficulties in power plant and other continuous processes connected with the batch process in question. If there are several parallel process units, difficulties can arise with parallel process unit sequencing and product quality equalization. However, with the aid of computer control these and other disadvantages are eliminated or minimized so that total automation of batch processes is possible.

In this paper the basic principles of batch process control design are considered, with particular emphasis on the economic justification criterion. As an example, a computer control design of sulphate batch digesters is considered. This approach is based on more than 20 implementations of batch process automation.     

Development and implementation of a hybrid scale up model for a batch high shear wet granulation operation

The high shear wet granulation (HSWG) operation consists of several rate processes influenced by the raw material properties, process operational parameters, and equipment design. Their combined effect determines the granule attributes. In literature, these rate processes have been modeled using different dimensionless numbers and their correlations. Each of these dimensionless numbers represent only certain rate processes. Since many of these rate processes occur at the same time, it is necessary to simultaneously model them to account for all the important degrees of freedom. Most of the HSWG scale up approaches in literature calculate scale up conditions based on a single rate process or operating parameter of interest that can lead to sub-optimal process design. We present the development of a hybrid HSWG scale up model accounting simultaneously for all the rate processes. The approach was successfully implemented to scale up the HSWG operation across laboratory, pilot, and commercial scales.     

Manufacturing pharmaceutical granules: Is the granulation end-point a myth?

The moist agglomeration process by high-shear mixing/granulation, i.e. the wet massing, screening and subsequent drying is a wide spread but critical unit operation. Since for decades formulators are looking for the correct “end-point” of this important process, i.e. when do you need to stop massing or stop with the addition of granulating liquid? What is the correct amount of granulating liquid? A similar situation exists in case of the moist agglomeration in fluidized bed equipment. In the latter case the simultaneous drying of the still moist granules have to be taken into account. Recently a science-based virtual equipment simulator could be developed mimicking the granule size evolution in a fluidized bed granulator during the addition of granulating liquid. For the simultaneous drying the Mollier chart is used. With this virtual equipment simulator it is possible to simulate “crash situations”, i.e. by overwetting or by an incorrect use of the parameter setting. However the determination of the “end-point” depends only on the operator, who desires a certain granule size distribution and a well-defined final moisture content of the batch. Thus the existence of a process intrinsic “end-point” has to be questioned. The same situation can be reported in case of high-shear mixing/granulation based on many years of research. In fact nobody could clearly show the existence of an intrinsic “end-point”. However during the continuous addition of a granulating low viscous liquid a sudden increase in power consumption can be measured, which levels off. Such a measurement depends on the formulation and leads to an “early signal” not to the “end-point”. This signal can be used for a tight control of the granulation process and leads to a low batch to batch variability in the final granule size distribution. The latter is the goal of the PAT (Process Analytical Technology) Initiative emphasizing “Quality by Design”.     

Breakage in granulation: A review

The study of breakage in granulation is important from a process and from a product quality perspective. Breakage is considered an important rate process in granulation, and plays roles in granule homogeneity and strength. Understanding this rate process has important implications in the design and control of the granulation process. From a product perspective, the study of breakage has important implications for the subsequent processing, transport, handling and final use of granular products. Breakage behaviour of granules can be a strong signature of the consistency of properties between nominally identical granular products. This paper reviews the study of breakage from the process scale down to the single granule and sub-granule scale, discussing largely experimental results complemented with some modelling results.     

Techno-economic analysis of dynamic,end-to-end optimal pharmaceutical campaign manufacturing using PharmaPy

Increased interest in the pharmaceutical industry to transition from batch to continuouos manufacturing motivates the use of digital frameworks that allow systematic comparison of candidate process configurations. This article evaluates the technical and economic feasibility of different end-to-end optimal process configurations, namely, batch, hybrid and continuous, for small-scale manufacturing of an active pharmaceutical ingredient. Production campaigns were analyzed for those configurations containing continuous equipment, where significant start-up effects are expected given the relatively short campaign times considered. Hybrid operating mode was found to be the most attractive process configuration at intermediate and large annual production targets, which stems from combining continuous reactors and semi-batch vaporization equipment. Continuous operation was found to be more costly, due to long stabilization times of continuous crystallization, and thermodynamic limitations of flash vaporization. Our work reveals the benefits of systematic digital evaluation of process configurations that operate under feasible conditions and compliant product quality attributes.     

筛分和破碎工序对系统的影响浅析

在复合肥生产过程中,各工序之间相互影响,只有各道工序均正常运行才能保证整个生产系统稳定。分析了筛分工序对系统返料、成品粒度分布、造粒和系统投料量的影响以及破碎工序对造粒和产品外观的影响,并介绍了筛分和破碎工序日常维护经验。     

制造球形粒子的晶体聚结方法

球形聚结技术能够在同一单元操作中耦合结晶和造粒过程以制备球形晶体。相比于传统流化床造粒技术,该技术具有工艺流程短,生产成本低,产品性能优良的优势,但是同时也面临研究方法不成熟、机理复杂、工业放大和特殊结晶器型等方面的挑战。总结了针对球形结晶产品的表征技术和关键产品指标,介绍了球形聚结过程机理、数学模型和新技术设备的研究进展,并提出关于深化机理、完善模型、开发新设备方面的新思路,最后对其在工业生产尤其是制药领域的发展进行了展望。     

A narrow size distribution on a high shear mixer by applying a flux number approach

High shear granulation is a common technology for particle size enlargement, but generally the product properties are badly affected by the broad size distribution generated in the process. A recently published approach by Michaels et al. [J.N. Michaels, G. Wang, L. Farber, K.P. Hapgood, J.H. Chou, S. Heidel, and G.I. Tardos, 2006, One-dimensional scale-up of high-shear granulators, Paper 243c, World Congress Particle Technology 5, Orlando (FL)] employs low binder solution spray rates and long granulation times, whilst the solids are kept in roping flow, to avoid coarse formation. The present work applies this approach to a two-component binder system with a dry powder gum and water spray as activation agent. Similarities with fluidised bed granulation and coating processes are explored. The work shows that indeed narrow size distributions of fine granules can be achieved with ease. Dimensionless numbers for spray fluxes are useful to identify operating regimes and to steer optimisation efforts. Comparison of flux numbers for different systems shows that they are not useful (yet) for detailed product and process design. Further work on material-specific quantities controlling nucleation and growth, e.g. particle wetting, is recommended.     

化学产品过程开发实验平台--公斤实验室的建设和应用

以化工产品设计和过程开发为导向,建立了一个化工产品过程开发实验平台--化工产品公斤实验室Kilo-lab.该公斤规模试验装置可进行反应、结晶、分离、提纯等系列产品的开发过程,研究了流程装置集成和柔性生产系统的规律和特征,为小批量、多品种、高附加值化学产品快速响应市场的变化和需求,以及过程开发的工业化放大提供理论和实验依据.     

Kinetic of a liquid/liquid/solid fine chemicals reactions – modelling of a continuous pilot plant reactor

In the field of fine chemicals batch process the implementation of synthesis paths results most often in the determination of the optimal operating conditions on a bench scale apparatus; successive scale-ups are then handled in an empirical way. For multi-phase reactions, this approach can be limited due to the coupling between the chemical kinetics and the physical kinetics of the mass transfer. This work proposes a more rational approach for the overall synthesis of Amiodarone, a widely used anti-arrhythmic drug produced by a liquid/liquid/solid reaction. After analysing the reaction scheme and identifying the limiting steps of the process, a simplified model is proposed to describe the overall process kinetics. The latter is used to model a continuous pilot loop-reactor packed with static mixers.     

Switch from single pot to multiphase high shear wet granulation process, influence of the volume of granulation liquid in a pilot scale study

Among the high shear wet granulation equipments used in the pharmaceutical industry, two configurations are current: single pot process for which blending, granulation and drying are performed in the same apparatus and multiphase process that usually associates a mixer granulator and a fluid bed dryer. Pharmaceutical formulations are often developed with regard to a specific industrial apparatus, but production imperatives may require a switch to another type of equipment. In this work, granulation process switch was investigated at pilot scale on a first intention excipient formulation and with two drug substances chosen as model drugs on the basis of their different water solubility. Each one was tested at two concentrations, 1 and 25%. The volume of granulation liquid was first fixed at the same level whatever the granulation equipment and the formulation. In the second part of the study, the effect of the volume of granulation was highlighted. Regardless of the formulation tested, single pot granules, compared to multiphase one, had improved flow properties, compressibility and tablet cohesion but higher sticking phenomenon was observed when tableting. In the second part, the effect of an adjustment of the volume of granulation liquid for horizontal transposition between high shear granulation processes was discussed.     

OPTIMAL DESIGN AND OPERATION OF BATCH PROCESSES

The economical design of continuous chemical processes to produce commodity products has reached an advanced state of development. Modern computer tools are used routinely to simulate and optimize these processes. This is not the case, however, for the manufacture of speciality products which must be made in batch operations. The continuing shift towards the production of higher value-added specialty products by the CPI has stimulated efforts aimed at developing good computer assisted design strategies for batch processes.

This paper discusses the formulation of the problem for the optimal design and operation of batch processes. The batch problem differs from the continuous one in a number of important ways. First, batch plants do not operate at steady state. There are important trade-offs between the processing time and the severity (intensity) of processing in single units. Cycle time and performance trade-offs also exist among the various units in the process. Second, batch plants produce multiple products in many cases. There is often a competition for shared resources (labor, utilities, and equipment) among the various products. This paper presents a hierarchical solution approach for the design and optimization of a batch process. The approach is demonstrated by solving an example problem which illustrates the fundamental economic trade-offs.     

Scale-up and Process Transfer of Freeze-Drying Recipes

This paper proposes a simple and effective methodology for the scale-up and process transfer of freeze-drying recipes. Process modeling allows the study of the silico product evolution in a given freeze-dryer, and calculation of the operating conditions that result in the same product dynamics in different equipment. Few experiments are necessary to determine model parameters and to characterize the two freeze-dryers. The problem of the batch non-uniformity and the effect of the parameters' uncertainty are also addressed. The effectiveness of this approach is demonstrated by means of various examples.     

Continuous granulation in the pharmaceutical industry

Traditionally the manufacturing of pharmaceutical dosage forms has been a batch-wise process and continuous processes have limited applications in a pharmaceutical manufacturing plant. However, several factors (reduction of cost, improved process efficiency, optimal use of equipment, flexibility in production capacity) are stimulating the pharmaceutical industry to investigate the opportunities offered by continuous processes. This paper discusses some of the techniques which could be implemented in a continuous granulation process of pharmaceuticals.     

Equipment and Separation Units for Flow Chemistry Applications and Process Development

Process development and small‐scale production gets more and more important in fine chemistry and pharmaceutical production. An equipment toolbox assists process synthesis presented in this contribution. A microfluidic calorimeter can measure kinetic and thermodynamic reaction data with commercial plate reactors. A tubular reactor coiled with 90° bends allows for long residence time with low axial dispersion, also known as coiled flow inverter (CFI). A similar setup is used for continuous‐flow cooling crystallization. Small‐scale columns with rotating internals are employed for distillation and liquid‐liquid extraction. Main emphasis will be put on automation and scale‐up in future steps.