New Delhi, December 21, 2018: Future production plants must operate efficiently, be user friendly and meet the typical requirements of the pharmaceutical industry. These include shorter development times with minimal API usage and direct transfer from development to production without scale-up, as well as flexible batch sizes and integrated quality monitoring. When it comes to oral solid dosage (OSD) forms, continuous manufacturing is in high demand. But there is more than one way to look at things, as Fritz-Martin Scholz, Product Manager at Bosch Packaging Technology explains.
Oral solid dosage (OSD) forms like tablets, capsules and sachets make up roughly 60 percent of the total pharmaceutical products market. Despite the development of new liquid biologics and parenteral medication, OSD products will continue to play an important role in the global pharmaceutical market in the future. Increasing cost pressure and high quality demands require efficient, modular and flexible processes. The trend towards highly potent and more personalized drugs will have an important influence on production and process requirements, leading to small and flexible production quantities with the shortest possible time to market.
With OSD batch production, the pharmaceutical industry traditionally uses manufacturing processes, which have been established for many decades.Accordingly, they have already been optimized and offer little opportunity for significant further efficiency improvements. As a result, large and medium-sized pharmaceutical producers alike have instead turned their attention to continuous manufacturing in recent years. Generic drug and contract manufacturers are also developing an increasing interest in continuous processing, which has long been used in the chemical industry, for example. Against this background, a paradigm shift is currently taking place, which will bring about fundamental changes in the coming years in terms of infrastructure, as well as internal processes of pharmaceutical manufacturers.
From batch to continuous manufacturing
In batch production, a set amount of raw materials is fed into the system at the start of a particular batch, and removed again at the end of each process step, resulting in nonvalue-added charging and discharging operations, as well as intermediate storage, larger plants and higher energy costs.In contrast, in continuous manufacturing, feeding of the starting materials and removal of the finished product are done simultaneously.
The typically separated production steps occur one after the other,without interruption, resulting in shorter throughput times, no intermediate storage, smaller plants, lower production costs and greater flexibility. The production volume is now controlled via the production time. The development costs also decrease, as scale-up becomes obsolete,which reduces development time and usage of API.What’s more, optimal quality monitoring ensures consistently high product quality.
Whether the changeover to continuous production pays off, depends on a number of parameters, including the active ingredient, the production amounts required and whether the product has already been approved or whether it is still in development. This needs to be considered by pharmaceutical manufacturers and machine providers together and on a case by casebasis.
Where do we stand with conti?
Continuous manufacturing is nothing new in the pharmaceutical industry. Even in batch production, some of the individual processing steps are continuous, like dry granulation using roller compactors, or tableting. Other processes such as dosing, mixing and wet granulation run in batches and need to be modified for continuous production.Current continuous production systems for wet granulation usually rely on continuous twin screw granulators. The subsequent drying in the fluidbed usually takes place package per package in separate chambers, amongst others to control the residence time, so that every particle sees the same amount of drying energy.
The biggest challenge when it comes to today’s continuous production systems is the precise dosing of the starting materials. Active ingredients and excipients have to be continuously dosed in a constant mass flow rate of milligrams per second. Because all the available dosing systems show fluctuations over time at the achievable mass flow rate, it is mandatory to check the amount of active ingredient online using process analytic technology (PAT). Back mixing is the only way to compensate for these fluctuations, which in turn broadens the product’s residence time distribution in the system, making traceability more difficult. In addition, the system requires a start-up phase before the steady state is achieved, resulting in start-up and shut-downlosses.
The changing characteristics of the granulate from the twin screw granulator present a further challenge compared to batch processing, since the granulate density is different and often has a bimodal particle-size distribution. This might cause segregation, which can, under certain circumstances, have a negative effect on the tablet properties– something that manufacturers should consider when transferring technologies. As such, there is still room for improvement when it comes to continuous production. In response,Bosch Packaging Technology is investigating processes and systems that can overcome these challenges.Pharmaceutical manufacturers were able to get a sneak preview of the new Xelum platform at the Bosch booth at interpack 2017 in Düsseldorf.
The most important differentiation of the Xelum platform from Bosch is that it doses active ingredients and excipients as discrete masses and not as continual mass flow. This means that even the smallest amounts of active ingredients can be precisely dosed.The system doses and mixes individual packages, so-calledX-keys, step-by-step,which continuously run through the process chain and are removed successively. This way it is possible to reduce not only the process complexity, but also the system’s failure susceptibility, which increases the accuracy and the quality of the end product.
At the same time, the necessary measurements of critical quality attributes can be carried out more easily, in part using soft sensors. The Xelum system does not require a steady state – and no start-up time –allowing it to reduce start-up and shut-downlosses to a minimum.All starting materials can be traced back in the production line and can be clearly matched to the final dosage form, as back mixing occurs only inside of each X-key.
Advantages offluid-bed technology
The Xelum platform has another decisive advantage: while most systems available on the market use twin screw granulators, the Xelum system relies on fluid bed processors – based ona proventechnology developed by the Bosch subsidiary Hüttlin. In the fluid bed, granulation and drying take place in the same process chamber. This eliminates the need to transfer wet granulate, which in turn has a positive effect on the system’s reliability. With fluid bed granulation, pharmaceutical manufacturers obtain granulates with the desired characteristics – including unimodal particle size distribution, as well as excellent flow and tableting properties combined with higher production yields.
Using the proven fluid-bed granulation process for existing products means that a technology transfer is not necessary, which significantly reduces the effort of changing to continuous processing. The same principle of dosing asa discrete mass also applies to the external phase. In the final processing step, the tableting takes place in the integrated Xelum tablet press. Connection to line controls and the flexible filling height control ensure smooth operation.Optimally placed nozzles for washing-in-place (WIP) make sure the system can be cleaned in short time and largely automated.
Fit for the future
Transferring processes from laboratory to the production is often a challenge for pharmaceutical manufacturers when it comes to traditional batch processes such as the top spray process.Thanks to continuous processing, this inherently risky and time-critical stage is eliminated in the Xelum system. New products can be developed using either suitable R&D equipment or with the integrated automatic DoE (Design of Experiments) function in the Xelum system, which features software with the relevant test-automation support functions.
One thing is for sure: when it comes to OSD production, continuous manufacturing will take on an important role alongside batch production. Which process is used for which product has to be decided on an individual basis. However, it is certain that there is not just one continuous process. With the Xelum platform, Bosch Packaging Technology has developed an industry 4.0-ready, economical alternative for the continuous production of OSD forms.To be prepared for future requirements, the platform is being constantly refined. Hence it is not limited to wet granulation and tableting, but is also conceived for other applications like direct compression.
The latest innovations from Bosch Packaging Technology can be seen at Achema in Frankfurt/Main, Germany, from June 11 to 15, 2018 in hall 3.1, boothC71.
Corporate Comm India(CCI Newswire)