A fresh perspective on oral solid dosage forms

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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.

OSD forms like tablets, capsules and sachets make up roughly 60% of the total pharmaceutical products market. Increasing cost pressure and high-quality demands require efficient, modular and flexible processes. The trend towards highly potent and personalised 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 optimised and offer little room for improvement. As a result, pharmaceutical producers have turned their attention to continuous manufacturing. A paradigm shift is currently taking place, which will bring about fundamental changes in terms of infrastructure, as well as internal processes of pharmaceutical manufacturers.

From batch to continuous

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. Conversely, 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. Development costs also decrease, as scale-up becomes obsolete, which reduces development time and usage of API. Optimal quality monitoring ensures consistently high product quality.

Whether the change to continuous production pays off, depends on a number of parameters: active ingredients, required production amounts, and whether the product has already been approved or is still in development. Continuous manufacturing is nothing new in the pharmaceutical industry. Current continuous production systems for wet granulation usually rely on continuous twin screw granulators. The subsequent drying in the fluid bed 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.

Current challenges

The biggest challenge of continuous production is the precise dosing of the starting materials. APIs 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 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-down losses.

The changing characteristics of the granulate from the twin screw granulator present a further challenge, 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.

Reduced complexity

In response, Bosch Packaging Technology is investigating processes and systems that can overcome these challenges — for instance the Xelum platform. The most important differentiation is that it doses active ingredients and excipients as discrete masses and not as continual mass flow. The system doses and mixes individual packages, so-called X-keys, step-by-step, which continuously run through the process chain and are removed successively. This way it is possible to reduce process complexity, and the system’s failure susceptibility.

At the same time, the necessary measurements of critical quality attributes can be carried out more easily, in part using soft sensors. If a steady state is not required, start-up and shut-down losses can be reduced 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 of fluid-bed technology

Although most available systems use twin screw granulators another possibility is the use of fluid-bed processors. In the fluid bed, granulation and drying take place in the same process chamber. This eliminates the need to transfer wet granulate, which 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 tabletting properties combined with higher production yields.

Using the 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 as a discrete mass also applies to the external phase. In the final processing step, the tabletting can take place in an integrated tablet press. Connection to line controls and flexible filling height control ensure smooth operation. Optimally placed nozzles for washing-in-place (WIP) can make sure the system can be cleaned in short time and largely automated.

Fit for the future

Transferring processes from laboratory to production is often a challenge for pharmaceutical manufacturers. Thanks to continuous processing, this inherently risky and time-critical stage is eliminated. New products can be developed using either suitable R&D equipment or with the integrated automatic DoE function, which features software with the relevant test-automation support functions.

One thing is for sure: continuous manufacturing will take on an important role in OSD production alongside batch production. Which process is used for which product has to be decided on an individual basis.