Predictive Model-Based Process Start-Up in Pharmaceutical Continuous Granulation and Drying.

Victoria Pauli,Peter Kleinebudde,Markus Krumme

doi:10.3390/pharmaceutics12010067

Victoria Pauli, Peter Kleinebudde + Show 1 more

Open Access

https://doi.org/10.3390/pharmaceutics12010067

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Abstract

Continuous manufacturing (CM) is a promising strategy to achieve various benefits in the context of quality, flexibility, safety and cost in pharmaceutical production. One of the main technical challenges of CM is that the process needs to handle transient conditions such as the start-up phase before state of control operation is reached, which can potentially cause out-of-specification (OOS) material. In this context, the presented paper aims to demonstrate that suitable process control strategies during start-up of a continuous granulation and drying operation can limit or even avoid OOS material production and hence can ensure that the provided benefits of CM are not compromised by poor production yields. In detail, heat-up of the drying chamber prior the start of production can lead to thermal energy being stored inside of the stainless-steel housing, acting as an energy buffer that is known to cause over-dried granules in the first few minutes of the drying process. To compensate this issue, an automatic ramping procedure of dryer rotation speed (and hence drying time) was introduced into the plant’s process control system, which counteracts the excessive drying capacity during start-up. As a result, dry granules exiting the dryer complied with the targeted intermediate critical quality attribute loss-on-drying (LOD) from the very beginning of production.

Highlights

The presented paper aims to demonstrate that suitable process control strategies during start-up of a continuous granulation and drying operation can limit or even avoid OOS material production and can ensure that the provided benefits of Continuous manufacturing (CM) are not compromised by poor production yields
Paradigm changes in R & D and health care politics increase the pressure on the pharmaceutical industry to achieve cost reduction of newly registered drug products, since the current pricing regime, ageing population and increasing cases of chronic illnesses pose a serious threat to the sustainability of national health care systems [1,2,3,4,5]
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Summary

Introduction

Paradigm changes in R & D and health care politics increase the pressure on the pharmaceutical industry to achieve cost reduction of newly registered drug products, since the current pricing regime, ageing population and increasing cases of chronic illnesses pose a serious threat to the sustainability of national health care systems [1,2,3,4,5]. CM is largely helpful for its suitability to manufacture products with smaller or more flexible production volumes, since the technology allows to tailor the batch size to available frame conditions or the current demand, by adapting production run-time. This feature is especially useful during early-phase clinical stages, where availability of active pharmaceutical ingredient (API) is typically limited and patient populations are small but difficult to estimate within common batch manufacturing lead times. The focus of many pharmaceutical companies has shifted to low-volume or even personalized medicine products, niche-markets and orphan-drugs, after it was recognized that a broader portfolio for smaller target groups can ensure a steadier cash flow and avoid impactful patent-cliffs [15,24,25,26,27]

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