CASE STUDY: Scale transfer and uniformity following recommended guidelines

In this case study, IMA Active and Zambon discuss how the Cyclops tumble bin blender assisted the formulation and blending from laboratory scale while following recommended guidelines.

The companies

Established in Vicenza in 1906, Zambon is now headquartered in Bresso and operates on three continents — Europe, South America and Asia — it employs 2,800 people in 15 countries. In addition to in-house research, an Open Innovation perspective, Zambon collaborates with external partners, research institutes, start-up companies, technology transfer and biotech companies.

The pharma technology department handles in-house pharmaceutical development, which includes pharmaceutical research devoted to formulation and process development in laboratory scale as well as analytical development, and pharmaceutical development and industrialisation for pilot scale and industrial transfer.

Established in 1961, IMA is a designer and manufacturer of automatic machines for the processing and packaging of pharmaceutical products. IMA Active, a division of the pharma group, provides solutions for its partners in the field of solid dose processing and manufacturing.

The project

Organisation is imperative in the development of a formulation and process, which interacts with analytical development and industrial perspective. This is particularly true when following recommended guidelines, such as ICH Q8, and for quality by design (QbD).

It is in this context that the project was originated, leading the pharmaceutical research facility of Zambon's pharma technology department to purchase an IMA blender with which to tackle the formulation and process study starting from the laboratory scale.

The IMA blender is compact and mounted on wheels for laboratory scale, which has been designed in accordance with GMP. It is consistent with larger scale systems and features a highly innovative bin-coupling system.

Cyclops — tumble bin blender

Due to its features, similar both in laboratory scale and in pilot and industrial scale, Cyclops optimises the scale-up steps. In general, laboratory scale blending is performed in bags or, alternatively, by means of small blenders that, due to their structural characteristics, facilitate the formation of segregation areas, which are harmful to the process.

Moreover, since the shape and movement of traditional equipment differs from that adopted in pilot and industrial scale, it does not allow the studying of directly scalable processes. Cyclops ensures blending uniformity and scale transfer at the same time.

Cyclops meets the pre-defined double and single tilting working requirements, modulating the rotating speed and stop time, selecting the rotating direction and changing it even during the rotation cycle, and has been equipped with bins of increasing capacities (5, 10, 20 litres) suitable both for the production of small trial batches and the systematic study of the blending process.

This project, with Zambon, is part of the process analytical technologies (PAT) implementation — the powder container was coupled to a NIR spectrometer for the in-line monitoring of the blending process. IMA verified cyclops suitability to support the weight and bulk of a rotating spectrometer in collaboration with Zambon Pharmaceutical Research through computer simulations. All bins have the same neck in order to use a modified cover, with the addition of a sapphire window to house the NIR spectrometer. Moreover, the cover has been fitted with inlets for the powder sampling probes. IMA and Zambon ran the FAT and SAT tests together on the blender coupled to the spectrometer.

The NIR spectrometer can perform a chemometric analysis through the continuous acquisition of spectra, evaluating their change according to blending uniformity. This is exactly where the real innovation of the Zambon project comes into play: setting up a PAT system that, being applicable both to laboratory scale and industrial scale, allows the achieving of a rational and correlated blending profile.

The solution: Formulation and process optimisation

Reformulating a product in sachets with the aim of improving patient compliance (palatability), by applying a novel, patented taste masking approach, led Zambon Pharmaceutical Research to change the composition of a blend in which flow optimisation was critical, not only to ensure the uniformity of the content of the active substance and the ingredients responsible for the taste masking, but also to improve efficiency during the packaging of the pre-existing product.

A study was conducted both on the formulation (optimisation of excipients, evaluation of active substances from different suppliers) and on the process parameters (blending speed and time). In the first part of the study, preliminary scale-down of the reference product was performed in order to correlate the industrial scale blending process with laboratory bins. Using a mathematical approach (based on Froude Number) and the in-line control with the NIR spectrometer, it was possible to obtain the starting parameters scaled by the industrial reference process, confirmed by the off-line analysis with UPLC on samples taken from the bin in different points (Figure 1) to determine blending uniformity. These parameters, preliminarily tested with the new formula, provided the expected NIR profile and the appropriate physical characteristics of the blend.

In the second part of the study, the effect of the critical variables (active substances from different suppliers and addition of an excipient having a different composition) was examined, through design of experiment, on the chemical-physical characteristics of the new blend, keeping constant the operating conditions specified by the NIR in the previous study.

The interpretation of data obtained through the qualitative/quantitative analysis (NIR profile/UPLC analysis) and the statistical evaluation of the various responses such as blending uniformity, flowability (Carr Index, %), repose angle and density have shown that the blend's flowability depended on the particle size of the active substance used. As expected, active substances from different suppliers have different physical properties that lead to different behaviours of the final blend.

Moreover, the variability of the physical properties has no impact on attaining blending uniformity, which is ensured even while significantly prolonging blending time, thus confirming the reliability of the screening study. As such, it was possible to correlate the NIR profile with powder flowability and type of active substances used, and this information was used in the next industrial scale up stage.

The high degree of innovation with which this study was conducted allowed Zambon to register its product without any observations on behalf of the examiners.