Zambon and IMA Active: paving the way towards process optimisation

In this case study, Zambon worked extensively to redefine the product profile due to the introduction of new raw material suppliers, with the concurrent aim to achieve an improvement of PSD with minimisation of fines and big agglomerates.

Established in Vicenza in 1906, Zambon is a modern healthcare company headquartered in Bresso and operates on three continents – Europe, America and Asia. With its 2,751 employees in 23 branches and a consolidated turnover of €696 million, Zambon manages the quality of its products as well as flexibility and care towards customers.

This identity is based on an integrated organisational structure: Zambon Company S.p.A. is the industrial holding of the group, made up of Zach System, the fine chemicals division, Zambon S.p.A., a multinational pharmaceutical company, and Zcube – Zambon (Research Venture) , OpenZone (the scientific campus dedicated to Health at the doorstep of Milan), Zambon Biothech and ItaliAssistenza (Home Care company).

The Innovation area includes R&D and activities dealing with process and product optimisation. 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 Manufacturing & Technological Support department is a unit of Industrial Business Operations which includes industrial research devoted to troubleshooting of existing processes and scouting of new technologies. This allows for targeting a systematic and coherent study aimed at innovation in either formulation or in production and technological characterisation, adopting a QbD approach, with the establishment of comprehensive and shared technical know-how.

It is in this context that the project was initiated to expand the production capacity of a Zambon key product, which has been in production for over 25 years on IMA Roto Cube using single-pot technology. The opportunity to install a new Roto Cube granulator vacuum dryer led Zambon Manufacturing & Technological Support to use IMA Active Laboratory as a trusted partner for process optimisation. IMA Active Laboratory’s experience and expertise in process understanding and development have been decisive in the choice.

"Pursuing the aim of expanding the production with a new granulator, Zambon adopts a like-to-like approach, taking advantage of the synergy with the IMA Active Laboratory to confirm process robustness in a program of business continuity, using the opportunity of Roto Cube SPP’s modern control system. Later, the development work was oriented towards a further optimisation within a wider corporate program for maximising production efficiency, of course still in a QbD perspective," says Gianfranco Keller, head of Manufacturing & Technological Support at Zambon.

Case Study

Initially, inside the Solids Technology Laboratory led by Marco Cantarini in Zambon Switzerland, Manufacturing & Technological Support worked extensively to gather information about the status of the current process, exploring various aspects including mapping API and raw materials’ physical and technological properties, troubleshooting through interviews with operators and collecting information from historical batch records.

This created the framework for a process understanding step where the product profile was redefined due to the introduction of new raw material suppliers, with the concurrent aim to achieve an improvement of PSD with minimisation of fines and big agglomerates. This was to improve granule flowability and facilitate the dosage of sachet filling in new-generation, high-speed packaging machines.

A control strategy and Design Space were determined on the basis of this work, completed with all the other steps foreseen by a QbD regime, Risk Analysis, redefinition of CQA and CPP and with the support of pilot trials carried out at the IMA Active Laboratory.

At first, a scale down of the process from a 1500-litre Roto Cube to a 60-litre version allowed generation of a DOE to explore the CPP at pilot scale. Pilot trials were then carried out with a first approach aimed at reproducing the current process with no changes to the process recipe, in order to verify the scale-down process. In this case the same process steps were kept unaltered with respect to the original recipe.

The following steps were subject to some minor process modifications, to achieve a short-term improvement.

Details of the recipe changes:

• Drying time end-point based no more on time (due to lack of sampling thief on the old equipment), but on product temperature, in correlation with LOD.
• Optimisation of vacuum cycles for the drying step.

Results obtained with pilot-scale batches were later scaled back up to production on Roto Cube 1500 with 3 successful batches carried out by a combined team from Zambon together with an IMA granulation specialist.

The first DOE brought about a significant reduction of process time (-40%).

Investigation was then extended, by carrying out additional trials still at pilot-scale level with Roto Cube 60 to explore CPP more closely and simplify the process steps, introducing major changes with a higher impact on improving process optimisation.

At this stage of the investigation, the process recipe was simplified, for example:

• Use of chopper was set at different stages of the process.
• Different amount of water was used for granulation.

These major changes brought about increased batch-to-batch consistency of the final product and the ability to better manage the variability of raw materials coming from new suppliers.

Collaboration between Zambon and the IMA Active Laboratory concerning process optimisation is still in progress to develop the application of a Viavi MicroNIR probe as a PAT sensor to monitor and control the most significant steps of the process. Feasibility trials performed on the lab unit were successful. In the near future, the instrument will be integrated on the Roto Cube 1500.

In conclusion, there is strong evidence of the importance of implementing a multidisciplinary approach where equipment vendor and end-user cooperate and where both parties leverage their respective competences, sharing them to gain further experience in the pursuit of successful results.

"Zambon’s perspective in this process optimisation project considers this initiative also as preparation for adopting continuous manufacturing or other emerging technologies," adds Gianfranco Keller.