References. Continuous Manufacturing Process Development Plant Realizations. Microinnova Engineering GmbH. Europapark Allerheiligen bei Wildon

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1 References Continuous Manufacturing Process Development Plant Realizations Microinnova Engineering GmbH Europapark Allerheiligen bei Wildon T +43 (0) office@microinnova.com

2 PROCESS DESIGN Microinnova is your One-Stop-Shop Decades of experience in process intensification, flow chemistry and continuous processing gives us the possibility to investigate the best approach and strategy to put your process into an efficient system. CHEMICAL & TECHNICAL FEASIBLITY SERVICES Inside our flow lab scale plants we have multiple technologies available to develop continuous experimental procedures with the principal objective of showing a reliable mode of operation. OPTIMIZATION & PILOT DEVELOPMENT Dependent on the inherent characteristics each verified continuous process is optimized. The optimal processing window is determined on scalable equipment to finally deliver a robust continuous system. ENGINEERING & PLANT SOLUTIONS Our Engineering team develops, designs and realizes continuous laboratory, pilot and manufacturing plants. According to the requirements the plants feature CE, ATEX or GMP compliance. The handover of the operating turnkey plant is our customers start into profitable continuous manufacturing.

3 Challenges Your research and production departments are facing one or more of the following challenges? Space-Time Safety Operation We are looking forward to solve those challenges for you! Headcount reduction Reduction of operation steps Solving bottlenecks Prevention of fail batches & leaps in quality Enhance yield, purity, selectivity Enabling efficient reaction routes Going for new process regimes Save energy and rew materials Handle toxic and hazardous substances safety Comply with the principles of Green Chemistry With our modular plant approach we offer solutions for each specific application!

4 Minimal intervention with maximum effect The request of a specialty chemical manufacturer was to double the production volume of a two-stage batch process, but the possibilities to a spatial extension were missing. This and two other problems could be solved with the proper technology in one shot! Because of a particularly volatile reactant, previously it has been necessary to cool the first reaction and the intermediate product extensively, and afterwards for the second reaction step, heated to a higher temperature level again. By increasing the pressure in the total system the boiling point was raised, the reaction rate increased and the costs of cooling were eliminated. By process intensification and use of a suitable micro structured reactor, the capacity of the existing plant has been doubled to 3.6 t/h and one process step could be saved. Investment costs were of about 1/10 of a conventional solution.

5 More Process Efficiency for Pharma Production Plant An API producer had problems with an extremely difficult step in a batch process, which reduced the overall yield to a level below being economic. Since the upstream and downstream processes were efficient enough (with yields of about 80%) the problem could be solved with a partial renewal of the process. The mixing sensitive process step, almost unmanageable in batchmode, was replaced by continuously operating mixing and reaction module of Microinnova. The promising laboratory tests were implemented after 6 months only and with a deviation of only 0.1% in the production scale. The yield of the critical step in the process was increased to 30%, thus enhancing the overall efficiency of the process by far! With a throughput of 200 l/h, the Microinnova module is one of the world's largest continuously operated cgmp compliant plants in the pharmaceutical sector using a micro reactor technology.

6 Small, flexible & modular pilot plant Microinnova successfully transferred a highly exothermic batch synthesis reaction to a continuously operated process. In the batch process the reaction heat was controlled by slow dosing of reactant, which required a reaction time of 12 h. This time consuming step was the crucial driver to develop a more efficient continuous process. The continuous approach on the one hand enabled a fast and excellent mixing quality thus transport rates were increased. On the other hand eased heat control enabled a new operation window by applying higher pressure and temperature, which decreased reaction time drastically to just 1 min. The final Flow-Miniplant with a capacity of up to 30 l/h and a possible processing temperature of up to 250 C was designed in a modular way. To integrate variability in residence time and come up with the customers need of a multipurpose and flexible production system an optional reaction module was provided.

7 Continuous Cryogenic API plant for a liquid solid reaction An API producer wanted a save and cost effective solution for an extremely difficult API synthesis step. The aim was to increase economics and safety level of his present batch process. The synthesis step required solid dosing of starting material under cryogenic conditions continuously into a highly corrosive solution at -80 C. After a successful feasibility study at Microinnova s labs the residence time was improved from 7 h to 15 min. The process was scaled-up without any losses and realized with a plant capacity of 6 l/h. The implemented Flow Miniplant significantly increased process safety and intensified the previous batch process to the customers expectations. The plant, GMP and ATEX compliant features a modular design thus a quick upgrade to a multipurpose system is possible in future.

8 Continuous Downstream Processing Microinnova delivered two modular continuous crystallization plants to the research center CMAC in Scotland and one continuous crystallization plant with an integrated filter-dryer unit to the University of Sheffield. Continuous crystallization, filtration and drying as an integrated system during continuous manufacturing is one of the most challenging topics in downstream processing. Microinnova successfully faced this challenge. The delivered plant systems are thoroughly used at the research institutions to develop efficient crystallization processes for API s and intermediates in pharmaceutical production. The delivered continuous crystallization plants were specifically designed for research purposes. The crystallization plants have a capacity of 1-8 l/h, are fully automated and were prepared for PAT integration such as FBRM and RT microscopy, which allows a model predictive control.

9 Continuous Liquid Formulation Microinnova together with GSK showed a pilot scale demonstration rig for the manufacture of toothpaste via a continuous process intensification method with parallelised streams, where individual specialised units were combined together into a complete system, enhancing production capability. A small pilot scale manufacture (20 kg/h), of the combined streams was demonstrated to show the potential of Process Intensification. Many hurdles were overcome especially de-aeration, high solids content work and micro-dosing of powders. In addition to tooth paste, Microinnova has during the last few years also developed pilot plants for continuous formulation of products like emulsions, suspensions and gels. We have handled mixing challenges like mixing very highly viscous substances with low viscous substances and we have achieved continuously produced liquid formulations with high solid content (>50% w/w). Objectives in addition to producing the formulation continuously have been energy saving and sterilisation. Typically pilot scale production plants have had capacities in the range kg/h.

10 Extensive experience in Process Development Microinnova is your ideal partner for switching your traditional batch process to an intensified continuous process. A high range of different conditions and chemistries is within our competence: Highly exothermic processes Catalytic processes Mixing-sensitive processes Processing toxic substances Processing high corrosive substances (conc. Oleum, HCl and HF) Processing high viscosities (up to 100 P) Processing unstable substances Continuously handling slurries and solid contents up to 40 % A wide range of different technologies are available in our labs.

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12 We identify all critical process parameters and select the best possible technology for each process to finally turn process performance into money Dr. Dirk Kirschneck, Managing director We focus our customer s process and provide high level solutions independent of any technology or supplier, starting from process design arriving at turnkey plant systems. Walter Linhart, Head of Sales