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Continuous Manufacturing as a Toolbox for Profitable Producing of Commodity APIs & their Intermediates in Europe and North America

Most of the commodity active pharmaceutical ingredients (API) are manufactured in the Far East. The current COVID-19 pandemic has demonstrated that global supply becomes an issue in crisis situations, which has led to shortages for different APIs and intermediatesTherefore, a regional manufacturing of APIs and their intermediates is intensively discussed. The key question is: How this can be done in an economically useful way?  Previous experience has demonstrated that key elements to reduce the cost per kg are process intensification and continuous manufacturing, both of which Microinnova has more than 15 years of experience in Microinnova works on several projects for developing concepts and designing continuous processes to realize commodity APIs (>1.000 t/a) with significantly lower consumption of chemicals and energy, as well as decreased personnel costs. 

Furthermore, the number of unit operations, solvent amounts and water demand can be significantly reduced. The first step of this is typically detailed theoretical evaluation of the processes by investigation of its critical parameters by means of a literature study in combination with Microinnovas broad competence of continuous manufacturing and process intensification. The core of Microinnovas working procedure is a close interaction of the process development and engineering teams, leading to higher process capability, resulting in a higher product quality level. This leads to a first process flow diagram, including a first plant cost estimation. Dimensioned mass and energy balances, as well as waste and energy streams, enable a fundamental evaluation of the process costs and can be used as decision making tool. Afterwards, the continuous process will be developed. The verified process will be the base for the basic engineering, including a complete safety concept. The GMP-compliant Smart Manufacturing plant will be constructed and started up by Microinnova and will contain tools like model predictive control (MPC) and process analytical technology (PAT). The work is based on a standardized MIC internal scheme, developed from more than a hundred process development projects.  


Great collaboration with Oliver Kappe and the CCFlow & the RCPE Team 


We have been working interactively on the development of chemical processes with the integration into engineering and plant aspects. We see the joint publication of bromine generators and photochemistry as a great success. Additionally, we are working together on the project SynthesisControl. A paradigm shift toward continuous flow processing enables a much higher process efficiency.
One important benefit of a continuous flow regime is the ease of implementation of process analytical technology (PAT) tools for real time monitoring of critical process parameters and quality attributes. Useful process information extracted from process data continuously obtained from the PAT monitoring of the reaction will be fed back to the controllers. Additionally, the reaction models will further improve during the manufacturing of the API as a “self-learning” type system. The control concept will be implemented and tested in a two-stage model (digital twin) reaction, processing a widespread API at laboratory scale, which can also be scaled to manufacturing. 

Find out more about SynthesisControl »





Continuous Manufacturing for 2nd Generation API Synthesis
 Process with Half of the Unit Operations 

Continuous manufacturing offers an interesting toolbox for process intensification of API manufacturing processes. Flow Chemistry offers a wide range of interesting processing options beside the “classics” of micro reaction technology/flow chemistry, like fast exothermic reactions and hazardous chemistry. An optimization of mass and heat transfer can reduce the necessary processing times by a factor of up to 10. By addressing the specific needs of a chemical reaction by means of specific reactors, by-product formation can be significantly reduced.

The consequence of a reduced by-product formation leads to reduced work-up effort. Blocks of three to four synthesis steps can be often executed without separation and work-upShorter processing times, by a factor of up to 10, have been demonstrated. In one project the number of unit operations has been reduced from 18 to 9. The amount of solvents for four key steps has been reduced from 14 kg solvent per kg of product, 2 of them chlorinated, to 7 kg solvent per kg of product, using only chlorine-free solventsSometimes these efficiency-increasing projects pay for themselves by the sheer reduction of working capital, since the amount of materials in process can be dramatically reduced. Continuous Manufacturing enables a reduced variability of batches. Quality costs can be reduced by the use of PAT tools. Safety is increased by much smaller reactor volumes and a much better process control can be achieved. Hazardous reagents can be generated in situ and do not need to be stored. Microinnova offers the development of new process concepts by keeping the synthesis route. 



In situ Bromine Generation for Photochemical Applications in Continuous Manufacturing

Continuous manufacturing enables options to generate hazardous or unstable reagents. This opens options to enable the use of hazardous reagents in a safe manner on manufacturing scale. In this study we present how in situ generated bromine can be used for a photochemical application. This combines the process intensification of a photochemical reaction with the in situ generation of the hazardous reagent bromine. The past decade has seen Photochemistry become a powerful tool in chemical synthesis. The development of efficient pseudo-monochromatic light sources enables a new efficient way for the energy supply. Continuous flow technology has been demonstrated as a solution to this problem, since narrow reaction channels can ensure homogeneous irradiation, alongside improved heat transfer and mass transfer (batch-to-conti). Benzyl bromides represent common photo-chemically accessible building blocks in the pharmaceutical and other industries, signifying that their scalable synthesis is of importance to multiple fields. The use of N-bromosuccinimide (NBS) instead is convenient, especially on lab scale since the associated risks are significantly lower and the crystalline solid is easier to handle. The trade-off when using NBS, however, is poorer reactivity, atom economy, and solubility.

In the current study that was conducted by the CCFlow Team in cooperation with our team, we can demonstrate a highly intensified process for photochemical benzylic bromination, using the chemical generator approach for in situ bromine formation. A commonly used oxidant is H₂O₂, but there are safety concerns associated with the storage and use of peroxides. Accordingly, we employed NaBrO₃, a crystalline solid with a high decomposition temperature of 310 °C, as a safer alternative. By using concentrated hydro bromic acid (one source for both bromide ions and protons), a concentrated sodium bromate solution and no organic solvent (substrate pumped neat), the bromine generator was considerably intensified. Modular plants enable a flexible use of the bromine generator in batch and in continuous applications.


Continuous Fluorination reagent Generators – Cost-competitive and safe transfer to manufacturing medium level manufacturing infrastructures

Microinnova presents a new approach to execute fluorination reactions in a safe manner with conventional equipment on manufacturing scale. These processes can be realized by continuous fluorination reagent generators on manufacturing scale. Former R&D Director Dr. Lorenzo Orsini has worked for Miteni, a historical global reference within the field of Fluorine Chemistry. Now he has joined the continuous manufacturing team of Microinnova. With Lorenzo Orsini on board, Microinnova is able to offer a wide range of possibilities to develop customized fluorination process.

The focus will be high value applications. That means we are focusing on efficient and scalable fluorination solutions to provide easy-to-implement options in every factory. Having a wider portfolio of possibilities will allow to evaluate novel synthetic strategies by considering all the possible advantages of a late stage fluorination. The second important focus is to provide solutions which significantly simplify the safety risk management compared to a more common fluorine chemistry approach by replacing possibly hazardous processes with “in situ” reactivity. These processes can be realized by continuous fluorination units which provide the desired reagents on manufacturing scale. The on-site fluorination units can often be implemented in existing plant setups. The aim is to provide more options and to make hazardous chemistry safer, so that it can be transferred to medium level manufacturing infrastructures.. The approach is cost-efficiency oriented compared to the other commonly known techniques.



8 Differentiators that make Microinnova Unique

Microinnova serves its customers as a one-stop-shop from development to manufacturing plants. This contains process research, process design, process development, pilot plants and pilot testing, basic engineering and skid-based plant. The following eight differentiators make Microinnova unique.    



 

  1. Microinnova focuses on end-to-end continuous manufacturing, dealing with processes in the area of synthesis, work-up and formulation.

  2. We work with a wide range of different process intensification technologies. We select the best technology for each process. We want to enable uniform process conditions for each molecule.

  3. We are used to working in regulated environments. We are DIN EN ISO 9001 certified. We can build plants that fulfill typical standards for regulated environments like GMP and ATEX.

  4. We can handle various conditions. We can process highly viscous materials like melts, suspensions, precipitates and solids in packed or trickle beds.

  5. The strong interaction between our chemists and our engineers makes us unique. The combined competences enable better processes. This team enables safe processes with hazardous materials.

  6. We operate continuous plants in the lab. We can engineer and scale them to the tons-per-hour scale.

  7. Our interactive team is very experienced. We have completed more than 200 projects within the last 15 years.

  8. Pilot and manufacturing solutions are often realized by means of modular continuous plants. This enables flexibility for continuous manufacturing and enables a quick time to market.



Microinnova partners with Malcom Berry (Ex-GSK) for Control Strategies and Regulatory Issues

A cooperation between MB Consulting and Microinnova Engineering GmbH has been signed. “We are delighted to be partnering with a worldwide continuous manufacturing expert for future activities”, says Head of Sales of Microinnova Engineering GmbH, Walter Linhart.

The owner of MB Consulting, Dr. Malcom Berry, is an expert in the application of continuous manufacturing for API, with 20 years’ experience in this field. He was a key player in the visionary GSK flow chemistry team for manufacturing purposes, who has now started his own consultancy business last year after being with GSK for 26 years, where he was a Director within API Chemistry.  Malcolm was the project leader for GSK’s flag ship continuous manufacturing project at Singapore.

Microinnova Engineering GmbH is a one-stop-shop for flow chemistry, continuous manufacturing and process intensification with 15 years and 200+ projects worth of experience in the fields of synthesis, work-up and formulation. The projects cover a wide range of different applications in the process industries with a focus on pharmaceutical applications. The design of modular multipurpose plants is one of Microinnova’s core competences.

The collaboration opens access to experienced development, engineering and plant construction resources for projects of MB Consulting. Microinnova gains access to high level consultancy services in the fields of Process Analytical Technologies (PAT) concepts, Quality by Design (QbD), control strategies for manufacturing systems and regulatory concepts. Both parties expect a fruitful collaboration in the innovative, strong and expanding field of continuous manufacturing.


Increasing Efficiency with MACBETH EU Project

Microinnova Engineering GmbH is once again a partner in a promising EU project. The Membranes And Catalysts Beyond Economic and Technological Hurdles (MACBETH) project is concerning itself with “a breakthrough technology for advanced downstream processing by combining catalytic synthesis with the corresponding separation units in a single highly efficient catalytic membrane reactor (CMR)”. Coordinated by Evonik Performance Materials GmbH (EPM), the project’s duration is from November 1st 2019 to April 31st 2024. One of this project’s main goals is to increase resource as well as energy efficiency by up to 70%. A safer and smaller production plant, thanks to the innovative reactor design, furthermore offers a significant competitive advantage by decreasing CAPEX and OPEX by up to 50% and 80%, respectively.

The case Microinnova Engineering GmbH is working on within the MACBETH project, is the BOC (Bio Catalytical Oil Cleavage) case. It “aims to establish a CMR-based system for the enzyme-catalysed selective hydrolysis of plant oil fatty acids in an aqueous-organic system followed by an integrated membrane separation to isolate selected fatty acids.” The plant will be tested by two project partners to ensure process robustness and long term-stability and a containerized set up of it is planned to make transportation between the two testing sites easier. This will also demonstrate the plant’s flexibility and adaptability of results to new areas of application.

This project H2020-EU.2.1.5.3. is funded by EU Horizon 2020 Grant Agreement No 869896.

Image Source: Enzymicals AG 

 



Continuous Manufacturing of Formulations in Minutes instead of Hours

Microinnova Engineering GmbH has successfully commissioned two continuous formulation production plants to a European client. The design of the fully automated plant is very compact, which makes it possible to easily transport & install it at a different manufacturing site on the other side of the world.  It possesses an integrated Plug & Play concept, which means that 14 tons per day can be produced. All streams are controlled with precise mass flow meters so no labor intensive pre-weight of substances is needed and instant change of recipe is possible. This provides an easy capacity increase for the client and enables the production of new products.

“This plant replaces several batch vessels, reduces processing time from hours to minutes, minimizes work hours and waste, enables constant product quality, increases safety and can be upgraded for different products”, says project manager Mitja Ogrizek.

Eight different liquid feeds with versatile viscosities are dosed into three static mixers to deliver the end product mixture, which is then used further in the production process. The plant can produce different polymer concentration mixtures and the produced amount can be regulated based on the daily supply demand of the customer. The continuous mixing system is fully automated and can easily be connected to the local site IT systems, such as SAP.

 

 





Performance 
Boost for Enzymatic Oxidations by means of Process Intensification and Continuous Flow Processing 

O2-dependent biotransformations are promising for chemical synthesis. Their development to the level of efficiency required in fine chemical manufacturing has proven difficult however, due to thermodynamic and kinetic limitations when supplying O2 to the enzymatic reaction creating a complex bottleneck on conversion efficiency using batch technology at atmospheric pressure.

Process intensification for oxidative O2-dependent biotransformations is a promising tool using a batch-to-conti approach. In a cooperation between the Austrian Center of Industrial Biotechnology (ACIB) and Microinnova Engineering GmbH it was shown that process intensification applying continuous flow technology offers a comprehensive solution. continuous flow reactor using up to 34 bars enables biotransformations to be conducted in a single liquid phase. Increased enzyme activity has been detected already at 10 bars. For glucose oxidase the intensification factor for enzyme activity was up to 2.5, and amino acid oxidase showed an intensification factor up to 6 for the enzyme activity. High product concentration, with the concentration being 6 to 10 times higher at 34 bars compared to atmospheric pressure has been demonstrated. Reactions of glucose oxidase and amino acid oxidase were used both as soluble enzyme in liquid flow and immobilized enzyme in a packed bed as exemplary cases to demonstrate that the pressurized continuous flow reactor presents a powerful engineering tool uniquely apt to overcome restrictions inherent to the individual O2-dependent transformation consideredThe base for the performance push when using up to 34 bars of pressure is a 34 – 170 fold increase of dissolved oxygen compared to oxygen dissolved at atmospheric pressure.  

published on May 11, 2020




Modular plants enable API production in Europe

Export bans of Active Pharmaceutical Ingredients (APIs) and intermediates by India and China, caused by the global COVID-19 crisis, have led many companies to consider bringing back their production to Europe. This can only be done with a cost-efficient technology approach. Universal engineering designs and intesified processes are a good base for this. Companies like Microinnova have 15 years of experience to apply in rapidly developing chemical processes for demanding reactions.

This competence of Microinnova enables a quicker response to a spontaneous demand of a specific molecule. As seen in the past, a considerable demand for specific APIs or intermediates can arise with short notice. The minimizing of development and production times are critical, especially in the case of the outbreak of a new disease. A new production process can be employed rapidly through already constructed or even pre-existing modules which are applied in new combinations. This aids in APIs and medical treatment being available sooner.

Microinnova has already technically specified and built multiple modular plants for various pharma companies. Aside from fast realization, economic advantages further facilitate the possibility to bringing back production of some intermediates and APIs from Asia to Europe. Based on a high level of research activities in the past, Microinnova is proud to offer effective solutions to many customers now.

published on May 7, 2020


Microinnova is proud to be a 3 Star Sponsor of the Flow Chemistry Conference by Scientific Update

We are proud to announce our 3 Star sponsorship of this online Flow Chemistry Conference, hosted by Scientific Update, taking place May 11 & 12, 2020. The focus of this conference will be on case studies from process chemists and engineers who will be sharing their insights, examples and opinions.

As an expert in flow chemistry, continuous mixing plants and continuous manufacturing, Microinnova is especially excited for this event to further enlighten more of the industry to the vast advantages flow chemistry offers. Our commitment to help producers make the switch from batch to continuous processing leads to a number of economic benefits that in turn help our customers become more profitable. We are proud to be able to offer you our one-stop-shop solutions. Not only will we do process design and feasibility studies, but we also optimize pilot plants and even build entire plants for you, which according to the requirements can feature CE, ATEX or GMP compliance.

Sign up here »

published on May 6, 2020


Environmental & economic impact of solvent-free continuous API manufacturing of Rufinamide

In the pharma and fine chemical industries, the development of continuous flow technologies is a process intensification step of primary importance towards the manufacturing of high‐quality products, while reducing the environmental impact and cost of production. The sustainability and profitability of a process can be measured through life cycle assessment and cost evaluation. However, when applied to emerging technologies based on flow chemistry, these need to be performed at different stages of the process development in order to limit the uncertainties arising from the scale‐up, and hence providing high‐fidelity projections of environmental impacts and costs at larger scales.

Therefore, in this article, we perform an assessment at two different scales of production, lab and mini pilot plant scale, with the aim of quantifying the uncertainties of the assessment related to the scale‐up, identifying the hotspots of the system, and hence providing guidelines for the further steps of process development. The subject of the assessment is the solvent-free continuous flow synthesis of Rufinamide. It is the first time that this synthesis is evaluated at pilot plant scale.

Grimaldi, F., de Leon Izeppi, G. A., Kirschneck, D., Lettieri, P., Escribà-Gelonch, M., & Hessel, V. (2020, February 27). Life cycle assessment and cost evaluation of emerging technologies at early stages: The case of continuous flow synthesis of Rufinamide. Journal of Advanced Manufacturing and Processing.

Find it here »

published on April 22, 2020

 

Microinnova is operating in a new way! Take a look: 

In light of nationwide restrictions in order to influence the impact of COVID-19, most of the Microinnova Team has transitioned to work remotely. The lab remains in operation according to current laws and regulations. Tasks demanding lab time are scheduled in such a way that our lab workers are able to minimize social contact, as well as keep up with the projects they are working on. 

Due to the effects of this outbreak there is a need for a reorganization of projects. We are working tirelessly to ensure that we fulfill the needs of our customers. Our flexibility ensures a response to varying project demands. 

We do our best to serve our customers the usual way. We are happy to discuss new projects as well. We see these unusual times as an excellent opportunity to discuss and develop future strategies. Take this chance to contact us!

published on March 19, 2020

 



Forging Flow Chemistry Bond

Microinnova Engineering GmbH and Research Center Pharmaceutical Engineering GmbH (RCPE) are entering into a very promising collaboration. Microinnova is specialized in continuous modular plant design and flow process scale-up, as well as realizing continuous pilot and manufacturing scale plants. RCPE is a global leader in pharmaceutical engineering sciences and with its CCFLOW Area (Center for Continuous Flow Synthesis and Processing) it offers, amongst others, core competences in flow chemistry, process development, control strategy and online analytics (PAT), taking the lead in developing chemical routes, chemical simulations and determining reaction kinetics.

Their cooperation intends to synergize the competences for continuous manufacturing of chemicals and APIs of both involved teams, using various methods of process intensification, leading to a competence hub for these innovative technologies in the Graz area. Johannes Khinast and Thomas Klein (CEOs of RCPE), C. Oliver Kappe (Scientific Director of CCFLOW) and Dirk Kirschneck (Strategic Director of Microinnova Engineering GmbH) see the region as an important hub of continuous manufacturing for the pharmaceutical industry.

published on February 10, 2020

 

 

Release of the VDI 2776 Guideline


Sheet number 1 regarding the topic "Process engineering plants - Modular plants - Planning modular plants" has been released. Access it here

published on February 26, 2020

 

 
 

 

 

 

 

 

 

Latest Research & Publications

 

Pressurized microreactors as practical embodiments of a general reaction-engineering concept for process intensification in enzymatic conversions requiring O2 as the co-substrate

Article written by MALENE S. THOMSEN, GÜNTER TEKAUTZ in the journal "Biotechnology and Bioengineering" (Vol. 116, Issue 3, pp. 503-514)

Take a look at it

Preliminary economic assessment of a polymer production plant in batch and continuous manufacturing

Article written by GERARDO DE LEON, CHRISTIAN DREXLER, DR. KIRSCHNECK in the Chimica Oggi-Chemistry Today Magazine 

Take a look at it

Is flexible continuous manufacturing an oxymoron?

Article written by GERARDO DE LEON, WALTER LINHART, DR. KIRSCHNECK in the La Chemica e L'Industria Magazine (pp. 30 - 33)

Take a look at it

Industry 4.0 Delivers Significantly Increased Competitiveness

Interview from DR. KIRSCHNECK in the Speciality Chemicals Magazine (pp. 36 & 37)

Read the Interview

End-to-End Continuous Manufacturing: Chemical synthesis, workup and liquid formulation

Article written by DR. KIRSCHNECK, SIMONE M. PETEK

Take a look at it

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