1 Department of Chemical and Biochemical Engineering, Technical University of Denmark2 CAPEC-PROCESS, Department of Chemical and Biochemical Engineering, Technical University of Denmark3 CHEC Research Centre, Department of Chemical and Biochemical Engineering, Technical University of Denmark4 H. Lundbeck A/S
Introduction of the Process Analytical Technolo gy (PAT) Initiative, the Quality by Design (QbD) approach and the Continuous Improvement (CI) methodology/philosophy is considered as a huge milestone in the modern pharmaceutical indust ry. The above concepts, when applied to a pharmaceutical production process, should enable better designs of products and processes. Furthermore, easier process monitoring, control and au tomation are just some of the advantages that can be achieved as a consequence. Traditional production methods of Active Pharmaceuti cal Ingredients (APIs) are based on batch and semi-batch processes which include plenty of supportive actions defined as non-value added activities (NVAs) or simply waste. It is therefore desirable to im plement a switch from batch based production to continuous manufacturi ng modes in order to minimize NVAs, as well as to enable easier satisfaction of the demands defined by the PA T Initiative. This approach could be considered as establishing a Lean Production System (LPS) whic h is usually supported with tools associated with Process Intensifaction (PI) a nd Process Optimization (PO). Development of continuous processes is often c onnected with many obstacles due to the very long reaction sequences, inhomogenous reaction mixtures, the presence of slurries.... It is therefore important to adapt the reaction conditions as much as possible to the desired production in continuous mode. Small-scale manufacturing could be supported with modern PI tools, such as microwave assisted organic synthesis (MAOS), ultrasounds, meso-scale flow chemistry and microprocess technology. Furthermore, developmen t of chemical catalysts and enzymes enabled further acceleration of some chemical reactions that were known as very slow or impossible to be performed. The main goal of this work is to develop a PI strategy that would include different chemical and physical approaches with the main purpose to accelerate slow chemi cal reactions and adapt them to continuous manufacturing modes. Detailed insight into the PAT, QbD, CI and Lean Production System (LPS) is additionally provided in the in troduction. The practical implementation of the PI strategy is covered with three different examples. The first example process is the dehydration of 9 ‐ Allyl ‐ 2 ‐ Chlorothioxanthen ‐ 9 ‐ Ol (“N714- Allylcarbinol”) to the mi xture of cis and trans 9H ‐ thioxanthene,2 ‐ chloro ‐ 9 ‐ (2 ‐ propenylidene) ‐ (9CI) (“N746-Butadienes”). Both components are in termediate products in the synthesis of Zuclopenthixol – a product of H. Lundbeck A/S. Su ccessful transfer from batch towards meso-flow chemistry is performed together w ith demonstration of th e potential for in-/at - and off-line process monitoring. The second example proce ss is the anti-Markovnikov hydroa mination between the “N746- Butadienes” and 1-(2-hydroxyethyl)piperazine (H EP) resulting into a mixture of cis/trans 4 ‐ [3 ‐ (2 ‐ Chlorothioxanthen ‐ 9 ‐ ylidene)propyl] ‐ 1 ‐ piperazineethanol (Clopenthixol). This chemical reaction is well-known as very slow and difficult to be accelerated by applying chemical catalysts. vi Some authors claim that hydroamination of unsatur ated hydrocarbons is known as one of the “ten challenges for homogeneous catalysis”. Neverthele ss, implementation of th e PI strategy by using microwave irradiation resulted in significant improvements. The third example process includes the small-s cale production of (2-Bromophenyl)(phenyl)sulfane. This important API intermediate is receiving si gnificant attention in the pharmaceutical industry due to the fact that there are pl enty of APIs which in cludes C-S bonds in thei r chemical structure. The production of such compounds is based on Car bon-Sulfur cross coupling reactions, involving expensive chemical catalysts, chemical ligands, bases and unfriendly solvents. Implementation of the PI strategy with a significantly modified chemi cal pathway resulted in several benefits from an economic, environmental and manufacturing point of view. Considering the results achieved in the case studies, it can be concluded that successful implementation of the PI strategy has been ac hieved while satisfying the PAT demands and implementing Lean Production System. Significant accelerations of often considered difficult chemical reactions have been achieved, and therefor e it can be concluded that a successful transfer from batch towards continuous manufacturing has been achieved.
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Dam-Johansen, Kim, Skovby, Tommy, Gernaey, Krist
Technical University of Denmark, Department of Chemical and Biochemical Engineering, 2014