Continuous Flow Manufacturing

Continuous Manufacturing Has a Strong Impact on Drug Quality

In 2012*, FDA expounded on the benefits of continuous manufacturing, which are greater reliability, safety, efficiency, responsiveness/flexibility, and reducing costs.

Since 2012, Takasago has been working on utilizing our specialized homogeneous catalyst technology in continuous flow manufacturing.

Although we faced a lot of difficulties to achieve that, now the continuous flow manufacturing is one of our specialties.

Takasago has Pipe Flow Reactor (PFR) and Continuous Stirred Tank Reactor (CSTR) and Intermittent Stirred Tank Reactor (iSTR) in R&D and Iwata and Kakegawa factory. They can be used for the production process for pharmaceutical intermediates.

From 2015, we carried out the commercial production by the continuous flow manufacturing facility. Now, the total production has reached 100 MT (million metric tonnes) at IWATA.In 2016, FDA inspected our Iwata facility.

In 2018, Takasago succeeded in production of ton scale with Lithium aluminum hydride (LAH) reducing agent by using our continuous flow manufacturing technology.
Takasago keeps developing continuous flow manufacturing equipment as a differentiated technology and contribute to customers’ satisfaction.

FDA Perspective on Continuous Manufacturing, IFPAC Annu. Meet. Jan. 22-25, 2012, Balt. MD, USA. (2012). PDF

(Progress of continuous flow manufacturing)

1983 Started Telomerization with Horizontal Pipe Flow Reactor
1985 Started Continuous Distillation
2013 Installed Vertical Pipe Flow Reactor (Kakegawa)
2014 Installed Vertical Pipe Flow Reactor (Iwata)
2014 Installed CSTR with Counter Current Extraction
2015 3 Process Validations for GMP intermediates with Continuous Flow
2015 Started commercial production
2016 FDA Inspected at Iwata
2018 GMP intermediate (ton scale) in continuous flow by the reducing agent LAH
2018 FDA inspection at Iwata Factory

Table. Facilities for Continuous Methodology
Stage Type Size Pressure Temp. Object Capacity
Laboratory Tube reactor
H-Cube
Pipe Flow Reactor
1~60ml 5MPa 0~150℃ Catalyst screening Feasibility study ~5kg
Demonstration Tube reactor 350ml 5MPa 0~150℃ Optimization ~50kg
CSTR X 2
Glass & Stainless Steel
10&20L -70~180℃ Optimization Commercial ~5MT
Factory Distillation Tower Various Full Vacuum Commercial ~100MT
Pipe Reactor 100L 5MPa 0~200℃ Commercial ~20MT
Pipe Reactor 200L 5MPa 0~200℃ Commercial ~70MT
CSTR 200L -50~150℃ Commercial ~100MT

Flow Applications at Takasago

Commercial:

  • • Asymmetric Hydrogenation
  • • Direct Asymmetric Reductive Amination (DARA)
  • • Achiral Reductive Amination / Leuckart-Wallach
  • • Dynamic Kinetic Resolution (DKR)
  • • Reduction using LAH
  • • Chan-Lam-Evans Cross Coupling

Under development:

  • • Grignard Reaction
  • • Ester reduction

*FDA Perspective on Continuous Manufacturing, IFPAC Annu. Meet. Jan. 22-25, 2012, Balt. MD, USA. (2012). PDF