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”, S. Chatterjee, IFPAC Annu. Meet. Jan. 22-25, 2012, Baltimore. MD, USA. 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)
  • Installed CSTR with Counter Current Extraction
2015
  • 3 Process Validations for GMP intermediates with Continuous Flow Started commercial production

2016
  • FDA Inspected at Iwata
2018
  • GMP intermediate (ton scale) in continuous flow by the reducing agent LAH
  • FDA inspection at Iwata Factory

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