1. What is industrial scale in CPC?
Laszlo Lorantfy - CSO
RotaChrom Technologiai Kft
Chicago

2. In medias res
Why has CCS experienced a low acceptance rate among the scientific community? (specially pharmaceutical production)
No real GMP compliant instruments - just ask about cleaning validation
Not all scales are available: semi-prep HPLC (<50ml/min) – HSCCC – CPC both available prep HPLC ( ml/min) – HSCCC limited – CPC available process HPLC (>500 ml/min) none available -> no industrial scale!
Why invest in a technology at small scale, if it cannot handle final production?

3. Nominal flow rate
A comparison between instruments is needed! – different manufacturers use different SS
A flow rate where
SF > 80%
Most common stable solvent systems (MTBE – AcN – H2O 4:1:5; EtOAc – H2O)
ARBITRARY! – SF can be calculated from different system
Alain P Foucault 1995

4. Role of RotaChrom Established 2014, Dabas, Hungary
Develop a CPC instrument for industrial scale multiliter flow
Increase performance higher SF higher plate number
GMP requirements first priority
Instrument is for Pharmaceutical Industry production
Contionous operation

5. Back to theory Cell geometry = performance
CFD simlations – results were misunderstood
1. back-mixing effect Marchal et al : positive effect Adelmann et al : negative
2. cause: coriolis-force
3. SF – N compromise (flow rate) Stokes-model

6. Changes in cell geometry
Assymetrical cells
Collection funnel
Inlet divided
Scalar sidewall
Difficult manufacturing nightmare for engineers?

7. Is there a simple solution
Can a cell geometry can be defined which is easy to manufacture?
Manufacturing can be done in simple machines without significant amount of waste?
Would this form give good performance parameters?
Is it scalable?
Can we provide a solution for all of this?

8. How? Just look at an HPLC column! Preferabry DAC Tube
Phase distributor plate
Collector plate
(filling)
Keep it simple, stupid! KISS - principle

9. Is it good? CFD says so Flow is even and stable
No significant coriolis-effect no backmixing
Scalable by ID just as HPLC

10. Is it really good?
Poster by David Ward et al – saccharide separation scale-up
SFs at 200 ml/min – for 15mm ID cell, 100 pcs, 2l total volume MTBE : H2O – 88% MTBE : AcN : H2O 4:1:5 – 84% MTBE : AcN : H2O 2:2:3 – 80% EtOAC : H2O – 80% i-Hex : Acetone : Water 2:3:1 – 80%
Total volume pumped in 10 minutes
Plate number was same or better than Armen SCPC-250 for every separation

11. Development steps What took us 2 years? Lots of ugly prototypes
Svetlana – filling material have to be good quality SS
Centrifuge machinery : S cells (200 ml/min) M cells (2,5 l/min) L cells (10 l/min)
rCPC – only S
iCPC – all 3 types kg to tonnes

12. Application examples Instrument Flow rate Volume Injection
Production /24h
rCPC – S
200 ml/min
2,0 l
6,1 g
0,30 kg
iCPC – M
2,5 l/min
25 l
76 g
3,8 kg
Oligopeptide – lipopeptide
Hexane – Acetone – Water system
70% yield
Exchanged LC
Solvent recycling by NF!

13. Examples continued
Peptide lypide sidechain 1 aliphatic amine 1 aromatic amine 4 carboxylic acid
Zwitter-ionic structure
Isoelectric point at around pH 2,5-3,0
Purification steps 2x IEX, 2x RPLC low yield (25-40%)
>95% puritiy
>80% yield

14. pH-zone PUFA derivative Material produced for Clinical Phase II trials
In cooperation with a CMO
Input 10 kg Output 3 kg
Column size 350 ml (less cells) flow 200 ml/min cycle time: 5 minutes
6 kg/day/l productivity
Solvent recycled >95%

15. Presentation is over I am happy to answer questions now, or later...
Still working on new solutions...
We are happy to cooperate with anyone on scale-up of CPC (or CCC) processes!
Let’s rock on...