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Continuous Chromatography: Varicol® Line

The Varicol® is an advanced, multicolumn chromatographic process, ideal for the following applications at laboratory, pilot, or industrial scale:

Chiral separations, diastereomer separations, complex mixture fractionations: natural compounds, fermentation product, synthetic products (peptides, etc.)
From 10’s grams to 100’s tons campaigns
Proof of concept or industrial process development tool (Varicol® LAB)
Pilot multi-purpose systems to dedicated industrial plants (Varicol®)

Varicol® pushes the limits of continuous chromatography. It gives the possibility to fully optimize the use of the stationary phase, thus improving productivity, solvent consumption and most importantly, operating cost.

Standard Features

Varicol® LAB systems

Varicol® pilot and industrial systems

A compact system, designed for production:

Rugged (industrial) design ensuring unattended, automatic operation (24/7)
Lab or pilot (ex-proof) versions available
Option for cGMP operation qualification

An industrial system, designed for production:

Qualified for cGMP operation, 21 CFR part 11 compliant software
Explosion proof (ATEX zone 0/1 – CE and FM/UL class I div. I/II – USA versions)
Rugged (industrial) design ensuring unattended, automatic operation (24/7)

Easy set-up and operation:

Only a few analytic HPLC experiments required prior to starting a run
Operating parameters obtained with Novasep® powerful simulation software
In-process monitoring and advanced control options

Easy set-up and operation:

Direct scale-up from Varicol LAB or analytical scale HPLC runs
Operating parameters obtained with Novasep® simulation software
In-process monitoring (through automatic HPLC analysis), and advanced control option

Specifications

Varicol® LAB product line

Varicol®	Varicol® LAB 25 - 50	Varicol® LAB 50 - 80
Productivity (g/day)	50 - 1000	250 - 2500
Columns diameters (mm)	25 - 50	50 - 80
Number of columns	3 to 8	3 to 8
Max flow rates (ml/min)
- feed	100	250
- eluent	250	700
- extract & raffinate	250	700
- recycling	600	1000
Max pressure (bar)	70	70
Operating temperature (°C)	15 to 35	15 to 35

Proper Design: Performance, Reliability and Robustness.

Varicol® units used for pharmaceutical applications include short columns (typically less than 10 cm) packed with relatively small particles (20 µm) and switched at a rather fast pace (less than 1 min.). This requires adequate equipment design and control, as well as proper modelling software and assistance in order to determine optimum operating conditions and provide safe, stable and trouble-free operation.

As for any chromatographic system, the column design is of paramount importance. All Varicol® units with a column diameter of 2" and above are equipped with Prochrom® DAC columns. This is particularly important for large size units where the column diameter can exceed the column length by a factor 10 or more!

Optimisation of Operating Conditions & Assistance

The proper adjustment of the operating conditions of a Varicol® unit requires knowledge of the physico-chemical data of the chromatographic system (such as the adsorption isotherms, the plate height parameters, the permeability of the columns, etc.). This information is used by the Helpchrom software to calculate the operating parameters. Helpchrom can also be used to compare different processes, simulate the effects of changing parameters, etc. See Modelling software.

Additionally, Groupe Novasep engineers are available to assist customers in other fields, such as the screening of different phase systems (thermodynamic conditions), the selection of optimal operating conditions, the scaling a process, the training of personnel, etc. See Process development.

Software

PLC controlled
Management of ancillary equipment (vessels, evaporators)
21 CFR part 11 compliant
License to modelling software “Help 10” included

More information on Software

Advanced Control System (ACS)

Fully compliant with the PAT guidelines of the FDA, the ACS (Advanced Control System) option makes our lab-scale Varicol units easy to use for non-specialists, and our industrial varicol systems even more robust for producers.

More information about ACS

Options

Solvent storage unit, with level sensing, automated eluent composition adjustment and nitrogen blanketing
Evaporation unit: automated rotary or wiped film evaporators, fully integrated with the Varicol® unit
Full cGMP IQ/OQ qualification
Extended temperature range from 10 to 60°C

Varicol® pilot and industrial systems

Model (mm i.d.)	Productivity range (kg/day)	Columns diameter	Stationary phase (kg)
Varicol® 6 -110/6 -150	1 to 10	110 - 150	3.6/6.75
Varicol® 6 - 200	5 to 50	200	12
Varicol® 6 - 300	10 to 150	300	25
Varicol® 6 - 450	25 to 250	450	60
Varicol® 6 - 600	40 to 400	600	110
Varicol® 6 - 800	70 to 700	800	190
Varicol® 6 - 1000	100 to 1000	1000	300

Solvent recycling

Automated falling film or wiped film evaporators, fully integrated with the unit.
Solvent recycling rates of up to 99,97 % have been reported.
Solvent recovery units, with automated adjustment of the recycled eluent composition for multi-component mobile phases.
Solvent storage unit, with level sensing, patented eluent composition adjustment system and nitrogen blanketing.

A Proven Technology

Complete Varicol® systems supplied by Novasep typically include the Varicol® unit itself and solvent recovery units, with automated adjustment of the recycled eluent composition for multi-component mobile phases.
Multi Varicol® systems separate over 1,000 tons/year of intermediates and APIs in FDA-approved plants.

Added Benefits

Novasep Process offers complete process development services with guaranteed performance.
Custom purification (from kg to multi-tons) is available at Novasep Process FDA-inspected facilities.

More information on Varicol® concept
A Varicol® unit includes 4 zones, but all inlet and outlet lines are not shifted simultaneously. Accordingly, the column distribution between zones varies during time. The Varicol® process then allows for optimising the column distribution among zones in a more efficient way in comparison with SMB, because the number of column per zone does not need to be an integer. This offers an infinite number of column distributions. A 3-column Varicol® is feasible but a 3-column SMB is impossible. Typically, Varicol® systems need one or two columns less than SMB systems to achieve similar performances, thus reducing separation costs.

The Varicol® is normally a periodic process: it returns to the same status at the end of the period.
The asynchronous shift of the lines can be better seen in a special diagram (a chronogram) which shows a time distribution of columns during one period. As an example, the figure below shows the chronogram of a 3-column Varicol® process. In the particular case described, the period is composed of four time intervals.

It is important to point out that the temporary superimposition of some lines leads to obvious consequences for the technical design of a Varicol® machine. Between each column, the two outlet lines (extract and raffinate) must be connected before the two inlet lines (eluent and feed) following the direction of the recycling flux.

The initial column configuration (t=0) is characterized by zero column in Zone I, one column in Zone II, one column in Zone III and one column in Zone IV. This column distribution stays the same for 15% of the period. At the end of the first time interval (t = 0.15 DT), the Extract and Feed lines are simultaneously shifted, whereas the Eluent and Raffinate lines are not shifted.

The column configuration becomes: one column in Zone I, one column is in Zone II, zero column in Zone III and one column in Zone IV. This column distribution stays constant until for 35% of the period. At the end of the second time interval (t = 0.50 DT), the Eluent line is shifted, whereas all other lines do not move. The column configuration becomes: zero column in Zone I, one column is in Zone II, zero column in Zone III and two columns in Zone IV. This column distribution stays constant for 25% of the period. At the end of the third time interval (t = 0.75 DT), the Extract and Eluent lines are simultaneously shifted, whereas the Feed and Raffinate lines do not move. The column configuration becomes: zero column in Zone I, one column is in Zone II, one column in Zone III and zero column in Zone IV. This column distribution stays constant until for 25% of the period. The system then returns to its original status. This column distribution pattern is repeated during the following periods.

The column distribution over a period is characterized by the average number of columns per zone. Zone I contains one column for 35% the period, Zone II contains one column for 100% of the period, Zone III contains one column for 40% of the period; and Zone IV contains one column for 50% of the period and two columns for 50%. The configuration of the unit during one period can then be described as: <0.35><1.00><0.40><1.25>, representing a total of 3 columns.

More information on Software

The Control Software has been designed to provide safe and reliable operation of the Varicol® units. The software is developed following GAMP4 and 21 CFR part 11 guidelines. The different actions and levels of interaction with the software are password protected. A standard industrial system utilises a Programmable Logic Controller (PLC) for direct control of the unit (open/close valves start/stop pumps, read sensors, etc.) and a PC for the user interface.

The systems provided by Novasep Process integrate ancillary equipment such as automatic evaporators, solvent recycling, eluent composition automatic adjustment, monitoring of tank levels, etc.

Novasep Process has developed hardware and software tools, consistent with the FDA’s Process Analytical Technologies (P.A.T.) guidelines . For instance, with the IPM option (In-line Process Monitoring), it is possible to automatically check the internal concentration profiles and product purities. This is very important in order to understand the behaviour of the system and adjust operating conditions if required.For a high level of comfort and reliability, Novasep Process has invented the EASY-Varicol® concept. It allows for efficient maintenance and troubleshooting of a unit, either locally or from a remote location.

More information on ACS

The use of PAT (Process Analytical Technologies) in continuous chromatographic processes is made possible by the implementation of an "advanced control system" (ACS) module. It will provide a better understanding and control of the process.

This module will adjust operating conditions to improve the process robustness. These adjustments are possible thanks to two kinds of measurements: an "in-line" measurement (UV detector, polarimeter, densimeter.) and an "at-line" measurement (HPLC analysis). The combination of these measurements allows a continuous control of the process operating conditions. This regulation is quick and simple with the "in-line" measurements, and precise and punctual with the "at-line" measurements.

The implementation of an ACS module greatly simplifies the use of the SMB or Varicol ® processes.

At a production scale, the goal is to secure the process and optimize the productivity. Thus, the ACS detects technical problems, secures the process, automatically corrects deviations and maximizes the productivity while maintaining high purity and yield.

At a laboratory scale, the goal is to simplify the use of such systems and to speed up the process development. Thus, for each new separation, the user sets the specifications (purity, yield) and the ACS automatically brings the system to the optimal separation conditions.

Varicol process : continuous chromatography