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Continuous Chromatography: Varicol® Line

Typical Applications

Binary separations:
- Enantiomers
- Other isomers
Complex mixture fractionations
From kilograms to hundreds of tons

Five APIs are commercially produced using our Varicol® technology, with two of them among the top 15 brand-name drugs at retail in 2006.

Varicol® - Principles

Varicol® is a multi-column continuous process with a non-synchronous shifting of the inlet and outlet lines. The number of columns varies periodically in each zone.

This ensures a more efficient use of stationary phase and a higher productivity compared to the SMB (Simulated Moving Bed).

Varicol® - Benefits & Features

Lower production costs / Fast and easy scale-up

Industrial design:

From lab to large-scale, the same choice of industrial components to maximize reliability
Robust design and full automation ensure unattended, 24/7 operation
Fully compliant with your regulatory environment (explosion proof, cGMP, GAMP…)

A complete offer:

Simulation and modelling tools are provided to speed up your process development
Ancillary equipment (solvent storage vessels, evaporation units, utilities…) is offered to maximize the performance and cost effectiveness of your process
Extensive training and full customer support allow you to become an experienced user in continuous chromatography

Varicol® Standard Product Line

Varicol®	LABORATORY			PILOT			INDUSTRIAL
Type	Micro	LAB(30-50)	LAB (50-80)	6-110 6-150	6-200	6-300	6-450	6-600	6-800	6-1000
Productivity range	g/day			kg/week			tons/year
Productivity range	10-40	50- 1000	250-2500	10-200	40-400	90-900	8- 80	15-150	25-250	40- 400
Stationary Phase (kg)	0.05	0.4-1	1-3	3-6	10	25	55	100	180	250

Example: Varicol® 6-200 has 6 columns of 200 mm i.d.

Our systems are designed with:

Operating temperature from 15 to 50°C
Operating pressure from 50 to 100 bars
4 to 8 columns

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 LicoHelp™ software to calculate the operating parameters. LicoHelp™ can also be used to compare different processes, simulate the effects of changing parameters, etc.

Software - Varicol®

User-friendly graphical interface
Novasep simulation software (LicoHelp™) is included to model and optimize the separation.
Validated software compliant with 21 CFR part 11 and GAMP 4
Option: Management of ancillary equipment (tankfarm, evaporators, utilities…), In-process monitoring, ACS™…

Additionally, 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.

More information on Software

Advanced Control System (ACS)

The only system making continuous chromatography fully PAT (Process Analytical Technologies) compliant
Automatic control of lab-scale Varicol® process operating conditions
Greatly simplifies the use of lab-scale Varicol® systems and speeds up process development
Secures the process and optimizes the productivity at commercial scale

More information about ACS

Customizable Solutions

Our engineers can customize a solution to match your specific purification needs:

Special design of our systems/processes to ensure maximum product purity and productivity
Solvent storage unit with patented eluent composition adjustment
Evaporation unit: automated rotary, wiped film or falling film evaporators, fully integrated with the Varicol® Unit
Fully integrated utilities (vacuum, heating or cooling units…)
Extended temperature range
Full cGMP IQ/OQ qualifications

Your Added Benefits

Novasep provides custom purification from kilograms to multi-tons.

Moreover, we are able to combine chromatographic purification with multi-step synthesis at our FDA-inspected sites.

Novasep’s strategic cooperation with Daicel/Chiral Technologies enables us to screen the unmatched library of Daicel chiral stationary phases to provide the most cost-effective chiral separation solution with Novasep Varicol® technology.

Please contact your local representative for further information.

Benefits & Features

Cost

An advanced continuous chromatography process, Varicol® provides the best productivity, return on investment and the lowest operating costs. Our systems fully integrate solvent recycling to reduce solvent costs by up to 99.9%.

Time

Novasep’s chemists efficiently design the right chromatographic separation method for your intermediate or API. The scalability and robustness of our chromatographic processes, guaranteed by Novasep, will ensure the quickest delivery of API for clinical supplies, process validation, registration and commercial production.

Ease of Use

Take it easy! Novasep patented technologies greatly simplify continuous chromatography.

Novasep simulation and modelling software facilitates the development of your process. Fully compliant with PAT guidelines of the FDA, the ACS™ (Advanced Control System) increases your understanding and control of your manufacturing process.

Other

Please challenge us!

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