Introduction

The Clean in Place (CIP) procedure for a chromatography column ensures thorough cleaning without disassembly. The process begins by flushing the column with deionised water to remove residual product. A cleaning solution, such as sodium hydroxide or ethanol, is then circulated through the column to break down contaminants, proteins, or biofilms. After sufficient exposure, the column is rinsed with deionised water until the effluent meets pH and conductivity specifications. This procedure is vital to adhere to the regulatory cleanliness standards followed in pharmaceutical processing, but is also necessary to maintain column performance and to ensure consistent results for each pack.

Sartorius chromatography columns have a standardised automated CIP procedure using software developed by Feed4ward Control. This case study follows the adaptation of the procedure to meet the following requirement set by BMS Cruiserath:

• The CIP procedure must use a liquid handling skid to pump liquid (flushing, cleaning and rinsing liquid) into the column. The liquid handling skid consists of a pump and multiple pipe routes to allow different liquids to be directed into and out of the column depending on which stage of CIP is currently running. The liquid handling skid is controlled by the BMS DCS (distributed control system)

Method

Our automation engineers worked closely with Sartorius process experts to develop a cleaning sequence that meets pharmaceutical standards as well as BMS requirements.

The standardised automated CIP procedure fills the column with liquid using the upward movement of the adjuster, this creates a negative pressure that draws the liquid in (see Diagram 1). It then drives the liquid out using the downward movement of the adjuster, periodically opening each valve route to clean every inner surface of the chromatography column.

In order to customise this so that the liquid is pumped in by the liquid handling skid we developed an automated sequence. This consisted of three procedures:

1. Pumped Fill: This first drives the column adjuster to maximum height. The column PLC then handshakes with the DCS to instruct the pump to turn on and the liquid to begin pumping into the column. The liquid fills the column until a liquid sensor detects that the column is full (see Diagram 2).

2. Pumped Scour: This process cleans the column by pumping liquid out through each valve route, with the amount of time liquid is pumped through each route sent from the DCS. Between each cleaning route the pump is switched off and back on to prevent an under pressure event which could cause damage to the pump or the column.

3. Purge: This procedure uses the downward movement of the adjuster to drive air through each valve route of the column to purge all remaining cleaning liquid.

All three procedures are used for the flushing, cleaning and rinsing phases necessary in a CIP.

Results

As part of the BMS Cruiserath project we produced a test document that specifies all testing necessary to validate requirements set out for the project. The sFAT (software FAT) was extensively documented according to GAMP standards on a column built for BMS with witnesses from both Sartorius and BMS. The Pumped CIP was executed in full and passed all tests. All hold and abort conditions were considered and tested such as engaging the operator kill switch, initiating an emergency stop and sending a critical alarm signal from the BMS DCS.

Conclusion

The Feed4ward team successfully met the BMS Pumped CIP requirements. Using efficient software design, teamwork alongside Sartorius process engineers and rigorous testing.