Clean In Place - Cycle Development

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Published on February 16, 2009

Author: ran_nwd

Source: slideshare.net

CIP Cycle Development Feb 15, 2009 Ranjeet Kumar M.Tech - Chemical

Contents Introduction Utilities Selection for CIP Parameter Setting Dead Legs CIP CD Issues (CASE STUDIES) Cleaning Mechanism Flex Hoses Instrumentation/Software Issues Planning of CIP CD

Introduction

Utilities Selection for CIP

Parameter Setting

Dead Legs

CIP CD Issues (CASE STUDIES)

Cleaning Mechanism

Flex Hoses

Instrumentation/Software Issues

Planning of CIP CD

CIP CD….? It is a three stage program of Water run to check CIP Path Chemical run to check rinsing of alkali soiled CIP Contamination Risk Management strategy - to determine control & alarm set points, and ensure cleaning cycle robust, repeatable & efficient. The purpose of the CIP CD program is to identify and resolve cleaning challenges prior to beginning the cleaning validation & Production. CIP CD is a Project Execution Strategy

It is a three stage program of

Water run to check CIP Path

Chemical run to check rinsing of alkali

soiled CIP

Contamination Risk Management strategy - to determine control & alarm set points, and ensure cleaning cycle robust, repeatable & efficient.

The purpose of the CIP CD program is to identify and resolve cleaning challenges prior to beginning the cleaning validation & Production.

Investment On…? What are some practical lessons learned from a CIP CD program? --- case study, parameters, safety, SOP practice, etc. What efficiencies can be gained which demonstrate a Return On Investment (ROI), in a CIP CD program?  Cost of problem solving, benefit of manufacturing improvement, research investment.

What are some practical lessons learned from a CIP CD program?

--- case study, parameters, safety, SOP practice, etc.

What efficiencies can be gained which demonstrate a Return On Investment (ROI), in a CIP CD program?

 Cost of problem solving, benefit of manufacturing improvement, research investment.

CIP CD program should have… System boundaries & mechanical configuration. Automation specification. Rationale for the configurable parameters. Understanding- Equipment, CIP circuit, & residue grouping strategies. Pre approved Protocol / checklist. Project management. Assurance for Cleaning Validation priorities – cleaning, repeatability, cycle time.

System boundaries & mechanical configuration.

Automation specification.

Rationale for the configurable parameters.

Understanding- Equipment, CIP circuit, & residue grouping strategies.

Pre approved Protocol / checklist.

Project management.

Assurance for Cleaning Validation priorities – cleaning, repeatability, cycle time.

Role of chemicals in CIP Efficient in cleaning. Simple alkali or formulated alkali solution. Not a part of manufacturing process. Should be rinsed off completely or up to a defined level. Optimize other rinses to remove cleaning chemicals.

Efficient in cleaning.

Simple alkali or formulated alkali solution.

Not a part of manufacturing process.

Should be rinsed off completely or up to a defined level.

Optimize other rinses to remove cleaning chemicals.

Rinse Time Robust enough to remove chemical and process residue. Should be based on – specifying circuit turnover volume monitoring return conductivity Obtaining grab samples – TOC, conductivity, pH, Bioburden, endotoxin level. Rinse volume Volumetric flow rate Circuit hold up volume Rinse time

Robust enough to remove chemical and process residue. Should be based on –

specifying circuit turnover volume

monitoring return conductivity

Obtaining grab samples – TOC, conductivity, pH, Bioburden, endotoxin level.

Volumetric flow rate

Circuit hold up volume

Rinse time

Air Blow Timing Air blow should be defined for draining CIP skid and draining & drying process lines. A dried line & vessel after CIP will have longer CHT (Clean Hold Time). During Air Blow intermediate drain ports should open. This will solve issues related to Dead Legs.

Air blow should be defined for draining CIP skid and draining & drying process lines.

A dried line & vessel after CIP will have longer CHT (Clean Hold Time).

During Air Blow intermediate drain ports should open. This will solve issues related to Dead Legs.

Dead Legs A section of the CIP circuit which does not experience turbulent flow. Can hold residue/detergents – Product contamination Excessive rinse time Identify with a chemical CIP cycle and not during soiled path cleaning. Remedy – Automation and/or Mechanical changes L D d  L/D =< 2

A section of the CIP circuit which does not experience turbulent flow.

Can hold residue/detergents –

Product contamination

Excessive rinse time

Identify with a chemical CIP cycle and not during soiled path cleaning.

Remedy – Automation and/or Mechanical changes

Dead Legs Dead leg identification and remedy can be overlooked due to speedy start up schedules.

Chromatography CIP CD Issues Achieving required flow rate in skid tubing. Diaphragm pumps are generally of small capacity. Priming of pumps and suction from CIP vessel. Bubble trap cleaning is challenging due to Pooling of CIP solutions. Manual cleaning may be required. Blowing Air in different tubing and Bubble trap. Positioning of manual valves at pumps entrance & at drain points need to be fixed. Mechanical positioning of pump inlet often create problem in delivering CIP solution at the end of the rinse. Rinse timing for different paths of the Chrom skid and their Air Blow timing are critical and should be optimize as per product contact area.

Achieving required flow rate in skid tubing.

Diaphragm pumps are generally of small capacity.

Priming of pumps and suction from CIP vessel.

Bubble trap cleaning is challenging due to Pooling of CIP solutions. Manual cleaning may be required.

Blowing Air in different tubing and Bubble trap.

Positioning of manual valves at pumps entrance & at drain points need to be fixed.

Mechanical positioning of pump inlet often create problem in delivering CIP solution at the end of the rinse.

Rinse timing for different paths of the Chrom skid and their Air Blow timing are critical and should be optimize as per product contact area.

Bubble Trap on Chrom Skid Pooling in Bubble Trap

Vessel Cleaning Ensuring adequate spray coverage Minimize pooling in the vessel Ensure turbulent flow through all inlet pathways Flow rate = +/- 20% of spray ball coverage test Draining rate should be equal to spraying rate. Portable CIP skid should be parked near to the vessel for recirculation or return pump should be near to vessel outlet. Vessel ports should be cleaned properly with spray ball action only. Directly mounted vent filter cleaning is not required.

Ensuring adequate spray coverage

Minimize pooling in the vessel

Ensure turbulent flow through all inlet pathways

Flow rate = +/- 20% of spray ball coverage test

Draining rate should be equal to spraying rate.

Portable CIP skid should be parked near to the vessel for recirculation or return pump should be near to vessel outlet.

Vessel ports should be cleaned properly with spray ball action only.

Directly mounted vent filter cleaning is not required.

Cleaning Mechanisms Primary cleaning actions:- fluid impingement, flow of a turbulent sheet on the side wall of the vessel >>> Pooling in the vessel bottom dish impedes these mechanisms.

Primary cleaning actions:-

fluid impingement,

flow of a turbulent sheet on the side wall of the vessel

>>> Pooling in the vessel bottom dish impedes these mechanisms.

Pooling Turbulent Falling Film Impingement Baffles on the side wall are placed inside vessel to minimize pooling.

Transfer Line Cleaning More challenging than it may appear. Flow velocity 5ft/sec…. why ??? Ensure complete wetting of the pipe Sweeping away of air pocket at high points Not Wet = Not Clean

More challenging than it may appear.

Flow velocity 5ft/sec…. why ???

Ensure complete wetting of the pipe

Sweeping away of air pocket at high points

Not Wet = Not Clean

Why 5ft/sec?

Transfer Line Cleaning… Constraint of different pipe diameters in a single CIP path. Inline reducers. Inline Filter housing. Wash Time = (Hold Up volume * Turnover Ratio) (volumetric Flow) Turnover ratio and hold up volumes should be documented during CIP CD. Parameters are starting points only & its efficacy must be verified during CV.

Constraint of different pipe diameters in a single CIP path.

Inline reducers.

Inline Filter housing.

Wash Time = (Hold Up volume * Turnover Ratio)

(volumetric Flow)

Turnover ratio and hold up volumes should be documented during CIP CD.

Parameters are starting points only & its efficacy must be verified during CV.

Centrifuge CIP CD Issues Most complex non vessel equipment & challenging to clean & important parameters to be considered – Product contact surface area boundaries. Volumetric flow rate, throughput & back press specification Discharge frequency & internal length Valve composite cycle timing for parallel paths Design Disassembling of BOWL internals is required for swabbing. Visual inspection is first test to confirm Cleaning

Most complex non vessel equipment & challenging to clean & important parameters to be considered –

Product contact surface area boundaries.

Volumetric flow rate, throughput & back press specification

Discharge frequency & internal length

Valve composite cycle timing for parallel paths

Design

Disassembling of BOWL internals is required for swabbing.

Bioreactor CIP CD Issues Most complex vessel equipment. Rinse Time >= Minimum time necessary to rinse the surface clear of riboflavin. Starting time for determining rinse time = 3 to 5 times of spray ball coverage time, and can be optimize based on the analytical & visual results. Swab sites based upon the mechanical design. Sparger tube is often utilized as a pathway for CIP solution to clean the bottom of impellers. During CIP of Media line, filter cartridge & housing should be removed with a CIP CAP.

Most complex vessel equipment.

Rinse Time >= Minimum time necessary to rinse the surface clear of riboflavin.

Starting time for determining rinse time = 3 to 5 times of spray ball coverage time, and can be optimize based on the analytical & visual results.

Swab sites based upon the mechanical design.

Sparger tube is often utilized as a pathway for CIP solution to clean the bottom of impellers.

During CIP of Media line, filter cartridge & housing should be removed with a CIP CAP.

TFF CIP CD issues The retentate side of the membrane is cleaned by “shear” while the permeate side flow is a function of Trans Membrane Pressure. Cleaning & rinsing of permeate line is more challenging. Permeate line is having flow pressure which is related to TMP and a flow velocity of 5 ft/sec may be difficult to achieve.

The retentate side of the membrane is cleaned by “shear” while the permeate side flow is a function of Trans Membrane Pressure.

Cleaning & rinsing of permeate line is more challenging.

Permeate line is having flow pressure which is related to TMP and a flow velocity of 5 ft/sec may be difficult to achieve.

Important parameters for TFF CIP – Required shear rate Rinse/wash volume Temp ranges Chemical concentrations Dirty/Clean Hold Strategies. Post CIP membrane storage requirement TFF CIP CD issues

Important parameters for TFF CIP –

Required shear rate

Rinse/wash volume

Temp ranges

Chemical concentrations

Dirty/Clean Hold Strategies.

Post CIP membrane storage requirement

Flex Hoses Flex hoses should have same diameter as of pipe. Gaskets should match with ID of the hoses & pipe. Wire reinforced hose to sustain pressure inside the hose. Hydro testing of hose is essential for safety of personnel. Steel hoses are required for steam supply. There should be safety arrangement for releasing pressurized hoses. Cleaned and not cleaned hoses should be kept separately.

Flex hoses should have same diameter as of pipe.

Gaskets should match with ID of the hoses & pipe.

Wire reinforced hose to sustain pressure inside the hose.

Hydro testing of hose is essential for safety of personnel.

Steel hoses are required for steam supply.

There should be safety arrangement for releasing pressurized hoses.

Cleaned and not cleaned hoses should be kept separately.

CIP CD Instrumentation Issues Diaphragm failures and valve faults Hold state due to – Valve fault Diaphragm valve failure With time diaphragm may be torn away from actuator, & the CIP flow path may be blocked. Diaphragm failure can be found through the pressurizing and venting of individual flow paths. Pathway that are blocked will not vent properly. Online sampling testing is available for conductivity. A HOLD state is justified if the efficacy of the restarted CIP cycle is equivalent to normal CIP. Proper connection of Profi Bus & Field Bus.

Diaphragm failures and valve faults

Hold state due to –

Valve fault

Diaphragm valve failure

With time diaphragm may be torn away from actuator, & the CIP flow path may be blocked.

Diaphragm failure can be found through the pressurizing and venting of individual flow paths. Pathway that are blocked will not vent properly.

Online sampling testing is available for conductivity.

A HOLD state is justified if the efficacy of the restarted CIP cycle is equivalent to normal CIP.

Proper connection of Profi Bus & Field Bus.

Automation in CIP CD Avoid operator prompts in between CIP rinses. Phase should be robust. All coding related issues should be solved during CD.

Avoid operator prompts in between CIP rinses.

Phase should be robust. All coding related issues should be solved during CD.

Carboys carrying chemicals supplied by vendor

CIP skid Parked in clean room

Chemical Dosing Bottles Preparation Define fixed concentrations for chemicals All safety precautions must be taken in presence of experienced personnel. Bottles should be leveled properly. Chemical bottles should be disconnected before moving. Vendor Carboys should be restricted in Clean area. Intermediate Nalgene bottles can be used to transfer chemicals from vendor carboy to dosing bottles.

Define fixed concentrations for chemicals

All safety precautions must be taken in presence of experienced personnel.

Bottles should be leveled properly.

Chemical bottles should be disconnected before moving.

Vendor Carboys should be restricted in Clean area. Intermediate Nalgene bottles can be used to transfer chemicals from vendor carboy to dosing bottles.

Transferring in unclassified Area Transferring chemical from vendor carboy to intermediate Nalgene Bottle.

Pneumatic Transfer Transferring chemical from intermediate bottle to dosing bottle

Movement of CIP skid Movement of Portable CIP skid- Extra care – skid ports may strike with wall All cables should be rolled up. Check for vessel level and hold up. Remove Flex Hoses before moving the CIP skid. Disconnect any expanders/reducers projecting outside the skid. Look for hanging lines inside the process area if the vent filter of the portable skid is elevated. Extra precautions needed during movement of portable CIP skid inside production area. Protect CIP skid, other equipments & wall

Movement of Portable CIP skid- Extra care – skid ports may strike with wall

All cables should be rolled up.

Check for vessel level and hold up.

Remove Flex Hoses before moving the CIP skid.

Disconnect any expanders/reducers projecting outside the skid.

Look for hanging lines inside the process area if the vent filter of the portable skid is elevated.

Extra precautions needed during movement of portable CIP skid inside production area.

Planning well for CIP CD CIP cycle development is a project strategy – Need a dedicated Team Starts at early stage of Plant commissioning – at P&ID development stage Identifying each CIP Circuits and their grouping. Evaluating worst case circuit in each group Identify action plan – Mechanical, Software, Parameter range, etc.

CIP cycle development is a project strategy –

Need a dedicated Team

Starts at early stage of Plant commissioning – at P&ID development stage

Identifying each CIP Circuits and their grouping.

Evaluating worst case circuit in each group

Identify action plan – Mechanical, Software, Parameter range, etc.

Planning well for CIP CD… Weekly meeting – participation CD Team, Process Engineer, Instrumentation Engineer, Validation, vendors, etc

Weekly meeting – participation

CD Team,

Process Engineer,

Instrumentation Engineer,

Validation,

vendors, etc

Planning well for CIP CD… Piping & equipment installation – P&ID walk down to check for Dead Legs Check for equipment accessibility Safety check – for utilities connections Software trial at simulation

Piping & equipment installation –

P&ID walk down to check for Dead Legs

Check for equipment accessibility

Safety check – for utilities connections

Software trial at simulation

CIP CD… next…? Water run to check CIP Path Chemical run to check rinsing of alkali Soiled CIP

Water run to check CIP Path

Chemical run to check rinsing of alkali

Soiled CIP

Thanks

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