Clean In Place Technlogies BioPharma Facilities

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Published on February 15, 2009

Author: ran_nwd

Source: slideshare.net

Cleaning Technologies in BIOPHARMA PROCESSES August 29, 2007 Ranjeet Kumar M Tech (Chemical)

Cleaning Overview Cleaning a challenge in Biopharmaceutical facility Steps of CIP Factors affecting Cleaning efficiency Effects of Turbulence Cleaning Mechanisms Validation

Cleaning a challenge in Biopharmaceutical facility

Steps of CIP

Factors affecting Cleaning efficiency

Effects of Turbulence

Cleaning Mechanisms

Validation

Principles Cleaning can be defined as removal of the previous active ingredients to the acceptable level. Carry over of dirt is influenced by: Nature of dirt. Nature of the surface of equipment – Vessel surface, centrifuge, filters Accessibility to cleaning – vessel top, agitators, valve body, hold up Typical Biopharma residues Proteins, Lipids Sugars, Salts Nucleic Acids, Viable Organisms Endotoxins

Cleaning can be defined as removal of the previous active ingredients to the acceptable level.

Carry over of dirt is influenced by:

Nature of dirt.

Nature of the surface of equipment – Vessel surface, centrifuge, filters

Accessibility to cleaning – vessel top, agitators, valve body, hold up

Typical Biopharma residues

Proteins, Lipids

Sugars, Salts

Nucleic Acids, Viable Organisms

Endotoxins

Challenges in Cleaning Cleaning can be done by any method so long as it cleans. Manual cleaning Semi-manual Automated Automation is required to – Track cleaning procedure & record data Assurance of repeatability Automation is to ensure repeatability and confidence and is not a necessity. 21 CFR Part 211.67 – guidelines for Equipment Cleaning & Maintenance.

Cleaning can be done by any method so long as it cleans.

Manual cleaning

Semi-manual

Automated

Automation is required to –

Track cleaning procedure & record data

Assurance of repeatability

Automation is to ensure repeatability and confidence and is not a necessity.

Clean In Place a Step Ahead Consistent Cleaning Process Resource Savings (water, electricity, chemicals) High Quality Result Time Saving Less Manual Work Higher Safety for Personnel Documented Process Minimum load on Waste Treatment.

Consistent Cleaning Process

Resource Savings (water, electricity, chemicals)

High Quality Result

Time Saving

Less Manual Work

Higher Safety for Personnel

Documented Process

Minimum load on Waste Treatment.

Steps of CIP Wash and drain (Ambient Temp) Alkali Wash (High Temp, Recirculation) Rinse - Purified water Acid Wash (Cleaning & Neutralization) Rinse – Purified water Rinse – WFI Rinse – WFI (Conductivity Check) AIR BLOW AFTER EACH RINSE TO REMOVE PREVIOUS SOLUTION

Wash and drain (Ambient Temp)

Alkali Wash (High Temp, Recirculation)

Rinse - Purified water

Acid Wash (Cleaning & Neutralization)

Rinse – Purified water

Rinse – WFI

Rinse – WFI (Conductivity Check)

AIR BLOW AFTER EACH RINSE TO REMOVE PREVIOUS SOLUTION

Factors Affecting Cleaning Efficiency Cleaning Solution Temperature Cleaning Solution Concentration Cleaning Time External Energy (Spray Device, Agitation, Baffle, Turbulence)

Cleaning Solution Temperature

Cleaning Solution Concentration

Cleaning Time

External Energy (Spray Device, Agitation, Baffle, Turbulence)

Solution Temperature Chemical cleaning is a chemical process & Increased Temperature ↔ Increases – Solubility, Reaction Rates & Precipitation Decreases – Bond Strength & Viscosity Optimum temperature should be defined for different type of equipment. Range – Alkali Rinse – 50-80 ° C & for Acid Rinse – 30-60 ° C. Defined on residual characteristics.

Chemical cleaning is a chemical process & Increased Temperature ↔

Increases – Solubility, Reaction Rates & Precipitation

Decreases – Bond Strength & Viscosity

Optimum temperature should be defined for different type of equipment.

Range – Alkali Rinse – 50-80 ° C & for Acid Rinse – 30-60 ° C.

Defined on residual characteristics.

Cleaning Agents Concentration of chemical increases Cleaning Efficiency Alkali Concentration- 0.25 M Acid Concentration- 0.1 M Adjustable for each cleaning operation based upon Residue Characteristics Chemical should be efficient in cleaning action – simple or formulated chemical Not a part of manufacturing process – should be rinsed off completely or up to a defined level

Concentration of chemical increases Cleaning Efficiency

Alkali Concentration- 0.25 M

Acid Concentration- 0.1 M

Adjustable for each cleaning operation based upon Residue Characteristics

Chemical should be efficient in cleaning action – simple or formulated chemical

Not a part of manufacturing process – should be rinsed off completely or up to a defined level

Cleaning Time Cleaning duration should be enough to remove process residue & chemicals Increased Contact Time ↔ will improve cleaning process but have more cost. Ensure repeatable results Alkali Wash : 5 – 40 min Acid Wash : 5 – 20 min Adjustable for each cleaning operation based upon residue characteristics Time should be based on – Specified turn over volume Monitoring return conductivity Rinse volume – Volumetric flow rate Circuit hold up volume

Cleaning duration should be enough to remove process residue & chemicals

Increased Contact Time ↔ will improve cleaning process but have more cost.

Ensure repeatable results

Alkali Wash : 5 – 40 min

Acid Wash : 5 – 20 min

Adjustable for each cleaning operation based upon residue characteristics

Time should be based on –

Specified turn over volume

Monitoring return conductivity

Rinse volume –

Volumetric flow rate

Circuit hold up volume

Fermentor & Its Transfer Lines

CIP Solution Collection

Recirculation Of CIP Solution

Cleaning of Transfer Lines

Design of CIP system Capable of heating through heat exchanger. Should have a pump to deliver flow at the rate of 1.5 m/ sec. Capable of adding Alkali & Acid and measuring concentration using conductivity. Capable of recycling Capable of repeating if temperature and velocity is incorrect. Capable of performing self CIP Capable of SIP if infectious organisms are handled.

Capable of heating through heat exchanger.

Should have a pump to deliver flow at the rate of 1.5 m/ sec.

Capable of adding Alkali & Acid and measuring concentration using conductivity.

Capable of recycling

Capable of repeating if temperature and velocity is incorrect.

Capable of performing self CIP

Capable of SIP if infectious organisms are handled.

CIP Cycle Development (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 also 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.

CD an Investment on Practical lessons learned from a CIP CD program – case study, parameters setting, safety study, 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.

Practical lessons learned from a CIP CD program –

case study, parameters setting, safety study, 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 & “DONE?”

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 & “DONE?”

 

Validation Riboflavin test for Coverage Conductivity for Cleanliness T.O.C for residual matter Swab test Flow Measurement Temperature stabilization Dead Leg & Drainability check Validation Assumes That Cleaning is: - Effective, Reliable, Repeatable

Riboflavin test for Coverage

Conductivity for Cleanliness

T.O.C for residual matter

Swab test

Flow Measurement

Temperature stabilization

Dead Leg & Drainability check

Validation Assumes That Cleaning is: -

Effective,

Reliable,

Repeatable

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