Use of Disposable Bag Technology in Downstream Processing at a CMO Facility
Dr Philip MilburnPrincipal Process Engineer
Talk Contents
►Background to ABC5000 manufacturing facility►Reasons that disposable bags adopted for
product handling in downstream processing►Challenges when adopting disposable bags►Example of current use
Talk Contents
►Background to ABC5000 manufacturing facility►►►Reasons that disposable bags adopted for Reasons that disposable bags adopted for Reasons that disposable bags adopted for
product handling in downstream processingproduct handling in downstream processingproduct handling in downstream processing►►►Challenges when adopting disposable bagsChallenges when adopting disposable bagsChallenges when adopting disposable bags►►►Example of current useExample of current useExample of current use
Facility Outline
Fermentation Separation Purification
Purification Suite Plan View
Fixed Vessels
Separations Purification
Vessels allow:•Accurate volume measurement•Mixing and sampling•Heating and cooling on feedback loop
•Conditioning (eg dilution, pH adjust)•Complete product recovery•Pressure relief safety systems
Talk Contents
►►►Background to ABC5000 manufacturing facilityBackground to ABC5000 manufacturing facilityBackground to ABC5000 manufacturing facility►Reasons that disposable bags adopted for
product handling in downstream processing►►►Challenges when adopting disposable bagsChallenges when adopting disposable bagsChallenges when adopting disposable bags►►►Example of current useExample of current useExample of current use
Fixed Vessels Lack Flexibility for Project Based Contact Manufacture
169283Column 5
169700215Column 4
13575664224Column 3
170195691160280Column 2
5901135231601540Column 1
B2770B2588B2436B2272B2007
Average Column Elution Volume (L) for Five ABC5000 Projects:
Not Possible to Demonstrate Sufficient Removal of High Toxicity Product from Fixed Vessels
► Cleaning Validation between one customer product and the next is a critical aspect of operation of a CMO facility
► The basis of this validation is the maximum carry over calculation from the first product to the next
► The important variables in this calculation are the Acceptable Daily Expose Limit (ADE) of the first product and the dose size of the second
► When a low ADE (high toxicity) product proceeds a high dose product, the allowable carry over amount can be below the limit of detection of the carryover analytical methods
► This is particularly a problem for large surface area equipment (eg vessels)
► Therefore, cleaning validation can mandate single use containers for high toxicity products
► While bag technology fits with single use, operator safety with low ADE products then requires rigorous SHE risk assessment
Disposable Bag Timeline
2004 - 2006 2007 - 2008
2009 - Present
2010 - Present
Talk Contents
►►►Background to ABC5000 manufacturing facilityBackground to ABC5000 manufacturing facilityBackground to ABC5000 manufacturing facility►►►Reasons that disposable bags adopted for Reasons that disposable bags adopted for Reasons that disposable bags adopted for
product handling in downstream processingproduct handling in downstream processingproduct handling in downstream processing►Challenges when adopting disposable bags►►►Example of current useExample of current useExample of current use
Challenges
►Require assessment of materials of construction for chemical compatibility
►Require assessment of materials of construction for potential for leachables
►Guaranteed security of supply►Plant floor issues
Chemical Compatibility
►Gap analysis of vendor/own data to determine requirement for laboratory studies.
►Perform (or have vendor perform) laboratory studies under process conditions with small bags
►Typical acceptance criteria based on solution pH, conductivity, visual appearance, protein concentration
►Assess microbial growth for “control” purposes
Leachable RA – Scoring Values
Ref: J. Bennan, et al., “Evaluation of Extractables from Product Contact Surfaces”,BioPharm International, Vol. 15 (12), pp. 3-11 (2002)
Leachable RA – RPN Calculation
Example: B2272 column fraction bag scoring by this method:
Security of Supply
►Use established vendors that have been subject to QA audit (which includes checks of financing and reference sites)
►Formal system for annually scoring vendor performance on factors that include delivery performance
►Be realistic about vendor design/manufacturing timelines – specify and order at least three months before required
►Standardize bag designs►Ask vendors to hold assigned stock►Avoid mixed vendor bag and filter combinations►Process Validation burden restricts dual sourcing
(analogous to filters and resins)
Plant Floor Issues
► Poor quality of supplied bags eg: leaks through inadequate packaging, variation in hose length and port position, change of irradiator spot colour, change of bag code – challenged/changed supplier
► Devil in detail of bag designs - require thorough operational assessment of design before sign off
► Suction collapse of hoses restrict outlet flowrate to typically <20L/min through “tapeworm” affect – use multiple bags or hoses
► Hoses can become kinked or punctured by frame –training/procedures
► Repeated ergonomic safety issue with loading of bags into stainless steel frames – frame design, training/procedure
► After tricky loading process, difficult to establish if bags properly loaded into frames – frame design, training/procedure
► Mixing systems much more complex than none mixed bags – specific procedures/additional training
Talk Contents
►►►Background to ABC5000 manufacturing facilityBackground to ABC5000 manufacturing facilityBackground to ABC5000 manufacturing facility►►►Reasons that disposable bags adopted for Reasons that disposable bags adopted for Reasons that disposable bags adopted for
product handling in downstream processingproduct handling in downstream processingproduct handling in downstream processing►►►Challenges when adopting disposable bagsChallenges when adopting disposable bagsChallenges when adopting disposable bags►Example of current use
Inclusion Body Solubilisation on B2878
From the vessel list previously, disposable bags now allow:•Accurate volume measurement•Mixing and sampling•Heating and cooling on feedback loop
•Conditioning (eg dilution, pH adjust)•Complete product recovery•Pressure relief safety systems
Acknowledgements
Graham McCreathRachel McCredieScott LowrieColin GallRob Fenny
SartoriusStedim