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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