Productivity with Pre-Packed Chromatography Columns Michael Dittmer - - PowerPoint PPT Presentation

Improving Downstream Manufacturing Productivity with Pre-Packed Chromatography Columns

Michael Dittmer

MedImmune, BioProcess Engineering

BPI West, San Francisco, CA March 2nd, 2017

• Motivation and Scope
• Technical Evaluation
• Details of study
• Results
• Economic Analysis
• Cost Comparison
• Impact on Plant Productivity
• Additional Topics

Outline

Motivation and Scope

Motivation and Goals

• MedImmune evaluated pre-packed columns as a potential

technology to improve productivity in antibody production

• Productivity improvements resulting from:

– Lower costs – Decrease processing time

• Two primary considerations:

– Does the technology work? (Technical Evaluation)

• Comparable to existing solutions
• Durable and robust

– Does the cost of the technology make financial sense? (Economic Analysis)

Scope

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• Focus on existing GMP facility
• Facility already contains significant stainless equipment

– Purification skids – Columns – Buffer and product tanks

• Facility is a “hybrid” facility in that it also contains many single-use and

disposable technologies – Single-use instrumentation – Buffer bags

• Facility would continue to support traditional chromatography columns

Technical Evaluation

Technical Evaluation – Study Details

• Collaboration with GE Lifesciences

(Ready-To-Process columns)

• Goal:

– Evaluate performance of 45cm prepacked column over 10+ cycles

• Bed stability
• Consistent column performance
• Impurity clearance
• Comparability to conventional packed

columns

– Provide feedback to vendor on prototype pre-packed column

Technical Evaluation – Study Details cont.

8

• Studies performed at MedImmune pilot facility in Gaithersburg, MD.

– Multi product facility – Scale: 500L bioreactor – Facility equipment: Mostly stainless. Disposable bags/tubing – Molecule type: mAb – Resin type: ProteinA (MabSelect SuRe) – Column dimensions: 45x20cm

• 19 Cycles recorded

– 12 cycles with protein load (5 different products) – 7 cycles with just buffer and hydroxide

• Data compared and normalized against manual packed 45cm
• column. Same projects.

HETP and Asymmetry Results

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• HETP and asymmetry

results used to monitor integrity of bed throughout study – Cycle# 1, 8, 19

• Results demonstrate stable

bed performance

0.01 0.02 0.03 0.04 0.05 5 10 15 20

HETP (cm) Cycle Number

0.7 0.9 1.1 1.3 5 10 15 20

Asymmetry Cycle Number

Column Performance Results

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• Column performance metrics:

– Elution Volume (CV) – Yield (%)

• Values are normalized against

historical data (w/ conventional manual pack column)

• Pre-packed column performed

consistent with conventional column

0.5 0.7 0.9 1.1 1.3 1.5 5 10 15 20

Cycle Number

Normalized Elution Volume

0.5 0.7 0.9 1.1 1.3 1.5 5 10 15 20

Cycle Number

Normalized Protein Yield

Impurity Clearance Results

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• Protein aggregate removal same as

conventional columns – Monomer % within (+/- 0.1)

• HCP and DNA clearance, bioburden, and

endotoxin levels all within range

Technical Evaluation – Summary

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• When compared to a gold standard (conventional manual packed

column), the pre-packed column performed the same: – Column Bed Integrity – Column Performance – Impurity Clearance

• Performance was consistent across 19 cycles and 5 different

projects

• No technical concern with repeated cycling on pre-packed column

Economic Analysis

Cost Analysis – Scope and Assumptions

• Facility – Existing stainless GMP production area
• Resin

– MabSelect SuRe – 2016 List Price

• Labor (employee-hours)

– Packing and unpacking – 48 – Cleaning and changeover – 28 – Buffer preparation – 12 – QC – 16

• Buffer

– Cost of water and chemicals

• Other

– Column maintenance and changeover – Depreciation

• Pre-Pack Premium

– Cost differential between resin and pre-packed column cost

Cost Analysis - Results

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45cm x 20cm MabSelect SuRe

100 200 300 400 500 600 700 Conventional Pre-Packed

Cost ($1k)

Total Column Cost

Pre-Pack Premium Other Buffer Labor Resin 10 20 30 Conventional Pre-Packed

Cost ($1k)

Column Cost (excl. Resin)

Cost Analysis (additional discussion)

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• Existing stainless GMP facility

– Equipment/cleaning validation not completely eliminated – CIP/SIP systems available

• Usage of production area is not factored in cost analysis.

– Significant advantage for pre-packed!

• Cost is comparable between pre-packed and manually packed

columns

Purification Suite Utilization

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Packing (3 days) Protein Purification (5 days) Unpacking (2 days)

Column Activities 5d Production 5d Column Activities 5d Production 15d Column Activities 5d Production 25d

1 Batch 3 Batches 5 Batches

Productivity Improvement

18

Column Activities 5d Production 15d

25% of time spent

• n Column Packing

5d Production 15d

Replace Columns w/ Pre-Packed

• 33% more grams of

protein per year

• Up to 18* more

batches per year

3 Batches per Campaign

Similar Cost No additional capital

*Facility runs year-round

Productivity Impact – Bottleneck discussion

19

• These time savings only realized if downstream processing is

primary bottleneck for production

• Other likely bottlenecks:

– Bioreactor turnover/production – Product and buffer tank availability – Support functions (buffer prep, cleaning) Productivity Improvement Save Time Save Cost 𝑕 ℎ𝑠 ∗ 𝑀𝑠𝑓𝑡𝑗𝑜 𝑕 ℎ𝑠 ∗ 𝑀𝑠𝑓𝑡𝑗𝑜 𝑕 ℎ𝑠 ∗ 𝑀𝑠𝑓𝑡𝑗𝑜

Productivity Improvement w/o bottleneck

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Column Activities 5d Production 15d

25% of time spent

• n Column Packing

Replace Columns w/ smaller Pre-Packed

• Smaller Columns =

Additional Cycles

• Replace column

packing days with additional production days

3 Batches per Campaign

Similar Processing Time Reduced Resin/Cost

Production 20d

Economic Analysis Summary

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• Pre-packed column cost is comparable to conventional manually

packed columns

• Can eliminate ~25% days in production suite while keeping costs

the same (avg. 3 runs per campaign)

• If cost and not time is primary concern, can reduce cost with

smaller pre-packed columns

• Pre-packed columns increase productivity

Additional Topics

Additional Pre-Packed Column Advantages

• Safety stock of ready to use columns. Inventory managed by

customer or vendor – Platform resins

• Streamlines storage of resin for reoccurring campaigns

– Wheel column into storage – No unpacking/storage/repacking required

Future Considerations

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• Recovery of resin

– Procedure and means for accessing resin. Troubleshooting

• Initial HETP testing

– Can further improve productivity by eliminating initial HETP testing

• Continuous Chromatography

– Pre-packed columns extremely advantageous for multi-column systems – Would require shorter bed heights than typical offerings

• 5 – 10cm

Overall Summary

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• Pre-packed columns perform identically to conventional manually

packed columns – Bed Integrity – Column Performance – Impurity Clearance

• Cost is comparable to conventional columns
• Pre-packed columns increase productivity in existing

stainless GMP facilities – Fewer days in production suite, or less resin

Thank You!

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