Improving Downstream Manufacturing Productivity with Pre-Packed Chromatography Columns Michael Dittmer MedImmune, BioProcess Engineering BPI West, San Francisco, CA March 2 nd , 2017
Outline • Motivation and Scope • Technical Evaluation • Details of study • Results • Economic Analysis • Cost Comparison • Impact on Plant Productivity • Additional Topics
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 • 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 5
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. • 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. 8
HETP and Asymmetry Results 0.05 0.04 HETP (cm) • HETP and asymmetry 0.03 0.02 results used to monitor 0.01 integrity of bed throughout 0 study 0 5 10 15 20 – Cycle# 1, 8, 19 Cycle Number 1.3 Asymmetry • Results demonstrate stable 1.1 bed performance 0.9 0.7 0 5 10 15 20 Cycle Number 9
Column Performance Results Normalized Elution Volume 1.5 1.3 • Column performance metrics: 1.1 – Elution Volume (CV) 0.9 – Yield (%) 0.7 • Values are normalized against 0.5 historical data (w/ conventional 0 5 10 15 20 Cycle Number manual pack column) Normalized Protein Yield • Pre-packed column performed 1.5 1.3 consistent with conventional 1.1 column 0.9 0.7 0.5 0 5 10 15 20 10 Cycle Number
Impurity Clearance Results • Protein aggregate removal same as conventional columns – Monomer % within (+/- 0.1) • HCP and DNA clearance, bioburden, and endotoxin levels all within range 11
Technical Evaluation – Summary • 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 12
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 Column Cost (excl. Resin) Total Column Cost 30 700 600 500 20 Pre-Pack Premium Cost ($1k) Cost ($1k) 400 Other Buffer 300 Labor 10 200 Resin 100 0 0 Conventional Pre-Packed Conventional Pre-Packed 45cm x 20cm MabSelect SuRe 15
Cost Analysis (additional discussion) • 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 16
Purification Suite Utilization Packing Protein Purification Unpacking (3 days) (5 days) (2 days) Column Activities Column 5d Activities 5d Column Production Activities 5d 5d Production 15d Production 25d 1 Batch 3 Batches 5 Batches 17
Productivity Improvement 3 Batches per Campaign • 33% more grams of Column protein per year Activities 5d 5d • Up to 18* more Production Production batches per year 15d 15d Similar Cost 25% of time spent Replace Columns No additional capital on Column Packing w/ Pre-Packed *Facility runs year-round 18
Productivity Impact – Bottleneck discussion • 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 Cost Save Time ℎ𝑠 ∗ 𝑀 𝑠𝑓𝑡𝑗𝑜 ℎ𝑠 ∗ 𝑀 𝑠𝑓𝑡𝑗𝑜 ℎ𝑠 ∗ 𝑀 𝑠𝑓𝑡𝑗𝑜 19
Productivity Improvement w/o bottleneck 3 Batches per Campaign • Smaller Columns = Column Additional Cycles Activities 5d • Replace column Production packing days with Production 15d additional 20d production days Similar Processing Time 25% of time spent Replace Columns Reduced Resin/Cost on Column Packing w/ smaller Pre-Packed 20
Economic Analysis Summary • 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 21
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 • 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 24
Overall Summary • 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 25
Thank You! 26
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