Improving Downstream Manufacturing Productivity with Pre-Packed Chromatography Columns

Transcription

1 Improving Downstream Manufacturing Productivity with Pre-Packed Chromatography Columns Michael Dittmer MedImmune, BioProcess Engineering BPI West, San Francisco, CA March 2 nd, 2017

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

3 Motivation and Scope

4 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)

5 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

6 Technical Evaluation

7 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

8 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

9 Asymmetry HETP (cm) HETP and Asymmetry Results HETP and asymmetry results used to monitor integrity of bed throughout study Cycle# 1, 8, 19 Results demonstrate stable bed performance Cycle Number Cycle Number 9

10 Column Performance Results Normalized Elution Volume 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 Cycle Number Normalized Protein Yield Cycle Number

11 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

12 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

13 Economic Analysis

14 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

15 Cost ($1k) Cost ($1k) Cost Analysis - Results Total Column Cost Column Cost (excl. Resin) Pre-Pack Premium Other Buffer Labor Resin Conventional Pre-Packed 0 Conventional Pre-Packed 45cm x 20cm MabSelect SuRe 15

16 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

17 Purification Suite Utilization Packing (3 days) Protein Purification (5 days) Unpacking (2 days) Production 5d Column Activities 5d Production 15d Column Activities 5d Production 25d Column Activities 5d 1 Batch 3 Batches 5 Batches 17

18 Productivity Improvement 3 Batches per Campaign Production 15d Column Activities 5d Production 15d 5d 33% more grams of protein per year Up to 18* more batches per year 25% of time spent on Column Packing Replace Columns w/ Pre-Packed Similar Cost No additional capital *Facility runs year-round 18

19 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) Save Time Productivity Improvement Save Cost g hr L resin g hr L resin g hr L resin 19

20 Productivity Improvement w/o bottleneck 3 Batches per Campaign Production 15d Column Activities 5d Production 20d Smaller Columns = Additional Cycles Replace column packing days with additional production days 25% of time spent on Column Packing Replace Columns w/ smaller Pre-Packed Similar Processing Time Reduced Resin/Cost 20

21 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

22 Additional Topics

23 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

24 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

25 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

26 Thank You! 26

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