Keeping ahead in biopharmaceutical manufacturing

Transcription

1 Keeping ahead in biopharmaceutical manufacturing Bioprocessing Network Annual Conference st October 2009 Dr Owen Tatford Process Development Manager May 2009 Biostate Process Overview 1

2 Introduction has been the national blood fractionator since 1952 Demand for plasma products, particularly intravenous immunoglobulin (IVIG) has risen globally! US market for IVIG has risen from US$437M in 1997 to US$2,397M in 2008 A similar increase in demand has been observed in Australia! The National Blood Authority has observed 14% growth/year in IVIG use for the last 10 years and predicts this will continue for the foreseeable future May 2009 Biostate Process Overview 2

3 2006 Production volume and revenue map May 2009 Biostate Process Overview 3

4 Broadmeadows site Completed and commissioned 1995 Designed for 250 T human plasma per annum, with a view to expand May 2009 Biostate Process Overview 4

5 IgG / Albumin Process May 2009 Biostate Process Overview 5

6 Common problems in Bioprocessing Ever-changing requirement of production facilities Maintaining quality requires increasing effort and cost to meet regulatory compliance Increasing production costs energy, material, resources, wastage Production downtime and equipment under-utilisation Maintenance requirements Poor use of statistical control and capture of process data! inability to understand causes of manufacturing problems Our solution! A philosophy of continuous improvement May 2009 Biostate Process Overview 6

7 PAT Chromatography optimisation Process modelling Efficiencies and yield increases Quality by Design New technology Risk assessment May 2009 Biostate Process Overview 7

8 PAT Chromatography optimisation Process modelling Efficiencies and yield increases Quality by Design New technology Risk assessment May 2009 Biostate Process Overview 8

9 Desired state of manufacturing environment An efficient, agile, flexible pharmaceutical manufacturing environment that reliably produces high-quality drug products without extensive regulatory oversight Use a risk based analysis to ensure efficiency and reliability of process equipment and utilities!! Provides direction for continuous improvement initiatives!! Highlights that manufacturing quality is as essential as the quality of the product and development process May 2009 Biostate Process Overview 9

10 Risk based analysis We apply a hybrid method of: Hazard and operability (HAZOP): process Failure mode and effect analysis (FMEA) : equipment and components Fault tree analysis (FTA) : deviations Analyses risks relating to: "! Design and installation "! Software and process control "! Validation activities "! Routine QC testing "! Process transfer "! Preventative Maintenance (PM) "! Documentation "! Production data "! Project management "! HSE "! GMP Chor Sing Tan s Poster at BPN 2009 May 2009 Biostate Process Overview 10

11 Risk analysis Risk 6 Risk Risk 1 1 Reliable, robust and high quality utility or system Risk 5 Item Risk 2 Risk 4 Risk 3 Information P&ID, SOP, validation files, GMP guidelines, maintenance record, site inspection and communication with internal and external departments Risk elimination and minimisation Recommendations Risk Risk 1 1 Risk 1 Current control Risk assessment Reliability, efficiency and robustness Quality and compliance Detection Product quality Workplace HSE May 2009 Biostate Process Overview 11

12 Case study Risk assessed the impact of the removal of an unnecessary filtration step on all steps of a process Item Issue Problem Control Assigned risk Solution Upstream reagent preparation tanks (prior to the filtration) Interchangeable tanks are plastic and hard to clean effectively Potential of Endotoxin absorbs to plastic Cross contamination Manual cleaning of tank HIGH Designated Stainless steel tanks introduced Process and product transfer pumps Pumps not designed for CIP Flushing may be insufficient to remove residual protein Pumps cleaned manually HIGH CIP capable pumps installed with scheduled PM and inspection May 2009 Biostate Process Overview 12

13 PAT Chromatography optimisation Process modelling Efficiencies and yield increases Quality by Design New technology Risk assessment May 2009 Biostate Process Overview 13

14 Quality by design Building quality through understanding of the design space Traditional design space Limit of investigation Process limits Target range Set point May 2009 Biostate Process Overview 14

15 Design of Experiments - 1 Design space is multidimensional and parameters are inter-related Aim: Perform as few studies as possible to achieve optimal conditions! Apply DOE principles May 2009 Biostate Process Overview 15

16 Design of Experiments - 2 Applied DOE to UF operations! Determine conditions to achieve reduced diafiltration time May 2009 Biostate Process Overview 16

17 PAT Chromatography optimisation Process modelling Efficiencies and yield increases Quality by Design New technology Risk assessment May 2009 Biostate Process Overview 17

18 Process modelling - 1 Important to have a swift process (Time = money) However! Biopharmaceutical processes consist of many steps! Not all steps take the same amount of time! Often operating batches back to back The key is to understand which steps are holding up your process (bottlenecks) But the complexity of the process may obscure the bottlenecks! e.g. hard to fathom the utilisation of common tanks and equipment Process Modelling overcomes this Generates data to show if a step! Affects other individual steps in the process! Impacts the process as a whole! Has a knock-on effect on other batches May 2009 Biostate Process Overview 18

19 Process modelling - 2 Modelling is only as good the data provided Vital to accurately collate and assess process data! Avoid assumptions, averages: both may hide the real situation! Obtain first hand data from process sheets, batch records Identify source data and collate! Resin binding capacity! Filtrate flux data! Mass balances! Process, wait and transfer times Analyse data! Select suitable software to generate the required output! Generate a picture of the current situation Perform simulations! Change one step at a time to determine impact! Identify and prioritise changes! Utilise to justify engineering solutions May 2009 Biostate Process Overview 19

20 Process modelling - 3 Equipment utilisation chart for one batch Hours DBM2 T1001/T1003 SHARPLES LF521/LF522 T501 T502 T503 T504 T505 T506 T507 T509 UF531 T621 T622 T623 F608 T625 T626 DEAE UF596 T591 T592 MACROPREP UF597 T593 T594 PV633 UF528 PV534 PV523 CM UF618 T627 T628 S200 UF646 T630 UF620 PV631 PV635 PV636 May 2009 Biostate Process Overview 20

21 Process modelling - 4 Utilisation chart for 7 batches during 5 day cycle operations (targeting 85% utilisation) May 2009 Biostate Process Overview 21

22 PAT Chromatography optimisation Process modelling Efficiencies and yield increases Quality by Design New technology Risk assessment May 2009 Biostate Process Overview 22

23 Chromatography Two chromatography steps in Intragam P process Three chromatography steps in Albumex process Vital to have optimised chromatography operations as multiple column cycles performed per batch May 2009 Biostate Process Overview 23

24 Chromatography optimisation - 1 Processing a batch requires many repetitive column cycles Determine optimal column size : resin cost Ensure each cycle is performed! Quickly! Reproducibly! At highest sample load that allows required separation May 2009 Biostate Process Overview 24

25 Chromatography optimisation - 2 Long periods taken performing non-product contact steps Buffer flushes! Key was to target ph and conductivity not column volumes or contact time! Optimised to reduce time and buffer volumes e.g. Macroprep column - 12 loads / 10T batch Equilibration buffer was 1200L/cycle now 600kg! Saving of 7200kg/batch (= 7 hours) Column monitoring! Separate HETP step for S200 column! Incorporation into equilibration cycles! Saving hours/ batch May 2009 Biostate Process Overview 25

26 Chromatography optimisation - 3 Improved cleaning regimes Extensive R&D trials (building QbD)! Karl McCann s presentation! Optimised contact time! Improved resin lifetime! Consistently high binding capacity! Improved column performance! Less column downtime and re-packing May 2009 Biostate Process Overview 26

27 PAT Chromatography optimisation Process modelling Efficiencies and yield increases Quality by Design New technology Risk assessment May 2009 Biostate Process Overview 27

28 New technology 14 years full operation at Broadmeadows! Need to replace obsolete equipment! High cost of maintaining original equipment Improved technology now available! Higher yield demonstrated at pilot scale! Automation, process control and monitoring Requires careful management! Extensive R&D compatibility studies! Demonstrate like for like to avoid clinical trials, IgG subclass analysis, impurity levels! Develop engineering and regulatory justification : Improved cleaning validation, reduced manual handling May 2009 Biostate Process Overview 28

29 Depth filtration Moved from Lochem to filter press! removed recirculation! reduced flush volume! faster, more consistent filtration May 2009 Biostate Process Overview 29

30 Updating ultrafiltration Spirals in use were made obsolete, forcing a switch! Flat bed cassettes! Reduced membrane area with higher permeate flux! 24 hour operation to produce 7500kg permeate became 6hr! Validated cleaning via cleaning station, not inline May 2009 Biostate Process Overview 30

31 UF automation Minimal operator input Set flow rate TMP via control valve Mass balance via load cells Stops automatically Highly reproducible operation May 2009 Biostate Process Overview 31

32 Chromatography technology - 1 New column technology! Reproducible packing at higher pressure! Self packing / unpacking! Higher flow rates! Improved process consistency May 2009 Biostate Process Overview 32

33 Chromatography technology - 2 Many new chromatography resins available on the market! Offering higher flow rates, improved binding capacity with new ligands offering more modes of separation! Tailored to specific requirements! Allows significant capacity improvements for limited capital expenditure May 2009 Biostate Process Overview 33

34 Evaluation of GE s CaptoDEAE v DEAE Sepharose FF DEAE Sepharose Fast Flow % of total loaded Protein load (g/l) May 2009 Biostate Process Overview 34

35 PAT Chromatography optimisation Process modelling Efficiencies and yield increases Quality by Design New technology Risk assessment May 2009 Biostate Process Overview 35

36 Process Analytical Technology (PAT) New philosophy! Real time monitoring! Feeding back data into batch process! For every batch, not just validation Working towards PAT system! QC testing Can still be considered PAT if data utilised in process However testing and obtaining results can mean delays! Working to improve all sample communications! First steps in process monitoring Protein concentration! Switching from QC assays to UV280nm and density measurements performed in the manufacturing plant May 2009 Biostate Process Overview 36

37 Process control technology Siemens control Full traceability Process monitoring Electronic batch records CFR 21 part 11 compliance Improved trending May 2009 Biostate Process Overview 37

38 Outcome Doubled design capacity of 250T! 524T plasma was processed during 2008/09! Without changing site footprint Shifted from 7 day to 5 day processing cycle Yield improvements May 2009 Biostate Process Overview 38

39 IVIG Yield Intragam P commenced CSL IVIG yield IVIG yield (g/l) Estimated average industry yield May 2009 Biostate Process Overview 39

40 Current focus Reduce cycle time further?! Increased capacity! Focus on resin changes Compatibility trials based protein purity Without clinical trials?! Encouraged by regulatory consultation (TGA) May 2009 Biostate Process Overview 40