Continuous Improvement of Prothrombinex-VF Manufacture

Transcription

1 Continuous Improvement of Prothrombinex-VF Manufacture Owen Tatford Process Development Manager and John Lontos Fractionation Manager BPN Conference, Adelaide 2011

2 Prothrombinex-VF (PTX) A Prothrombin complex concentrate (PCC) Mixture of Clotting Factors II, VII, IX and X Developed for treatment of congenital deficiencies More commonly used to reverse the clinical effects of Warfarin (Warfarin reversal) 2

3 Jul-04 Oct-04 Jan-05 Apr-05 Jul-05 Oct-05 Jan-06 Apr-06 Jul-06 Oct-06 Jan-07 Apr-07 Jul-07 Oct-07 Jan-08 Apr-08 Jul-08 Oct-08 Jan-09 Apr-09 Jul-09 Oct-09 Jan-10 Apr-10 Jul-10 Oct-10 Jan-11 Apr-11 Jul-11 Oct-11 Jan-12 Apr-12 Jul-12 Oct-12 Jan-13 Apr-13 Jul-13 Oct-13 Jan-14 Apr-14 PTX Performance and Forecasts Trial 2 results ASTH 09 Revision WRCG ASTH Trial 1 results ASTH Launch of PTX-VF Trial 2 results IMJ publication WRCG Launch ASTH 2004 Initiation trial 1 PTX - no FFP 5 fold increase in demand since 2004 Growth forecast ~21% for 2011/12 Strong driver to reduce cycle time, increase yield and capacity 3

4 History of PTX PTX process based on initial PCC developed by the SNBTA 4

5 History of PTX at CSL 1977 Prothrombinex first manufactured at Parkville 1984 Addition of a 60 o C dry heat treatment step 1991 Name changed to Prothrombinex HT upon adoption of 80 o C dry heat step and formulation with ATIII in addition to Heparin 2006 Name changed to Prothrombinex-VF upon addition of a virus filtration step 5

6 FRESH FROZEN PLASMA (FFP) CRYOSUPERNATANT SUPERNATANT I Process steps of PTX-VF DE-32 ION EXCHANGE CHROMATOGRAPHY PROTHROMBIN CONCENTRATE VIRUS FILTRATION STERILE FILTRATION, DISPENSING, FREEZE-DRYING HEAT INACTIVATION ºC PROTHROMBINEX-VF 6

7 PTX-VF process flow chart 2500 L plasma Equivalent per centrifugation Buffer W Buffer E Regenerated DE-32 Resin PFW PFW Buffer W Buffer W DE-32 Resin Slurry 2500L plasma equivalent Supernatant I Absorbed PTX Resin Slurry PTX absorbed resin is removed manually from the centrifuge bowl and slurried Axial Flow Column 2500L plasma equivalent PTX Bulk 1 PTX depleted supernatant is collected for IG/ALB Operations Spent DE-32 resin is removed and regenerated for next batch Waste Pre Viral Inactivation Area Post Viral Inactivation Area PTX Bulk 1 PF Buffer Heparin ATIII PF Buffer (required if formulating to a target potency) PTX bulk L plasma equivalent PCC Bulk Virus Filter PCC VF Bulk Filtered PCC VF Bulk To Pharmaceutical Services for dispensing 7

8 Areas for improvement 1. Collection of resin via centrifugation 10 x Sharples centrifuges Cumbersome, time consuming cleaning High level of maintenance Used for both DE32 and Cryoprecipitate separations Incomplete recovery of PTX-bound resin 8

9 Areas for improvement 2. Manual Resin Packing Manual handling Column packing and unpacking 9

10 Areas for improvement 3. Chromatography Fully manual process Low tech Poor process consistency Packing Washing Elution 10

11 Areas for improvement 4. Resin regeneration Double handling of resin Packed in axial flow column for chromatography Transfer into radial flow columns for regeneration 11

12 Process Development Goals Minimise manual handling Increase process automation Increase PTX-VF process scale to 5T throughout Minimal MoM changes for maximum efficiency gains (yield and time) Maintain product characteristics 12

13 Process Changes Sharples Centrifuge Replacement FRESH FROZEN PLASMA (FFP) CRYOSUPERNATANT SUPERNATANT I DE-32 ION EXCHANGE CHROMATOGRAPHY Westfalia separator Filter Press 13

14 Filter press collection of resin Recent transition of upstream depth filtrations to filter press operations Schedule currently allows different operations on the same press Full filter area for Delipidation (paste discarded) Partial filter area for 5T PTX operation (DE32 resin collected) 14

15 Strategies to improve DE32 chromatography DE-32 ION EXCHANGE CHROMATOGRAPHY PROTHROMBIN CONCENTRATE VIRUS FILTRATION STERILE FILTRATE Improve packing of DE32 resin Shift from pressure to vacuum packing (short term option) Add an ultrafiltration step at VF filtrate Pressure pack Allows increased collection of the elution peak Develop an in situ DE32 resin regeneration method Removes double handling of resin and saves time Automated packing/unpacking Improved process robustness Vacuum pack Size DE32 column to suit 5T process scale More even profile, with a steep ascending peak 15

16 Automated chromatography GE Healthcare AxiChrom Manual chromatography 800 self packing/unpacking column and ÄKTA Process work station 16

17 Drawing the PTX-bound DE32 slurry into the AxiChrom column Controlled packing of the PTX-bound DE32 resin bed 17

18 Project support and validation R&D and Pilot scale data to support Cat III submissions to the Therapeutic Goods Administration (AUS regulatory body) IQ/OQ, HAZOP, FMEA Software development and validation Cleaning and process validation To assess process consistency and confirm batch segregation All process trials performed under validation protocols Product characteristics assessed by extensive QC and R&D testing 18

19 Normalised total FIX Impact of changes upon process yield 160% 140% FIX/kg plasma present at PCC bulk 120% 100% 80% 60% 40% 20% 0% Sharples with pressure pack Sharples with Vacuum pack and UF Westfalia and Filter press with Vacuum pack 25% increase in PTX-VF yield in the last year 19

20 Summary The process changes outlined will make a significant impact upon the PTX-VF process Increased capacity (2.5 5 T process stages) Increased Automation Reduced manual handling Reduced maintenance Increased yield (~ 50% overall) Reduced PTX process time by 2 days Integrated plant Significantly improved efficiency 20

21 Conclusions Continued development of established processes is a worthwhile endeavour Allows capture of technological advancements to assist with increasing automation and improving process robustness Can lead to increased process yields and operating efficiency gains 21

22 Acknowledgements Sharples replacement project team Manufacturing Broadmeadows George Tsirbas John Lontos 22