A dedicated DSP plant for the production of ClairYg, a LFB liquid Immunoglobulin G preparation for intravenous use

Transcription

1 A dedicated DSP plant for the production of ClairYg, a LFB liquid Immunoglobulin G preparation for intravenous use Christophe SEGARD Technical Director Industrial Exploitation LFB 1 1

2 Objectives of a new intravenous Ig development Meet the expectations of patients and doctors with an Ig IV: highly purified and secure with an optimized administration well tolerated with sufficient amounts to treat patient safely ClairYg, the new LFB IgIV meets the four challenges : Highly purified Well tolerated Highly secure Higher quantities availaible 2 2

3 ClairYg Process Plasma Cryo separation Ethanol fractionation Fraction I+II+III intermediate product Caprylic acid fractionation Activated carbon depth filtration Ultrafiltration 1 SD treatment Anion-exchange chromatography Affinity chromatography Nanofiltration (20nm) Ultrafiltration 2 Formulation and filtration ClairYg (5% IVIg) 3 Patent : EP B1 3

4 Process main features Caprylic acid fractionation preferred to ethanol More selective, precipitates almost all plasma proteins except Ig Performed at room temperature, less energy use No use of organic solvent, less risk and waste treatment Anion exchange chromatography Highly selective purification step to increase IgG purity and maintain sub-classes distribution Remove SD reagents High molecular weight proteins removing to allow nanofiltration on Planova 20nm Results Ig purity > 99% Ig Sub-classes distribution similar to plasma including the IgG3 and IgG4 4 4

5 Highly secure Ig Different specific steps or contributive steps during the process for viral reduction capacity Specific steps Spiked viruses ENVELOPED VIRUSES NON-ENVELOPED VIRUSES HIV-1 Sindbis BVDV PRV SV-40 EMCV HAV PPV Enveloped Highly Parvoviru Model for HIV HCV DNA virus resistant HAV (HBV) virus s B19 S/D treatment Nanofiltration through 20 nm filter e 4.4 e 5.4 NT e 4.3 N/A N/A N/A N/A 5.6 (1) 5.6 (1) (1) 5.4 (2) e 5.2 NT 4.3 Caprylic acid fractionation e 4.0 NT 5.1 e 5.0 NT e 5.6 e Contributive steps 5 Anion-exchange chromatography Final product: Low ph incubation in the final container Final product: Virus-neutralising capacity by the antibodies NT NT NT NT NT 1.3 NT NT 3.2 NT NT NT NT NT N/A N/A N/A N/A N/A N/A 3.3 (3) N/A Overall viral reduction capacity e 18.0 e e e 12.1 e

6 Increase of Ig production capacity for LFB with a new dedicated workshop Specifications for ClairYg Production Area Design standard : GMP EU / US Capacity : 6 tons Batch size : 4500 l of plasma (raw material : Fraction I+II+III) Process duration : 80 h 6 6

7 Key equipement for ClairYg Production Area A production area of 1200 m2 grade C (class ) 43 fixed tanks from 100 l à 5500 l cleaned and sterilized in place 2 press filters 3 chromatography columns 2 nanofiltration areas 3 Ultrafiltration units 7 7

8 Workshop plan 8 8

9 Key equipement for ClairYg Production Area Pre/post viral areas are totally separated (HVAC, airlock, equipements, WFI) A technical area of 2000 m2 for HVAC, PW / WFI storages and loops 4 CIP stations Skids for cold and hot process regulation 9 9

10 Automated System structure Automated system is connected to H 3000 elements (valves, pumps, sensors), control batches and record all parameters 2 redundant servers for process control associated to 2 PLC 1 dedicated server for batch production report 13 HMI Use of fielbus to reduce wiring and facilitate maintenance Loop network architecture to reduce communication failure 10 10

11 Design studies from Jan to Sept months GMP EU / US Standard LFB project team : 6 people 11 11

12 Building November 2007 / Juin months 9 months An average of 70 people during the construction area with peaks up to

13 Commissioning July 2008 / December 2008 LFB project and commissioning teams : 18 people First feasibility batch in december 2008 Validation batches Q1/Q Commercial batches Q

14 FAT/SAT/IQ/OQ/PQ FAT/SAT were performed by : Technical project team and future production team As much as possible, documentation used during FAT and SAT had been directly integreted in IQ IQ/OQ/PQ were carried out by the production team Allow users to see how equipements operate during failure Improve users training Automated systems require a specific attention for the training of maintenance people 14 14

15 Project key figures 8000 working days for LFB team 30 months between kick off and the last validation batch Investment : 20 M 15 15

16 Return after 3 years in operation Planning and budget were conform to the objective Yield and capacity are conform to the objective Results obtained on 4500l batch size are similar to 1250l (clinical batch size) After H 350 batches, no specific technical or quality problems related to the plant design itself 16 16

17 A dedicated DSP plant for the production of ClairYg, a LFB liquid Immunoglobulin G preparation for intravenous use Christophe SEGARD Technical Director Industrial Exploitation LFB 17 17