Use of disposable technology in biologics manufacture

1. Use of disposable technology in biologics manufacture Alain Pralong Head of PTBB-T Prague, 20th of February 2006

2. Contents • Background information • Project • Strategy • Current state of the existing facility • Strategy to implement the process into the existing facility • Possible targets to implement disposable technology • Tools and solutions • Impact of using disposable technology • Comparison traditional VS fully disposable setup • Major advantages of using disposable technology

3. Background information: Project • A registered antibody production process is transferred from an US production site to Roche’s new biologics production site (MAB95)

4. Background information: Strategy • The technology transfer is performed in parallel to the construction of the MAB 95 • The technology transfer is performed in two steps: • In the first step the process technology is transferred into an existing facility (B66) into which a scale down model process is implemented • In the second step the process technology is transferred from the existing facility into MAB 95 and scaled up to production scale • Advantages of this strategy: • Save time and personnel resources • Gather experience with the process • Train personnel

5. Current state of the existing facility: B66 • Roche Basel disposes of a 22-year old bacterial fermentation facility consisting of 10-L / 100-L and 1000-L bioreactors including a purification suite which have been used for the GMP-production of Roferon-A • All equipment is designed for bacterial fermentation and outdated in comparison to state of the art technology • Purification suite can be easily adapted to antibody purification • Fermentation can not be adapted ad hoc to mammalian cell culture: • No space available for major transformations of the facility layout • No delay of the technology transfer possible to allow adaptation or transformation of existing facility

6. Strategy to implement the process into the existing facility • Process has to be adapted to existing bioreactor volumes: • Run fermentations in parallel to maintain split ratios (ex. 3 x 10-L to inoculate a 100-L bioreactor) • Perform Solera operations to reproduce a passage within the same bioreactor • Purchase of an intermediate volume bioreactor (ex. 30-L) • Media preparation and bioreactor operation has to be adapted for being performed with disposable ready-to-use equipment or equipment that can be purchased within a short lead time

7. Strategy to implement the process into the existing facility: target media preparation • All media and solutions used in fermentation are prepared following a fully disposable strategy • Vessels up to 100-L used to prepare media and solutions are made of plastic and dedicated. They can be integrated into the fully disposable strategy. Larger volumes are prepared in disposable bags. • Purchase of mobile equipment to prepare, dispense and store media and solutions which can be used following minor modifications of the electricity and water supplies • Media and solution preparation is performed without need for sterile connections. Only the separations have to be performed sterilely

8. Strategy to implement the process into the existing facility: target bioreactor operation • All media and solutions used in fermentation can be connected to a bioreactor following a fully disposable strategy • No sterile connections are needed as they are steamed prior use (exception: cell solutions are connected through welding) • Sampling of bioreactors is performed following a fully disposable strategy

9. Strategy to implement the process into the existing facility: tools and solutions Bag setup for mixing station for media preparation 500-L

10. Strategy to implement the process into the existing facility: tools and solutions Mixing station for media preparation 500-L

11. 1 2 3 4 5 6 Strategy to implement the process into the existing facility: tools and solutions Preparation of media

12. Strategy to implement the process into the existing facility: tools and solutions Example for bag setup used for dispensing

13. 1 2 3 4 5 6 Strategy to implement the process into the existing facility: tools and solutions Dispensing of media from 500-L mixing station

14. 1 2 3 4 Strategy to implement the process into the existing facility: tools and solutions Sterile disconnection of bags

15. Strategy to implement the process into the existing facility: tools and solutions Connection of media or solution to bioreactor

16. Strategy to implement the process into the existing facility: tools and solutions Sample isolation from a bioreactor

17. 1 2 3 Strategy to implement the process into the existing facility: tools and solutions Sample isolation from a bioreactor

18. 1 2 Strategy to implement the process into the existing facility: tools and solutions Performing a Solera operation in a bioreactor

19. 3 4 Strategy to implement the process into the existing facility: tools and solutions Performing a Solera operation in a bioreactor

20. Impact of using disposable technology Comparison traditional VS fully disposable setup • The solutions shown in this presentation are the result of a project with the following constraints: • Lead time before project start: 5 months  • Facility in use during lead time: no shut down possible  • Solutions have to fulfill the following conditions: • Solutions can be realized within given time period  • Solutions can be realized without disturbing ongoing activities  • Solutions can be realized with given personnel resources  • Solutions can be realized without major investments into  hardware • A fully disposable concept for media preparation and bioreactor operation is realizable within 5 months!

21. Major advantages of using disposable technology • Major advantages • Significant reduction of lead time for project setup • Significant time reduction to prepare media and solutions • Significant increase of production capacity: bioreactor runs • Significant reduction of contamination risk (1 out of 59 runs) • Practically no cleaning time • Significant reduction of personnel due to simplicity if trained • Major disadvantages • Intensified logistical effort • Extra training for personnel needed due to complexity • Operating costs depending on process type