Detlef Eisenkrätzer Pharma Biotech Production & Development

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Benedict Welch
7 years ago
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1 Speed up Process Development by Implementation of new Bioreactor & Information Technology Detlef Eisenkrätzer Pharma Biotech Production & Development picture placeholder

2 Topics 1. Roche s Activity to Expand its R&D Capacity 2. Focus of Technology Evaluation 3. Evaluation of Single Use Bioreactors (SUB) Engineering Characterization Methods & Results Performance of Rockers for Seed Train Cultivation Process Performance of Stirred SUBs for Material Supply Rating of Control & Bag Systems for Stirred SUBs Single Use Sensors fit Optimal to SUB Technology 4. One IT-System to Manage & Analyze Informations 5. Lessons learned 2

changing demands establish a transfer platform from research to clinical supply evaluation of new technologies to fulfill goals - = > concentration

3 Roche s Activity to Expand its R&D Capacity project Therapeutic Proteins - Expand started in January 2008 ~ 172 Mio for expansion of biotech R&D to support the therapeutic protein pipeline cost effective expansion of capacity acceleration of GLP-TOX and phase 1 supply increase flexibility to changing demands establish a transfer platform from research to clinical supply evaluation of new technologies to fulfill goals - = > concentration on single use technology to build up process platforms & paper less IT-system to speed up transfer of processes Roche site Penzberg in upper Bavaria 3

4 Calculation of Scope for Animal Cell based Processes # of new biotherapeutics to be launched per year attrition rate in clinical development # of TOX & phase 1 studies per year average demand of proteins / antibodies per phase average product titer in current & future processes ~ 3 batches to be done per supply campaign bioreactor size for supply platform: 250 L working volume expansion of existing bioreactor capacity by 27 bioreactors (incl. seed trains): for process transfer to 10 kl bioreactors as supply platform for non clinical & clinical development to supply technical development plus many 2 L bioreactors for process validation & PAT 4

5 Focus of Technology Evaluation 1. test different SUBs in different departments to ensure objective results combine automation & bag systems in different variants whenever possible to evaluate both components separately 2. evaluate tools to increase equipment utilization validated single use sensors with high reliability & accuracy optimal connectors for connection steel/plastic and plastic/plastic 3. install a new IT-system for all labs & plants to collect all data on line and archive data in centralized data bases to support interpretation of results and automate reporting integrate existing & new process equipment e of all plants in one PCS avoid efforts for data mining and support automated & mainly paperless process transfer between labs & plants More time for our core business - to develop new products, not asset management & data mining! 5

6 Evaluation of Single Use Bioreactors 6

technical performance of SUBs with Stainless

suitability for scale up studies prognosis of

-supply and CO 2 removal delivery of data for

resistance number of impeller & POWER INPUT by

drives and installation of torque meters) MIXING

7 Engineering Characterization - Methods determination of engineering numbers to compare technical performance of SUBs with Stainless Steel Bioreactors (SSB). suitability for scale up studies prognosis of limitations by poor substrate distribution, O 2 -supply and CO 2 removal delivery of data for dimensioning of energy supply for new plants resistance number of impeller & POWER INPUT by torque measurement (dismounting of stirrer drives and installation of torque meters) MIXING TIME by decolourization method OXYGEN TRANSFER COEFFICIENTS k L a by dynamic method (gas in/out) 7

8 Engineering Characterization - Results POWER INPUT of all SUBs is to low for scale up MIXING TIME and OXYGEN TRANSFER COEFFICIENT of rocking bioreactors are to low for main fermentations with high cell density & concentrated feeds every vendor of stirred SUBs has at least one bag type with acceptable MIXING TIME and k L a (if O 2 is used to increase the oxygen transfer rate) 8

Performance of Rockers for Seed Train Cultivation Viable Cell D ensity Cell Diam meter SUB Classical Classical SUB Classical Viability 17 parallel fermentations

between systems related to control system & single use sensor technology: no workaround with classical sensors less clean benches needed in plant no penetration of bag

9 Performance of Rockers for Seed Train Cultivation Viable Cell D ensity Cell Diam meter SUB Classical Classical SUB Classical Viability 17 parallel fermentations (compared to stainless steel vessels) showed identical results for: growth & productivity cell size distribution apoptosis formation of byproducts main differences between systems related to control system & single use sensor technology: no workaround with classical sensors less clean benches needed in plant no penetration of bag => higher reliability DO & ph controllers with recalibration functionality for optical sensors SUB system with plug & play functionality replaces all our classical seed bioreactors 9

CH ~ 34,33 CH ~ 35,1 CH ~ 59,1 CH [-] 10,0 Disposable Reaktor, 250L Disposable Reaktor,

10 Process Performance of Stirred SUBs for Mt Material ilsupply 100,0 Homogenization Number, Disposable Reaktor (1 PBT) in Comparison to 100L Model Reactor (3 PBT) CH ~ 74,8 CH ~ 54,0 CH ~ 34,33 CH ~ 35,1 CH ~ 59,1 CH [-] 10,0 Disposable Reaktor, 250L Disposable Reaktor, 200L Disposable Reaktor, 150L Disposable Reaktor, 125L 100L, 3 SBR 1,0 1,0E+04 Re [-] 10 1,0E+05

11 Process Performance: Control & Bag Systems control system Control System I bag system SUB 1 with 1 bag type Control System II Control System III SUB 2 with 3 different bag types Control System IV SUB 3 with 2 different bag types Control System V SUB 4 with 2 different bag types differences between control systems: integration of optical sensors based on network or local control based on WinCC or DCU or DeltaV differences between bag types: availability of optical sensors sparger types (micro/macro sparger) stirrer (Rushton, inclined impeller, paddle) 11

12 Process Performance - Examples antibody #9: tox study supply SUB #2: bag 2b without problems SUB #3: problems with accuracy of ph-sensor SUB #4: max. working volume reduced by foaming cells are clumping in bag 4a 12

13 Process Performance Product Titer of > 40 Fermentations 13

14 Process Performance Product Quality analysis of supply campaigns of 6 different therapeutic proteins from SUBs o product was always comparable to classic bioreactors regarding IEC- & glycosylation pattern until now no differences in product quality between products from classical fermentations & fermentations in SUBs have been observed analysis for endotoxins & bioburden are unremarkable influence of extractable & leachable substances must be excluded by use of certified materials (USP <88> Cl. VI) surprising - not all vendors have these certificates for their products available 14

15 Rating of Control & Bag Systems for Stirred SUBs 15

Single Use Sensors fit Optimal to SUB Technology rocking systems are used for seed train cultivation cultivation time is relatively short & culture is light

sensor drift sensors are pre-calibrated and ready to use grounded single use sensors deliver better signals 50.0 45.0 40.0 35.0 30.00 25.0 20.0 15.0 10.0 5.

16 Single Use Sensors fit Optimal to SUB Technology rocking systems are used for seed train cultivation cultivation time is relatively short & culture is light protected sensor drift is in acceptable range stirred SUB systems for main cultivation sensors are not light sensitive (DO) or protected (ph) insignificant/no sensor drift sensors are pre-calibrated and ready to use grounded single use sensors deliver better signals Single Use DO Single Use Temp Electrochemical DO RTD Batch Duration (Hours) 16

17 One IT-System to Manage & Analyze Informations * 3 different IT architectures & process control systems have been evaluated 17

18 The IT-Architecture respects Different Requirements Research NonGMP-Dev. Process Validation Supply Phase I&II 18

19 Increased Efficiency by new Process Control Systems all data enter our data bases automatically the only operator inputs are comments & signatures all data on raw materials & consumables (and their performance) are stored centralized & ready for analysis reduced or no effort for sensor calibration and maintenance only single use sensors enable the reduction of change over time of the bioreactors features of the process control system like process save&load ease process transfer and reproduction of successful runs genealogy between processes & availability of data supports the generation of process knowledge estimated savings per operator/engineer: 210 hours/year 19

20 Combined Process Technology & IT-Project: Lessons learned 1. The involvement of the end-user is very intense compared to a project for stainless steel equipment with standard automation, where many aspects are routinely handled by engineering departments. 2. A highly detailed user requirement specification is needed, as many options exist for the different technical solutions. 3. Vendor audits should be done in early project phases as critical issues are related to QA-systems and company resources. 4. Close cooperation with supplier is recommended to ensure that the product fulfills the requirements (e.g. weekly meetings or telephone conferences). project team TP-Expand 20

21 Special Thanks to the SUB Project Team: Frank Trach & Elodie De Roo (Pharma Biotech Production) Wolfgang Paul & Roman Hirschauer & Rainer Reithmeier & Marion Traverse & Kurt Lang (Pharma Tech. Research) Alexander Herrmann & Gero Lipok (Pharma Tech. Development GMP) Ulrike Caudill & Olivier Guilmaille (Pharma Tech. Development NonGMP) Erwin Obersteiner & Philipp Kühne (Roche Automation) Patrick Vogel & Matthias Schmidt (Roche Process Engineering) Klaus Hermansen & Niels Guldager (nne pharmaplan) 21

22 We Innovate Healthcare 22

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