A Quality Perspective on Continuous Biomanufacturing Frank Lammers 22-Oct-2013

| 2 The storyline in Quality… …circles around three basic questions: - Where do we see risks ? - How do we rank those ? - How do we grip them in an - How do we grip them in an efficient control modus ? efficient control modus ?

| 3 …how to apply to continuous biomanufacturing ?

| 4 Outline ● Process design objectives, perceived risks & potential mitigations ● Specific Quality Assurance objectives, perceived risks & potential mitigations ● Continuous biomanufacturing and the QbD arena ● Conclusion

| 5 Outline ● Process design objectives, perceived risks & potential mitigations ● Specific Quality Assurance objectives, perceived risks & potential mitigations ● Continuous biomanufacturing and the QbD arena ● Conclusion

| 6 Consistent Product Quality ● Objective ● High and consistent product quality through optimal steady state ● Perceived risk ● Non-reliable and/or slow feedback control to really reach steady- state-conditions ● Reliability and robustness of process automation (soft- and hardware) ● Different loading of columns in continuous chromatography impacts purification outcome ● Potential mitigation ● validated PAT (if available) ● Appropriate equipment qualification and software validation

| 7 Decrease of impurity level ● Objective ● Lower level of impurities in the bioreactor due to high cell viability reduces DSP efforts ● Perceived risk ● impurity trending with less priority during continuous biomanufacturing ● Process related impurities (eg HCP) may increase in long operation mode ● Potential mitigation ● continuous impurity monitoring by means of customized PAT, eg on- line-HPLC/UPLC ● Definition of alert & action level to assess OOT results

| 8 Decrease of holding times ● Objective ● Improved product quality through tremendous decrease of product hold time by minimization of residence times and elimination of multiple non-value-added hold steps ● Less intermediate testing and stability studies through elimination of hold steps ● Perceived risk ● Elimination of holding steps decreases time-buffer and flexibility to re- adjust industrialized process in time while being in operation ● No intermediate processing-stop ● Potential mitigation ● Time- or volume-based segmentation of manufacturing-flow to coordinate re-adjustment in concrete segments

| 9 Less Bioburden ● Objective ● Minimized bioburden risk through closed system operation ● Perceived risk ● higher probability of contamination issues due to long term manufacturing ● Potential mitigation ● Strong focus on contamination control both in equipment qualification and microbio monitoring design

| 10 Lower environmental monitoring ● Objective ● Low environmental monitoring due to closed system operation in lower environmental class ● Perceived risk ● Decrease of sterile barrier due to sampling process in lower environmental class ● Potential mitigation ● local sampling booth

| 11 Outline ● Process design objectives, perceived risks & potential mitigations ● Specific Quality Assurance objectives, perceived risks & potential mitigations ● Continuous biomanufacturing and the QbD arena ● Conclusion

| 12 Batch definition ● Objective ● Crystal clear batch definition to link starting materials and in-process- information with final product and to assure post-manufacturing traceability (eg. recall-situation) ● Perceived risk ● In- and post-process events (eg., deviation, OOT, recall) potentially affect whole manufacturing campaign instead of limited batch volume ● Potential mitigation ● Batch record design reflecting time- or volume-based segmentation of whole manufacturing campaign

| 13 Change Control Management ● Objective ● Continuous improvement of industrialized processes by means of change control management ● Perceived risk ● Due to long processing times of continuous manufacturing, probably longer time needed to generate data for evaluation of envisaged changes ● Potential mitigation ● Development in QbD paradigm to result into design space ● changes only within elaborated design space

| 14 Deviation/OOS handling ● Objective ● Deviation/OOS assignment ● Perceived risk ● No clarity how far deviation/OOS affect whole manufacturing campaign or only limited segment (time/volume) ● Potential mitigation ● be able to isolate non-spec- from in-spec-segments ● Set deviation/OOS in order with volume/time based segmentation and resulting batch pedigree

| 15 Validation design ● Objective ● State-of-the art validation design reflecting current experiences in biomanufacturing (x process runs, LIVCA batches, cleaning, product change over) ● Perceived risk ● Stock piling through lengthy validation runs and following data evaluation in conflict with product stability ● Potential mitigation ● CM specific validation (different from batch/semi-batch operations) ● Concurrent validation approaches ● Exclude stock piling (depending on product stability)

| 16 Viral safety ● Objective ● Validation of viral removal / safety ● Perceived Risk ● Previously used spiking study design may not reflect in continuous chromatography different loading status of columns ● Potential mitigation ● Spiking experiments tailored to continuous chromatography ● Higher effort with more spiking experiments

| 17 Cleaning Aspects ● Objective ● Cleaning processes ● Perceived Risk ● No cleaning of equipment during continuous manufacturing increases eg. risk of membrane moulding, DSP performance etc. ● Potential mitigation ● Design cleaning process/agents/detergents with special focus on CM characteristics ● Adapt frequency of cleaning & (membrane) maintenance ● Include tailored sanitising of chromatography process

| 18 Outline ● Process design objectives, perceived risks & potential mitigations ● Specific Quality Assurance objectives, perceived risks & potential mitigations ● Continuous biomanufacturing and the QbD arena ● Conclusion

| 19 ICH Q landscape on biotech manufacturing Wild vector Host cell Expression system (1 clone) Master cell bank Working cell bank Upstream processing Downstream processing Drug Substance Sterile filtration / aseptic filling Drug Product Expression vector Gene of interest Genetic development Cell banks Production Sterilisation Aseptic filling Q5A Q5B Q5D Q5E Q5A Q5C Q5E Q6B Q11 Q5E Q6B Q8 Q8R Q7A Q9 Q10 QbD package

| 20 Quality by Design (QbD) „A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management“ ICH Q8(R2)

| 21 Elements of QbD approach Quality Target Product Profile Risk assessment Risk assessment Risk assessment A-Mab Case study, Continuous Biomanufacturing Process Analytical Technology Key elements in QbD Key elements in CM

| 22 Traditional vs PAT approach Traditional approach Process developed, „freezed“, validated through 3 commercial batches Process assurance via SOPs, training etc. QC performed later with product off-line-testing in lab PAT approach on-line/at-line analysis allows flexible adaption statistical based process control (release without off-line-tests) Static endproduct oriented claim Process as black-box Dynamic object oriented Process understood Closed loop Bioprocess control for improved & predicted product quality - +

| 23 QbD & continuous biomanufacturing in perfect fit ● Continuous biomanufacturing ambassador in catalyzing QbD ● As clear difference to batch manufacturing, continuous biomanufacturing in marriage with PAT only ● but batch-/semi-batch manufacturing in use of PAT as well ● Appropriate PAT is key ● NIR, UV/VIS, on-line-HPLC/UPLC etc. ● Risk based approaches as enabler to rank quality attributes and control strategy elements ● Benefits as highlighted in process design objectives

| 24 Outline ● Process design objectives, perceived risks & potential mitigations ● Specific Quality Assurance objectives, perceived risks & potential mitigations ● Continuous biomanufacturing and the QbD arena ● Conclusion

| 25 Back to the original questions… - Where do we see risks ? - How do we rank those ? - How do we grip them in an - How do we grip them in an efficient control modus ? efficient control modus ?

| 26 …and the resulting conclusion

| 27 Take home messages ● In comparison to batch manufacturing, continuous biomanufacturing certainly characterized with new & challenging but manageable QA tasks ● Several risk identified, but a couple of potential mitigations already available ● Some mitigations probably active since years, others to be further developed or refined ● Currently no QA show stoppers visible

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