A Quality Perspective on
Continuous
Biomanufacturing
Frank Lammers
22-Oct-2013
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
efficient control modus ?
|
2
…how to apply to continuous biomanufacturing ?
|
3
Outline
● Process design objectives, perceived risks & potential
mitigations
● Specific Quality Assurance objectives, perceived risks
& potential mitigations
● Continuous biomanufacturing and the QbD arena
● Conclusion
|
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
Consistent Product Quality
●
●
●
Objective
● High and consistent product quality through operation @ optimal
steady state
Perceived risk
● Non-reliable and/or slow feedback control to really reach steadystate-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
|
6
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 online-HPLC/UPLC
● Definition of alert & action level to assess OOT results
|
7
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 readjust 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
|
8
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
|
9
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
|
10
Outline
● Process design objectives, perceived risks & potential
mitigations
● Specific Quality Assurance objectives, perceived risks
& potential mitigations
● Continuous biomanufacturing and the QbD arena
● Conclusion
|
11
Batch definition
●
●
●
Objective
● Crystal clear batch definition to link starting materials and in-processinformation 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
|
12
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
|
13
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
|
14
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)
|
15
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
|
16
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
|
17
Outline
● Process design objectives, perceived risks & potential
mitigations
● Specific Quality Assurance objectives, perceived risks
& potential mitigations
● Continuous biomanufacturing and the QbD arena
● Conclusion
|
18
ICH Q landscape on biotech manufacturing
Wild vector
Host cell
Gene of interest
Expression vector
Genetic
development
Expression system (1 clone)
Master cell bank
Q5A
Q5B
Q5D
Q5E
Cell banks
Q7A
Working cell bank
Upstream processing
Downstream processing
Production
Drug Substance
Sterile filtration / aseptic filling
Drug Product
Sterilisation
Aseptic filling
Q5A
Q5C
Q5E
Q6B
Q11
Q5E
Q6B
Q8
Q8R
Q9
Q10
QbD package
|
19
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)
|
20
Continuous
Biomanufacturing
Elements of QbD approach
Quality Target Product Profile
A-Mab Case study, www.casss.org
Risk
assessment
Risk
assessment
Process
Analytical
Technology
Risk
assessment
Key elements in QbD
Key elements in CM
|
21
Traditional vs PAT approach
Traditional approach
•
Process developed, „freezed“,
validated through 3 commercial
batches
•
Process assurance via SOPs,
training etc.
•
PAT approach
•
on-line/at-line analysis allows
flexible adaption
•
statistical based process control
•
(release without off-line-tests)
QC performed later with product
off-line-testing in lab
•Static endproduct oriented claim
•Process as black-box
•Dynamic object oriented
•Process understood
+
Closed loop Bioprocess control for improved & predicted product quality
|
22
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
|
23
Outline
● Process design objectives, perceived risks & potential
mitigations
● Specific Quality Assurance objectives, perceived risks
& potential mitigations
● Continuous biomanufacturing and the QbD arena
● Conclusion
|
24
Back to the original questions…
- Where do we see risks ?
- How do we rank those ?
- How do we grip them in an
efficient control modus ?
|
25
…and the resulting conclusion
|
26
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
|
27
|
28