Filing established conditions and life cycle management of ... · Filing established conditions and...
Transcript of Filing established conditions and life cycle management of ... · Filing established conditions and...
Filing established conditions and life cycle management of a bioprocess.
9-11th May 2016: CASSS- CMC Forum
Europe 2016
Christine Mitchell-Logean UCB
■ Revenue: €3.88 billion
■ rEBITDA: €821 million
■ More than 7500 employees globally
■ Operations in ~40 countries
■ R&D Spend: 27% of revenue
■ Listed on Euronext
UCB: A Patient-Centric Biopharma Company
Stephanie, living with rheumatoid arthritis
We have a shared ambition to transform the lives of people living
with severe diseases.
We focus on central nervous system and immunology disorders –
putting patients at the center of our world.
© UCB Pharma S.A. 2016. All rights reserved.
3
QBD from then to now…
The Issues • Dr.Janet Woodcock, FDA Nov.2001
• Increasing manufacturing defect trend
• Low manufacturing and QA process efficiency – cost implications
• Innovation, modernization, adoption of new technologies slowed or not adopted for US market
• High burden on FDA resources
The Responses from HA:
• PAT, QBD, ICH Q8, 9,10,11, and now 12
Today:
• Full QBD submissions are not the norm
• Mostly Approved so far without design space*
Regulatory Industry
Excessive cGMPs
More inspections,
Warning letters
Change is difficult,
innovation is risk.
Recalls, withdrawals,
supply issues
cGMP violations
More severe
enforcement
Cost / political
pressures
Persistent cGMP
violations
Regulatory Industry
Not convinced QBD
is making live easier
Cautious in
Approving QBD
(Design space)
*http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002547/WC500141004.pdf
Opposing forces ?
4
Health Authorities needs: Insurance of safety, efficacy,
efficiency of resources
Industry needs: Flexibility, quick
approval, efficiency and quality
Common ground and win-win aspects
5
• Science based submission with a well characterised process that
demonstrates good understanding and a good management of risks:
• Win for HA as they are more confident that patient safety will be met
• Win for Industry as they will have less batch rejection and more flexibility.
The entire paradigm of QBD
• Still not full clear how file QBD:
• How much details to present.
• What is binding and not binding and how to file process improvements.
• Reviews of file may be reviewer dependent.
Established conditions guidance and ICHQ12 will bring value to clarify binding
and non binding information in filings.
Process development 3.2.S.2.6
6
Process
history
Comparability
of processes
CQA
Process characterisation:
• Scale down model
qualification
• DOE results: PAR
• Resin reuse
FMEA
CPP,
IPC
Control Strategy
Process Validation 3.2.S2.5
Verification of process
consistency.
CPP, IPC’s and additional
parameters monitored.
CPV, Hold times
Control of Critical steps
3.2.S.2.4
CPP
IPC with action limits
IPC with acceptance criteria
Binding
Process Description
3.3.S.2.2
Process steps information
with parameters and In-
process controls
Binding
File schematic
Specifications 3.2.S.4.1
Set of analytical tests with
define limits for CQA’s
on DS, DP and for stability
Binding
Case study of a Mab purification chromatography step
7
1. S.2.6 description of development process; risk analysis, robustness studies
and control strategy
2. S 2.5 description of the process validation
3. S 2.2 description of the manufacturing process
4. S 2.4 description of the controls
5. Management of changes
2.6 Process characterisation of chromatography step
8
Based on FMEA, the parameter to be studied were prioritized and tested.
Parameter Range Studied PAR Impact on
Load pH 7.5 to 8.3 7.5 to 8.3 None
Equilibration / wash conductivity
(mS/cm) 1.7 to 4.5 1.9 to 4.5 None
Equilibration / wash pH 7.5 to 8.3 7.5 to 8.3 None
Load conductivity (mS/cm) 1.7 to 4.5 1.7 to 3.6 HCP, Protein A
ligand
Load Challenge (g mAb / L resin) 30 to 60 30 to 60 None
Nb of cycle 100 100 None
Peak collection end point 0.3 to 0.7 0.3 to 0.7 None
3.2.S.2.6 CPP determination: significant* impact on
CQA
9
Impact on HCP and on Protein A ligand
for load conductivity.
Assessment value:
25U/mg for HCP
1ppm for protein A ligand
PAR : Load conductivity
≥ 1.7 (limit of experimentation)
≤ 3.6 (limit of failure)
NOR: Based on equipment capability
≥ 2.6
≤ 3.6
Control:
Parameter: Load conductivity is a CPP (PAR 1.7-3.6)
IPC: Endotoxin, Bioburden, Yield
Monitoring: process impurities
* significant: with regard to analytical
variability and relevance with regards
to specification range.
3.2.S.2.5 Process validation of chromatography step
10
* Will be defined after sufficient batches are manufactured
Parameter Criteria Range Run 1 Run 2 Run 3 Status
Load conductivity
(CPP) (mS/cm)
NOR 2.6-3.6 3.2 3.2 3.2 Pass
PAR 1.7-3.6
IPC Criteria
Yield (%) Action limit ≥ 85* 99 99 98 Pass
Endotoxin (EU/ml) Action limit ≤ 2 < 0.03 < 0.03
< 0.03
Pass
Bioburden (cfu/10ml) Action limit ≤ 50
0 0 0 Pass
Asymmetry Action limit 0.6-2.0 1.3 1.3 1.3 Pass
HETP Action limit >2000 2615 2373 2592 Pass
Aggregates Monitor n/a 0.4 0.4 0.4 n/a
HCP Monitor n/a 2 2 4 n/a
Beta-Glucans (ppm) Monitor n/a 0.77 1.12 1.18 n/a
Protein A (ng/mg) Monitor n/a <1 <1 <1 n/a
DNA (pg/mg) Monitor n/a ≤8 ≤4 ≤16 n/a
3.2.S.2.5 Process Validation considerations
11
Control elements explained in 2.6 should be included in the validation:
• CPP (NOR and PAR are typically added to demonstrate control)
• IPC (limits are defined based on specification and process clearance)
• Additional parameters such as process impurities that may not be
measured long term should be monitored. These may be monitored for a
few additional batches beyond validation to confirm clearance with
additional data.
3.2.S.2.2 Manufacturing Process description
12
* limit to be confirmed after 30 batches
Parameter Type Range values (defined by)
Column height PP x-y (Based on early experiments)
Loading capacity PP x-y ( Limit of testing)
Nb of Cycle PP x-y (Limit of testing)
Volume of equilibration buffer PP x-y (Based on early experiments)
Equilibration: buffer pH PP x-y (Limit of testing)
Equilibration: buffer conductivity PP x-y (Limit of testing)
Load: conductivity (controlled at
previous step)
CPP 1.7-3.6 (limit of testing)
Load / wash: flow rate PP x-y (Based on early experiments)
Elution: start peak collection PP x-y (Based on early experiments)
Elution: end peak collection PP x-y (Limit of testing)
IPC Type Range
Bacterial endotoxins (product pool) IPC (AL) ≤ 2EU/ml
Step yield (product pool IPC (AL) ≤ 85 %*
Bioburden (product pool) IPC (AL) ≤ 50 cfu/ml
3.2.S.2.4 Control of critical step: chromatography step
13
Parameter Criteria PAR
Load: conductivity CPP 1.8-4.5
IPC
Bacterial endotoxins (product pool) IPC (AL) ≤ 2EU/ml
Step yield (product pool IPC (AL) ≤ 85 %*
Bioburden (product pool) IPC (AL) ≤ 50 cfu/ml
2.2 Process description and 2.4 control of critical step
considerations
14
Enough details should be presented to describe the step
■ Parameters that were not CPP had to be included.
■ Level of details and parameters to be presented were defined based on what seemed necessary to
describe the step adequately.
■ NOR were presented when PAR were not available for parameters that were not studied.
■ The FMEA prioritize the parameters that need to be studied and thus the ones with PAR.
■ Buffer compositions are also part of the process description.
Parameter
• Process parameter: input of the process that may have defined and/or NOR
• CPP: Input parameter that if varied can have an impact on a CQA and thus should be controlled
or monitored.
IPC:
• Action limit: Either the IPC is adjusted to bring the parameter within the limit or an appropriate
action is taken and processing is continued.
• Acceptance criteria: must be met to ensure that the product is conform to its specification and
critical quality attribute
3.2.S.2.2 Change to a parameter 15
2.2 Change to IPC
16
ן The difficulty for reporting lies often with the parameters that are not
specifically studied and not prioritized during the risk assessment,
but still need to be described in the manufacturing processes. A
good justification needs to be available to explain why these are not
critical.
ן The level of details to be filed in the manufacturing description is
somewhat subjective.
ן For the DOE parameters where co-dependency has been
demonstrated a change in one parameter may have an impact on
ranges of another.
This needs to be evaluated carefully if a full design space has not
been validated.
Conclusions: touchy points
17
Process development S2.6
18
Process
history
Comparability
of processes
CQA
Process characterisation:
• Scale down model
qualification
• DOE results: PAR
• Resin reuse
FMEA
CPP,
IPC
Control Strategy
Process Validation S2.5
Verification of process
consistency.
CPP, IPC’s and additional
parameters monitored.
Hold times
CPV
Control of Critical steps
S2.4
CPP
IPC with action limits
IPC with acceptance criteria
Binding
Process Description S2.2
Process steps information
with parameters and In-
process controls
Binding
Established conditions
Specifications S4.1
Set of analytical tests with
define limits for CQA’s
on DS, DP and for stability
Binding
Thanks! Elaine Harris
Jennifer Halley
Vanessa Auquier
Laurence Vroye
Jonathan Monck
Mareike Harmsen
Richard Jones
Ansah Kwame and many others