Implementation of Quality by Design at Merck Serono

Transcription

44th International SFSTP Conference – June 6 and 7 2012
FROM SCIENTIFIC UNDERSTANDING TOWARDS PRODUCT
QUALITY (by Design)
Implementation of Quality
by Design at Merck Serono
Lessons learnt from the FDA QbD Pilot Program
Dr Hervé Broly – V.-P. Biotech Process Sciences
Dr Hervé BROLY - MERCK SERONO
44th International SFSTP Conference
June 6-7 2012
Contents
 Brief Introduction to QbD
 FDA Pilot Program Outcomes
 Next Steps and Activities
June 6-7 2012
Low Biotech Industry Efficiency
and High Regulator Workload
Triggered New Initiatives
The Issue:
Observation of
disturbing
industry trends
(Dr. Janet Woodcock,
FDA Nov. 2001)
Regulatory Agency
perception
Industry
perception
Insufficient
Product / process
understanding
Recalls, withdrawals,
Approval delays
Persistent cGMP
violations
More inspections,
observations
More severe
enforcement
Excessive cGMPs /
Regulatory pressure
Cost / political
pressures
Change is difficult,
innovation is a risk
Quality by Design (QbD) related guidelines: ICH Q8, 9, 10, 11
June 6-7 2012
The
Response:
FDA's
"GMPs for
the 21st
Century“
and
the PAT
initiative
Knowing functional links between
clinical safety/efficacy, CQAs and
CPPs is key
Link
Link
Clinical
safety and
efficacy
Attributes by design
Variants
Impurities
CQA: a Quality Attribute which, when
outside a controlled range, induces a
change of efficacy and/or safety
CPPs:
CQAs:
Process parameters
Raw materials
CPP: a Process Parameter which, when set
outside of the Design Space, induces a
change of a Critical Quality Attribute outside
of its acceptable range
June 6-7 2012
Quality by Design is an enhanced
approach to drug substance and
drug product development
A systematic approach to pharmaceutical
development
Development starts with clear pre-defined objectives
In-depth scientific understanding of the
molecule, the product and the process
CQA-driven process and control strategy
Natural, “seamless” transition to manufacturing
operations
Quality risk management throughout
development and production
June 6-7 2012
Poor product/process knowledge
causes rigid control strategies and
tighter regulatory oversight
When the CQAs do not drive the development of
the manufacturing process:
Process-capability defines target quality
Quality of product not “fit for purpose”
Limit opportunities for process improvements
Inadequate or overly rigid control strategy
End-product testing main criterion for Manufacturing
operations
Tight acceptance criteria
Little possibility to adapt process to variability of materials
Tighter regulatory oversight
June 6-7 2012
QbD implies several loops of
continuing activities and iterative
progression
TPP
Target molecular
properties
Product knowledge
Q-TSP
Large scale
Manuf acturing
in vitro, non-clinical
clinical experience
Q-TPP
Prior knowledge
and literature
Process
development
Process
Qualif ication at
small scale
Process
Characterization
DoE
Critical
Quality
Attributes
Quality
Risk
Management
Critical
Process
parameters
Control
strategy
Raw Material
qualif ication
Process knowledge
Continuous
verif ication
Def inition of
design space
Robustness
Validation
Expanded
Change
Protocol
Quality systems
June 6-7 2012
Contents
June 6-7 2012
FDA and Sponsors need to gain
experience with QbD submissions
for biotechnology products
FDA QbD Pilot Program aims at:
Submitting quality data for biotechnology products
Quality by Design principles and risk management
Control strategy
Expanded change protocol
Gain information and facilitate Agency review of
quality-by-design dossiers
Several meeting with applicants
Development of new guidance for industry in
partnership with selected biotech companies
June 6-7 2012
The development of atacicept BDS
process using a QbD approach has
been discussed with FDA
Three face-to-face meetings with the FDA were
held between Aug. 2010 and Oct. 2011 + one
additional meeting planned in 2012
August 2010: General concepts
July 2011: Selection of CQAs and CPPs
October 2011: Control Strategy
Q4 2012: Continuous verification, Expanded Change
Protocol, Engineering Design Space
June 6-7 2012
The atacicept QbD program
encompassed a first meeting to
discuss the general concepts
Identification of cQAs
through risk ranking
• Identification of CPPs
• Qualification of scaledown models
• Process characterization
by DOE
Implementation of adaptive
control strategies
Clarified cell culture
harvest
HMW ≤ 26%
26% ≤ HMW ≤ 33%
Capture elution
at 3.75 ≤ pH ≤ 4.10
DSP anywhere
within Design Space
MOR
Definition and validation of a global
multi-step design space
A: Load aggregates
10.9
Cell culture
process
9.4
HMW: 2.8
7.9
MOR
6.5
230
5.0
6.0
6.3
6.5
6.8
7.0
C: elution N aC l
210
B: Elution pH
Protein A
190
170
MOR
150
130
7.00
4 .5 0
7.25
7.50
7.75
8.00
8.25
8.50
B: elution pH
Cation
exchange
B: Load conductivity
Process flow
Definition of MOR
3 .8 8
3 .2 5
MOR
2 .6 3
1 0 .9
2 .0 0
7 .0 0
7.5 0
8 .0 0
8 .5 0
A: Load pH
Anion
exchange
A: Load aggregates
6 .5 0
9 .4
7 .9
MOR
6 .5
5 .0
6.0
6 .3
6 .5
B: Elution pH
6 .8
7 .0
Hydroxyapatite
DS
June 6-7 2012
33% < HMW ≤ 41%
Capture elution
at 3.75 ≤ pH ≤ 4.10
Yes
HMW ≥ 41%
HMW
Capture elution
at 3.90  pH  4.10
HMW 
15%
No
DSP steps at
centerpoint or BC
Reject
Step characterizations were used
to define a Global Multi-Step
Design Space
MOR
Single step design space determination (MOR)
• guarantees drug substance quality for all CQAs
• overlap of models of all CQAs defines MOR
Cell culture
process
A: Load aggregates
33.10
28.63
HMW forms: 18
MOR
24.15
Multi-Step Design Space determination:
• Start from drug substance
• Move up to the cell culture process
• Link between steps defined
by most limiting
CQAs
19.67
230
15.20
3.72
3.85
3.97
C: Elution pH
Protein A
4.10
210
C: elution NaCl
3.60
190
MOR
170
150
4.5 0
130
7.00
7.25
7.50
7.75
8.00
B: elution pH
8.25
8.50
B: Load conductivity
Process flow
Definition of MOR
Cation exchange
3.8 8
3.2 5
MOR
2.6 3
1 0 .9
Link between steps:
The most limiting CQAs are both input Anion exchange
variables (CPP: quality of load) and
process outputs (quality of eluate)
2.0 0
7 .00
7 .5 0
A: Load pH
8.0 0
8 .50
A: Load aggregates
6.5 0
9 .4
7 .9
MOR
6 .5
5 .0
6 .0
6 .3
6 .5
B: Elution pH
6.8
7 .0
Hydroxyapatite
June 6-7 2012
DS
An adaptive manufacturing
strategy for aggregates delivers
DS with QTPP target quality
Process flexibility: Control strategy of individual steps adapted to incoming material quality
Clarified cell culture
harvest
Yes
No
HMW  26%
Yes
No
26  HMW  33%
Yes
Capture elution
at pH  3.75
Capture elution
at pH  3.80
Yes
DSP anywhere
within Design Space
Capture elution
at pH 3.75
HMW  15%
Capture elution
at 3.90  pH  4.10
HMW  41%
No
No
DSP steps at
centerpoint or BC
June 6-7 2012
Reject
General QbD development
approach seemed to be in good
agreement with FDA expectations
The general QbD approach is consistent with
ICH guidelines
The concept of Global Multi-Step Design Space
and Design Space confirmation in robustness
studies appear adequate
Adaptive process control strategies are
acceptable
But some aspects deserved further discussions
June 6-7 2012
Identification of CQAs is expected
for all molecules – regardless of
development approach
Start from the complete list of molecule quality attributes
Avoid early elimination of CQAs – a comeback is difficult
Extracellular
Extracellular
domain
domain
of
TACI
of TACIreceptor
receptor
• 12 Cys form 6 intrachain
• 12 Cys form 6 intrachain
disulphide
disulphidebridges
bridges
• • Cleavage
Cleavagesites:
sites:positions
positions32,
32,
49,
81
49, 81
• • Met
Metoxidation:
oxidation:positions
positions2,2,19
19
Fc
Fcdomain
domainof
of
human
human
immunoglobulin
immunoglobulin
• • 66Cys
Cysform
form22intra
intra/ /22interchain
interchain
disulphide
disulphidebridges
bridges
• • Potential
Potentialcleavage
cleavagesites:
sites:
positions
positions137,
137,144,
144,173,
173,176
176
• • Met
oxidation:
positions
Met oxidation: positions118,
118,
294
294
• • Potential
Potentialdeamidation
deamidationsites:
sites:
positions
positions181
181and
and250
250
• • N-glycosylation:
N-glycosylation:position
position163
163
• • Heterogeneity
HeterogeneityofofC-terminal
C-terminal
Lys:
position
313
Lys: position 313
Product properties
–
–
–
–
Conformation
Potency / Product concentration
Post-translational modifications
Physico-chemical modifications
Other quality attributes
Product-related substances or
impurities
Process-related impurities
Contaminants
Any cQA should be considered critical unless proven otherwise
June 6-7 2012
Suitability of the Design Space
defined at small-scale must be
confirmed at large scale
Option 1: Large-scale process outside center
points
?
pH
Option 2: Engineering Design Space
The definition of Design Space requires to
include consideration of all input variables
June 6-7 2012
Ba s
e
…the second meeting covered
Critical Quality Attributes and
Critical Process Parameters
TPP
Product knowledge
Q-TSP
Critical
Quality
Attributes
Target molecular
properties
Q-TPP
in vitro, non-clinical
clinical experience
Prior knowledge
and literature
Large scale
Manuf acturing
Process
development
Process
Qualif ication at
small scale
Process
Characterization
DoE
Critical
Process
parameters
Quality
Risk
Management
COMBINATIONS
Binding site
Glycation
Raw Material
qualif ication
Cleavage
Deamidation
Oxidation
Mutations
FcRn interaction
FcγRs interaction
Process knowledge
Def inition of
design space
Robustness
Validation
June 6-7 2012
Prot A interaction
C1q binding
Linkage between CQAs and CPPs
is of key importance
Develop the approach to establish linkages in
great detail
Justify the design attributes (e.g. CDR, Absence
of Fc – effector functions…)
Consider interactions with impurities, input
materials, other CQAs
Clinical
Safety and
Efficacy
Linkage
Linkage
cQAs
cPPs
Attempting to minimise the number of CQAs, CPPs or release tests to be
performed may be risky: justify selection based on sound scientific grounds
June 6-7 2012
Any QA will remain critical until
proven otherwise through quality,
nonclinical or clinical data
Induce variant
Molecular modelling
Isolate variant
Bioassay
no
Bioactivity?
– Model to explain variants
CQA
yes
no
Target
binding?
Biacore
CQA
yes
no
In vitro
metabolism?
Metabolism in serum
CQA
Fill knowledge gaps
yes
no
PK/PD in
animals
Rodent study
CQA
yes
no
PK/PD data
convincing?
yes
Non critical QA
CQA
– Cleavage products should be
evaluated in the CQA
assessment
– Confirm non-criticality of C-term
lysine on PK/PD profile for
subcutaneous route
June 6-7 2012
Risk assessment needs to build on
each other and covers all
manufacturing steps
Quantitative rankings for impact and severity
June 6-7 2012
…and the third meeting focused
on the control strategy
…and overall the Control Strategy ensures that the
product is produced to meet all quality targets
 Find the Critical Control Points
Run next QA
no
Was this the last QA to evaluate?
The Control Strategy is a planned set of controls that
assures performance and product quality
yes
End
Product knowledge
Start
 Hazard Analysis and Critical Control
Points
Run next step
Is the QA identified as a CQA?
Not a Critical Control Point
no
Critical
Quality
Attributes
yes
yes
 Assign the right testing strategy
Does the step increase CQA levels?
Does the step decrease the CQA
no
yes
 Raw material or equipment qualification
no
Is this the last step?
no
no
Control Strategy
yes
Is this the last step where the CQA
increases?
no
Continuous
verification
yes
 Process parameter and procedural
controls
 Release and / or stability testing
Are the follow steps decreasing the
CQA level?
yes
Critical
Process
parameters
Is CQA below target of LoQ/LOD?
no
yes
yes
Is testing at this step necessary for
safety or input to next step?
Can input material be tested?
no
yes
yes
Process targets for
critical quality attributes
Test input material
 Establish verification and monitoring
process
Is testing of the CQA at this step
possible?
yes
no
Develop analytical procedure and implement
Critical Control Point
Design space
 Trending
Is the CQA defined by the process
alone, e.g., by a design space?
 Periodic quality review
yes
Apply design space Critical Process
Parameters (Process parameter control,
procedural procedure)
no
Is the CQA to be defined by analytical
procedure ?
yes
Apply testing controls (IPC, release and/or
stability testing)
no
Is the CQA to be defined by Raw
material or equipment qualitication?
Quality
Risk
Management
Testing targets for
critical quality attributes
yes
Apply testing controls (IPC, release and/or
stability testing)
Process knowledge
Quality
Risk
Management
Input material
controls
Raw Material
qualification
Control
strategy
Raw Material
qualification
Quality systems
June 6-7 2012
Expanded
Change
Protocol
Process parameter
controls
Procedural controls
Testing
Characterisation
Stability Testing
Large scale
Manufacturing
Process controls
Process monitoring
Release Testing
In Process Testing
GMP
PPs are in a continuum – a PP not
critical inside a given range may
be critical outside
CPPs determine the desired quality
Systematically evaluate all process
parameters
Carefully control the PP continuum
Procedural / process parameter
controls
ensure they remain in the
predetermined range
Limits of the PPs
Control strategy preserves status at
Design Space definition
June 6-7 2012
Immunogenicity will remain an
area of remaining risk
The overall risk assessment for immunogenicity should include
use of concomitant medications
patient immune status
assay performance
potential for anti-drug antibodies to
cross-react with an endogenous non-redundant
protein,
links between CQAs
The evaluation of the criticality of aggregates on immunogenicity is
independent of the amount present in the Drug Substance or Drug
Product
Combine in silico, in-vitro, in-vivo, clinical data to evaluate the
impact of product-related substances and impurities on
immunogenicity
June 6-7 2012
Much focus is put on input
materials where column resins life
time prediction will be a challenge
Develop the raw materials qualification concept
Impurities derived from non-bioactive raw materials should be
considered for potential interaction with the product or other
impurities
Chromatographic resins have a particular issue :
repeated use
Stability of performance needs to be ensured over their life-cycle
How can this stability be predicted upon arrival of a new batch?
Ideas:
Online composite quality measure
Establishment of quality parameters linking loss of performance to
column age for each used resin and performance test at receipt
Surrogate marker or proxy, e.g., the most limiting CQA for the step
June 6-7 2012
The control strategy must cover
all relevant QAs and PPs and
include a convincing monitoring
plan
Set acceptance criteria for CQAs based on effects on
safety and efficacy
Do not base on process capability only
Justify experiments performed, trying to find the edge of failure is a
good concept
Control Strategy - a complex network of controls
permitting consistent achievement of desired quality
Process targets
Testing targets
Knowledge management and Process monitoring, e.g., using a
SDMS
Need to consider developing a robust testing strategy that will enhance
process understanding and build confidence in the Design Space
June 6-7 2012
The quality is in focus, not in
process performance or
manufacturing costs
Avoid to refer to process performance – the
Agency is interested in quality
Reduce failures / Introduce innovation
Closely adhere to concepts and definitions as
found in ICH guidances
Pre-submission meetings to outline
the dossier contents will be a “must”
Change management vs Reg. Authorities
“What they have always seen before” -syndrome
Example : charge variants.
June 6-7 2012
Contents
June 6-7 2012
The main areas for improvement
are the input material and variant
qualification
Develop continuous verification and expanded
change protocol concepts
Complete the activities in the identified areas for
improvement
Input material qualification
Variant qualification
Immunogenicity
Scale qualification
June 6-7 2012
In summary
QbD
QbDimproves
improves
product
productand
and
process
process
understanding
understanding
MercK
MercK Serono
Serono
has
hasvalidated
validatedits
its
approach
approachto
toQbD
QbD
with
withthe
theFDA
FDA
June 6-7 2012
Merck
MerckSerono
Serono
needs
needsto
todeepen
deepen
product
productvariant
variant
and
andinput
input
material
material
knowledge
knowledge
Starting medicinal product
development with the end in
mind by applying Quality by
Design principles has in-depth
product and process knowledge
as the principal outcome
June 6-7 2012

Implementation of Quality by Design at Merck Serono

Transcription

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