Implementation Activities for
QbD: EU PAT Team
WCBP CMC Strategy Forum
Washington, 19 July 2010
Kowid HO
Afssaps, France
1
Council of Europe
European Directorate for the
Quality of Medicines
European Pharmacopoeia
Strasbourg
& health care (EDQM)
STRASBOURG
47 member states
European Union
http://www.ich.org/cache/compo/276-254-1.html
Commission
European Medicines Agency (EMEA)
London
(DG enterprise & industry)
BRUSSELS
27 member states
2
European Medicines Agency (EMA)
•
1995: European Agency for the
Evaluation of Medicinal Products
(EMEA)
•
2004 (EC No 726/2004): European
Medicines Agency (EMA)
– Coordinates scientific resources for
the evaluation, supervision and
pharmacovigilance of medicinal
products
http://www.ema.europa.eu
– Scientific resources: 27 member
states
3
European Medicines Agency (EMA)
EMA
Inspection
sector
CVMP
CHMP
Committee for Medicinal
Product for Human use
Committee for Medicinal
Product for Veterinary use
EMA Scientific
Committees
CAT
Committee for
Advance Therapy
PDCO
Paediatric
Committee
COMP
HCMP
Committee of Orphan
Medicinal Product
Committee for Herbal
Medicinal Product
4
European Medicines Agency (EMA)
Vaccine Working Party
(VWP)
Biologics Working Party
(BWP)
Blood Product
Working Party (BPWP)
Quality Working Party (QWP)
Joint CHMP/CVMP
Patients' and Consumers'
Working Party (PCWP)
Similar Biological (Biosimilar)
Medicinal Products Working
Party (BMWP)
CHMP
Cell-based Products
Working Party (CPWP)
Gene Therapy
Working Party (GTWP)
Efficacy
Working Party (EWP)
Scientific Advice (SAWP)
Pharmacovigilance
Working Party (PhWP)
Safety Working Party
(SWP)
Pharmacogenomics
Working Party (PgWP)
+ Specific ad-hoc working groups or subgroup meetings when needed
5
European Medicines Agency (EMA)
EMA
Inspection
sector
GMDP IWG
PAT TEAM
BWP
EMA Scientific
Committees
SAWP
QWP
CHMP
Committee for Medicinal
Product for Human use
6
EMA PAT TEAM
• EMA PAT Team started its activities in January 2004
– Composition
• quality assessors for chemical products (appointed by QWP)
• GMP inspectors (appointed by the GMDP IWG)
• an observer appointed by BWP
– Activities:
• guidance documents currently published on the EMA website
• co-organised with industry training and workshops on QbD,
• Discussion/advice to several pharmaceutical companies on
QbD/PAT elements and strategies
• December 2006:
– quality assessors for biological products (appointed by BWP)
were added to the team.
• 2011…
7
Process change after MA
Variations Regulation 1234/2008/EC
• Community legal framework regarding variations
since 2003:
– Regulation (EC) No 1084/2003
– Regulation (EC) No 1085/2003
• “In the light of practical experience in the application
of those two Regulations, it is appropriate to proceed
to their review in order to establish a simpler, clearer
and more flexible legal framework, while
guaranteeing the same level of public and animal
health protection.”
• Applies from 1 Jan 2010
8
Process change after MA
Variations Regulation 1234/2008/EC
• Revision of the Variations Regulations
– Type IA: "do & tell"
• notification within 12 months following the implementation
• IN: immediate notification when required
– Type IB (by default): "tell & do"
• accepted if no unfavourable opinion sent within 30 days
– Type II variation:
• upon request from the holder
• where the competent authority concludes that the variation may
have a significant impact on the quality, safety or efficacy
• Opinion within 60 days, but may be reduced or extended (i.e.
90 days)
9
Process change after MA
• Without change management protocol
– Type IB variation: change in batch size without process change
that does not require an assessment of comparability
– Type II variation: Comparability (ICH Q5E) + Process
considerations + Stability considerations
• With change management protocol
– Initiation: Type II variation registering Change Management
protocol (Comparability + Process considerations + Stability
considerations)
– Implementation: Type IB variation presenting results in
compliance with Change Management Protocol
• Within an approved design space
– No variation: ~ Change management protocol ? + Continuous
process verification protocol ? + Stability protocol ?
10
Change Management Protocols
• Step-wise approach to facilitate
implementation of changes post-approval
• A change management protocol describes
specific changes that the MAH would like to
implement during the lifecycle of the product
and how these would be prepared and
verified.
11
Change Management Protocols
Strategy
•Planned
studies
•Acceptance
criteria
•Methods
+ Results
Strategy
•Planned
studies
•Acceptance
criteria
•Methods
Early Step 1:
Currently
Evaluation of a proposed
variation as a ‘whole’
(Strategy + Results)
Approve the
protocol
Type II Variation
From E. Korakianiti, EMA
+ Results
Quick Step 2:
Implementation of
the change
Type IA or IB Variation
12
Change Management Protocols
Step 1: Introduction - Type II variation
• Some expectations:
– Description of the proposed change,
– Risk assessment of the impact of the change
– Description of the control strategy (including
elements of comparability exercise)
• Description and justification of the methods used to
evaluate the effect of the change and materials/samples
to be tested,
• Description of the studies to be carried out and the
acceptance criteria based on which the effect of the
proposed change will be evaluated.
– Process consideration
• Approach to process validation/evaluation
– Stability consideration
• Approach to stability verification
13
Change Management Protocols
Step 2: Implementation - Type IB variation
• Some expectations:
– Confirmation that results are in accordance with registered
change management protocol
– Provide assurance that based on these planned studies and
results, pre and post change products could be considered
as “comparable” (i.e. no need for further characterisation or
non-clinical/clinical studies)
– Process considerations:
• Confirm that no impact of change on downstream and
upstream steps
• Confirm that modified step as well as well as complete process
operate as expected
• Demonstrate that process (i.e. modified step as well as well as
complete process) is / would be capable of consistently
delivering product of the desired quality
– Stability considerations:
• Stability protocol + results as appropriate
14
Process change after MA
Change within registered design space(s)
• Application of design space:
– Cover one or more unit operation(s) or up to
complete process
– Implementation before or after MA
• Regulatory requirement:
– Proposed by Applicant, subject to regulatory
approval
– Working within the design space: not considered
as a change
15
Critical Quality Attributes
Controlled
QA
DESIRED
QUALITY
Unknown QA
QA
« under control »
16
Critical Quality Attributes
Where do you
draw the line ???
High risk
Do we need
a line ???
What is the most
appropriate tools???
QA
Low risk
17
Design space
…
Design space for Bioreactor
Bioreactor
CQA
Harvest
non-CQA
Column 1
CQA
Eluate 1
…
non-CQA
Drug
substance
CQA
non-CQA
CQAs used for design space ?
Process
parameters
CPP
CPP
CPP
non-CPP
non-CPP
non-CPP
Intermediate (e.g. harvest)?
Drug substance ?
18
Registration including design space(s)
S.4 –
Control of
drug substance
S.3 –
Characterisation
S.2.2 –
Description of
manufacturing
process and
process
controls
Design
space(s)
S.2.6 –
Process
development
What & Where to put the
information ???
S.2.3 –
Control of
materials
S.2.4 –
Controls of
critical steps and
intermediates
S.2.5 –
Process
validation and/or
evaluation
19
Registration including design space(s)
•
S.2.2 – Description of manufacturing process and process controls
–
–
–
–
Description of the manufacturing process and controls, including design space(s) where applicable
Less detailed description of step(s) covered by design space(s)? Scale?
Description of controls: CPP vs. non-CPP? CQA vs. non-CQA? Acceptance criteria vs Action/alert
limits? …
Description of the design space:
•
•
•
•
•
S.2.3 – Control of materials
–
–
•
Description of step(s) covered by the design space(s)
Description of input variables, process parameters and quality attributes covered by the design space(s)
Description of input material controls and process controls
Model representation (algorithm, summary…)? Combination of ranges?
Detailed information on input material controls (where applicable)?
CQA for starting material? raw materials? …
S.2.4 – Controls of critical steps and intermediates
–
–
Detailed information on about input material controls and process controls covered by the design
space(s)?
CQA of intermediate products (output)? CPP covered or not covered by the design space(s)?
MANUFACTURING PROCESS
DEVELOPMENT, EVALUATION & VALIDATION
S.2.6
Development
Evaluation
- Process development &
optimization
- Experimental up to
commercial scale
- Representative of
commercial process and/or
scale
- Appropriate number of
representative batches
- Development strategy
- CQA, CPP selection
- QRM
- Prior knowledge
- DOE, MVA / univariate
analysis, Interaction studies
- Lot/process filiation/history
- Comparability
…
DATA TO BE
SUBMITTED
FOR REVIEW
QUALITY
SYSTEM
S.2.5
Validation
- Commercial process &
scale
- Appropriate number of
commercial batches
- Evaluation of operating units
(including impurity clearance,
Reprocessing/ Back-up,
Storage/hold time, Column
lifetime, Compatibility with
equipment, Scalability,
Microbiology, Viral safety…)
- Evaluation of complete
process on batches
representative of commercial
process
CONVENTIONAL
ENHANCED
Q7
Q10
- Confirmation of
Consistency (in-process
and end product)
- Continuous process
verification
20
21
Registration including design space(s)
• S.2.5 – Process validation and/or evaluation
– Evaluation of process performance
• Clearance, hold time, column lifetime, viral safety…
• Justification of IPT and acceptance criteria
– Evaluation of the design space(s)
• Model verification (down scale model, continuous process
verification…) ?
– Evaluation of consistency:
• ≥3 full scale validation batches still required ?
• Relevance of small scale experiments?
• Continuous Process Verification: How to achieve?
22
Process change after MA
Change within registered design space(s)
• Some expectations…
– Process considerations
• Validated state
• Verification that process and process steps operate as
expected
• Maintenance of validated state and models
-> Continuous process verification protocol ?
– Comparability considerations
• Confirmation that does not negatively impact product Quality,
Safety and Efficacy
• Confirmation that models not impacted by process change
 ~ Change management protocol ?
– Stability considerations
• Stability maintained
 Stability protocol ?
23
Data registration
Data registered
More
flexibility
Evaluation
(~2-3 months)
Where do you
draw the line
???
Less
flexibility
Development
(~5-10 years)
Data available on site
Inspection
(~1 week)