0. Implementation Activities for QbD: EU PAT Team
WCBP CMC Strategy Forum
Washington, 19 July 2010
Kowid HO
Afssaps, France

1. Council of Europe http://www.ich.org/cache/compo/276-254-1.html
European Directorate for the
Quality of Medicines
& health care (EDQM)
STRASBOURG
47 member states
European Pharmacopoeia
Strasbourg
European Union
Commission
(DG enterprise & industry)
BRUSSELS
27 member states
European Medicines Agency (EMEA) London

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
Scientific resources: 27 member states

3. European Medicines Agency (EMA)
EMA Inspection sector
CVMP
Committee for Medicinal Product for Veterinary use
CHMP
Committee for Medicinal Product for Human use
EMA Scientific
Committees
PDCO
Paediatric Committee
CAT
Committee for Advance Therapy
COMP
Committee of Orphan
Medicinal Product
HCMP
Committee for Herbal Medicinal Product

4. European Medicines Agency (EMA)
Vaccine Working Party (VWP)
Similar Biological (Biosimilar)
Medicinal Products Working Party (BMWP)
Biologics Working Party (BWP)
Blood Product
Working Party (BPWP)
Quality Working Party (QWP)
Joint CHMP/CVMP
Cell-based Products Working Party (CPWP)
Patients' and Consumers'
Working Party (PCWP)
CHMP
Gene Therapy
Working Party (GTWP)
Efficacy
Working Party (EWP)
Scientific Advice (SAWP)
Pharmacovigilance
Working Party (PhWP)
Pharmacogenomics Working Party (PgWP)
Safety Working Party (SWP)
+ Specific ad-hoc working groups or subgroup meetings when needed

5. European Medicines Agency (EMA)
EMA Inspection sector
GMDP IWG
PAT TEAM
BWP
SAWP
QWP
EMA Scientific
Committees
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
Strategy
Planned studies
Acceptance criteria
Methods + +
Results
Results
Early Step 1:
Quick Step 2:
Approve the protocol
Implementation of the change
Currently
Evaluation of a proposed variation as a ‘whole’ (Strategy + Results)
Type II Variation
Type IA or IB Variation
From E. Korakianiti, EMA

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 QA
« under control »
DESIRED
QUALITY
Unknown QA

16. Critical Quality Attributes
High risk
Where do you draw the line ???
Do we need
a line ???
What is the most appropriate tools??? QA QA QA QA QA QA QA QA QA
Low risk

17. … … Design space CQAs used for 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 ?
Intermediate (e.g. harvest)?
Drug substance ?
Process parameters
CPP
CPP
CPP
non-CPP
non-CPP
non-CPP

18. Registration including design space(s)
What & Where to put the information ???

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:
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?
S.2.3 – Control of materials
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)?

20. MANUFACTURING PROCESS DEVELOPMENT, EVALUATION & VALIDATION
- Representative of commercial process and/or scale
- Appropriate number of representative batches
- Commercial process & scale
- Appropriate number of commercial batches
- Process development & optimization
- Experimental up to commercial scale
- Development strategy
- CQA, CPP selection
- QRM
- Prior knowledge
- DOE, MVA / univariate analysis, Interaction studies
- Lot/process filiation/history
- Comparability …
- 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
- Confirmation of Consistency (in-process and end product)
- Continuous process verification
DATA TO BE SUBMITTED FOR REVIEW Q7
Q10
CONVENTIONAL
ENHANCED
QUALITY SYSTEM

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. Where do you draw the line
Data registration
Data registered
More
flexibility
Evaluation
(~2-3 months)
Where do you draw the line
???
Less
flexibility
Inspection
(~1 week)
Development
(~5-10 years)
Data available on site