Implementation Activities for Qb D EU PAT Team

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

1 Council of 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 – Scientific resources: 27 member states http: //www. ema. europa. eu

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 COMP Committee of Orphan Medicinal Product PDCO Paediatric Committee HCMP 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 (Ph. WP) Safety Working Party (SWP) Pharmacogenomics Working Party (Pg. WP) + Specific ad-hoc working groups or subgroup meetings when needed

5 European Medicines Agency (EMA) GMDP IWG EMA Inspection sector 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 Qb. D, • Discussion/advice to several pharmaceutical companies on Qb. D/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 Q 5 E) + 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 complete process operate as expected • Demonstrate that process (i. e. modified step 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 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 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: • • • 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)?

MANUFACTURING PROCESS DEVELOPMENT, EVALUATION & VALIDATION S. 2. 6 Development Evaluation Validation - Process development & optimization - Experimental up to commercial scale - Representative of commercial process and/or scale - Appropriate number of representative batches - Commercial process & scale - Appropriate number of commercial 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 - 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 Q 7 Q 10 - 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)