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

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

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

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

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

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

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…

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

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)

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 ?

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.

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

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

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

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

Critical Quality Attributes Controlled QA QA « under control » DESIRED QUALITY Unknown QA

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

… … 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

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

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 - 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

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?

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 ?

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