Update on FDA-EMA QbD Pilot Presented by: Sharmista Chatterjee, PhD Branch Chief (Acting) Office of Process & Facility Office of Pharmaceutical Quality CDER, FDA Dolores Hernán, PhD Quality Office Specialized Scientific Disciplines European Medicines Agency
Presentation Overview FDA-EMA QbD Pilot Aim Scope Submission Process Communication timelines Q&As FDA-EMA Collaborative Research on QbD for Analytical Methods Next steps Concluding remarks 1
FDA-EMA Parallel Assessment Pilot Announced in March 2011 http://www.fda.gov/downloads/drugs/developmentapprovalprocess/howdrugsaredev elopedandapproved/ucm248526.pdf http://www.ema.europa.eu/docs/en_gb/document_library/other/2011/03/wc500103 621.pdf Build on other harmonization programs FDA-EMA Joint Inspection Program Parallel FDA-EMA Scientific Advice Program Extended for 2 more years in March 2014 Applications can be accepted till March 2016 Japan participating as observer 2
EMA-FDA QbD pilot Aim Allow EU and US assessors exchange their views on the implementation of ICH Q8-Q10 using actual applications and facilitate harmonisation. Share knowledge gained with the EU network and Industry through lessons learnt. Scope Submissions that include an enhanced approach to pharm. development leading to at least one of the following: Design Space, PAT tools for control, Continuous process verification, Models to support real time release testing Continuous processes Post-approval regulatory flexibility 3 3
Participation Participation in the pilot is voluntary. Standard EMA and FDA submission requirements apply. Types of applications: MAAs/NDAs Type II Variations/sNDAs Scientific Advice/CMC meeting requests 4
Modalities: 2 options Parallel assessment: 1 application completed The application is submitted to both agencies at the same time, for parallel evaluation by both agencies. Consultative advice: 9 completed Several on-going The application is submitted to either EMA of FDA, and the agency doing the evaluation requests to obtain consultative advice from the other agency. The application is submitted to both agencies but NOT at the same time. Type of products Chemicals There are some informal interactions on biologicals as well. The legal EMA and FDA submission requirements apply 5 5
Process for Submission to the Pilot Parallel Assessment Interested applicants and sponsors should notify both agencies in writing three months prior to submission of an application. Application is submitted for assessment concurrently to both agencies: FDA: newdrugcmc@fda.hhs.gov EMA: qbd-pilot@ema.europa.eu Consultative Advice Application is submitted to only one agency. Depending of the precedence setting nature of the QbD elements in the application, the reviewing agency seeks consult from the other agency. * US specific: applicants need to provide a letter allowing sharing of trade 6 secret and confidential information between agencies.
Communication Timelines for Parallel Assessment Evaluation Days (Standard) Clock Stop 35 60 80 110- Day 150 180 115 120 Clock Stop 210 Opini on NDA Receipt Initial TCdiscuss review and inspection Interim TC TC Discuss IR/ LoQs Exchange Draft Reviews and Questions List of Questions/ Information Requests Sent to Applicant Applicant Response Exchange Comments, Discuss Deficiencies via Telecon Complete & Exchange Review of Applicant Responses EMA-FDA Lessons Learned Telecon Review Month Standard) 1 2 3 4 5 6 7 8 9 10 Post Action Filing Meeting 74 Day Letter Midcycle Meeting 7 Primary Review Completion Target Action Date 7
Communication Timelines for Consultative Advice Triggered by the Agency that has received the application. Timelines defined by the Agency receiving the application, upon consultation with the other Agency. The other agency: -Peer reviews AR/LoQ/IR. -Attends review discussions and provides input. -Attends meetings with applicants as an observer. 8
Outcome One of the projected outcomes of the pilot: Joint presentations of key findings will be presented publically through conferences and/or publications, as appropriate Findings have been jointly presented via: Multiple international conferences Three Q&A documents 9
Q&A Documents Jointly published by both EMA and FDA Based on learning's from the first parallel assessment application Includes comments from PMDA Objective: To serve as a reviewer guide Communication to industry/academia Method of publishing: FDA : Web updates EMA : Press release Publication timelines: Q&A Set (1) published on Aug 20, 2013 Q&A Set (2) published on Nov 1, 2013 Q&A Set (3) published on Dec 19, 2014 10
Q&A (1) QTPP and CQAs Include in the submission: A list describing the QTPP of finished product and a rationale that links it to the intended use of the product (e.g. target patient population); CQA of drug substance and drug product and its role in the control strategy Criticality Based on impact (severity) not on the residual risk after the implementation of the control strategy Use only ICH supported terms Level of detail in manufacturing process descriptions The manufacturing process description should be adequately detailed and include all relevant parameters (both critical and non critical) with their target values or ranges. Describe steps in a sequential manner including batch size(s) and equipment type http://www.ema.europa.eu/docs/en_gb/document_library/other/2013/08/wc500148215.pdf 11
Q&A (1) Cont. QbD for Analytical Method Analytical Target Profile acceptable as a qualifier of method performance. Not acceptable to switch between methods that have same ATP but different operating principles, without any regulatory over sight. Requirements to justify and support a MODR (Method Operable Design Region) is similar to that of a Design Space. This would include data to support proposed MODR ranges/conditions and demonstration of statistical confidence throughout the MODR. 12
Design Space verification Q&A (2) Includes discussions on: Necessity of verification of design space over the product life cycle Typically, initial verification of design space at commercial scale occurs at or near the target operating ranges Approach to verify a design space, dependent on: Risk of scale up Ability of control strategy to detect potential product failures Documentation of plan for design space verification FDA expectation is that plans be available at the manufacturing site EU expectation is that a protocol for design space verification be included in the dossier http://www.ema.europa.eu/docs/en_gb/document_library/other/2013/11/wc500153784.pdf 13
Q&A (3) Level of detail regarding Risk Assessment (RA) Factors considered to determine requested level of detail include: significance of the outcome of the RA to the control strategy, complexity of the dosage form, amount of commercial scale data available at the time of submission. For example RA to identify parameters in order to establish a design space is considered of high significance. Level of detail regarding Design of Experiments (DOEs) and Design Space Level of detail for a DOE commensurate with significance of outcome of DOE to define the control strategy. Level of detail for a design space is dependent on significance of the design space and its extent. Mathematical regression model to define a design space is not always needed. 14 http://www.ema.europa.eu/docs/en_gb/document_library/other/2014/12/wc500179391.pdf
FDA-EMA Collaborative Research on QbD for Analytical Methods Joint research with FDA s laboratory/review divisions and EMA Initiated in January, 2013 Goal of this project is to: Develop analytical methods (e.g. HPLC) based on QbD paradigm. Define protocols for method transfer. Establish methodology for validation of MODR upon site transfer. Define review criteria for evaluation of QbD based analytical methods. 15
Next Steps Ongoing work to make the process easier for applicants and assessment / review teams. Several consultative advice applications ongoing, including Newer/novel technologies Continuous manufacturing Additional Q&A will be drafted if needed based on learnings from on-going consultative advice applications. 16
Concluding Remarks Are we there yet? No, BUT progress is being made. Very useful interactions. Pilot: established platform for continuous dialogue between the Agencies. Process improvements to facilitate interaction with Industry during the pilot process already in place for the next application. What is the benefit for industry? Short term: Unrealistic to expect full convergence, e.g. 100% harmonisation in IR/LoQs at once, but some convergence was reached already. Lessons learned at the end of each evaluation to be made public Share knowledge; better guidance on how to prepare dossiers. Long term: Harmonization in regulatory requirements, where possible. What to expect, when being part of the pilot? No procedural delays in approval timelines due to quality / CMC issues. The pilot is resource intensive for Regulators. Need for flexibility in providing responses to the Agencies (the regional RA departments in companies need to coordinate). 17
To discuss your new drug QbD submission in US: Contact the Clinical Division and/or CMC Project Manager to request a meeting Address general questions to: newdrugcmc@fda.hhs.gov 18
Acknowledgements: EU PAT Team: J-L Robert, K.Pugh, EU PAT Team EMA: E. Korakianiti, A.M. Van Nederkassel US FDA: C. Moore, D. Henry, ONDQA staff 19
Thank you for your attention! 20