An agency of the European Union
Summary EMA activities
Francesca Luciani, ISS, Italy, Steffen Gross, PEI, Germany & Mats Welin, MPA, Sweden
Major issue affecting EU work 2019
Move of EMA from London to Amsterdam March2019
Business continuity plan affects activities outside of product-related core-business (i.e. handling of new MAAs, post authorisation procedure and scientific advices) such as guideline development & stakeholder engagement
What is then still on-going?
• EU contribution to ICHQ12
• Preparation of a Guideline on quality requirements of medicinal products containing a device component for delivery or use of the medicinal product (H)
• Public consultation (until July 2019): Quality, non-clinical and clinical aspects of medicinal products containing genetically modified cells
• PRIME/ Breakthrough Therapies workshop ( Nov 2018) with FDA and Industry report preparation and follow-up ongoing
Prime/ Breakthrough therapies workshop
Meeting held at EMA, London on 26 November 2018
Scope: Small molecules & Biotech including cell/ gene therapies
Numbers of participants: 110 (38 EMA/EU, 7 FDA, 1 PMDA, 64
Industry representatives/companies including SMEs (PRIME &
Breakthrough Applicants))
Regulatory presentations and case studies followed by discussions
Live broadcasted- appr. 2400 viewers.
Video recordings & meeting report in preparation
Material including presentations can be found here:
https://www.ema.europa.eu/en/events/stakeholder-workshop-
support-quality-development-early-access-approaches-such-prime-
breakthrough
Topics discussedBackgroundProcess validationControl strategiesGMP-considerationsSplit sessions: • Biologics: Case studies on process validation/
control strategy, Comparability, Stability• Small molecules: Control strategy, StabilityRegulatory tools to support expedited approvalSummary and path forward
Selected observations
Challenges: e.g. limited manufacturing and clinical experience, too few batches to assess consistency, process and method validation studies not finalized and understanding of criticality and interactions may still not be mature
Qualification in line with ICH Q3A/B and ICH Q6 is a challenge. Small molecules and Biotech differ. Prior knowledge important factor.
Performance based and intelligent control strategies?
Platform stability proposal for monoclonals based on prior knowledge
Biosimilarity
Biosimilar development - & Manufacturing changes - need consistent regulations
Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (EMA/CHMP/BWP/247713/2012)
• Quantitative ranges should be established for the biosimilar comparability exercise, where possible. These ranges should be based primarily on the measured quality attribute ranges of the reference medicinal product..”
• “A descriptive statistical approach to establish ranges for quality attributes could be used, if appropriately justified”
• “The ranges identified before and after the observed shiftin quality profile could normally be used to support the biosimilar comparability exercise at the quality level, as either range is representative of the reference medicinal product.”
Some challenges
Reference Medicinal Product for Quality biosimilarity comparability
study
• side-by-side comparability EEA sourced Reference Product
• non-EEA sourced Reference Product as supportive information (for establishment of the QTPP for the Reference Product); regulatory authority with similar scientific and regulatory standards as EMA
• Demonstration of EEA and non-EEA sourced Reference Product comparability is under the Applicant’s responsibility
Sampling
• Batches representativeness
– Is random sampling possible?
• Sample size
Statistic tools
Statistical considerations
Workshop on the reflection paper on statistical methodology for the comparative assessment of quality attributes in drug development (3-4 May 2018 @EMA)
• EMA, FDA and Industry
• Definition of allowable differences (in quantitative terms) still missing – CQA related?
– Right balance between type I and Type II errors: flexibility vs rigorous scientific standards
– Reference material batches variability
– Statistics cannot be still a decisive method for regulators
– https://www.ema.europa.eu/en/events/workshop-reflection-paper-statistical-methodology-comparative-assessment-quality-attributes-drug
Consensus on statistical considerations
After considering public comments, in June 2018 FDA Withdraws Draft Guidance for Industry: Statistical Approaches to Evaluate Analytical Similarity
• Future draft guidance will reflect state-of-the-art techniques in the evaluation of analytical data to support high similarity to a reference product.
• Among main challenges– recommended number of reference product lots to be sampled
& statistical methods to be used
– choice of appropriate methods to evaluate analytical data to account for potential lot-to-lot variability of the reference product.
– appropriate flexibility for sponsors to allow efficient development along with rigorous scientific standards
Outline
- Variations (TT, procedures, classification)
- ICH Q12 tools
- continuous manufacturing/RTRT
- process validation
- single use equipment (leachables and extractables)
Flexibility in regulatory submissions
Continous manufacturing/RTRT
Proposed timetable
It is anticipated that the draft guideline will be released for consultation in the first quarter
of 2012, followed by a 6 month external consultation period prior to finalisation of the
document.
Guideline on process validation
Little detailed requirements given in current regulatory GMP-Guidelines
Create the your own supporting documents (e.g. specifications) on the basis of guidelines on primary packaging materials & containers, e.g.
Ph. Eur., USP EMA -Notes for GuidanceEU-GMP-Guide, Parts I & II
Industry based documentsBPSA- Guides availablePDA & ISPE working on documents for SUS-technology
Guidance Single Use Systems
Requirement for close interaction assessors-inspectorsAssessment: stronger focus on IPC
Existing Existing GMPGMP ’’ss
Quality by Design(Pharmaceutical
Development)
Quality Risk Management
The Regulatory Quality System
Quality Systems
Quality Systems (Q10)
Quality Risk Management
(Q9)
Quality by Design
(Q8)
Development and Manufacture
Development and Manufacture
(Q11)
Interaction assessors-inspectors