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