An agency of the European UnionIFPAC, February 2010

Implementation of QbD and PAT-

EU Regulatory Perspective

Evdokia Korakianiti, PhD

Quality Sector, Chemicals European Medicines Agency

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Presentation Overview• Evolution of Quality

• Current status – QbD submissions in the Centralised Procedure– Issues commonly raised during assessment– Pre-approval inspections

• Activities to facilitate implementation in EU– Revision of existing Guidelines– Post-approval Change Management Protocols– Role of assessor and inspector– Areas for additional guidance– Knowledge transfer to Assessors & Inspectors– EU PAT Team

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Evolution of Quality

EMPHASIS ON PRODUCTPRODUCT AND MARKET

DRIVEN ORGANIZATIONSQUALITY BY TESTING

QUALITY BY DESIGNEMPHASIS ON SYSTEMS

KNOWLEDGE DRIVEN AND AGILE ORGANIZATIONS

INNOVATION

INSPECTION

PREVENTION

HOLISTIC

PPROCESS MONITORINGWASTE AND VARIABILITY

MINIMIZATIONDOING MORE WITH LESS

AGILITY

QUALITY CONTROL

QUALITY ASSURANCE

TOTAL QUALITY MANAGEMENT

LEAN, 6-SIGMA, TOC, SYSTEMS THEORY,FLEXIBLE - AGILE MANUFACTURING

USE O

F STATISTIC

AL

TOO

LS INC

REA

SED

KN

OW

LEDG

EIN

CR

EASED

VAR

IAB

ILITY R

EDU

CED

QU

ALITY

IMPR

OVEM

ENT

APPROACH GUIDING PRINCIPLE RESULT

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ICH Vision

Develop a harmonised pharmaceutical quality system applicable across the life cycle of the product emphasising an integrated approach to quality risk management and science

Guidelines: ICH Q8, Q9,Q10 and draft Q11

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Quality by Design

• Quality should be designed and not tested into a product, which is too late too costly and inefficient

• Development is no more isolated and is living across the lifecycle of the product

• The new Paradigm to Quality is based on science, risk management tools and the establishment of an efficient Quality System.

• An integration of these three elements should enhance the process for ensuring quality and facilitate continual improvement.

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Implementation of ICH vision in EU

Build knowledgeIdentify knowledge gaps

Share Knowledge

Interactions with Industry Evaluation of applicationsContacts with EU PAT team

Workshops with Industry Expert meetings

Guidance developmentTraining

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Implementation of ICH vision in EUThe pursuit of Quality is a never ending journey

Quality by Testing

Quality by Design

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Implementation of ICH vision in EU

Current status with regards to submissions and inspections

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QbD submissions in the Centralised Procedure

• Some applications with QbD and / or PAT elements have already been received by the Agency and the numbers are slowly, but steadily increasing

• It seems that the companies that have received approval for one product are quickly implementing the QbDapproach across several of their products

• No of submissions received so far

• Initial MAAs: 16

• Post-authorisation: 4

• Sci. Advice requests: 2

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QbD submissions in the Centralised Procedure

•Design Space for one or multiple steps: 13

•Design Space coupled with RTR testing: 4

The vast majority of these submissions come from Big Pharma and refer mainly to chemical active substances

(NCE: 15, BIO: 1)

BUT there is strong interest from the BIO side and initial discussions with smaller companies show that they are studying how to implement a QbD approach, but it might take some time before we receive MAAs

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Issues commonly raised during assessment

Risk assessment:

• Minimal or no data to justify scoring of variables in a FMEA

• No justification for the selection of variables for further study.

• Often only the R/A conclusions are presented with no explanation about how have they have been reached

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Issues commonly raised during assessmentDesign Space (DS):

• How have the critical parameters been established?

• DS in most cases is developed at lab/pilot scale. Validity at production scale? And /or during the lifecycle?

• Information about interactions between the factors under study?

• Verification of DOE results?

• DS boundaries not clearly described (which parameters consist the DS and their ranges)

• Ranges investigated in lab scale not corresponding with the DS boundaries with no further explanations

• Clinical relevance of DS

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Issues commonly raised during assessment

NIR of on-line or at-line testing

• Questions on method development and validation

• composition of training set for the creation of calibration model, for cross-validation and independent validation corresponding goodness of fit and goodness of prediction,

• pre-treatment data used.

• How will the model validity be verified through the product lifecycle?

• What change constitutes a variation and what a necessary model update (GMP)?

Questions on the use of MVDA for MSPC

• Similar with the above

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Issues commonly raised during assessment

Post-approval flexibility:

Proposals for post approval flexibility had to be rejected, since the former Variations Regulation did not foresee such cases

Terminology

Sometimes applicants use their own terminology different from the ICH one, causing confusion to assessors

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Pre-approval inspections

Usually when RTR is involved.

Up to now 3 pre approval inspections have been performed (one jointly with FDA)

Example of an Inspection request:

– Implementation of an adequate batch record review and verification of CPPs that will replace end-product testing

– Batch release procedures

– GMP management system

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Pre-approval inspections• The Inspector needs an understanding of:

– Relevant PAT analytical techniques (applications and limitations of techniques (e.g. NIR) , data handling and interpretation, operation of analytical instruments, comparability of instruments, method validation aspects

– DOE, Multivariate Data Analysis, Risk Assessment methods– Relevant ICH and QWP guidelines (ICH Q8-10, real time

release, NIR, etc)– A thorough understanding of the application (the issues

raised, the assessors’ concerns)

• Interaction and close collaboration between Assessor and Inspector is fundamental

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• Important is the borderline between assessment and inspection,

• We cannot expect an inspector to evaluate MVDA models during the inspection

• Or to review raw data (unless there is a specific concern)

• The Inspector will mainly focus on system related issues e.g. how the DS is implemented in batch records, how excursions from DS are handled, MVDA model lifecycle (change management), validation etc

Pre-approval inspections

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Implementation of ICH vision in EU

Build knowledgeIdentify knowledge gaps

Share Knowledge

Interactions with Industry Evaluation of applicationsContacts with EU PAT team

Workshops with Industry Expert meetings

Guidance developmentTraining

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Activities to facilitate implementation in EU

• Revision of existing relevant Guidelines

• Framework that enables post-approval regulatory flexibility

• Areas for additional Guidance have been identified

• Activities to facilitate transfer of knowledge to the network of Assessors and Inspectors

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Revision of existing Guidelines

• Use of Near Infrared Spectroscopy (NIRS) by the Pharmaceutical Industry and the Data Requirements for New Submissions and Variations (EMEA/CHMP/CVMP/WP/17760/2009 Rev 1)*

• Parametric release (CPMP/QWP/3015/99 ), Concept paper on the proposed revision(CHMP/QWP/569959/2008 )*

*http://www.ema.europa.eu/Inspections/QWPGL.html

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Post-approval regulatory flexibility• Annex II of Regulation (EC) N° 1234/2008

• A Post-approval 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.

• They are means to facilitate post-approval regulatory flexibility for all types of products (NCEs + BIO) and applications (traditional and QbD).

• BUT their full potential (risk-based protocols) is expected to realize setting

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Post-approval Change Management Protocols

+

Strategy•Planned studies

•Acceptance criteria

•Methods

Results +

Strategy•Planned studies

•Acceptance criteria

•Methods

Results

CurrentlyEvaluation of a

proposed variation as a ‘whole’ (Strategy +

Results)

Early Step 1:Submission of

a Protocol

Quick Step 2:Implementation of

the change

Type II Variation or in initial MAA

Type IAIN or IB Variation

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Post-approval Change Management Protocols

•It’s a new concept and experience is needed with regards to: – Scope of the changes

–Can the applicants submit protocols for any type of changes? Is there a need to restrict their scope initially? QWP seems to be taking a wide approach

– Content.–Types of studies to be included in the protocol

– Amount of data in the protocol. –How to ensure that the proposed strategy is robust and that the effect of the change on product quality can be accurately predicted.

•There is ongoing work at QWP and BWP level

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Role of assessor and inspector

• Need to bring down the silos and increase collaboration

• It’s crucial to improve the flow of informationbetween them

• Assessment Reports Guidance

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Areas for additional guidance

• Level of info in a dossier for :

– Design Space development and scale up (narrative description vs data)

– Level of info in a dossier for R/A– RTR requirements– MVDA models for MSPC

• Acceptance criteria for large sample sizes (ongoing work from EDQM)

• Management and maintenance of MVDA models

• QbD and analytical development

• Continuous processing

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Knowledge transfer to Assessors & Inspectors

•Training and Guidance documents

– ICH WG Q&As– Activities within Quality and Biologicals Working Parties – Joint meetings QWP and GMP/GDP IWG– Training of Assessors (2 trainings for assessors and

Inspectors focused on QbD /PAT, ICH WG training in 2009)– Guidance for drafting Assessment Reports– Peer review

•Interactions with Industry

– EMEA-EFPIA Design Space (2006) and ‘Quality by Design' (2009)Workshops

– Mock Inspections– Mock submissions

• EU PAT Team

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EU PAT Team

General objective:

• Prepare a harmonised approach within EU on assessment of applications and performing GMP inspections of systems/facilities for Process Analytical Technology, including quality by design principles and manufacturing science in the context of PAT for Human and Veterinary products.

Composition:• Assessors and GMP inspectors and BWP members• EDQM-observer• Support from EMEA secretariat

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EU PAT Team activities

• Advice to Industry

• Publication of Q&As

• Training

• Scientific advice

• Participation at ICH activities (IWG Q8, 9, 10)

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Conclusions• ICH Q8-9-10 concepts are still relatively new

• Issues keep arising as experience is gathered

• Assessors are requested to evaluate new types data –Need for appropriate expertise

• Guidance documents are being drafted/revised

• Training is organised

• EU is actively participating in the ICH IWG activities to ensure a harmonised approach in the implementation

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Thank you for your attention!

Questions?