QbD: A Global Implementation

Perspective
The EU Perspective

Riccardo Luigetti, EMEA

The Siena Conference on Product and Process

Optimization
6 October 2008

The views presented in this presentation/these slides are those of the author and should not be understood or quoted as being made on behalf
of the EMEA and/or its scientific committees
 Overview of the Presentation
• QbD: The EU Vision
– Available regulatory tools
– Different approaches to pharmaceutical
development
– Benefit for industry and additional opportunities
• Implementation of QbD in the EU
– The Regulatory System in the EU
– EU PAT Team
– Work Sharing Project
ICH Q8/9/10/(11) – A New Vision

“Develop a harmonised pharmaceutical

quality system applicable across the
lifecycle of the product emphasizing an
integrated approach to quality risk
management and science”
Brussels, 2003
 Quality by Design
• Quality: The suitability of either the drug substance or drug product
for its intended use. This term includes such attributes as the identity,
strength, and purity (from ICH Q6A and ICH Q8)
• Quality by Design: A systematic approach to development that begins
with predefined objectives and emphasises process and product
understanding and process control, based on sound science and
quality risk management (from ICH Q8 annex, step 3)
• Process Analytical Technology (PAT): A system for designing,
analysing, and controlling manufacturing through timely
measurements (i.e., during processing) of critical quality and
performance attributes of raw and in-process materials and
processes with the goal of ensuring final product quality (from ICH
Q8)
• QbD approaches often need the use of Process Analytical
Technology (PAT) tools; PAT is an enabling tool to a more systematic
approach to pharmaceutical development (QbD)
 Current vs Desired State
Current State
• Pharmaceutical products marketed in the EU
are of good quality (quality itself is not an
issue) but pharmaceutical development and
manufacturing can be improved
Desired State
• Enhanced product and process
understanding through enhanced, Quality by
Design approach to pharmaceutical
development
 Regulatory Tools
• ICH Q8 – Pharmacutical Development (Implemented)
• ICH Q8 annex (step 3 of the ICH process – public
consultation)
• ICH Q9 – Quality Risk Management (step 5 – regional
implementation)
• ICH Q10 – Pharmaceutical Quality System (step 5 – regional
implementation)
• ICH Q11 – Development and Manufacture of Drug Substances
(step 1 – concept paper)
• Q/As from the ICH Q8-9-10 Implementation working Group
clarifying concepts in the guidelines e.g. Pharmaceutical
Quality Systems, Knowledge Management, Design Space,
Real Time Release, Control Strategy (early draft to be
discussed at ICH meeting in Brussels beginning of November
2008)
 ICH Q8 – Approaches to
Pharmaceutical Development
Minimal approach Enhanced, QbD approach
• Empirical development • Systematic approach to development
• One variable at a time • Multivariate experiment
• Fixed manufacturing • Manufacturing process adjustable
process within the design space
• Focus on reproducibility • Focus on control strategy and
• Off-line analysis robustness of the process
• Quality assured by • PAT tools utilised for feed forward and
testing feed back process control
• Reactive lifecycle • Risk based control strategy (Real Time
management (corrective Release)
actions) • Preventive lifecycle management (and
continual improvement)

9 The enhanced approach leads to enhanced product and process

understanding
9 Both approaches (and everything in between) are acceptable, QbD is
preferable and provides the basis for flexible regulatory approaches
 QbD: Benefit for Industry

• Better understanding of the process

• Less batch failure
• More efficient and effective control of
change
• Return on investment/cost savings
 QbD: Additional Opportunities for
Industry
• An enhanced, QbD approach to pharmaceutical
development provides opportunities for more
flexible regulatory approaches, for example:
– Risk-based regulatory decisions (assessment and
inspections)
– Manufacturing process changes within the approved
Design Space without further regulatory review
– Reduction of post-approval submissions
– Real-time quality control, leading to a reduction of
end-product release testing (Real Time Release)
 Design Space
• Design Space: The multidimensional combination
and interaction of input variables and process
parameters that have been demonstrated to provide
assurance of quality (ICH Q8)
• DS defines a multidimensional space; once a DS
has been authorised, movements within the DS are
not considered a change from a regulatory point of
view (no variation to be submitted)
• This is accepted in the EU and it has been
recognised in the recently adopted revised
Variations Regulations
 EMEA and the Regulatory System
in the EU
• EMEA is not the European FDA
• EMEA co-exists with over 40 National Competent
authorities in the EU/EEA, forming an integrated
network
• The centralised procedure (EMEA) for Marketing
Authorisation co-exists with MA procedures at
national level (national procedures, de-centralised
procedures, mutual recognition procedures)
• EMEA co-ordinates the existing scientific resources
in Member States and provides an interface
between all parties
• EMEA works towards harmonisation of regulatory
and technical requirements within the EU
 EU PAT Team
• Mandate (general objective)
– A forum for dialogue and understanding between Quality
and Biologics Working Parties and GMDP Inspectors
Working Group to prepare a harmonised approach in
Europe on assessment of applications and inspections of
products/systems/facilities for Process Analytical
Technology, including Quality by Design principles and
manufacturing science in the context of PAT
• Composition
– Chair; 5 quality assessors (chemicals and biologicals); 4
GMP inspectors; chairs of the QWP, BWP and GMDP
IWG; observer from EDQM; EMEA staff (4).
– 1 delegate only (either quality assessor or GMP inspector)
per involved country
– Representation to cover both human and veterinary
products expertise
 EU PAT Team Activities
• 4 meetings/year
• Liaison with a number of companies, equipment
manufacturers and PAT topic groups, including
biologicals
• Liaison with FDA (Teleconferences)
• Participation to workshops e.g. Design Space
Workshop (May 2006), Workshop on PAT for
Biologicals (March 2007), Seminar on Quality by
Design/PAT (April 2008)
• Site visits to manufacturers using PAT techniques
• Training of assessors and inspectors
 EU PAT Team: Progress to Date
• Published documents:
– PAT Q/As: clarifying regulatory requirements for changes to the
manufacturing process when PAT use is implemented
– Reflection Paper on PAT related information in the MA dossier
• A mock (CTD P.2) submission (examplain) for a QbD/PAT
finished product application has been discussed with industry
and published by EFPIA
• Input to QbD/PAT applications in the Centralised Procedure
and in the context of the Work Sharing Project
• Input to future PAT applications by discussion with applicants
• Training for assessors and inspectors (Sep 2004/Jan 2006)
 EU PAT Team: Ongoing Activities
• Continue and build the existing dialogue with
companies on both general and product-related
issues
• Further develop existing expertise
• Work with industry on a mock (CTD S.2) submission
for a QbD/PAT biotech active substance application
• Develop guidance for assessors, inspectors and
applicants on:
– Impact of PAT on batch release
– Impact of PAT on assessment of quality
– Impact of PAT on inspection practise
 Other Ongoing Related Activities

• Revision of the NIR Guideline

• Revision of the Parametric Release
Guideline (to take into account RTR
concepts)
 Work Sharing Project
• The Work Sharing Procedure for PAT Variations to Nationally
Authorised Products was published in June 2006
• Describes an approach for work sharing between NCAs in the EU
• Has been developed for QbD/PAT related variations to nationally
authorised products
• Before the procedure was published, companies were coming to
EMEA identifying difficulties in dealing with purely national variations
• Dealing with QbD/PAT variations at national level was perceived by
companies as a major barrier to introduction of QbD and/or PAT
techniques
• The procedure is co-ordinated by EMEA and aims at pooling and
using the best available expertise in the EU on QbD/PAT
• The procedure is not legally binding, however, it has been agreed by
the Head of Medicines Agencies and EMEA
 WS Project: Results
• 3 applications were assessed within the
project, involving the EU PAT Team
• All the applications were successfully
finalised
• RTR was authorised for one product within
the project, based on combination of
extended knowledge of the process, use of
information obtained using PAT techniques
and use of conventional information
 Conclusion
• QbD approach is supported by the regulatory community in the
EU
• Appropriate regulatory tools, developed in the ICH context, for
the implementation of QbD are available; others are under
development
• QbD implementation in the EU is ongoing; however,
applications including QbD and PAT elements have been
already authorised both in the centralised procedure and within
the work-sharing project (variations to nationally authorised
products)
• The Design Space concept is now included in the EU
legislation
• The PAT Team is the key for implementation of QbD in the EU
 WEB References

• PAT page (EMEA website):

http://www.emea.europa.eu/Inspection
s/PAThome.html
• QWP page (EMEA website):
http://www.emea.europa.eu/Inspection
s/QWPhome.html
Thank you for your attention!

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