Quality by Design A modern Systems Approach An Industry perspective

1
Quality by Design A modern Systems ApproachAn
Industry perspective

• Dr John C Berridge
• Senior Regulatory Consultant
• Pfizer

2
QbD Presentation Outline

• Where did Quality by Design originate?
• What?
• When?
• Why?
• Conclusions

The views expressed in this presentation should
not be taken as an official EU Industry
position!
Topics for further consideration during the
workshop
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Why QBD? July 2003 An ICH vision
Our vision The future Pharmaceutical Quality
System
For companies with
Quality Risk
1.
Good design and
Management
The Regulatory
control strategies
Quality System
(Q9)
2.
Good Risk
Management strategies
Quality Risk
Management
3.
Good Quality Systems
Quality by Design
Quality
(Pharmaceutical
Development)
by Design
Quality
(Q8)
Systems
Quality
Existing
Existing
GMP
GMP


s
s
Systems
(Q10)
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Tremendous Opportunity
Pharmaceutical Development Quality by Design Q8
Quality Risk Management Q9
Modern Effective Pharmaceutical Quality
Systems Q10


Lower Risk Operations Innovation and Continual
Improvement Optimized Change Management
Process Flexible Regulatory Approaches
GPM
5
Perhaps our vision should be updated?
Our vision Quality By Design
Quality by Design
For companies implementing Quality by Design
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Systems and QbD
Pharmaceutical Development Quality by Design Q8
Quality Risk Management Q9
Modern Effective Pharmaceutical Quality
Systems Q10


QbD Systematic approach to pharmaceutical
development and product lifecycle
management. J-L Robert Jan 2007
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Our Industry 2006/7 ICH Vision is a QbD vision

• Pharmaceutical and Manufacturing Sciences leading
  continuous product and process improvement
• A transparent, science- and risk-assessment based
  approach to product development, dossier
  submission, review, approval and post-approval
  changes
• Manufacturers empowered to effect continual
  improvement throughout the product life-cycle and
  supply chain
• Efficient, effective and consistent Regulatory
  oversight
• Across and between regions
• With the level of process and product
  understanding and quality systems

What are the gaps? How can they be addressed?
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What is QbD?
Procedures
Process
Integrated, systematic and scientific approach to
design, development and delivery of performance
attributes that ensure consistent delivery of
specific quality, safety and efficacy objectives.
People
Facilities Equipment
Product
How many components and dimensions?
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Quality by Design - a life-cycle activity
Ph 1 Ph II Ph III -NDA-
Commercial Manufacture
Product Enhancement
Target Product Profile Product Design
Process Design
Process Performance
Material Science API Development
Continuous Process Verification
Process Development Tech Transfer
Product Development
Continual Improvement
Quality Risk Management
People, Equipment and Facilities
Knowledge management
Process Analytical Technology????
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When QbD?
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Are we doing QbD now?Yes at least in part.

• Which Attributes?
• Consensus decisions
• Draw on prior experience
• with unit operation
• Draw on current state of
• knowledge
• Focus on the Voice of
• The Customer
• DP as a customer of API

• Which Prameters
• Cause and Effect Matrix
• with Effects focused on
• KQAs
• Draw on prior experience
• with unit operation
• Draw on current state of
• knowledge

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Typical Risk Assessment Work Flow
5. Risk Assessment Prioritize Experiments
6. Decision Analysis
1. Create a Process Flow Chart
4. ID experiments needed to understand CQA f
(CPP)
3. Risk Assessment Identify and Prioritize
Process Parameters
2. Identify Quality Attributes and How Measured
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Formal tools (quality risk management) support a
systems approach (Q9)
Define critical.
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PAT is key component

• power consumption granulation end point
• acoustic granulation end point
• on-line particle size analysis
• NIR LOD
• on-line UVcleaning

PAT (on-line) for Process Monitoring
NIR core potency
imaging of blisters
NIR coating thickness
on-line blend uniformity
NIR material identification
dry compaction
com- pression
blister packaging
raw material testing
wet granulation
dispensing
blending
coating
FBD milling
capsule filling
bottle filling
Lab Based root cause
NIR chemical imaging
vision particle analyzer
NIR Conformance testing
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Process Analytical Technology

• Definition ICH Q8
• 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 assuring
  final product quality. (also FDA EU definition)

Can we do QbD without PAT? Should we redefine PAT
to focus on tools and technology?
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Design Space new word or old concept?
60C
2.0
5.0 pH
30C
Baseline Method Carry out the reaction at pH 2-5
and between 30 and 60C Proven Acceptable
Ranges
It may be a new concept for some, but how do we
describe the ltcriteriongt, relationship and
associated control strategy?
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Does a systems approach/ enhanced understanding
demand DOE?

• Formal Experimental Design a structured,
  organized method for determining the relationship
  between factors affecting a process and the
  output of that process. Also known as Design of
  Experiments.
• DoE a systematic approach to investigation of
  a system or a process (thequalityportal.com)
• Why is DoE important?
• It has more to offer than one at a time
  experimentation since it allows judgement on
  significance to the output of input variables in
  combination.

60C
What actually happens here?
5.0 pH
2.0
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DoE more usual to establish Design Space

• Full /Fractional factorial or Central Composite
  Designs for Response Surface analyses

Ying-Ming Jou Schering
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Granulate Particle Size d90 Response 4
dimensional!
P Doherty Pfizer
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Proven acceptable ranges Design Space?

• Do we need to present the Target or control
  ranges?

Many in industry desire univariate approaches
flexibility.. BUT can Design Space be the sum
of univariate PARs?
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Why are we implementing QbD and its systems?

• Good for the business
• Greater supply chain reliability and
  predictability
• Innovation and improvement encouraged and
  facilitated
• Good for the patient
• Greater supply chain reliability and
  predictability
• Improved product reliability and reproducibility
• AND
• QbD should provide opportunities for more
  flexible regulatory approaches

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Regulatory Flexibility

• Many of my Industry colleagues seek clarification
  of Regulatory Flexibility (Flexible Regulatory
  Approaches)
• This is in danger of being misinterpreted
• Legislators worry this is de-regulation (it
  isnt!)
• Q8 indicates flexibility is a consequence of
  provision of enhanced understanding and its
  approval in the dossier
• BUT Flexibility and Flexible Approaches are
  probably not the same
• Flexibility may challenge legislation

Can we be more concrete about flexible approaches?
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Flexibility we should be able to derive more
meaningful specifications

• We should get out of the procrustean state of
  mind!
• Specifications based on batch data cannot
  incorporate scientific understanding and be
  risk-based
• Step 1 Design Specification
• Establish what the customer/patient needs and
  design product and process accordingly
• Step 2 Do the science
• Understand the Critical to Quality Attributes
  (CQA) and Process Parameters (CPP)
• Establish the Design Space
• Step 3 Establish a specification that verifies
  the CQAs that will form a public standard and can
  be used to assure Q is maintained from time of
  release to end of shelf-life (i.e. the same SE
  characteristics as explored during development)

I sense many Regulators and Industry colleagues
prefer a more traditional (batch data) approach
why?
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Process Description Flexibility?

• Utilisation of Design Space should create
  intrinsic Flexibility
• Process descriptions could be less specific
• Reactions described by end-points rather than
  time/temperature
• Non-critical elements can be proven to be
  non-critical and could be removed from process
  descriptions
• Scale, equipment, site?
• Control strategy could reduce, potentially
  eliminate, end-product testing
• Would have to demonstrate would comply if
  tested
• But we should recognise this is all pre-approved

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QbD process can be more flexible and capitalise
on different control strategy
Inputs
Process
Product
IPC
Fixed (variability unknown) test reject
Fixed within univariate ranges
Variable test and reject
Classical
Test reject
Learning adaptive to variability
Reproducible minimal variability
Variability understood
QbD
Feedforward Feedback
Feedforward Feedback

• Adaptive, learning processes only work with
  in-depth process understanding and a flexible
  environment Design Space

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What can we clarify about Regulatory Flexibility?

• Investment by Industry in enhanced process and
  product understanding should lead to more
  flexible regulatory approaches
• More meaningful and realistic specifications
• Parametric/real-time release
• Skip-lot testing
• Flexible, adaptive and learning (manufacturing
  and analytical) processes
• Reduction in routine commitments (e.g.,
  stability)
• Reduction in categorisation of post-approval
  changes (pre-approval -gt notification)
• As in a Regulatory Agreement?

Can there be anything other than pre-authorised
Regulatory Flexibility?
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Flexible Regulatory Approaches

• Objective greater empowerment to self-manage
  innovation and improvement

• Question Do we have to do things differently?

P Quality Systems (in line with Q10) plus Q Risk
Management (Q9)
Enhanced product and process understanding
(multi-variate) leading to Design Space
Flexible Approaches
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My Observations Industry implementation Do we
have to do different things/things differently?

• For many companies, probably not, but what is
  done needs to be presented differently
• For others, there may be opportunities to invest
  in more systematic development paradigms
• For Industry as a whole it will be useful to gain
  clarity over regulatory expectations, and ensuing
  opportunities of flexibility

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Conclusions

• QbD is a holistic, systematic, lifecycle approach
  to product realisation and manufacture
• QbD is not new but there are new concepts which
  need more consistent understanding and
  interpretation
• Industry would welcome continued collaboration
  with Regulators to understand full implications,
  expectations and potential benefits of QbD for
  all elements of the CMC dossier
• Chemical entities and biotech
• Pre-approval (what should be submitted)
• Post-approval (Regulatory Agreement) and
  inspections
• This workshop is an excellent forum for
  understanding the changes we might all need to
  take to bring us to the desired state

With thanks to colleagues at Pfizer for input
materials