Process Analytical Technology: Neue Trends in der Pharmaceutischen Industrie

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Process Analytical TechnologyNeue Trends in
der Pharmaceutischen Industrie

• Dr. Fritz Erni
• NOVARTIS Pharma
• Global Quality Operations
• CH-4002 Basel, Switzerland

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Outline

• The Vision of the desired state
• What is PAT and QbD
• ICH Q8 is a Door Opener for
• Describing Quality by Design
• Including more Science and Risk Management
• Introduces the Concept of Design Space
• Design Space Concept for Analytical Methods
• Summary

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Global Challenges

• Rising Global Regulatory Bar
• Consent decrees and enormous fines from
  manufacturing compliance deficiencies
• Higher safety hurdles for marketing approval
• Challenge of Sustaining Product Pipeline Flow
• Biotech contribution less than expected
• Government price control
• Challenge of Earning Stakeholders Trust

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What is the Problem with Pharma? Is there a
Problem with Pharma?
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A Paradigm in Crisis
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PAT in the Wall Street Journal Europe 3.9.03

• FDA Commissioner Mark McClellan
• ... You need to improve!
• ... has room for improvements
• Semiconductor industry 1 ppm defects
• Pharmaceutical industry 5 to 10
• .. Acknowledging the FDA role in inhibiting
  changes ...

• WSJE on the Lauch of the FDA PAT guideline

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Impact Process Capability

• Process Capability
• 2 s
• 3 s
• 4 s
• 5 s
• 6 s

• Rejected Batches
• 31.9
• 6.7
• 0.7
• 1 o
• 10 ppm

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Process Understanding

• Pharma

• Air Plane

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Typical Ingredients of a Tablet
Lactose 100µm
Active 5µm
Corn Starch 30µm
Microcrystalline Cellulose 102 100µm
Dr. Susanne Keitel
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Where to Go?

• Internal and external Pressures
• Cost
• More consistent Quality
• No rejects/ First Time Right
• What will be GMP 21st Century
• What is the Desired State
• More Science
• Risk Management
• ICH Q8 / Q9 / Q10

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Industrys Vision to be achieved in 2-5 years

• A single global harmonized
• Drug Quality Standard
• Interpretation of the Drug Quality Standard
• A Drug Quality Standard based on
• Risk Management
• Science
• Mutual recognition of
• equivalent quality system evaluations
• CMC review and approval
• Across all 3 regions.

Brussels July 2003
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Desired State

• Product quality and performance achieved and
  assured by design of effective and efficient
  manufacturing processes
• Product specifications based on mechanistic
  understanding of how formulation and process
  factors impact product performance
• An ability to effect Continuous Improvement and
  Continuous "real time" assurance of quality

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GMP and Regulatory Actions
FDA Pharmaceutical cGMP for the 21st Century
a Risk based Approach
FDA PAT guideline
2004 2005 2006
FDA Draft Quality Systems
FDA Innovation and Continuous Improvement in
Pharmaceutical Manufacturing
Q10 Pharmaceutical Quality System
Q8 Pharmaceutical Development
ICH
Update Q6A/B ?
Q9 Risk Management
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The Paradigm Change

• From
• blind compliance to
• science and risk based compliance
• Ajaz Hussain, FDA

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Process Understanding
Key in the Future of Manufacturing
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What? Process Understanding

• Ajaz S. Hussain

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A Process is well understood when

• all critical sources of variability are
  identified and explained
• variability is managed by the process and,
• product quality attributes can be accurately and
  reliably predicted over the design space
• http//www.fda.gov/cder/guidance/6419fnl.htm

The PAT Guidance
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Challenges to Understanding

• Understanding involves Measurements

Plan
Evaluate
Measure
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Challenges to Analytical Science
The need for increased Process understanding is
a massive Boost for Analytical Science
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Challenges to Analytical Science

• adequate Tools?

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Challenges to Analytical Science

• adequate Tools !

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Challenges to Analytical Science

• We need the adequate Tools

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PAT Process Understanding

• Improved Process Knowledge to Identify and Remove
  Sources of Variability
• Identify Critical to Quality parameters
• Process understanding as input to Risk Management
• Control what is critical

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What is Quality by Design

• Elements of a QbD
• Systematic Development Approach
• Formulation Understanding
• Process Understanding
• Packaging Understanding
• Application of Quality Risk Management
• Advanced Control Strategy

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Quality by Design
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What is ICH Q8

• Guideline for the description what is in P2
• Describes the minimal Standard for P2
• Opens door to get closer to the
• Desired State
• Science based
• Includes Risk Management
• Continuous improvement
• Real Time Release

ICH Q8Door opener for Quality by Design
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Design Space The multidimensional
combination and interaction of input variables
(e.g., material attributes) and process
parameters that have been demonstrated to provide
assurance of quality. Working within the design
space is not considered as a change. Movement out
of the design space is considered to be a change
and would normally initiate a regulatory post
approval change process. Design space is proposed
by the applicant and is subject to regulatory
assessment and approval.
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Design Space

• Is Key for claiming Process Understanding
• Process understanding is Key for Quality Risk
  Management
• QRM is the base for any Control Strategy

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Design of Experiments (DoE)
Effect of inlet temperature and air flow on
degradation and generation of fines
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Examplain Design Space Graphical Description
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Quality Risk Management Q9and the Control
Strategy
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The Quality Risk Management Process
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Cause and Effect Process
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QRM ToolsFailure Mode Effects Analysis (FMEA)
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Risk Management process
Significant influence
Initialassessment
Prior knowledge
First Second review cycle
Formulation and Process understanding
Thirdreview cycle
ControlStrategy
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Control Strategy

• Justification of necessary controls
• Raw Materials Control
• In-Process Controls
• End Product Controls (if necessary)
• Based on Process and Formulation Understanding
• Drives the Process in the Design Space
• Based on Quality Risk Management
• To ensure conforming Quality according
  Specifications

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Control Strategy
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Q8 Design Space

• Can the design space concept also be applied to
• Analytical Methods?

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Q8 Design Space

• What is Analytical Method Understanding?

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Dr.Imre Molnar,Institut für angewandte
Chromatography,Berlin, Germany
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Global Challenges

• Rising Global Regulatory Bar
• Consent decrees and enormous fines from
  manufacturing compliance deficiencies
• Higher safety hurdles for marketing approval
• Industrys pain for post approval changes
• Biotech contribution less than expected
• Government price control
• Challenge of Earning Stakeholders Trust

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Industrys pain for post approval changes

• Many are method changes
• Most of the changes are urgent
• Many of them are improvements
• US FDA has recognized the issue
• Moheb Nasr (FDA) offers working together with
  industry
• Industry needs to show interest and takes it up

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Design Space of a Separation Method

• What do we need to understand?
• What does Industry need as flexibility
• Separation parameters fixed or with ranges
• Separation parameters as a design space
• Variability of HPLC columns included
• How is understanding related to the flexibility
• How to put it in a dossier
• How is it reviewed and approved

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Design Space of a Separation Method

• The role of
• Method development
• Method validation
• System suitability
• How to describe the enhanced understanding
• How to describe the design space
• How to update the analytical design space
• What is the regulatory flexibility

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Summary

• The Vision of the desired state
• What is PAT and QbD
• ICH Q8 is a Door Opener for
• Describing Quality by Design
• Including more Science and Risk Management
• Introduces the Concept of Design Space
• Design Space Concept for Analytical Methods

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• Alles zu messen was messbar ist -
• Und messbar machen was noch nicht messbar ist!
• Galileo Galilei
• 1564-1642