1. Global Quality Operations
Process Analytical Technology: Neue Trends in der Pharmaceutischen Industrie
Dr. Fritz Erni
NOVARTIS Pharma
Global Quality Operations
CH-4002 Basel, Switzerland

2. 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
Fritz Erni

3. Rising Global Regulatory Bar
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
Fritz Erni

4. What is the Problem with Pharma? Is there a Problem with Pharma?
Fritz Erni

5. “A Paradigm in Crisis” (CAMP, R. Scherzer. FDA Sci. Board. 4/9/02)
Quality by Design: A Challenge to the
Pharma Industry
(CAMP, R. Scherzer. FDA Sci. Board. 4/9/02)
Fritz Erni

6. 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:
Fritz Erni

7. Impact Process Capability
2 σ
3 σ
4 σ
5 σ
6 σ
Rejected Batches
31.9 %
6.7 %
0.7 %
1 %o
10 ppm
Fritz Erni

8. Process Understanding
Pharma
Air Plane
Fritz Erni

9. Typical Ingredients of a Tablet
Lactose 100µm
Active 5µm
Corn Starch 30µm
Microcrystalline
Cellulose 102
100µm
Fritz Erni
Dr. Susanne Keitel

10. 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
Fritz Erni

11. Industry’s 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
Fritz Erni

12. 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
Fritz Erni

13. 2004 2005 2006 ICH GMP and Regulatory Actions FDA PAT guideline
FDA Pharmaceutical cGMP
for the 21st Century –
a Risk based Approach
FDA PAT guideline
2004
2005
2006
FDA : Innovation and Continuous
Improvement in
Pharmaceutical Manufacturing
FDA Draft
Quality Systems
Q10
Pharmaceutical Quality System Q8
Pharmaceutical Development
ICH
Update
Q6A/B ? Q9
Risk Management
Fritz Erni

14. ‘science and risk based compliance’
The Paradigm Change
From
‘blind compliance’ to
‘science and risk based compliance’
Ajaz Hussain, FDA
Fritz Erni

15. Process Understanding
Key
in the Future of
Manufacturing

16. What? Process Understanding
Intended Use
1st Principles
Modeling
Optimization
Continuous
Improvement
CAPA
Risk based Regulatory Assessment
DISCIPLINE
Epidemiology
Pharm. Engg.
Clinical
Clin.Pharm
Pharm/Tox
Pharmaceutics
Chemistry
Biology
ORGANIZATION
Marketing
Information Technology
Quality Assurance
Manufacturing
Regulatory
Development
Discovery
TIME
TIACC
Generic
AER/Complaints.
Approval
Phase III
Phase II
Phase I
Fritz Erni
Ajaz S. Hussain

17. 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 …
The PAT Guidance
Fritz Erni

18. Challenges to ‘Understanding’
Understanding involves Measurements
Plan
Evaluate
Measure
Fritz Erni

19. Challenges to Analytical Science
The need for increased
Process understanding is
a massive Boost for
Analytical Science
Fritz Erni

20. Challenges to Analytical Science
adequate Tools?
Fritz Erni

21. Challenges to Analytical Science
adequate Tools !
Fritz Erni

22. Challenges to Analytical Science
We need the adequate Tools
Fritz Erni

23. 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
Fritz Erni

24. 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
Fritz Erni

25. Quality by Design Conventional PD Quality by Design(ideal)
Mainly empirical approach
A systematic approach
Quality assured by end-product testing and inspection
Quality assured by well understood product and process, moving controls upstream without relying on end-product testing as much as possible
Process is fixed, disallowing changes
Flexible process within design space, allowing continuous improvement
Focus on process reproducibility – often avoiding or ignoring variability
Focus on formulation and process robustness – understanding and controlling variability
Limited and simple IPC
Extended PAT tools replacing the need for end product testing
Fritz Erni

26. ICH Q8 Door opener for Quality by Design
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 Q8 Door opener for Quality by Design
Fritz Erni

27. 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.
Fritz Erni

28. Design Space Is Key for claiming Process Understanding
Process understanding is Key for Quality Risk Management
QRM is the base for any Control Strategy

29. Design of Experiments (DoE)
Effect of inlet temperature and air flow on degradation and generation of fines
Fritz Erni

30. Examplain Design Space – Graphical Description
Figure 33 (p.41/54) "Graphical description of the design space for the drying operation for examplain hydrochloride tablet manufacture"
Fritz Erni

31. Quality Risk Management Q9 and the Control Strategy
Fritz Erni

32. The Quality Risk Management Process
Fritz Erni

33. Cause and Effect Process
Fritz Erni

34. QRM Tools: Failure Mode Effects Analysis (FMEA)
Fritz Erni

35. Risk Management process
Unit operation
Granulation
Drying
Blending
Tableting
Dispensation
Quality Attributes
Dissolution
Disintegration
Hardness
Assay
Content
Uniformity
Degradation
Stability
Appearance
Identification
Water
Microbiology
Significant influence
Initial assessment
Prior knowledge
First & Second review cycle
Formulation and Process understanding
Third review cycle
Control Strategy
Fritz Erni

36. 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
Fritz Erni

37. Blend Homogeneity -NIR Extent of Wet Massing - Power Consumption
Control Strategy
Unit Operations
Attributes
Controls
Content Uniformity NIR
Water Content – NIR
Particle size – FBRM
Dispensation
Blending
Fluidized Bed Dryer
Packaging
Tableting
Identity-NIR
Blend Homogeneity -NIR
Granulation
Extent of Wet Massing - Power Consumption
Air
Scale
Multivariate Model (predicts
Disintegration)
Raw Materials
Fritz Erni

38. Can the design space concept also be applied to
Q8 Design Space
Can the design space concept also be applied to
Analytical Methods?
Fritz Erni

39. What is Analytical Method Understanding?
Q8 Design Space
What is Analytical Method Understanding?
Fritz Erni

40. Dr.Imre Molnar,Institut für angewandte Chromatography,Berlin, Germany

42. Rising Global Regulatory Bar
Global Challenges
Rising Global Regulatory Bar
Consent decrees and enormous fines from manufacturing compliance deficiencies
Higher safety hurdles for marketing approval
Industry’s pain for post approval changes
Biotech contribution less than expected
Government price control
Challenge of Earning Stakeholders Trust
Fritz Erni

43. Industry’s 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
Fritz Erni

44. 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
Fritz Erni

45. 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’
Fritz Erni

46. 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
Fritz Erni

47. Alles zu messen was messbar ist -
Und messbar machen was noch nicht messbar ist!
Galileo Galilei
Fritz Erni