Process Analytical Technology: Neue Trends in der Pharmaceutischen Industrie

1. 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

3. 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

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

5. 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:

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

7. Process Understanding • Pharma • Air Plane

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

9. 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

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

11. 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

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

13. Process Understanding Key in the Future of Manufacturing

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

15. 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

16. Challenges to ‘Understanding’ • Understanding involves Measurements Plan Evaluate Measure

17. Challenges to Analytical Science The need for increased Process understanding is a massive Boost for Analytical Science

18. Challenges to Analytical Science adequate Tools?

19. Challenges to Analytical Science adequate Tools !

20. Challenges to Analytical Science We need the adequate Tools

21. 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

22. 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

23. Quality by Design

24. 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

25. 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.

26. Is Key for claiming Process Understanding • Process understanding is Key forQuality Risk Management • QRM is the base for any Control Strategy Design Space

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

28. Examplain Design Space – Graphical Description

29. Quality Risk Management Q9and the Control Strategy

30. The Quality Risk Management Process

31. Cause and Effect Process

32. QRM Tools:Failure Mode Effects Analysis (FMEA)

33. 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

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

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

36. Q8 Design Space What is Analytical Method Understanding?

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

39. 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

40. 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

41. 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

42. 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’

43. 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

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