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

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

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

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

“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

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

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

Process Understanding Pharma Air Plane Fritz Erni

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

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

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

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

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

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

Process Understanding Key in the Future of Manufacturing

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

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 Fritz Erni

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

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

Challenges to Analytical Science adequate Tools? Fritz Erni

Challenges to Analytical Science adequate Tools ! Fritz Erni

Challenges to Analytical Science We need the adequate Tools Fritz Erni

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

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

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

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

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

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

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

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

Quality Risk Management Q9 and the Control Strategy Fritz Erni

The Quality Risk Management Process Fritz Erni

Cause and Effect Process Fritz Erni

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

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

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

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

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

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

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

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

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

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

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

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

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