II. 3 Quality risk management as part of…

1. II. 3 Quality risk management as part of… Development Industry Competent Authorities See also next chapters using the intention to be applicable for development II.4: Facilities, Equipment and Utilities II.5: Materials Management II.6: Production II.7: Laboratory Control and Stability Studies II.8: Packaging and Labelling Note: Process understanding and criticality may be applied only to new products

2. CONSIDERATIONS Critical Parameters that contribute to variation in customer requirements Parameters that impact customer requirements All parameters and dimensions that define a product About development T. Matsumura, Eisai Co.

3. II.3: QRM as part of development • To design a quality product and its manufacturing process • to consistently deliver the intended performance of the product (see ICH Q8) • To enhance knowledge of product performanceover a wide range of • material attributes (e.g. particle size distribution, moisture content, flow properties) • processing options • process parameters ICH Q9

4. EXAMPLE Quality by design: “Special Cause” or “Common Cause” Note: Non detected OoS could result in a patient risk • Consequence: Frequent, major OOS • Corrective actions eliminate “Special Cause” Result: Unstable process Production Validation Based on A. Hussain, FDA, September 2004

5. EXAMPLE Quality by design : “Special Cause” or “Common Cause” • Reduce “Common Cause” Variability • Consequence: On the continuous improvement path Result: Stable & Capable Production Validation A. Hussain, FDA, September 2004

6. EXAMPLE Quality by design : “Special Cause” or “Common Cause” • Consequence: Minor, occasional OoS • Reduce “Common Cause” Variability Result: Stable- Yes; Capable? Production Validation A. Hussain, FDA, September 2004

7. II.3: QRM as part of development • To assess the critical attributes of • Raw materials • Solvents • Active Pharmaceutical Ingredient (API) • Starting materials • Excipients • Packaging materials • To establish appropriate specifications, identify critical process parameters and establish manufacturing controls ICH Q9

8. II.3: QRM as part of development • To decrease variability of quality attributes: • reduce product and material defects • reduce manufacturing defects • To assess the need for additional studies (e.g., bioequivalence, stability) relating to scale up and technology transfer • To make use of the “design space” concept (see ICH Q8) ICH Q9

9. EXAMPLE P2 of CTD as part of a regulatory submission In line with Quality Risk Management ?

10. EXAMPLE Initiate Quality Risk Management Process Risk Assessment Risk Identification Risk Analysis Risk Evaluation unacceptable R i n s o k i t a M c Risk Control a i n n a u g m Risk Reduction e m m o e C n t k t s Risk Acceptance o i o R l s Output / Result of the Quality Risk Management Process Risk Review Review Events P2 of CTD as Quality Risk Management process ? Formulation & Process design Process understanding Manufacturing Concept Process control Concept Product release Concept Regulatory strategy Review the submission

11. EXAMPLE Research Phase 1 Phase 2 Launch Phase 3 FORMULATION DESIGN SPACE PROCESS DESIGN SPACE BY UNIT OPERATION Review events Development Target Product Profile Drug substance properties; prior knowledge Developm. Proposed formulation and manufacturing process Determination of Cause – Effect relationships (Risk Identification with subsequent Risk Analysis) Risk-based classification (Risk Evaluation) Process understanding Re-evaluation and confirmation Re-evaluation and confirmation Formulation understanding Parameters to investigate (e.g. by DOE)(Risk Reduction 1. proposal; 2. verified) Product and process characteristics on the final drug product CONTROL STRATEGY Operation EFPIA PAT TG, 2006

12. Risk Management approach to focus on critical attributes EXAMPLE Unit operation Dispensing Granulation Drying Blending Tableting Quality Attributes Dissolution Disintegration Hardness Assay Content Uniformity Degradation Stability Appearance Identification Water Microbiology Significant influence Initialassessment Prior knowledge First & Second review cycle Formulation and Process understanding Thirdreview cycle ControlStrategy EFPIA PAT TG, 2006

13. EXAMPLE Risk to patient Unit operation Quality Attributes EFPIA PAT TG, 2006

14. EXAMPLE Initiate Quality Risk Management Process Risk Assessment Risk Identification d e s u c o f Risk Analysis m a e T Risk Evaluation unacceptable R i n s o k i t a M Risk Control c n a i o n n i t a u a t g l m Risk Reduction u e s m m n o o e c C n l t a k t n Risk Acceptance s r o i e o t R n l I s t n Output / Result of the e m Quality Risk Management Process e v l o v n i r Risk Review e d l o h Review Events e k a t S Responsibilities in regulatory operations Industry B) Inspectorates A) Reviewers

15. EXAMPLE QRM as part of developmentprovide risk-based knowledge to manufacturer Past Future Parameters and range We have additional dimensions • Open question: How to challenge information for submission? Answer the questions in ICH Q9 Chapter 4: • What might go wrong? • What is the likelihood (probability) it will go wrong? • What are the consequences (severity)?

16. EXAMPLE Conventional approach: Testing after each step to minimize the risk prior to the next step Raw Materials Blending Tabletting Packaging Raw Materials Blending Tabletting Packaging PAT: Continuous or more frequent testing and control during each step to minimize/control the risk prior to the next step PAT: Process Analytical Technology Development and Manufacturing Validation Takayoshi Matsumura, Eisai