Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Mumbai, India Date: May 2008

1. QUALITY BY DESIGN Training Workshop on Pharmaceutical Development with focus on Paediatric Formulations Mumbai, India Date: May 2008

2. QUALITY BY DESIGN Dr Tom Sam President Industrial Pharmacy Section International Pharmaceutical Federation (FIP)

3. QUALITY BY DESIGN products processes

4. What is Quality? Quality Requirements = need or expectations Target Product Quality Profile Patient (or surrogate) “Good pharmaceutical quality represents an acceptably low risk of failing to achieve the desired clinical attributes.”

5. Which quality do we want for our medicines ? 6σ Source: Motorola, Air Safety Online

6. With which quality do we manufacture our medicines: 6σ, 5σ, 4σ, 3σ, 2σ ? Source: Motorola, Air Safety Online Current Mfg Quality provided to patients

7. How do we fill this quality gapin the pharmaceutical industry? Sigma ppm Defects Yield Cost of Quality Sigma ppm Defects Yield Cost of Quality s 69.2% 25-35% s 69.2% 25-35% 2 308,537 2 308,537 s 93.3% 20-25% s 93.3% 20-25% 3 66,807 3 66,807 s 99.4% 12-18% s 99.4% 12-18% 4 6,210 4 6,210 s 99.98% 4-8% s 99.98% 4-8% 5 233 5 233 s 99.99966% 1-3% s 99.99966% 1-3% 6 3.4 3.4 6 Current Mfg Quality provided to patients ……by testing !!!! Data from: Dr. Doug Dean & Frances Bruttin PriceWaterhouseCoopers

8. The quality mantra “Quality can not be tested into products; it has to be built in by design”

9. How can we modernize our industry? • More knowledge of our products and processes, allowing better design and more control • Better management:- introduction of quality risk management- expansion of GMP to more extensive pharmaceutical quality system

10. Dr Ajaz Hussain ‘Pharmaceutical GMPs for the 21st Century’

11. The knowledge pyramid Desired State Knowledge based decisions First Principles Why? MECHANISTIC KNOWLEDGE How? “CAUSAL" KNOWLEDGE What “Causes” What? Need for regulatory oversight CORRELATIVE KNOWLEDGE What Is Correlated to What? Current State DESCRIPTIVE KNOWLEDGE: What?

12. The New Quality Paradigm – The Evolving Regulatory Framework Product Life Cycle Product Design Process Design Scale-up & Transfer Commercial Manufacture Product ICH Q8/Q8(R) - Pharmaceutical Development PAT Guidance ICH Q9 – Quality Risk Management ICH Q10 – Pharmaceutical Quality Systems

14. Definition: Quality by Design Quality by Design is a systematic approach to development that begins with predefined objectives and emphasizes - product and process understanding - and process control, based on sound science and quality risk management. EMEA/CHMP/ICH/518819/2007

15. Quality by Design approach can be used for • Active pharmaceutical ingredients • Materials incl excipients • Analytics • Simple dosage forms • Advanced drug delivery systems • Devices • Combination products (e.g. theranostics)

16. Impact of QbD • Companies re-organize their science • Universities change their curriculum • Health authorities change their assessment and inspection

17. QUALITY BY DESIGN Step 1. Agree on the Target Product Profile Step 2. Determine the Critical Quality Attributes (CQAs) Step 3. Link the drug and excipient attributes and the process parameters to the CQAs Step 4. Define the Design Space Step 5. Define the Control Strategy Step 6. Prepare QbD registration file Step 7. Product lifecycle management and continual improvement EMEA/CHMP/ICH/518819/2007

18. What are the steps in aQuality by Design approach? 2. CRITICAL QUALITY ATTRIBUTES 3. LINK MAs AND PPs TO CQAS 1. TARGET PRODUCT PROFILE 4. ESTABLISH DESIGN SPACE 6. PRODUCT LIFECYCLE MNGMNT 5. ESTABLISH CONTROL STRATEGY

19. Step 1. Agree on the Target Product Profile Target Product Profile:- a prospective and dynamic summary of the quality characteristics of a drug product - that ideally will be achieved to ensure that the desired quality, and hence the safety and efficacy, of a drug product is realised. The TPP forms the basis of design of the product. Consider: dosage form route of administration strength release / delivery of the drug pharmacokinetic characteristics(e.g., dissolution; aerodynamic performance) drug product quality criteria(e.g., sterility, purity).

20. TPP for paediatric dosage form TPP adult TPP paediatric (may depend upon age group)

21. What are the steps in aQuality by Design approach? 2. CRITICAL QUALITY ATTRIBUTES 3. LINK MAs AND PPs TO CQAS 1. TARGET PRODUCT PROFILE 4. ESTABLISH DESIGN SPACE 6. PRODUCT LIFECYCLE MNGMNT 5. ESTABLISH CONTROL STRATEGY

22. CRITICAL QUALITY ATTRIBUTES - definition A critical quality attribute (CQA) is a - physical, chemical, biological, or microbiological property or characteristic - that should be within an appropriate limit, range, or distribution - to ensure the desired product quality. EMEA/CHMP/ICH/518819/2007

23. Step 2. Determine the Critical Quality Attributes (CQAs) solid oral dosage forms: typically those aspects affecting - product purity - product potency- product stability- drug release. Drug product CQAs are used to guide the product and process development. • other delivery systems: • can additionally include more product specific aspects, such as- aerodynamic properties for inhaled products- sterility for parenterals, - adhesive force for transdermal patches.

24. Product-centric Quality by Design Chemical purity Physical form Raw Material quality Excipient Quality Attributes API Purity API Quality Attributes Particle size Mechanical Properties Excipient Compatibility Formulation Process Related Formulation Parameters DRUG PRODUCT

25. What are the steps in aQuality by Design approach? 2. CRITICAL QUALITY ATTRIBUTES 3. LINK MAs AND PPs TO CQAS 1. TARGET PRODUCT PROFILE 4. ESTABLISH DESIGN SPACE 6. PRODUCT LIFECYCLE MNGMNT 5. ESTABLISH CONTROL STRATEGY

26. Step 3. Link the drug and excipient attributes and the process parameters to the CQAs People Process Parameters Quality Attributes Inputs to the process control variability of the Output Equipment I N P U T S (X) y = ƒ(x) Measurement y Process OUTPUT Materials Source: Moheb Nasr, FDA Environment

27. Mapping the Linkage Outputs: Inputs: CQA1 M1 Critical Quality Attributes M2 CQA2 Material Attributes CQA3 P1 P2 Relationships: CQA1 = function (M1) CQA2 = function (P1, P3) CQA3 = function (M1, M2, P1) P2 might not be needed in the establishment of design space Source: Moheb Nasr, FDA P3 ProcessParameters

28. Experimental Approach for Identifying Parameters Design of Experiments (DOE) is an efficient method to determine relevant parameters and interactions 2. Conduct randomized experiments 1. Choose experimental design (e.g., full factorial, d-optimal) 3. Analyze Data Determine significant factors

29. ICH Q9 Quality Risk Management Initiate Quality Risk Management Process 1. Risk Assessment 2. Risk Control Output / Result of the QualityRisk Management Process 4. Risk Review FormalRisk Management Process The new language

30. What are the steps in aQuality by Design approach? 2. CRITICAL QUALITY ATTRIBUTES 3. LINK MAs AND PPs TO CQAS 1. TARGET PRODUCT PROFILE 4. ESTABLISH DESIGN SPACE 6. PRODUCT LIFECYCLE MNGMNT 5. ESTABLISH CONTROL STRATEGY

31. Step 4. Define the Design Space • The linkage between - the process inputs (input variables and process parameters) and - the critical quality attributes • can be described in the design space.

32. Definition of Design Space Roll pressure Gap width Screen Size • The material attributes and process parameters that assure quality. • The multidimensionalcombination and interaction of input variables (e.g. material attributes) and process parameters that have beendemonstrated to provide assurance of quality.

33. What are the steps in aQuality by Design approach? 2. CRITICAL QUALITY ATTRIBUTES 3. LINK MAs AND PPs TO CQAS 1. TARGET PRODUCT PROFILE 4. ESTABLISH DESIGN SPACE 6. PRODUCT LIFECYCLE MNGMNT 5. ESTABLISH CONTROL STRATEGY

34. Design Space 1a EMEA/CHMP/ICH/518819/2007 Response surface plot of in-vitro release as a function of two critical parameters of the mixing and lamination process. Contour plot of in-vitro release

35. Design Space Design Space ControlSpace Knowledge Space

36. Step 5. Define the Control Strategy The control strategy should describe and justify how • in-process controls and • the controls of - input materials (drug substance and excipients), - container closure system, - intermediates and • the controls of end products contribute to the final product quality

37. 5. CONTROL STRATEGY Elements of a control strategy can include, but are not limited to, the following: • Control of input material attributes (e.g., drug substance, adhesive polymer, primary packaging materials) based on an understanding of their impact on processability or product quality • Product specification(s) • Controls for unit operations that have an impact on downstream processing or end-product quality (e.g., the impact of solvent on degradation) • In-process or real-time release in lieu of end-product testing • A monitoring program (e.g., full product testing at regular intervals) for verifying multivariate prediction models.

38. What are the steps in aQuality by Design approach? 2. CRITICAL QUALITY ATTRIBUTES 3. LINK MAs AND PPs TO CQAS 1. TARGET PRODUCT PROFILE 4. ESTABLISH DESIGN SPACE 6. PRODUCT LIFECYCLE MNGMNT 5. ESTABLISH CONTROL STRATEGY

39. Step 7. Product lifecycle management continual improvement

40. Better processes will lead to products with less variability Variable Input Fixed Process Variable Output Now (GMP) Drug Product PAT/QbD Variable Input Adapted Process Consistent Output

41. The Revolution in Quality Thinking Quality by Testing and Inspection • Enhanced • product knowledge • process understanding Quality by Design quality assured by well designed product & process