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

2. Slide 2 May 2008 Dr Tom Sam President Industrial Pharmacy Section International Pharmaceutical Federation (FIP) QUALITY BY DESIGN

3. Slide 3 May 2008 QUALITY BY DESIGN processes products

4. Slide 4 May 2008 What is Quality? Quality Patient (or surrogate) Target Product Quality Profile Requirements = need or expectations “Good pharmaceutical quality represents an acceptably low risk of failing to achieve the desired clinical attributes.”

5. Slide 5 May 2008 Which quality do we want for our medicines ? 6σ Source: Motorola, Air Safety Online

6. Slide 6 May 2008 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. Slide 7 May 2008 How do we fill this quality gap in the pharmaceutical industry? Sigma ppm Defects Yield 2 2   3 3   4 4   5 5   6 6   308,537 66,807 6,210 233 3.4 69.2% 93.3% 99.4% 99.98% 99.99966% Cost of Quality 25-35% 20-25% 12-18% 4-8% 1-3% Current Mfg Quality provided to patients Data from: Dr. Doug Dean & Frances Bruttin PriceWaterhouseCoopers ……by testing !!!!

8. Slide 8 May 2008 The quality mantra “Quality can not be tested into products; it has to be built in by design”

9. Slide 9 May 2008 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. Slide 10 May 2008 Dr Ajaz Hussain ‘ Pharmaceutical GMPs for the 21st Century’ for the 21st Century’

11. Slide 11 May 2008 The knowledge pyramid CORRELATIVE KNOWLEDGE What Is Correlated to What? “CAUSAL" KNOWLEDGE What “Causes” What? MECHANISTIC KNOWLEDGE How? DESCRIPTIVE KNOWLEDGE: What? Need for regulatory oversight Knowledge based decisions Desired State Current State First Principles Why?

12. Slide 12 May 2008 The New Quality Paradigm – The Evolving Regulatory Framework ICH Q8/Q8(R) - Pharmaceutical Development PAT Guidance ICH Q9 – Quality Risk Management ICH Q10 – Pharmaceutical Quality Systems Product Design Process Design Scale-up & Transfer Commercial Manufacture Product Life Cycle Product

13. Slide 13 May 2008

14. Slide 14 May 2008 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. Slide 15 May 2008 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. Slide 16 May 2008 Impact of QbD Companies re-organize their science Universities change their curriculum Health authorities change their assessment and inspection

17. Slide 17 May 2008 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 QUALITY BY DESIGN

18. Slide 18 May 2008 What are the steps in a Quality by Design approach? 1. TARGET PRODUCT PROFILE 2. CRITICAL QUALITY ATTRIBUTES 6. PRODUCT LIFECYCLE MNGMNT 3. LINK MAs AND PPs TO CQAS 5. ESTABLISH CONTROL STRATEGY 4. ESTABLISH DESIGN SPACE

19. Slide 19 May 2008 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. Slide 20 May 2008 TPP for paediatric dosage form TPP adultTPP paediatric (may depend upon age group)

21. Slide 21 May 2008 What are the steps in a Quality by Design approach? 1. TARGET PRODUCT PROFILE 2. CRITICAL QUALITY ATTRIBUTES 6. PRODUCT LIFECYCLE MNGMNT 3. LINK MAs AND PPs TO CQAS 5. ESTABLISH CONTROL STRATEGY 4. ESTABLISH DESIGN SPACE

22. Slide 22 May 2008 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. Slide 23 May 2008 Step 2. Determine the Critical Quality Attributes (CQAs) solid oral dosage forms: typically those aspects affecting - product purity - product potency - product stability - drug release. 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. Drug product CQAs are used to guide the product and process development.

24. Slide 24 May 2008 Product-centric Quality by Design API Purity Chemical purity Physical form Raw Material quality Formulation Process Related Particle size Mechanical Properties Excipient Compatibility DRUG PRODUCT API Quality Attributes Formulation Parameters Excipient Quality Attributes

25. Slide 25 May 2008 What are the steps in a Quality by Design approach? 1. TARGET PRODUCT PROFILE 2. CRITICAL QUALITY ATTRIBUTES 6. PRODUCT LIFECYCLE MNGMNT 3. LINK MAs AND PPs TO CQAS 5. ESTABLISH CONTROL STRATEGY 4. ESTABLISH DESIGN SPACE

26. Slide 26 May 2008 Step 3. Link the drug and excipient attributes and the process parameters to the CQAs People Equipment Measurement Process Materials Environment I N P U T S (X) y = ƒ(x) OUTPUT y Inputs to the process control variability of the Output Quality Attributes Process Parameters Source: Moheb Nasr, FDA

27. Slide 27 May 2008 Mapping the Linkage Inputs: Outputs: P1 P2 P3 M1 M2 CQA1 CQA2 CQA3 Relationships: CQA1 = function (M1) CQA2 = function (P1, P3) CQA3 = function (M1, M2, P1) P2 might not be needed in the establishment of design space Process Parameters Material Attributes Critical Quality Attributes Source: Moheb Nasr, FDA

28. Slide 28 May 2008 Experimental Approach for Identifying Parameters 1. Choose experimental design (e.g., full factorial, d-optimal) 2. Conduct randomized experiments ExperimentFactor AFactor BFactor C 1 +-- 2 -+- 3 +++ 4 +-+ 3. Analyze Data Determine significant factors Design of Experiments (DOE) is an efficient method to determine relevant parameters and interactions

29. Slide 29 May 2008 ICH Q9 Quality Risk Management 4. Risk Review 1. Risk Assessment 2. Risk Control Initiate Quality Risk Management Process Output / Result of the Quality Risk Management Process Formal Risk Management Process The new language

30. Slide 30 May 2008 What are the steps in a Quality by Design approach? 1. TARGET PRODUCT PROFILE 2. CRITICAL QUALITY ATTRIBUTES 6. PRODUCT LIFECYCLE MNGMNT 3. LINK MAs AND PPs TO CQAS 5. ESTABLISH CONTROL STRATEGY 4. ESTABLISH DESIGN SPACE

31. Slide 31 May 2008 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. Slide 32 May 2008 Definition of Design Space The material attributes and process parameters that assure quality. The multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality.

33. Slide 33 May 2008 What are the steps in a Quality by Design approach? 1. TARGET PRODUCT PROFILE 2. CRITICAL QUALITY ATTRIBUTES 6. PRODUCT LIFECYCLE MNGMNT 3. LINK MAs AND PPs TO CQAS 5. ESTABLISH CONTROL STRATEGY 4. ESTABLISH DESIGN SPACE

34. Slide 34 May 2008 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. Slide 35 May 2008 Knowledge Space Design Space Control Space Design Space

36. Slide 36 May 2008 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. Slide 37 May 2008 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. Slide 38 May 2008 What are the steps in a Quality by Design approach? 1. TARGET PRODUCT PROFILE 2. CRITICAL QUALITY ATTRIBUTES 6. PRODUCT LIFECYCLE MNGMNT 3. LINK MAs AND PPs TO CQAS 5. ESTABLISH CONTROL STRATEGY 4. ESTABLISH DESIGN SPACE

39. Slide 39 May 2008 Step 7. Product lifecycle management continual improvement Minimal ApproachQbD Approach Reactive (i.e., problem solving and corrective action) Preventive action Continual improvement facilitated

40. Slide 40 May 2008 Better processes will lead to products with less variability Now (GMP) Drug Product Variable Input Fixed Process Variable Output Variable Input Adapted Process Consistent Output PAT/QbD

41. Slide 41 May 2008 The Revolution in Quality Thinking Quality by Testing and Inspection Quality by Design Enhanced product knowledge process understanding quality assured by well designed product & process