Quality by Design 2007 Gail Burnett, Ph.D.

1. Regulatory ٠ Quality ٠ Compliance Clinical Quality Quality by Design2007 Gail Burnett, Ph.D.

2. Clinical Quality QbD Definitions Quality: The suitability of either a drug substance or drug product for its intended use. This term includes such attributes as the identity, strength, and purity (from ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances). (ICH Q8) • noun:   an essential and distinguishing attribute of something or someone • noun:   a degree or grade of excellence or worth • noun:   a characteristic property that defines the apparent individual nature of something

3. Clinical Quality QbD Definitions Design : • Verb: to conceive or fashion in the mind; invent • Verb: to create, fashion, execute, or construct according to plan: • Verb: to conceive and plan out in the mind <he designed the perfect crime • Verb: to devise for a specific function or end • noun:   the act of working out the form of something (as by making a sketch or outline or plan) • noun:   a decorative or artistic work • noun:   a preliminary sketch indicating the plan for something • noun:   an arrangement scheme (Example: "The awkward design of the keyboard made operation difficult") • noun:   something intended as a guide for making something else • noun:   the creation of something in the mind • noun:   an anticipated outcome that is intended or that guides your planned actions (Example: "He made no secret of his designs")

4. Clinical Quality QbD Definitions 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. (ICH Q8) Design presupposes knowledge and/or creates knowledge. • Design Space cannot expand into areas of which we have no knowledge! • As we gain more knowledge, we may modify our design space.

5. Clinical Quality The Development Process • Emphasis on Development History - how did development lead to identification of critical process steps, critical process parameters, specifications, validation protocol, batch record and controls? • Designed experiments can lead to identification of critical and non-critical parameters, optimize process, and uncover interactions • Better understanding of process and product can lead to better science and risk-based regulation of individual products Product Specification File MFs, test methods, specs Process parameter assessment Batch execution Lot disposition Test against specs Assess re critical parameters and unknowns

6. Clinical Quality QbD Framework Create the Knowledge Space • Identify the Critical Quality Attributes • Apply QbD by Unit Operation, working backwards from Drug Product • Do a Risk Assessment on each Unit Operation • Conduct Designed Experiments

7. Clinical Quality QbD Framework • Identify theCritical Quality Attributes of the intended drug product • What do we know from research and pre-clinical development? • Determine if there are any surrogate measures for clinical safety and efficacy • Do we know what affects clearance? • Do we know what affects CDC or ADCC? • What do we know from work with molecules of the same class?

8. Clinical Quality QbD Framework Apply QbD by Unit Operation • Work backwards from Drug Product • The purpose of each unit operation should guide definition of critical attributes at that step • Define unit operations (process steps) by specific output required – e.g. cell mass vs product titer • The outputs of one unit operation may be the input variables for the next step • Consider the order of unit operations

9. Clinical Quality QbD Framework Apply QbD by Unit Operation • Start with a risk assessment for each unit operation • Consider and document all parameters that could affect output • Which process parameters might affect the desired quality attributes at the end of that step? • Which input variables might affect the output quality?

10. Clinical Quality QbD Framework • Apply QbD by unit operation - Example – anion exchange column • Purpose of step – remove host protein / viral clearance* Therefore critical attribute (output) studied in experiments should be host protein * Viral Clearance is considered high risk – can we justify combined experimentation? • What are the input variables that could affect this step? • What process parameters could affect quality? e.g. load, flow rate, pH, conductivity • Design of Experiments (DOE) should evaluate those input variables along with process parameters that have been assessed to have potential to impact host protein clearance.

11. Clinical Quality QbD Framework Design of Experiments • How small can we make the experiments? • Understand what design fits what need – screen, uncover interactions, refine • Plackett-Burman • Half-factorial • Full factorial • Etc. • Make sure we are looking at the right outputs • Multiple outputs analyzed separately • Implications for order of operations? • Consider where stability is an output

12. Clinical Quality QbD Framework Incorporating scale into design space • Should scale be a variable or input factor in DOE? • Can we identify surrogate factors that might vary with scale? • Approach will vary for batch or continuous process • Time • Contact surface • Mixing • Heat transfer

13. Clinical Quality QbD Framework Create the Design Space • Identify the Critical Steps • Identify Critical Process Parameters • Identify Critical Input Variables

14. Clinical Quality QbD Definitions Acceptable Range Definition unclear? • Critical Process Parameter: A process parameter that must be controlled within predetermined criteria to ensure the bulk drug substance meets its specification/quality attributes. A process parameter is critical if the target range (TR) is near the acceptable range (AR) or as determined by a technical expert. Industry not unanimous in regard to importance or relevance of ability to control the parameter. Acceptable Range

15. Clinical Quality QbD Framework Acceptable Range Selection of Critical Process Parameters • What if there is no impact on Quality Attributes (e.g. Yield)? • By “expert opinion” • By risk assessment • By lack of significant effect in robust DOE • By six sigma • By ratio to CpK • ??? Critical Parameter Non-Critical Parameter Acceptable Range

16. Clinical Quality QbD Framework Acceptable Range Selection of limits to test in DOE • Do we need to test to failure? • How far beyond control capability is far enough? • Consider all sources of error Critical Parameter Non-Critical Parameter Acceptable Range

17. Clinical Quality QbD Framework Design Space Example

18. Clinical Quality QbD Framework Design Space Example

19. Clinical Quality QbD Framework Design Space Example

20. Clinical Quality QbD Framework Now that we’ve determined Design Space – what next? • Validation of critical steps with focus on critical parameters • Documentation of limits • Specifications – link to Quality Attributes • Action Limits – when the parameter is critical • Alert Limits – when the parameter is non-critical and when we need a step before Action Limits • How to describe Design Space in Regulatory Filings • Can we or should we express design space with a formula? • Do we need to describe our entire knowledge space? • Link to Quality Systems