1. Quality by Design (QbD) Myth : An expensive development tool ! Fact : A tool that makes product development and commercial scale manufacturing simple ! Actually saves money ! How ?

2. Outline FDA initiatives for quality The desired state Quality by design (QbD) and design space (ICH Q8) Application of statistical tools in QbD Design of experiments Model building & evaluation Statistical process control How can Innoworks assist you?

3. FDA’s Initiative on Quality by Design In a Quality-by-Design system: The product is designed to meet patient requirements The process is designed to consistently meet product critical quality attributes The impact of formulation components and process parameters on product quality is understood Critical sources of process variability are identified and controlled The process is continually monitored and updated to assure consistent quality over time

4. Quality by Design

5. Design Space (ICH Q8) Definition: 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

6. Current vs. QbD Approach to Pharmaceutical Development Current ApproachQbD Approach Quality assured by testing and inspection Quality built into product & process by design, based on scientific understanding Data intensive submission – disjointed information without “big picture” Knowledge rich submission – showing product knowledge & process understanding Specifications based on batch historySpecifications based on product performance requirements “Frozen process,” discouraging changes Flexible process within design space, allowing continuous improvement Focus on reproducibility – often avoiding or ignoring variation Focus on robustness – understanding and controlling variation

7. Pharmaceutical Development & Product Lifecycle Candidate Selection Product Design & Development Process Design & Development Manufacturing Development Product Approval Continuous Improvement

8. Design of Experiments (DOE) Model Building And Evaluation Process Design & Development: Initial Scoping Process Characterization Process Optimization Process Robustness Statistical Tool Product Design & Development: Initial Scoping Product Characterization Product Optimization Manufacturing Development and Continuous Improvement: Develop Control Systems Scale-up Prediction Tracking and trending Statistical Process Control Pharmaceutical Development & Product Lifecycle

9. Design of Experiments (DOE) Structured, organized method for determining the relationship between factors affecting a process and the response of that process Application of DOEs: Scope out initial formulation or process design Optimize product or process Determine design space, including multivariate relationships

10. DOE Methodology (1) Choose experimental design (e.g., full factorial, d-optimal) (2) Conduct randomized experiments (4) Create multidimensional surface model (for optimization or control) (3) Analyze data ExperimentFactor AFactor BFactor C 1 +-- 2 -+- 3 +++ 4 +-+ A B C www.minitab.com

11. Models for process development Kinetic models – rates of reaction or degradation Transport models – movement and mixing of mass or heat Models for manufacturing development Computational fluid dynamics Scale-up correlations Models for process monitoring or control Chemometric models Control models All models require verification through statistical analysis Model Building & Evaluation - Examples

12. Chemometrics is the science of relating measurements made on a chemical system or process to the state of the system via application of mathematical or statistical methods (ICS definition) Aspects of chemometric analysis: Empirical method Relates multivariate data to single or multiple responses Utilizes multiple linear regressions Applicable to any multivariate data: Spectroscopic data Manufacturing data Model Building & Evaluation - Chemometrics

13. Quality by Design & Statistics Statistical analysis has multiple roles in the Quality by Design approach Statistically designed experiments (DOEs) Model building & evaluation Statistical process control Sampling plans

14. How can Innoworks assist you? We can help you every step of the way in implementing Quality- by- Design in your work processes. Contact us : drshrutibhat@gmail.comdrshrutibhat@gmail.com