Key Components of Pharmaceutical QbD, an Introduction

In the past few years, US FDA has implemented the concepts of Quality by Design (QbD) into its approval processes. FDA is insisting that quality should be built into a product with an understanding of the product and process, through development and manufacturing. QbD is a successor to the "quality by QC" (or "quality after design") approach.

1. Key Components of Pharmaceutical Quality by Design ( QbD ) – An introduction By Dr . Saurabh Arora Managing Director Auriga Research Limited

2. Contents Introduction Current approach vs QbD Why QbD is Win-Win Implications of QbD Overview of QbD Key Components Conclusion

3. How do we establish product quality? Then and Now

4. Historical approach to quality No testing required Testing of final products Testing of ingredients and final product Extensive testing of ingredients, final products and control of process parameters Testing and control based on process validation and strict adherence to process

5. Just get from A to B Traditional approach focused on achieving compliance to product specifications Only minor variations studied to established that the product is reproducible Not necessarily the best way to get from A to B

6. A better way to cross the river?

7. QbD What is the best way to get from A to B? What are the other routes can I take to safely get from A to B? It is like having a GPS navigation system for your product and process!

8. New level of quality Systematic development process Moving away from “hit and trial” Quality is built into the product not only controlled by testing

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

10. Think win-win QbD is good for both the manufacturers and the regulators

11. QbD is win-win Wins for the regulator More pharmaceutical products approved in shorter timeline Better quality products reaching the market Lower-cost products available to the consumer Reduced audit frequency

12. QbD is win-win Wins for the manufacturer Reduced time to market Space and flexibility for more innovation Reduced documentation Better communication between authorities and industry Guaranteed quality for every unit produced Decreased cost of production by improved productivity Competitive advantage in the market Image improvement Creating value using existing data and resources Better knowledge management

13. IMPLICATIONS ON THE ORGANISATION Implications on of QbD

14. QbD Implications QbD Organization Process Management Personnel QA/QC IT Technology Understanding

15. Implications on Personnel Employees need new skills Scientific data analysis Statistics Process control Very similar to 6 Sigma training structure Master black belts Black belts Green belts

16. Implications on Personnel Structural changes might be required There might be need for new Department There is a need for increased collaboration between departments and functions Increased contact with regulatory authorities Clearly defined to accountability roles and responsibility Interdisciplinary project team, QA, R&D, IT, manufacturing

17. Implications on Management Commitment of management Initial phase will require more investment, though there will be saving in the long run. Define the QbD development strategy, team, goals, objectives, commit to resources, expected benefits Might be risky to ignore QbD Regular review of the progress Choice of outsourcing partner Ensuring proper communication

18. Implications on QA Must be aware of changes in the regulatory process The structure of audits will change Scrutiny will challenge scientific understanding of quality factors and risk mitigation More focus on the development Department Comparison between real design space and documented design space Documentation of improvements, changes and deviations

19. Implications on QA Validation Validation to focus on management of critical to quality parameters Could be, real-time using PAT instead of three batch Better process understanding  Reduced validation effort Software validation Documentation Better process understanding may change specifications Submissions would need to include design space and control space

20. Linking 4 Areas of Process Understanding

21. Basic terminology Definitions and acronyms

22. What is PQ? What is Pharmaceutical Quality (PQ )? According to USFDA – a product should be called as of pharmaceutical quality when it is - Free of Contamination Reproducibly delivers the therapeutic benefits promised in the label to the consumer Pharmaceutical Quality = f (Properties of Drug Substance, excipients, Mfg. Process, Packaging)

23. What is Pharmaceutical QbD ? It is a systematic approach to pharmaceutical development that begins with predefined objectives and emphasizes product and process understanding and process control , based on sound science and quality risk management .

24. Overview of QbD Labeled Use Safety & Efficacy Identify Critical Material Attributes ( CMA ) & Critical Process Parameters ( CPP ) Design Formulation Design Process Define Target Product Quality Profile ( TPQP ) Knowledge Space Establish Control Strategy Monitor & Update Process Target ---------------------------  Design ----------------------- Implementation

25. Key Components of QbD Target Product Profile (TPP) It is patient & labeling centered concept It includes Route of administration Dosage form and size Max. & Min. Doses Pharmaceutical elegance (appearance) Target patient population

26. Key Components of QbD Target Product Quality Profile (TPQP) It is quantitative surrogate for aspects of clinical safety & efficacy It includes quantitative targets for Impurities & stability Dissolution release profile & Other product specific performance requirements e.g. Bioequivalence to the RLD for generic products Resuspendability for an oral suspension Adhesion for a transdermal system Viscosity for a topical cream etc.

27. Key Components of QbD Critical Quality Attributes (CQAs) These are Physical, chemical, biological or microbiological properties or characteristics of final product that need to be controlled (directly or indirectly) to ensure product quality e.g. Dissolution test CQAs include both Aspects of product performance Determinants of product performance

28. Key Components of QbD Critical Material Attributes (CMAs) These are Physical, chemical, biological or microbiological properties or characteristics of raw materials & mfg. process parameters that need to be controlled to ensure product quality These are independent of each other e.g. Particle Size & Hardness areCMAs CQA of RM & Mfg. Process Parameters = CMA

29. Key Components of QbD Process Parameters (PP) It is any input operating parameter (mixing speed, flow rate) and process state variable (temperature, pressure) of a process or unit operation Classification of PP for a Unit Operation Unclassified Process Parameters (UPP) Critical Process Parameters (CPP) Non-critical Parameters (non-CPP)

30. Classification of Process Parameters Parameter Type Definition Sensitivity non-CPP Not critical • No failure in target product quality profile (TPQP) observed or predicted in the potential operating space (POS), and • No interactions with other parameters in the proven acceptable range (PAR) UPP Criticality Unknown • Not established • The default in the absence of pharmaceutical Development CPP Critical (control needed to ensure quality) • Failure in target product quality profile (TPQP) observed or predicted in the potential operating space (POS), or • Interactions with other parameters in the proven acceptable range (PAR)

31. Identification of Process Parameters Wet Granulation Material Attributes Drug Substance DS Amount DS Form DS Particle Size DS Moisture Content DS Bulk Density Material Attributes Excipients Exp. Amount Exp. Particle Size Exp. Bulk Density Granulation Operating Parameters Chopper Configuration Impeller Speed Granulation Time Order of Addition Temperature Spray Nozzle Type Binder Addition Rate Granulation State Conditions Power Consumption Temperature Material Attributes After Granulation Blend Uniformity Granule Size Distribution Agglomerate Size Moisture Bulk Density Flow Properties

32. Key Components of QbD 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 A design space may be constructed for a single unit operation, multiple unit operations, or for the entire process

33. Tools to implement QbD Design of experiments (DOE) Risk assessment Process analytical technology (PAT)

34. Design of Experiment (DOE) Structured, organized method for determining the relationship between factors affecting a process and the response of that process DOE Methodology Choose Experimental Design (e.g. Full Factorial design) Conduct randomized experiments Analyze data Create multidimensional surface model

35. Risk Assessment Risk It is defined as the combination of the probability of occurrence of harm and the severity of that harm Risk assessment A systematic process of organizing information to support a risk decision to be made within a risk mgmt process. It consists of the identification of hazards and the analysis and evaluation of risks associated with exposure to those hazards

36. Process Analytical Technology (PAT) A system for designing, analyzing and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes of raw & in process materials and processes with the goal of ensuring final product quality. The term analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical and risk analysis conducted in an integrated manner.

37. Conclusion The End

38. Conclusion Quality by design is an essential part of the modern approach to pharmaceutical quality QbD is Win-Win PAT, DOE and Risk Assessments are tools to facilitate the implementation of QbD .

39. Thank You! Dr. Saurabh Arora Presentation will be available for download @ WWW.Lab-Training.Com