Implementing Quality by Design Principles and Concepts to Drug Delivery and Formulation Development. S Betterman 15Apr2015

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1 Implementing Quality by Design Principles and Concepts to Drug Delivery and Formulation Development S Betterman 15Apr2015

2 Agenda Background Implementation Strategy Infrastructure Building Project Application Challenges

3 Background

4 Quality by Design (QbD) Definition 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. Source: ICH Q8(R2)

5 Why QbD? Regulatory Expectations Demonstration of product and process understanding Inclusion of QbD elements in submissions (MAPP ) Business Benefits Time and cost savings Reduced raw material needs during development and technology transfer Reduced rework and failures Reference: Kourti T, Davis B, The Business Benefits of Quality by Design, PharmEng, 2012, 32(4) QbD saved 166 hours of work and $28,600 for one study.

6 Many Published Case Studies & Examples Conformia Working Group ACE Tablets Case Study Published 2008 QbD for ANDAs: An Example for MR Dosage Forms Final version published 2011 QbD for ANDAs: An Example for IR Dosage Forms Final version published 2012 These emphasize the finished product (submission) How do we get there?

7 A QbD Program Should Include: Knowledge Transparency Business Processes Collaboration Science Quality Risk Management Tools Training Consistency

8 Implementation Strategy Infrastructure Building

9 Use Layers of QbD Teams Champions Oversee QbD Strategy Team Support long-term vision to institutionalize QbD Executive Leadership level R&D and Quality Strategy Team Oversee QbD Tactical Teams Identify organizational gaps Define strategic action plans and implementation projects Senior Level - multiple functional areas Tactical Teams Own implementation projects Create new or revise current practices Junior Level - multiple functional areas

10 Core Team Ad Hoc Team QbD Strategy Team Structure Pharmaceutical Development Analytical Development Clinical Engineering Leadership Options: Champion Member from Core Team Regulatory Affairs Quality Technical Services Operations Quality Control Finance Legal Marketing Information Technology Supply Chain Membership: Senior level employees Leaders within their functional area Have QbD experience and/or knowledge Timeframe: Long-term team (multiple years)

11 QbD Strategy Team Purpose & Outputs Purpose defined through: Mission Why team exists Vision What we want to be Strategy How we will get there Execute towards Vision Ensure annual plans are executed Purpose Outputs Identification & prioritization of organizational gaps Decisions that affect Tactical Teams Communication to and from functional areas Short and long-term action plans Identification of Implementation Projects Selection of Tactical Team members

12 QbD Tactical Team Details Leader is member of Strategy Team Membership Junior level employees Users of the to-be-defined process 1 year or less in duration Structure Purpose Execute project per project charter Initial charter from Strategy Team Focused on a single tool Create a best practice Documented procedures RACI assessment Templates Training Outputs

13 QbD Continuum as a Toolbox Quality Target Product Profile (QTPP) Critical Quality Attribute (CQA) Mapping Risk Assessment Development Design Space Control Strategy Lifecycle Management Each phase has: Training module QbD Reference Guide Templates Post on company Intranet site Tools apply to both ANDA and NDA programs

14 Implementation Strategy Project Application

15 Start by Defining Targets Quality Target Product Profile (QTPP) Critical Quality Attribute (CQA) Inputs: Target Product Profile Reference Listed Drug (RLD) information Safety & efficacy information on drug substance Safety information on excipients Template: Excel file with multiple tabs Process: Answer a series of questions to probe discussion on product requirements (brainstorming) Tease out drug product attributes and associated tests with targets Use patient impact scale to identify Critical Quality Attributes (CQAs) Outputs: Design targets (attributes) of the product to be developed Attributes prioritized according to patient safety and efficacy

16 Visualize the Manufacturing Process Mapping Inputs: Manufacturing process steps (unit operations) Raw materials Process parameters and material attributes Templates: Visio files Flow Down Map, Process Map Process: Brainstorm unit operations and their order Outputs: Visual representation of the manufacturing process

17 Mapping: Flow Down Map Key Softgood Raw Material Softgood Raw Material: Active pharmaceutical ingredient (API), excipients, solvents, etc. Process Process: Manufacturing process such as blending, compression, wet granulation, etc. Intermediate Intermediate: In-process material such as a powder blend, uncoated tablet, extrudate, etc. Hardgood Raw Material Hardgood Raw Material: Typically packaging components such as bottles, caps, desiccants, etc.

18 Mapping: Flow Down Map Example Encapsulated Multi- Particulate Bead Finished Product Encapsulated Multi-Particulate Beads Packaging Material Package Insert Final Product Packaging Capsules Sized Coated Beads Capsule Filling Sieving Coated Beads Coating Solution Sized Uncoated Beads Würster Coating Release Retarding Polymer(s) Solvent Mixing Sieving Dried Beads Fluid Bed Drying Wet Beads Spheronization Extrudate Wet Mass Extrusion High Shear Granulation API Excipients Wet Binder

19 Mapping: Process Map Key Process Parameters Independent variables Inputs Raw material attributes In-process material attributes Unit Operation Critical Outputs Critical material attributes that act as inputs to the next process State Conditions Dependent variables In-process material attributes

Mapping: Process Map Example Blending Process Parameters Blender Fill Volume Order of Addition Number of Rotations Rotational Speed Compression Process Parameters Press Speed Compression Force

20 Mapping: Process Map Example Blending Process Parameters Blender Fill Volume Order of Addition Number of Rotations Rotational Speed Compression Process Parameters Press Speed Compression Force Tooling Design Coating Process Parameters Product Temperature Spray Rate Atomization Coating Weight Gain Blending Inputs Raw material attributes Raw material levels Blending Material Attributes After Blending API Uniformity Excipient Uniformity Compression Material Attributes After Compression Tablet Weight Tablet Hardness Dissolution Content Uniformity Aesthetic Coating Material Attributes After Coating Dissolution Blending State Conditions API Uniformity Excipient Uniformity Moisture Content Compression State Conditions Tablet Weight Tablet Hardness Tablet Thickness Tablet Disintegration Dissolution Content Uniformity Coating State Conditions Visual Uniformity Dissolution

21 Assess Risk to the Drug Product Risk Assessment Inputs: Quality Target Product Profile Maps Templates: Excel file with conditionally formatted cells Process: Populate all drug product attributes, material attributes, and process parameters For each cell, ask the question What is the risk that variation in this MA or PP would impact this drug product attribute? Select risk level from scale Outputs: Risk to the product attributes from the raw materials and process Critical material attributes (CMAs) and critical process parameters (CPPs)

22 Risk Assessment Example

23 Investigate Risks Further Development Design Space Inputs: Risk Assessment Experimental data Tools/Template: Statistical software package Design of Experiments (DOE) planning worksheets Process: Use the risk assessment output as a guide Investigate relationships between material attributes or process parameters and CQAs Decide the best method for investigation: paper exercise, OFAT experiment, DOEs, etc. Outputs: Proven acceptable ranges (PARs) for CMAs and CPPs Targets/set-points Failure regions

24 Establish Controls Control Strategy Inputs: Critical material attributes (CMAs) and critical process parameters (CPPs) Proven acceptable ranges (PARs) for CMAs and CPPs Targets/set-points Templates/Tools: Word tables per CQA or per unit operation Statistical software package (SPC) Process: Include confirmed high risks from risk assessment Document all controls in one place Outputs: Set of controls that ensure process performance and product quality Residual risk assessment of each control Plan for continuous monitoring

25 QbD Never Ends. Lifecycle Management Inputs: Information from all phases New knowledge Templates: Version tracking on all templates via revision log or software versioning capabilities Process: Continuously revise all templates based on the current state of knowledge Outputs: Updates to QTPP, process map, risk assessment, design space, and control strategy, as needed Continuous improvement

26 Project Application Strategies QbD Facilitator Expert leads discussions Keeps discussions focused Creates consistency across projects Project Milestones Incorporates QbD-related activities into the project plan Ensures tools are used Aligns functional areas Standardized Processes Right people at the right time (RACI) Clearly defined expectations Creates consistency across projects

27 Challenges

28 Challenges Metrics to show uptake of QbD program Tangible examples of benefit to the company Making exercises valuable not just copying case studies Defining risk tolerance level Balancing speed with thoroughness

29 Acknowledgements Lisa Shafer Nancy VanGieson Anita Tavakley Steve Berge Chris Wertz

30 Questions

How to Identify Critical Quality Attributes and Critical Process Parameters

How to Identify Critical Quality Attributes and Critical Process Parameters Jennifer Maguire, Ph.D. Daniel Peng, Ph.D. Office of Process and Facility (OPF) OPQ/CDER/FDA FDA/PQRI 2 nd Conference North Bethesda,