Industry Perspective on Lifecycle Management

Industry Perspective on Lifecycle Management and Post-Approval Building Changes the Best title here Focus on Quality by Design FDA/PQRI Conference on Evolving Product Quality Sep. 16-17, 2014 Michael Kimball Executive Director, Transdermal Development Actavis plc Salt Lake City, Utah 1

Disclaimer The views expressed herein are strictly those of the presenter and are not necessarily the views of Actavis plc or its affiliates 2

Topics... Scientific Perspective on Prior-Approval Supplement Process (PAS) Quality by Design Prior Knowledge Quality Target Product Profile (QTPP) Risk Assessment Examples Equipment Change Case Study - Drying Oven A Transdermal Patch Case Study Process Analytical Technology (PAT) Case Study Final Thoughts 3

Resting on what's considered great has always been a recipe for decline. - Robert K. Cooper 4

Post-Approval Changes Scientific Perspective Simply stated: Is the drug product made after the change equivalent to the drug product made before the change? -- Guidance for Industry: Changes to an Approved NDA or ANDA (2004) Science and Risk-Based Approach Future of Guidances (SUPAC, etc.)? Dosage Form Complexity Modified Release QbD Integration with Post-Approval Change Process QTPP Risk Assessment PAT Other Tools 5

QbD Definition QbD defined: 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. (ICH Q8) 6

Overview of QbD Labeled Use Safety and Efficacy (TPP) DEFINE Quality Target Product Profile (QTPP) DESIGN Formulation and Process IDENTIFY Key Quality Attributes, Raw Material Attributes and Process Parameters CONTROL Materials and Process Target Design and Implementation Understanding 7 Lawrence Yu. Pharm. Res. 25:781-791 (2008)

QbD, Scale-up, and Product Lifecycle Business / Therapeutic Need TPP Elements Patient / Consumer Population Labeling Indication Dosage Form Route of Administration Target Product Profile R&D Focus Lab-Scale / Formulation QTPP Elements Design Elements CQA s CMP s Risk Assessment Quality Target Product Profile Iterative Process Re-assess risk Design Space Pilot Plant Scale-up Process Design / Experimentation Prior Knowledge Design of Experiments Modelling Pilot Plant Post-Approval Lifecycle management Continual improvement Risk Management / Control Strategy Commercial Plant 8

Quality by Design Complex / modified release dosage forms especially benefit from QbD Quality Target Product Profile (QTPP) Cornerstone of QbD Generics: Design for Equivalence Should include clinically-relevant specifications Importance of prior knowledge Comprehensive and appropriate Framework of change assessment Regulatory and scientific perspective 9

QTPP: Appropriate and Comprehensive? Scope of QTPP As Defined 10

QTPP: Appropriate and Comprehensive? 11 Prior knowledge Risk assessment Appropriate process and product characterization May evolve during development

Case Study: Equipment Change Success Story Solid Oral Product: Drying Oven change from Gruenberg to Vacuum Oven Different design and operating principle Guidance -> PAS QbD and Scientific Principles -> CBE 0 QTPP: Change did not impact and degradation profile improved Equipment/Process Parameter Equipment Gruenberg Oven Tenney Vacuum Oven Comment Manufacturer Thermal Products Solutions Thermal Products Solutions Same manufacturer Drying Method Process Parameter Inlet Temperature Set Point Wet granules are placed on trays. Drying is accomplished by heat convection from hot air flow to the wet granules. Moisture is carried away by air flow. Wet granules are placed on trays. Drying is accomplished by heat conduction from fluid heated racks to the wet granules. Moisture is carried away by vacuum pump. Convection versus Conduction 50ºC (45ºC to 55ºC) 50ºC (45ºC to 55ºC) No change Vacuum Pressure N/A 40 Torr (30 to 50 Torr) Addition of vacuum setting for Tenney vacuum oven Drying Time Approximately 7 hours Approximately 7 hours No change Drying End Point Until loss-on-drying is not more than 0.5% Until loss-on-drying is not more than 0.5% No change 12

13 Case Study: Transdermal Patch (Hypothetical)

Background: Side View of a Typical Transdermal Patch Each adhesive contains several constituents (i.e., polymers, diluent, tackifier, etc.) Consider: post-approval change: removal of minor constituent from Adhesive A Backing Film Release Liner Drug Reservoir Adhesive Layer (Adhesive A) Skin-Contact Adhesive Layer (Adhesive B) In addition to Design Space, QbD-based development introduces other tools that have potential to reduce regulatory burden 14

Example QTPP: Transdermal Patch QTTP Element Target Measure of Equivalency: Post-Change Active Ingredient Match RLD Dosage Form Dosage Form Appearance and Characteristics Route of Administration Film, Controlled Release Unchanged Unchanged Similar to RLD Unchanged Patch, rectangular Transdermal Unchanged Unchanged Dosage Strength Match RLD Container Closure System Equivalent to RLD Unchanged Unchanged 15

Example QTPP: Transdermal Patch, cont d QTTP Element Target Measure of Equivalency: Post-Change Appearance Drug Product and Quality Attributes Assay Content Uniformity Identity Residual Solvents Degradation Liner Peel Physical Tests Drug Release Microbial Limits Cold Flow Continued compliance with established specifications Stability Bioequivalence At least 24 month shelf life at 25 C (15 30 C permitted) 1. Non-inferior Adhesion 2. Non-inferior Irritation/ Sensitization 3. Equivalent PK Profile QbD - > Excipient compatibility, formulation challenge studies: mechanistic understanding of degradation pathway(s) 1. Skin-contact adhesive is unchanged; lab assessment of patch integrity 2. (see 1, and no components added) 3. In-vitro Franz cell testing (cadaver skin and/or synthetic membranes) 16

Formulation Understanding is Increasing QbD -> Excipient Compatibility or Similar Formulation Challenge Studies Mechanistic understanding of degradation and role each excipient plays Stability documentation required?: Customized based on risk assessment and product sensitivities. [1] (context of PAT) Repeat excipient compatibility with modified adhesive? Time (Simulated) Excipient Compatibility: Total Impurities and Degradation Products, % API + Adhesive A API + Adhesive B API + Backing API + Liner Zero 0 0 0 0 0 2wk 25C 0 0 0 0 0 2wk 40C 0 0 0 0 0.4 2wk 60C 2.6 2.7 2.7 2.1 3.2 4wk 25C 0 0 0 0 0 4wk 40C 1.8 1.4 0.8 1.1 1.6 4wk 60C 4.3 4.2 4.1 4.5 3.9 API 17 1. Van Buskirk, et.al. Best Practices for the Development, Scale-up, and Post-approval Change Control of IR and MR Dosage Forms in the Current Quality-by-Design Paradigm. AAPS Pharmscitech Vol 15 no 3, June 2014

Interval Flux (µg/cm²/hr) In Vitro Release Testing (Franz Cell): API Diffusion through Cadaver Skin, Before and after Change Demonstrates noncriticality of change Advances in IVRT Synthetic Membranes 18 0 3 6 9 12 15 18 21 24 Time (hrs)

Risk Assessment QTTP Element Target Measure of Equivalency and Risk: Post-Change Risk Assessment Active Ingredient Dosage Form Dosage Form Appearance and Characteristics Route of Administration Dosage Strength Stability Bioequivalence Match RLD Unchanged Low Film, Controlled Release Similar to RLD Patch, Rectangular Transdermal Match RLD At least 24 month shelf life at 25 C (15 30 C permitted) 1. Non-inferior Adhesion 2. Non-inferior Irritation/ Sensitization 3. Equivalent PK Profile Unchanged Unchanged Unchanged Unchanged Unchanged QbD - > Excipient compatibility, formulation challenge studies: mechanistic understanding of degradation pathway(s) 1. Skin-contact adhesive is unchanged; lab assessment of patch integrity 2. (see 1, and no components added) 3. In-vitro Franz cell testing (cadaver skin and/or synthetic membranes) Low Low Low Low Low Low Low 19

Risk Assessment QTTP Element Drug Product and Quality Attributes Container Closure System Target Measure of Equivalency and Risk: Post-Change Risk Assessment Appearance Assay Content Uniformity Identity Residual Solvents Degradation Liner Peel Physical Tests Drug Release Microbial Limits Cold Flow Continued compliance with established specifications Equivalent to RLD Unchanged Low Low 20

The Point Being... Industry is embracing the tools offered by QbD-based development, meaningful and intelligent risk assessment, and other recent advances in the science, which provide an improved framework to reassess change guidance Mechanistic understanding and review of formulation design could reduce the need for testing and expand the design space beyond past experience. (emphasis mine) (R. Lionberger) How will this look moving forward? PQRI white paper on IR and MR Dosage Forms (June, 2014) 21

Use of Process Analytical Technology (PAT) to Mitigate Risk for Scale-up, Site Change, and Equipment Change OPQ: Innovation is not increasing [1] Various uses in oral formulation processes Endpoint semi-solid/liquid mixing processes Solvent coating / extrusion processes (patches, oral thin films, etc.) Others 1. Iser, Robert. Office of Pharmaceutical Quality. Global Drug Development and its Impact on CDER s Drug Review Process Symposium, June, 2014 22

Endpoint Mixing Processes: Key Measures Homogeneity Viscosity Time to dissolve or disperse components Lends itself to Process Analytical Technology (PAT) 23

24 Case Study: Realizing PAT in Process Development by Implementation of NIRS: Mitigate Risk for Scale-up, Site Change, and Equipment Change Work published in Sep/Oct 2013 issue of Pharmaceutical Engineering (Fowler, et. al.)

Hydrogel Mixing: Realizing PAT in Process Development by Implementation of NIRS IR spectrums recorded for each raw material - Can be used for release, reference, investigations 25

Case Study: Realizing PAT in Process Development by Implementation of NIRS Flat spectrum = homogeneity Viscosity prediction / modeling 26

Stage Case Study: Realizing PAT in Process Development by Implementation of NIRS Pre-PAT Process Mix #1 Mix #2 Mix #3 Stage 1 30 mins 21 mins 15 mins 22 mins Stage 2 30 mins 28 mins 17 mins 4 mins Stage 4 15 mins 12 mins 11 mins 5 mins Cumulative Mix Time % of Control Mix Time 75 mins 61 mins 43 mins 31 mins N/A 81% 57% 41% Viscosity (cp) N/A 1,435 ~1,485 N/A Result: Increased Process Understanding and Efficiency Uniformity controlled via scale-independent method (NIR) => Mitigation of reporting requirement for significant scale or site change? 27

Perspective on Process Analytical Technology Industry is embracing PAT including generic Gx R&D Great potential for risk mitigation in a variety of process, equipment, scale-up, and site change scenarios Consideration of PAT in lifecycle management and future/ongoing discussion of change guidance 28

QbD Implementation Example: Risk Assessment - FMECA: Endpoint Batch Mixing Processes Potential for greater utilization, especially with complex dosage forms Potential Impact of Potential Cause Risk Method of Parameter Failure Mode Change of Failure Controls S O D RPN Rating Investigation Mixing CU, viscosity, Equipment, BPR: Speed Too slow or fast degradation Operator inspection 7 5 3 105 H DoE Final Mix Time Too short or long CU, viscosity, degradation Operator BPR: inspection 7 5 3 105 H DoE BPR: Constant in Fill Level Too low or high CU or spilling Operator visual 7 5 3 175 H DoE Too small or BPR: Mix Scale large CU Operator visual 7 7 3 245 H DoE Temp Too low or high CU, degradation Friction, ambient temp Visual 5 5 3 75 M Monitor in DoE 29

Final Thoughts Science and risk-based approach to lifecycle management is welcomed As QbD and science advance, post-approval change process should improve QbD tools, including PAT, and other recent advances in the science have untapped potential to mitigate risk and streamline post-approval change process Goal is to change the paradigm and improve the public health: Traditional Development Emphasis on Testing No Risk Assessment or DoE Minimal Formulation Knowledge PAS Systematic Development Emphasis on Design Risk Assessment, DoE Substantial Formulation Knowledge Annual Reportable, CBE 30

Thank You Acknowledgements PQRI Gordon Johnston Susan Rosencrance, U.S. Food and Drug Administration Francois Menard, (former) Vice President, R&D, Watson Pharmaceuticals Janie Gwinn, Director, Regulatory Affairs, Actavis plc Michael Fowler, Principal Engineer, Actavis plc 31