QbD Biologics: Regulatory Perspective Biologics Challenges versus Small Molecules •Analytical...
Transcript of QbD Biologics: Regulatory Perspective Biologics Challenges versus Small Molecules •Analytical...
QBD BIOLOGICS:
REGULATORY PERSPECTIVE
8Jun2015
Mark Alasandro
Acknowledgements
• Thomas Little
• Dilip Choudhury
• Curt Monnig
• Others…
Outline
• Regulatory Perspective
• Building a QbD based Infrastructure
• Regulatory – Governance Guidances
• Building the Control
• Analytical Testing – Molecule Based
• QbD for Analytical Methods
• Modeling -- Linear or Non-linear
• Stability Key Concerns
• Lean Stability Approach
• Summary
REGULATORY
PERSPECTIVE
QbD Principles
• Target Product Profile
• Risk Assessment
• Critical Control Attributes
• DOE
• Model
• Control Strategy
• Continuous Improvement
• Knowledge Management
QbD Biologics Challenges versus Small
Molecules • Analytical Method Dependent
• Small molecule
• “Can determine the structure and the molecules entire makeup from an
efficacy and safety perspective.”
• Biologics
• “Can look at amino acid sequence, the secondary and tertiary structure
of the protein but really never fully characterize the molecule.”
QbD Success
• “…To date, FDA “QbD design space” biologic approvals
include an expanded change protocol for a drug
substance transfer in 2010, and a new biologic (Gazyva)
with design space in 2013 (both Genentech)…”
Key Elements of Success
• Need a clear and logical relationship between QTPP and
CQA
• Well defined Control Strategy (Post-Approval Lifecycle
Management (PALM))
Regulatory Perspective
Need to Show Control • Need to show an understanding of the process
• A mathematical model of the process shows control
BUILDING THE
INFRASTRUCTURE
Building the Company Infrastructure
• QbD Culture -- company-wide acceptance from the top • QbD Champion
• Development Platforms – provide history to build upon • Formulation
• Manufacturing Process
• Analytical Control Platform
• Site Transfer
• QbD Strategy Playbook • Forced Degradation Studies/QbD Analytical Methods
• Technical Design and Evaluation Committee
• Oversight Governance • Senior management
• Knowledge Management
QbD Team
• Team
• Formulation
• Process
• Analytical
• Statistics
• QA
• RA
• PAI review process
• Infrastructure in place for PAI
REGULATORY –
GOVERNANCE
GUIDANCES
Regulatory Perspective Key Governing Guidances • QbD
• ICH Q8 (R2), Q9, Q10, Q11
• Q&A and Implementation Guide
• Process Validation • FDA Guidance 2011
• Specifications • ICH Q6B
• Stability • ICH Q1A–Q1E
• ICH Q5C
• 21 CFR 211.166
• USP general chapters <1049> and <1046> biopharmaceuticals and cell and gene therapies, respectively
ICH Q8, Q9 and Q10 Q&A and Points to
Consider • Quality Implementation Working Group on Q8, Q9 and
Q10 Questions & Answers (R4) Current version dated
November 11, 2010
• ICH QUALITY IMPLEMENTATION WORKING GROUP
POINTS TO CONSIDER (R2) ICH-Endorsed Guide for
ICH Q8/Q9/Q10 Implementation Document date: 6
December 2011
• Discusses Model
Regulatory Perspective EMA guidelines
• CPMP/QWP/609/96: Declaration of Storage Conditions
• CPMP/ QWP/2934/99: In-Use Stability Testing (applies to
products in multidose containers)
• CPMP/ QWP/159/96: Maximum Shelf Life for Sterile
Products After First Opening or Following Reconstitution
Regulatory Perspective Publications and Presentations
• “EMA-FDA pilot program for parallel assessment of
Quality-by-Design applications: lessons learnt and Q&A
resulting from the first parallel assessment”, 20 August
2013
• EMA/430501/2013, Human Medicine Development and
Evaluation
• “Questions and Answers on Design Space Verification”,
October 2013, EMA/603905/2013
QbD FDA Presentations
• Role of Models in the Quality by Design (QbD) Paradigm: Regulatory Perspective, Sharmista Chatterjee, Ph.D., October 23, 2011, AAPS Annual Meeting
• Quality by Design Approaches to Analytical Methods -- FDA Perspective, Yubing Tang, Ph.D., October, 2011, AAPS Annual Meeting
• QbD Approaches and Analytical Procedures Yubing Tang, Ph.D. FDA/CDER/ONDQA IFPAC, Arlington, VA January 24, 2014
• Implementation of Quality by Design A Regulatory Perspective Sarah Pope Miksinski, Ph.D. Division Director (Acting) Division of New Drug Quality Assessment 2 FDA/CDER/OPS/ONDQA, DIA. Jun 2014
Regulatory Perspective Rest of the World Guidances
• World Health Organization
• ASEAN: Association of Southeast Asian Nations
• Emerging markets outside the ICH region
• ANVISA: Brazil
• China
• South Korea
FDA Accelerated Approval Initiatives
• Guidance for Industry Expedited Programs for Serious
Conditions – Drugs and Biologics (May 2014)
• Accelerated Approval
• Fast Track
• Priority Review
• Breakthrough Therapy
ANALYTICAL TESTING –
MOLECULE BASED BUILDING THE ANALYTICAL TOOL
KIT
Biologics
QbD Design Based on Molecule • Monoclonal Antibodies
• Proteins
• Antibody-Drug Conjugates
• Combination Products
• Cell and gene therapies
• High concentration biologics
Selecting Analytical Tools
Molecule Based – Antibodies, Proteins • Structure
• NMR
• FTIR
• UV circular dichroism
• X-ray crystallography of the fc region
• Monosaccharide analysis
• Sialic acid analysis
• Oligosaccharide profile
• N-glycan analysis
• Aggregates • SEC, SEC-MALS
• Sedimentation velocity analytical ultracentrifugation
• Purity • Capillary gel electrophoresis
• Charged variants • Isoelectric focusing, IC
• Function/Bioactivity • TNF, SPR, C1q
• Thermal Stability • DSC
Analytical Tool – Molecule Based
• Protein instability
• Deamidations (hydrolysis of asparagine and glutamine side chain)
• Oxidation of methionine, histidine, cysteine, tyrosine and
tryptophan residues
• Aggregation (association of monomers or native multimers covalent
or noncovalent)
• Glycoproteins (most common instability of glycosylation hydrolysis
of sialic acid residues)
• Impurities in formulation and excipients
QBD FOR METHOD
DEVELOPMENT AND
VALIDATION METHOD OPERATING RANGE DESIGN SPACE
FDA-EMA Collaborative Research on QbD for Analytical Methods
Initiated Jan, 2013
QbD Analytical Filing Success
Analytical Method
• Risk Assessment
• Based on molecule, what are the key analytical tools needed
• Define Critical Analytical Attributes
Mark S. Alasandro, Thomas A. Little, Jeffrey Fleitman, “Method Validation by Design to Support
Formulation Development”, Pharmaceutical Technology, Volume 37, Issue 4, pp. 84-92, Apr 2,
2013
Design Space from the 3 Factor Case Study: API Percent
Recovered versus amount of Excipient 3 in formulation
The top Contour Profile is a plot of Precision (Mean Std Dev) versus Bias (Mean Percent Recovery – 100%). Any
combination of precision and bias that falls in the white space will give acceptable results. The bottom
Prediction Profiler is a tool where Bias and Precision can be varied by moving the cross hairs to determine the
impact on % Acceptance Rate.
Mark S. Alasandro, Thomas A. Little, “Process and
Method Variability Modeling to Achieve QbD
Targets”, AAPS PharmSciTech, submitted
What is Modeling
• Being able to predict
• Some examples
• Challenges in Applying to Biologics
• Based on type of molecule
• Not directly measuring the active as with small molecules
Why Do We Need Modeling
• Required in guidances
• Increased in-licensing and acquisition late stage
development compounds
• 65% of 41 Molecular Entities approved in 2014 were in-licensed or
acquired.
• 25% of the 41 were antibodies, peptides, and enzymes (3 out of 27
were biologics in 2013)
• FDA accelerated approval initiatives
• Reduced R&D resources
Examples
• Linear
• Non-Linear
LINEAR – ACCELERATED
MODELING
• Yan Wu, Anita Freed, David Lavrich, Ramesh Raghavachari, Kim
Huynh-Ba, Ketan Shah and Mark S. Alasandro, “Bringing Drug
Product Marketing Applications to Meet Current Regulatory
Standards: Trials and Tribulations", AAPS PharmSciTech, in press
• Degradation
• Aggregation
• Deamination
• Oxidation
• Etc.
Linear events
Linear Fit
Fit Model Software
Model of Expiry Predictions for Linear
Profile
Based in Linear Model
Can Predict Expiry Based
On Any Temperature
NON LINEAR – ACCELERATED
MODELING MOISTURE INGRESS/EGRESS, LEACHABLES,
DISSOLUTION
Application of the QbD (Quality by Design) Approach for Coating Drug Eluting Stents
(DES) Martin K. McDermott, FDA/CDRH/OSEL/DCMS & Sharmista Chatterjee,
FDA/CDER/OPS/ONDQA IFPAC 2014 Annual Meeting 23 January 2014
• Packaging moisture ingress/egress
• Leachables
• Dissolution
• Stent coating procedure
• Implants
Non Linear Changes
Yan Wu, Anita Freed, David Lavrich, Ramesh Raghavachari, Kim Huynh-Ba, Ketan Shah and Mark
S. Alasandro, “Bringing Drug Product Marketing Applications to Meet Current Regulatory Standards:
Trials and Tribulations", AAPS PharmSciTech,
Mark S. Alasandro, Thomas A. Little, “Multifactor Non-linear Modeling for Accelerated Stability
Analysis and Prediction”, Pharmaceutical Technology, Volume 38, Issue 7, pp. 46-49, Jul 2, 2014
Non-Linear Profile Drug Release Based on Storage Temperature
Non-Linear Profile
Modeling the Profile
Expiry Determination for Non-Linear
Models
Model with blood levels for a In-vitro in-vivo correlation (IVIVC) Model
KEY STABILITY TOPICS TO STAY IN CONTROL
Key Stability/Control Topics
• Photostability
• ICH Q1B can be used
• Shipping Studies
• USP Good Distribution Practice Guidance Chapter 1087
• In-Use and End-Use Studies
• Temperature Excursions
• Use Force Degradation Studies to support
• Emerging Characterization Methods
• Analytical Developments for Control Strategies
• Lean Stability
Summary
• Need to show understanding of how to control
• Mathematical Modeling is one approach
• Need to confirm it is accurate
• Need to build an analytical tool kit to get the best
characterization of the molecule
• Need to build the internal commitment to a QbD approach
THANK YOU Questions?