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?