Biosimilar and Interchangeable Biologics
From Cell Line to Commercial Launch, Two Volume Set

What?s the Deal with Biosimilars?

Biosimilars are gaining momentum as new protein therapeutic candidates that can help fill a vital need in the healthcare industry. The biological drugs are produced by recombinant DNA technology that allows for large-scale production and an overall reduction time in costs and development.

Biosimilars and Interchangeable Biologics: From Cell Line to Commercial Launch covers the strategic and tactical elements of biosimilars in two volumes.

The first volume, Biosimilars and Interchangeable Biologics: Strategic Elements, explores the strategic planning side of biosimilar drugs and targets issues surrounding biosimilars that are linked to legal matters. This includes principal patents and intellectual property, regulatory pathways, and concerns about affordability on a global scale. It addresses the complexity of biosimilar products, and it discusses the utilization of biosimilars and related biological drugs in expanding world markets.

This volume also examines the science, technology, finance, legality, ethics, and politics of biosimilar drugs. It considers strategic planning elements that include an overall understanding of the history and the current status of the art and science of biosimilars, and it provides detailed descriptions of the legal, regulatory, and commercial characteristics. The book presents a global strategy on how to build, take to market, and manage the next generation of biosimilars throughout their life cycle.

The second volume, Biosimilars and Interchangeable Biologics: Tactical Elements, explores the development and manufacturing of biosimilars and targets challenges surrounding the creation of these products. This includes manufacturing, production costs, and intellectual property barriers, particularly in regulated markets (regulatory agencies are still in the process of developing guidelines). It addresses the complexity of biological drugs, and it discusses specific structural elements vital to the functionality, immunogenicity, and safety of biosimilar products.

This volume also provides an overall understanding of the hurdles, difficulties, and practicalities of developing a strong plan. It introduces a step-by-step approach for creating a strategy that helps develop and manufacture a biosimilar product while reducing overall production costs and meeting the requirements of biosimilarity based on analytical and functional, pharmacokinetic, pharmacodynamic (where applicable), and nonclinical toxicology or toxicokinetic similarity (where appropriate) while remaining competitive in the market.

Thus, Biosimilars and Interchangeable Biologics: From Cell Line to Commercial Launch, Two-Volume Set supplies practitioners, researchers, and scientists in the biopharmaceutical industry with a valuable resource for practical information at all stages of the biosimilar product process.

BIOSIMILARS AND INTERCHANGEABLE BIOLOGICS: STRATEGIC ELEMENTS

Introduction to Biosimilar and Interchangeable Products
Background
Manufacturing Systems
Characterization Systems
European Perspective on Interchangeability
Legality of Interchangeability
Interchangeability Practices
The Naming Controversy
Label
Regulatory Approvals
EMA Status
Regulatory Filing Under 505(b)(2)
eCTD Filing Requirements
Analytical Similarity
FDA Views on Development of Biosimilars
Nonclinical Testing
Immunogenicity
Phase III Trials
Pharmacovigilance
Commercial Opportunities
Epilogue
Bibliography

Intellectual Property Issues for Biosimilars
Global Patenting Perspective
Biological Patents
Patent Linkage
Purple Book
Patent Term Extension
Patent Term Adjustment
Determination of Target Launch Dates for Biologics
Loss of Patent Exclusivity
Freedom-to-Operate Opinions
Filing the 351(k) Triggers the Patent Dance
First Patent Dance Failed
Notice of Commercial Marketing and Preliminary Injunction
Sources of Uncertainty
Interchangeability
Bibliography

European Regulatory Guidance
Background
Publication of Clinical Data
2014 Update
Product-Specific Guidance
Clinical Safety
Conclusion
Bibliography

EMA-Approved Biosimilars
Background
Somatropin (Omnitrope)
Hyaluronidase
Enoxaparin
Filgrastim
Somatropin
Erythropoietin
Follitropin Alfa
Infliximab
Conclusion
Bibliography

FDA Regulatory Guidance
Background
Historical Perspective
Nonclinical Studies for Biologics
Biologics License Application
Guidance for Biosimilars
Biosimilarity
Clinical Pharmacology Data to Support Biosimilarity
Purple Book
Conclusion
Bibliography

ROW Regulatory Guidance
Background
Argentina
Australia
Brazil
Canadian Guidelines on Subsequent Entry Biologics (SEBs)
Singapore
China
India
Islamic Republic of Iran (National Regulatory Authority)
Japan
Jordan Food and Drug Administration
Mexico
Russia
South Korea
Turkey
United States of America
World Health Organization (WHO)
Bibliography

US Commercialization
Background
Competition
Evolving Pharma Market
Industry Overview
Commercializing a Biosimilar
Industry Events and Forums
Print Materials
Advertising
Social Media
Website
Bibliography

Global Commercialization
Background
Product Naming Issues
Bibliography

Quality and Lifecycle Management
Background
Pharmaceutical Development
Critical Quality Attributes
Product Life Cycle Management and Continual Improvement
Quality Risk Management and Product and Process Development
Differing Approaches to Pharmaceutical Development
CMC Considerations for the Drug Substance
CMC Considerations for the Drug Product
Life Cycle Management
FDA Comparability Protocol (CP)
CP Compilation Summary
Applicability of a CP
Components of a CP Submission
Reporting of the Manufacturing Change(s) Implemented Using an Approved CP
Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process (Q5e)
Operational Systems
Quality Control Systems
Bibliography
Appendices

BIOSIMILARS AND INTERCHANGEABLE BIOLOGICS: TACTICAL ELEMENTS

Structural and Functional Elements
Basics
Multidimensional View
Primary Structure
Secondary Structure
Tertiary Structure
Quaternary Structure
Posttranslational Modification (PTM)
Protein Folding
Protein Structural Variability
Recombinant DNA
Bibliography

Immunogenicity Considerations
Introduction
Immune System
Antigens
Antibody
Protein Immunogenicity
Biosimilar Product Immunogenicity
Immunogenicity Testing
Conclusion
Bibliography

Product Development Strategies
Background
Selection of Product
Manufacturing System Selection
Cell Line Choice
Reference Product
Test Method Development
Specifications
Reverse Engineering
Analytical and Functional Similarity
Nonclinical Studies
Clinical Pharmacology Studies
Interchangeability Protocols
Regulatory Uncertainty
Legal Teams in Place
Commercialization Challenges
Bibliography

Stability and Formulation Considerations
Introduction
Formulation of Biosimilar Products
Common Formulation Elements
High Concentration Formulations
Stability Testing Guidance
Bibliography

Biosimilarity Tetrahedron
Tetrahedron Concept
Similarity Concept
Comparability versus Similarity
Analytical and Functional Similarity
Analytical Instrumentation
Identity
Purity
Potency
Safety
Clinical Data
Risk-Based Critical Quality Attributes
Nonclinical Data
Stages of Analytical Similarity
Level of Similarity
Statistical Modeling of Similarity Data
Interchangeability
Conclusion
Bibliography

Recombinant Expression Systems
Background
Expression System Development
Manipulations to Improve Yield
Mammalian Cells Expression Systems
Mammalian Cell Expression Improvements
Yeast Expression Systems
Insect Cells
Transgenic Animals
Cell Banks
Bibliography

Upstream Systems Optimization
Background
Bacterial Manufacturing Systems
Mammalian Manufacturing Systems
Yeast Cell Manufacturing Systems
Transgenic Animal Systems
Cell Lines and Characterization
Future Prospects
Bibliography

Downstream Systems Optimization
Introduction
Bacterial Downstream Processing
Mammalian Downstream
Yeast Downstream Processing
Insect Cell Processing
Transgenic Animals Processing
Bibliography

Single-Use Manufacturing Systems (SUMS)
Background
Safety of Single-Use Systems
Polymers and Additives
Regulatory Requirements
Risk Assessment
Single-Use Containers
Summary
Single-Use Mixing Systems
Connectors and Transfers
Filtration
Controls
Filling and Finishing Systems
Environmental Concerns
Bibliography

Commercial Manufacturing Overview
Introduction
Media
Culture Growth
Process Overview
Process Maturity
Validation
Scale-Up
Specific Scale-Up Issues
Specific Economy Issues
Process Materials
Environment Control
Biosafety Levels
Good Manufacturing Controls of Active Pharmaceutical Ingredients
Cleaning Procedures
Processing and Filling
Laboratory Testing
Laboratory Controls
Documentation
Bibliography

Outsourcing Considerations
Background
Value of Outsourcing
Factors to Consider in Outsourcing
Key Requirements
What to Outsource?
Cell Line Suppliers
CMOs
Biopharmaceutical Support Services
Analytical Support Providers
Contract Research Organizations
Product Development Services
Fill and Finish Providers
Legal Matters
Managing Outsourcing
Outlook