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Challenge of CMC Regulatory Compliance for Biopharmaceuticals

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ISBN-10: 0306480409

ISBN-13: 9780306480409

Edition: 2004

Authors: John Geigert

List price: $279.99
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This book highlights the challenges facing quality assurance/quality control (QA/QC) in today's biopharmaceutical environment and presents the strategic importance and value generated by QA/QC for their involvement in control of manufacturing. It will put into perspective the need for a graded approach to QA/QC from early clinical trials through market approval.
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Book details

List price: $279.99
Copyright year: 2004
Publisher: Springer
Publication date: 12/31/2003
Binding: Hardcover
Pages: 350
Size: 6.75" wide x 9.75" long x 1.00" tall
Weight: 1.738
Language: English

List of Tables
List of Figures
Biopharmaceutical CMC Regulatory Compliance: What is It?
Defining Our Terms
What is a 'Biopharmaceutical'?
What is 'CMC'
What is 'CMC Regulatory Compliance'?
Under the Biopharmaceutical Umbrella
Recombinant DNA-Derived Proteins
Monoclonal Antibodies
Gene Therapy
Animal/Plant Transgenics
Rapid Pace of Biopharmaceutical Development
Regulatory Development of Biopharmaceuticals
The Drug Development Process
Regulatory Agency Review
CMC Regulatory Compliance Track Record
Drugs and Biologics
Are Biopharmaceuticals Really Different?
Perception or Reality?
Five Questions Frequently Asked
Bottom Line Question
Regulatory Agencies Speak
Three Unique CMC Challenges for Biopharmaceuticals
The Use of Living Recombinant Organisms
The Products Themselves
The Impact of the Manufacturing Process
CMC Meetings with the FDA Take on Greater Importance
CMC Communication with FDA is Critical
Preparing for the CMC Meeting
Pre-IND Meeting
End of Phase 2 (EOP2) Meeting
Pre-BLA/NDA Meeting
What About CMC Meetings with EMEA?
Biopharmaceuticals Need to be Treated Differently
Developing the Corporate CMC Regulatory Compliance Strategy
Three Key Elements for a Complete CMC Strategy
Element 1: The Broad CMC Scope Must Be Considered
Element 2: Any Unique CMC Issues Must Be Addressed
Element 3: Must Meet Minimum CMC Regulatory Requirements
The Minimum CMC Continuum
Minimum CMC Requirements for Clinical Development
An Overview
Phase 1
Phase 2 and 3
Full CMC Requirements for Dossier Filing
Comparison of BLA/NDA and CTD CMC Formats
Adequate Resources Required to Compile the Full CMC Dossier
Quality of CMC Content Present in Dossier is Critical
'Case-By-Case' CMC Strategy Specifics
Can't Ignore cGMPs
Not Optional
What are 'cGMPs'?
Three main GMP questions
GMPs for Everything
For Finished Drug Products
Required for APIs Also
Extra GMPs for Biopharmaceuticals
Where in the Manufacturing Process Should GMP Begin?
When During Clinical Development Should GMP Begin?
API Clinical Trial Materials
Drug Product Clinical Trial Materials
Consequences of Not Following GMPs
Issues with Market Approved Biopharmaceuticals
Issues During Clinical Development
How to Avoid GMP Difficulties with the FDA
Strategic CMC Tips for GMP Compliance
Recombinant Source Material: Master/Working Banks
Needed: Reliable, Continuous, Stable Genetic Source
Three Primary CMC Concerns for Banks
Genetic Construction of a Bank
So Many Hosts to Choose From
Bank Terminology
Choosing the Host
Drivers to Reach a Decision
Why Choose Recombinant Cells?
Why Bioengineered Animals or Plants?
CMC Guidance on Preparation of a Bank
Accurate and Thorough Description of Preparation
Recombinant Cell Banks
Transgenic Banks
Why Does The FDA Want So Much CMC Documentation?
When is Full CMC Documentation Needed?
What If CMC Documentation is Missing?
Don't forget GMPs During Preparation of the Bank
CMC Guidance on Characterization of a Bank
Appropriate and Sufficient Characterization
Six Key Elements for a Thorough Characterization
Recombinant Cell Bank Characterization
Example of Characterization of a Bacterial Cell Bank
Example of Characterization of a Mammalian Cell Bank
How Much Characterization and When?
Critical Concern for Virus Safety in Banks
Minimizing the Risk of TSEs
A Successful CMC Strategy for Banks
Production: Expansion of the Recombinant Organism and Expression of the Biopharmaceutical
Goals: Identity, Capacity and Consistency
Two Major CMC Regulatory Concerns for Production
Need for High and Consistent Expression of the Biopharmaceutical
What is a 'Production Process'?
Types of Bioreactors for Cell-Based Production
Harvesting Procedures for Biopharmaceuticals
Production Processes Familiar to the FDA
Adequate Description of the Production Process
During Clinical Development
Phase 1 IND Submission
Phase 2 IND Submission
Phase 3 IND Submission
Preparing the BLA/NDA Submission
Validation of a Cell-Based Production Process
When Should Validation of the Production Process Occur?
Five Major Areas Involved in Validation of the Production Process
The Production Facility, Utilities and Process Equipment
Monitoring of Growth Parameters
In-Process Controls
Genetic Stability
Cleaning Validation
Final Comments on Process Validation
Additional Production Controls and Concerns
Cell-Based Production Processes
Cell Culture Media Acceptance Criteria
Avoidance of Animal- and Human-Derived Raw Materials
Containment of the Recombinant Organism
Contamination Control for Aseptic Processing Operations
Gene Therapy Production Processes
Control of the Cells
RAC Review and Approval of the Production Process
Transgenic Animal Production Processes
Production Controls
Protecting the Gene Pool
Transgenic Plant Production Processes
'Pharming' Controls
USDA/APHIS Protecting the Gene Pool
What Can Go Wrong
Strategic CMC Tips for Production
Purification of the Biopharmaceutical
Goals: Purity, Recovery and Consistency
Two Major CMC Regulatory Concerns for Purification
Need for High Recovery of a Pure Product
What is a 'Purification Process'?
Physical Separations Methods for Biopharmaceuticals
Chromatographic Purification Methods for Biopharmaceuticals
Purification Processes Familiar to the FDA
Adequate Description of the Purification Process
During Clinical Development
Phase 1 IND Submission
Phase 2 IND Submission
Phase 3 IND Submission
Preparing the BLA/NDA Submission
Facility and Utility Concerns
Design and Operation
Environmental Monitoring
Purification Process Validation
When Should Purification Validation Occur?
Process Validation Concerns for a Chromatographic Step
Process Validation Concerns for a Filtration Step
In-Process Controls
Process-Related Impurity Profile
Viral Safety Evaluation
General Study Design
Justification of the Choice of Viruses
Calculation of Virus Reduction Factors
Virus Safety Calculation
Worth All the Trouble and Cost?
When Should the Viral Clearance Studies Be Performed?
Purification Controls for Gene Therapy Processes
What Can Go Wrong
Strategic CMC Tips for Purification
Biopharmaceutical Drug Product Manufacturing
Three Basic CMC Regulatory Concerns
Formulation of a Biopharmaceutical
Formulations Familiar to FDA
Chemical Modification of API Prior to Formulation
Biopharmaceutical Manufacturing Processes
Adequate Description of the Manufacturing Process
During Clinical Development
Phase 1 IND Submission
Phase 2 IND Submission
Phase 3 IND Submission
BLA/NDA Submission
Adequate Control Over the Manufacturing Process
Regulatory Requirements for Market Approved Products
Regulatory Expectations During Clinical Development
What Can Go Wrong
Strategic CMC Tips for Drug Product Manufacturing
Physicochemical/Biological Analysis of the Biopharmaceutical Product
A Challenging Analysis
Goals: Consistent, Safe, Potent and Pure Product
Relationship Between Product Characterization and QC Testing
Unraveling the Molecular Properties
Molecular Variants for DNA
Molecular Variants for Proteins
Plethora of Analytical Methods Available For Proteins
Characterization of Biopharmaceuticals
Regulatory Expectations During Clinical Development
Phase 1 IND Submission
Phase 2 IND Submission
Phase 3 IND Submission
Regulatory Expectations for the BLA/NDA Submission
Full Characterization of Recombinant Proteins and Monoclonal Antibodies
What is 'Full' Characterization?
Host-Dependent Glycosylation
Host-Dependent Impurities
Impact of Molecular Variants on Biological Activity
Characterization of a Gene Therapy Biopharmaceutical
Applying the Minimum CMC Continuum to Characterization
Release Testing and Specifications
Regulatory Expectations During Clinical Development
Phase 1 IND Submission
Phase 2 IND Submission
Phase 3 IND Submission
Regulatory Expectations for the BLA/NDA Submission
Appropriate Release Test Methods
Not All Release Testing is at API or Drug Product Stage
Elimination of Release Testing by Process Validation
Test Method Parameters Required for Release: Proteins
Test Method Parameters Required for Release: DNA Vectors
The Bioassay--Absolute Requirement for a Biopharmaceutical
Test Method Validation--How Much and When?
Regulatory Expectations for Test Method Validation
Assay Qualification During Clinical Development
Applying the Minimum CMC Continuum to Test Method Validation
The Art of Setting a Specification
Development of a Specification
Release Versus Shelf-Life Specifications
Are There Required Purity/Impurity Limits?
Strategic CMC Tips for Setting Specifications
Biopharmaceutical Stability and Expiration Dating
Regulatory Expectations During Clinical Development
Phase 1 IND Submission
Phase 2 IND Submission
Phase 3 IND Submission
Regulatory Expectations for the BLA/NDA Submission
Stability-Indicating Test Methods
Setting an Expiration Date
How Much Change is Acceptable?
Applying the Minimum CMC Continuum to Stability
What Can Go Wrong
Incomplete Release/Stability Testing Requirements in BLA/NDA Filing
FDA 483 Inspectional Observations
Biopharmaceutical Product Recalls
Misuse in the Clinic
Strategic CMC Tips for Biopharmaceutical Analysis
Managing Process Changes--Demonstrating Product Comparability
Not as Easy as it Seems!
Regulatory Management of Process Changes
Pre-IND Stage
IND Clinical Development Stages
BLA/NDA Filing Stage
Post-Approval Market Stage
Demonstrating Product Comparability
Guidance Documents on Product Comparability
A Three-Tiered Testing Hierarchy
Designing the Comparability Study--Four Major Factors
Factor 1: Clinical Development Stage for the Change
Factor 2: Where in the Process the Change is Introduced
Factor 3: Quality Criteria Considerations
Factor 4: Suitability of Available Analytical Methods
Regulatory Agencies Have Final Approval
If in Doubt, Ask!
Comparability Protocols
Case Examples of Biopharmaceutical Comparability
Comparability Success Stories
Comparability Surprises
Not Comparable
Biopharmaceutical CMC Outsourcing
Regulatory Expectations for Contracted Work
Why Outsource?
Written Quality Agreements Required
Regulatory Requirements During Clinical Development
Regulatory Requirements for the BLA/NDA Submission
Regulatory Requirements Post-Market Approval
Developing the Intercompany Quality Agreement
Two Viewpoints
The Biopharmaceutical Company Seeking to Outsource
The Contact Manufacturer Offering Outsourcing
Maximum Leverage
Contents of an IQA
Strategic CMC Tips for Outsourcing
Concluding Thoughts on Biopharmaceutical CMC Regulatory Compliance
Most Helpful Websites for Biopharmaceuticals
Website Resources from FDA
Resources from EMEA
Resources from Professional Associations