Training Course Syllabus:

Analytical Methods in Development and Manufacture of Drugs and Biologics: 2-Day In-Person Seminar by Ex-FDA Official

Course Description:

Analytical methods ensure quality of drugs and biologics. During last 2 decades, paradigm for quality of pharmaceutical products has shifted from ensuring quality by testing representative samples to building quality during manufacture of such products, leading to the concept of Quality by Design (QbD). This course starts with discussing the new paradigm of quality, QbD, and role of analytical methods in ensuring quality.

Methods play a critical role in development and manufacture of drugs and biologics and should be considered as a "Life Cycle" approach throughout the life cycle of a pharmaceutical product. The methods must be suitable for intended purpose during different stages of development and for commercial manufacture of the product. Understanding regulatory expectations and requirements for the methods is important to develop and design methods that are not only suitable for intended purpose, but support manufacturing operations in release of the product in a timely manner. All methods used in manufacturing operations must be maintained in a compliant state with acceptable method performance during life cycle of the product. This course will go into details of the life cycle of analytical methods, including verification, qualification and validation of methods for various stages of product development and for various purposes during manufacturing operations. Appropriate methods attributes and parameters will be discussed that need to be monitored (tracking and trending) to evaluate method performance.

Biologics products being complex and of biological origin, often require biological methods to release starting materials, intermediates and final product. Biological methods or bioassays with large inherent variability have challenges in developing appropriate method so that these are suitable for intended purpose. Focus on science and regulatory expectations during product development is essential to develop appropriate biological methods. This course will further go into the challenges, regulatory expectations and myths about bioassays with focus on developing suitable bioassays for intended purposes.

One of the challenges in developing cutting edge products, including cellular, tissue, gene therapy products, vaccines and blood products is developing appropriate potency method for these products. Often protective mechanisms for such products or surrogate markers for efficacy of such products are not clearly defined. There are examples of use of highly variable animal based methods as potency tests, which are sometimes poor indicators of human efficacy. In such cases, the concept of consistency in manufacture is employed to develop appropriate potency test, which may be a single test or a combination of tests. This course will go through regulatory expectations in developing potency tests for biological products.

Critical Reagents, Reference Standards and Internal controls play an important role in ensuring validity of results generated by analytical methods, particularly biological methods, and also to ensure acceptable performance of the method over time. This course will also discuss about selection and qualification of critical reagents, reference standards and internal controls for generating reliable results.

Throughout the course, specific examples with regard to achieving regulatory compliance during inspections, audits and review of methods sections, as part of license applications or supplements to license applications will be discussed. More importantly, information on the design of robust methods "Suitable for Intended Purposes" will be provided to mitigate risks of mistakes/errors and out of specification (OOS) results.

At times, it may be required to modify or change a method or a specification for a product. Appropriate validations and comparability studies are required to have these changes accepted by regulatory agencies. Ways to make these changes that are acceptable to regulatory agencies and are effective in manufacturing quality products will be discussed in this course.

Learning Objectives:

Upon completing this course the participants will understand:

Ensuring quality by the new paradigm of Quality by Design(QbD)
Building quality in the product
Analytical Method Life Cycle during Product Development and commercial Manufacturing
Regulatory Expectations and Requirements for the Methods during Product Development
Methods Verification, Qualification and Validation with Examples
Methods Validation Characteristics – Robustness, Specificity, Accuracy, Precision, Linearity, Limit of Detection, Limit of Quantitation, Range
Tracking and Trending of Method Performance
Challenges with Biological Methods or Bioassays
Myths and Regulatory Expectations about Bioassays
Potency Tests for complex Biological Products
Regulatory Expectations for a Potency test
Role of Critical Reagents, Reference Standards and Controls and their Development and Qualification
Risks and Inherent Variability of Analytical Methods
Designing Methods “Suitable for Intended Purposes” to Mitigate Risks due to Errors and Out of Specification (OOS) Results
Changes to Approved Methods – Change Control, Comparability Protocols
How to Continuously Monitor Method Performance and achieve sustainable compliance of methods for regulatory requirements?

Course Outline:

Day One (8:30 AM – 4:30 PM)

Registration Process: 8:30 AM – 9:00 AM

Session Start Time: 9:00 AM

Introduction – Ensuring Quality by Testing Representative Samples and Building Quality in the Product

New Quality Paradigm
Shift from “Final Testing” on Product to “Build Quality” in the Product during Manufacture
How to Build Quality in the Product?
Good Manufacturing Practices (GMP)
Quality by Design (QbD)
Process Analytical Technologies (PAT)
What do you get by Building Quality in the Product?
Role of Analytical Methods in Ensuring Quality

Critical in Assuring Quality for both Conventional and New Paradigms
Analytical Methods in Ensuring Quality by Testing Representative Samples
Manufacturing
Release Testing
Stability Testing
Consistency in Manufacture
Analytical Methods in QbD
Identifying Starting/Raw Materials & CPP affecting Quality
Identifying CQAs
Designing Process and Defining Design Space
Implementing PATs
Analytical Methods, Probes, Chips, etc.
Analytical Method Life Cycle during Product Development

Selection, Design, Development/Optimization, Validation
Characterization Tests
Qualification versus Validation
Method Verification
Method Qualification
Method Validation
Review of Definitions
ICH/FDA Guidelines
Examples for Effective Method Validation Studies
State of Analytical Methods with regard to Development/Qualification/Validation
Pre-Investigational New Drug (IND)
IND (Clinical Development)
Pre-BLA (Biologics License Application), BLA
Inspections

Day Two (8:30 AM – 4:30 PM)

Challenges in Developing Testing Criteria for Biological Products

Complexity of Biological Products
Made from Starting Materials that are Biological in Nature
Thorough Characterization of Starting Materials for Inherent and Adventitious Agents
Require Aseptic Manufacturing Process
Risks of Tumorigenicity (Continuous cell lines & Adventitious Agents), and Teratogenicity
Risk of Impurities (Immunological & Toxic)
Biological Methods or Bioassays – Regulatory Expectations, Myths

Role in Development and Manufacture of Biological Products
Challenges in Development and Validation
Misconceptions
Example of Understanding Science
Importance of Method Design for “Intended Use”
Considerations for Bioassay Validations
Potency Test for Complex Biological Products

Biological Products & Potency Test
Animal Based Potency Tests
Potency Tests
Definitions, Regulations, Guidelines, Views
Paradigm Shift
Lot Release Testing to Consistency in Manufacture
Alternate Potency Methods
Physico-Chemical Methods
Immunochemical Methods
Suitability of Potency Method for “Intended Purpose”
Inherent Method Variability in context of Design of a method that is “Suitable for Intended Purpose”

Normal Distribution, Understanding Variability
Example of Managing Variability with Appropriate Method Design
Critical Reagents, Reference Standards and Internal Controls

Definitions
Development and Qualification
Monitoring of Method Performance – Tracking and Trending

Overview of Critical Quality Attributes
Relation to Quality
Identifying CQAs
Examples
Key Performance Attributes
Trending and Tracking
Selection of Attributes and Parameters
Periodic Reviews
Actions
Change Control for Changing Methods, Comparability Protocols

History and Need for Change Control
FDA Regulations for Change Control
What is Required for Making a Change?
Pre-Approval Supplement
Changes Being Effected (CBE) & CBE – 30
Changes in Annual Report

Seminar Summary:

This course starts with discussing the new paradigm of quality, QbD, and role of analytical methods in ensuring quality. (see full course description)

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