Environmental Monitoring

Analytical Methods in Monitoring and Managing Manufacturing Process Rajesh K. Gupta, Ph.D. Biologics Quality & Regulatory Consultants, LLC Analyze, Strategize & Operate – Different & Smart

[email protected] 1 240 246 0126 3rd Fall Meeting – Cell Banking, Contamination Control and Process Analysis & Automation Rosslyn, VA, September 28 – 30, 2015

Outline of Presentation  Quality Paradigm of Biological Products  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 2

Biologics Quality & Regulatory Consultants, LLC

Conventional Quality Paradigm Quality by Testing of Representative Samples  Historically, Biological Products, mainly Vaccines & Antitoxins were Made in Flexible Manufacturing Environment with Rigorous Testing  Empirical Development  Manufacturing Process Based on Retrospective Data

 Focus on Testing to Document Quality  Product Release based on Batch Data  Intermediate Products (Process is the Product)  Final Products (Animal Tests for Safety and Potency)

 Regulations Based on Testing Final Product  21 CFR 610 General Biological Product Standards  Pharmacopoeial Monographs (USP, EP, JP, etc.) 3


Shift in Quality Paradigm Quality by Consistency in Manufacture & Testing  Good Manufacturing Practices (GMP) Regulations Started Shift in Quality Paradigm  Quality Systems Concept  Documentation  Investigations  Prospective Validations (Facilities, Process, Utilities, Methods, Cleaning, etc,)

 Monitoring of Facilities, Environment, Utilities, Processes, etc  Components, Intermediates and Final Product Testing

 Deletion of Product Specific Requirements  21 CFR 620 (Bacterial Vaccine) & 21 CFR 630 (Viral Vaccines) 4


New Quality Paradigm Build Quality in the Product  Quality cannot be Tested; should be Built in by Design  Quality by Design of Effective and Efficient Manufacturing Processes

 Use of Scientific and Quality Risk Management Principles and Quality Control Strategies based on understanding & Knowledge of Product and Process  Identify Critical Starting & Raw Materials and Process Parameters (CPP) Affecting Quality  Evaluate and Determine, if possible, their Relationship with Critical Quality Attributes (CQA)

 Design a Process with On-line or At-line Monitoring of CPPs and CQAs 5


Building Quality in a Biological Product Challenges in Building Quality for Biologics  Requirement for Sterility of Biologics in Design and Control of the Manufacturing Processes  Understanding and Managing Inherent Variability in Manufacture  Starting and Raw Materials of Biological Origin  Complex Biological Processes  Unstable and Microbial Growth Supporting Intermediates  Bioassays with large Inherent Variability

Recommendations  Focus on Science and Understanding of Product, Process & Variability  Understand Process and Product to Identify and Manage Sources of Variability 6


Quality by Design (QbD)  A Systematic Approach to Development, Starting with Predefined Objectives

 Science and Risk Based Assurance of Quality  Emphasis on Understanding Product and Process based on Sound Science and Quality Risk Management  Determine Design Space (Relationship between Process Inputs i.e. Material Attributes, Process Parameters and CQAs)  Design Process with Online Monitoring & ability to Adjust CPPs (within Design Space) by Measurement of CQAs  Continuous “Real Time” Quality Assurance 7


FDA’s View on QbD

(Riley & Li, AAPS Pharma Sci Tech 2011, 12:114-118)

 Product/Process Design & Development  Define Desired Product Performance  Identify Product CQA  Design Process and Formulation to meet Product CQAs

 Risk Assessment & Risk Control  Understand Impact of Material Attributes and Process Parameters on Product CQAs  Identify & Manage/Control Sources of Variability in Materials & Process  Continually Monitor and Update Process to Assure Consistent Quality 8


Process Analytical Technologies (PAT)  Tool or System to Design, Analyze, and Control Process to Implement QbD  To Understand Scientific & Engineering Principles  To Identify Variables affecting Quality

 To Monitor and Control Process (in Real Time) with FeedForward and Feed-Back Controls  To Facilitate Tracking & Trending of Process Operations to Support Continuous Improvement Changes

 FDA started PAT discussion publicly in 2001 with FDA’s PAT Guidance in 2004  Pharmaceutical Quality for the 21st Century Initiative included both fundamental concepts of QbD and PAT 9


Benefits of New Quality Paradigm (QbD)  Robust Process based on Science with Flexibility to Make Changes within Design Space without Regulatory Notifications/Approvals  Allows Continuous Improvement for Enhanced Compliance and Efficiency, and a Better Product

 Upstream Quality Control with Possibility of Real-Time Release or Reduced End-Product Testing  Reduction in Cycle Times

 Reduction in Product Reject & Waste

 Provides a higher level of Assurance of Product Quality  Flexible Regulatory Policies to Accommodate New Scientific Knowledge and Modern Technologies  Increased Use of Automation and New Methods 10


Analytical Methods in Assuring Quality  Critical in Assuring Quality for both Conventional and New Paradigms  Drug Development  Discovery  Formulation Development  Pre-Clinical (Pharmacology, Toxicology, Immunogenicity)  Clinical (Pharmacology, Immunogenicity)

 Validation Studies  Process Validation  Cleaning Validation

 Viral Clearance Studies

 Comparability Studies 11


Analytical Methods in Assuring Quality  Critical in Assuring Quality for both Conventional and New Paradigms  Manufacturing  In-Process Testing and Characterization  Formulation  Monitoring (PAT) – Critical Tool of QbD

 Release Testing  Raw Materials  Intermediates  Components (API), Drug Substance, Drug Product

 Stability Testing  Consistency in Manufacture 12


Role of Analytical Methods in QbD  Scientifically Sound & Reliable (Specific, Accurate & Precise) Methods – Critical for  Drug Development  Manufacture by Conventional Paradigm (Quality by Testing)  Manufacture by New Paradigm (QbD)

 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. 13


Assuring Microbiological Quality of Biologics  Microbiological Methods & Testing Do NOT Provide Complete or Absolute Absence of Viable Organisms  Robust Microbiology Programs Provide Assurance of Microbiological Quality

How to Assure Microbiological Quality?  Testing, Validation, Monitoring & Verification  Aseptic Processing & Environmental Monitoring

 Terminal Sterilization  Biological Products Generally Not Terminally Sterilized

 Microbial Removal/Reduction/Inactivation  Validation of Manufacturing Process

Build Microbiological Quality into a Product 14


Monitoring & Managing Process  Historically, Manufacturing Processes for Biologicals have been Monitored “Process is the Product” Philosophy  Surrogate Markers (pH, DO, metabolites Levels, etc. during fermentation) to Ensure Expected Process – Indicator of Purity  Microscopic Examination (Gram’s Staining) – Indicator of Purity  Immunochemical Methods (Flocculation Test [Lf, Kf], Agglutination, ELISA, etc.) – Indicator of Yield  Intermediate Products (Toxins for Lethality)

 Action Taken to Terminate or Continue Process 15


Analytical Methods for PAT & QbD  New and Modern Methods  Technological Development in Analytical Sciences and Instruments  Powerful Tools to Characterize Biologicals

 Developments in Proteomics and Genomics  Highly Sensitive, Precise and Accurate Methods to Characterize Biologicals and to Assess Purity of Biologicals

 Concept of Well Characterized Biologicals  Implemented Modern Analytical Methods  Not Applicable to Complex Biological Products, Vaccines at DP 16


Reliability of Methods for QbD  At Least as Reliable as Characterization Tests  Tests used Extensively during Development to Understand Product (Structure, Purity) and Mechanisms of Action (Proof of Concept)  Scientifically Sound, with Robust Method Design

 Usually Not Validated, Varying Degree of Qualification (Suitable for Intended Purpose)  Usually Not Part of Release Tests

 Used in Support of Process or Other Changes to Approved Applications

 Probes or Chips  Appropriately Validated and Periodically Calibrated and/or Verified 17


Selection of Analytical Methods/Probes  Purpose of Test (Monitoring)/Intended Use  To Measure Purity, Yield

 Preferably Online or Atline Monitoring or Rapid

 Sound Scientific Principles  Process Decisions and Quality Depend on Method

 Method Capability/Inherent Variability  Important for Process Decisions and in Defining Design Space

 Technology/Instrumentation  Compatible with Manufacturing Environment

 Big Picture Consideration – Same Technology/ Method with appropriate Design can be Used in Formulation, Pre-Clinical & Clinical Evaluation, Lot Release and Stability Testing 18


Design of Analytical Method  Sound Scientific Principles  Logistics  Critical Equipment, Software

 Critical Reagents  Reference Standards  Not Necessary for Monitoring Process Continuously (Relative)  Reference Standard Against Which Test Results are Calculated

 Controls – Part of System Suitability (Not Necessary)  Initial Measurements as Controls 19


Summary and Conclusions  New Paradigm of Building Quality in the Product rather than Testing of Representative Samples  Regulatory Agencies Support and Encourage Use of Quality by Design Approach for New Products  Design Manufacturing Process based on Sound Scientific Principles and Quality Risk Management Approach  Analytical Methods Play a Central Role in Assuring Quality of the Product  Analytical Methods Need to be Scientifically Sound and Reliable as the Outcome of Quality from the Process depends upon Methods 20
