Quality for Biologics

Published by: Biopharm Knowledge Publishing

Published: Jan. 1, 2009 - 287 Pages

Table of Contents

Chapter 1

What Controls the Quality of a Biologic?

Alain Bernard PhD, Vice President, Global Process Development & Industrialization, UCB Group, Belgium

Dr Stefanos Grammatikos MSc PhD, Senior Director, Biological Process Development & Industrialization, UCB Group, Belgium

1. Introduction

2. Critical quality attributes: Aspects of a biological that may impact function and safety

2.1. Understanding and establishing critical quality attributes and validating them

2.2. The link between critical quality attributes and clinical safety and efficacy

2.3. When critical quality attributes should be established

2.4. Case studies, product recalls and safety alerts

2.4.1. EPO and EPREX® (erythropoietin)

2.4.2. Tysabri® (Natalizumab)

2.4.3. Recombinant Protein X

2.4.4. Anti-CD28 (TGN1412)

3. Impact of the process on the product

3.1. How the process can impact quality: raw materials

3.2. Critical process parameters

3.3. Influence of cell line on product quality

3.4. Design of the perfect process (high yield, consistency, high purity, fast and economical)

4. Setting the specifications

4.1. Analysis testing required for impurities, aggregation, post-translational modifications, physicochemical characterization and functional activity

4.2. Building an experience database

5. Comparability, product lifecycle management and regulatory guidelines

6. Regulatory perspectives

7. Conclusions

Chapter 2

Process Development and Technical Stewardship Through the Lifecycle of APIs Manufactured by Cell Culture/Fermentation

Graham McCartney PhD, Technical Lead Biotechnology, Eli Lilly, Ireland

1. Introduction

2. The importance of process understanding and process validation

2.1. Bioprocess development is driven by establishing criticality

2.2. Critical Quality Attributes

2.3. Critical Process Parameters

2.4. Process validation within a QbD environment

2.5. Ongoing technical stewardship and a lifecycle approach to process validation

3. Value of generic platforms for manufacturing processes

3.1. Introduction

3.2. Strategic aspects and practical application of a platform approach

3.3. Platform approaches: Implications for process development

4. Viral clearance requirements

Chapter 3

Process Analytical Technology (PAT): Application in Manufacturing of Biologics

Anurag S. Rathore PhD, Research Scientist, Process Development, Amgen Inc., USA

1. Introduction

2. Regulatory guidance

3. Approaches and applications

3.1. Reviews on PAT

3.2. Applications in fermentation and cell culture applications

3.3. Applications in refolding, filtration and ultrafiltration unit operations

3.4. Applications in process chromatography

3.5. Applications in freeze-drying, lyophilization and other drug product unit operations

3.6. Use of chemometric tools for statistical analysis

3.7. Economics of PAT

4. Summary including pitfalls of implementation of PAT in manufacturing

Part Two: Characterization and Analytical Methods

Chapter 4

Introduction: Characterization of the Biologic Product

Thomas Schreitmueller PhD, Head of Analytical R&D and Quality Control Biotech Products, F. Hoffmann-La Roche, Switzerland

1. The historical perspective

2. The current status

3. The perspective

4. Some examples

5. Conclusions

Chapter 5

Technology Selection for Physicochemical Characterisation

John O’Hara BSc PhD, Characterisation Group Leader, Analytical Research and Development, UCB-Celltech, UK

Andy Hooker BSc PhD, Senior Director of Analytical Research and Development, UCB-Celltech, UK

1. Introduction

2. Well characterised biologicals and specified biotechnology products

3. Heterogeneity of biopharmaceutical products and physicochemical testing

3.1. Heterogeneity of biopharmaceuticals

3.2. Physicochemical testing

4. Evolution in physicochemical characterisation during development

5. Physicochemical characterisation and bioactivity

6. Physicochemical lot release testing

7. Case studies

7.1. Physicochemical characterisation to identify PTMs

7.2. Physicochemical characterisation as part of comparability

7.3. Physicochemical characterisation as part of cell line selection

7.4. Physicochemical characterisation as part of forced degradation studies

Chapter 6

Bioassays for Lot Release and Comparability

C. Jane Robinson PhD Principal Scientist, Biotherapeutics, National Institute for Biological Standards and Control, UK

1. Introduction

2. Biological activity, potency, functional assays

3. Selection of appropriate bioassay systems

3.1. Theoretical considerations

3.2. Logistical considerations

4. Types of functional bioassay system

4.1. Readouts for cell-based potency assays

4.2. Early-stage in vitro bioassays

5. Binding assays

6. Immunoassays

7. Bioassays and unwanted immunogenicity

8. Assay variability, reference standards and relative potency

9. Assay Design

10. Assay precision

11. Surrogate potency assays

Chapter 7

Impact of Formulation Design on Stability and Quality

Dr Patrick Garidel, Department of Process Science, Formulation Development, Boehringer Ingelheim, Germany

1. How the choice of excipient can affect quality

2. Precautions regarding the use of animal derived materials

3. Industry experience with the use of novel materials

4. Potential impact of preservatives and anti-oxidants

5. Container closures, extractables and leachables: current thinking and recommended precautions

6. How to ensure stability of the product in the formulation

7. Robustness of formulation development studies

8. Potential for improved formulations to affect the critical quality attributes (eg Roferon with introduction of more robust formulation no longer has oxidation as a critical quality attribute)

9. Regulatory issues with optimising formulation

10. Further case studies

11. Factors affecting product stability

11.1. Excipients, lyophilisation etc

11.2. Issues to do with storage and stability from bulk to the patient

12. Genetic stability

13. Methods for stability testing

13.1. How to conduct real-time and accelerated stability studies

13.2. Levels of stability testing required

14. Application of analytical technologies to engineer a product with greater stability

15. ICH guidelines on stability testing

15.1. Acceptable levels of degradation products

15.2. Where investigators may go wrong

15.3. Common problems and pitfalls

Chapter 8

Specifications and Drug Substance for Lot Release

Siegfried Schmitt PhD MRSC CChem CSci, Principal Consultant, Parexel Consulting, UK

Ralf Hess MSc PhD, Principal Consultant, Parexel Consulting, Germany

1. EU and US perspectives on setting specifications

1.1. Implementation of ICH Q6B

1.2. Limitations of regulatory guidance with some biological products

1.3. Challenges of determining specifications in the absence of clear guidelines

2. Setting the specifications (acceptance criteria) and the action limits (critical product quality attributes) for quality control for specific products

2.1. Determining what is and is not relevant

2.2. Importance of having consistency of batches and a robust process

2.3. Utilising the appropriate clinical experience with sufficient product variability

2.4. Determining shelf life

3. How specification requirements tighten during development and how to update the package

4. How design space helps with the determination of specifications, especially for generic products outside the originator product specifications

5. Parametric release, i.e. real-time product release

5.1. Parametric release and drug product

5.2. Parametric release and drug substance

6. Methodologies that need validation

Part Three: Impurity Profiles and Product Variation

Chapter 9

Impurity Profile: How the Process can Impact on the Impurity Profile, and Characterisation of Product and Process Related Impurities

Stefan Zietze MSc PhD, Head of Quality Control,

Marco Riedel PhD, Director of Q A, Qualified Person,

ProBioGen, Berlin, Germany

1. Nature of product- and process-related impurities

2. Characterization of product- and process-related impurities

3. Impact of impurities on product quality

Chapter 10

Impact of the Process on Aggregation, and Technologies for Aggregation Analysis

Professor Nigel Jenkins, Principal Investigator, National Institute of Bioprocessing Research and Training (NIBRT), University College Dublin, Ireland

Dr Ray Tyther, Senior Scientist, NIBRT Laboratory, National Institute for Cellular Biotechnology (NICB), Dublin City University, Ireland

Dr Lisa Murphy, Senior Scientist, NIBRT Laboratory, National Institute for Cellular Biotechnology (NICB), Dublin City University, Ireland

1. Introduction

2. Interventions in the protein secretory pathway

3. Disulphide bond formation

4. Chaperones

5. Multiple gene activators

6. Environmental conditions

7. Analytical methods to detect misfolding and aggregation

8. Conclusions

Chapter 11

Importance of Non-Clinical Testing

Nadja Prang-Richard PhD MBA, Program Director for Monoclonal Antibodies, LFB, France and Co-Founder & Scientific Advisory Board Member, Lophius, Biosciences, Germany

1. Introduction

2. Regulatory aspects

3. In vitro systems

3.1. In vitro methods to assess toxicity

3.2. In vitro / ex vivo pharmacodynamic studies

4. In vivo systems

4.1. The relevance of the animal model

4.2. In vivo disease models

4.3. Secondary pharmacodynamic studies

4.4. Safety pharmacology studies

5. Pharmacokinetics

5.1. Pharmacokinetic parameters

5.2. Absorption

5.3. Distribution

5.4. Metabolism and elimination

6. Toxicology studies

6.1. Acute toxicity

6.2. Subacute toxicity (Repeated dose studies)

6.3. Immunotoxicity/ local tolerance studies

6.4. Genotoxicity studies

6.5. Reproductive performance and developmental toxicity studies

6.6. Carcinogenicity studies

7. Non-clinical testing in (BIO)pharmaceutical development

7.1. Risk assessment for new (bio)pharmaceuticals

7.2. Considerations for first in human (FIM)studies

7.3. (Bio)assays fit for purpose

7.4. Non-clinical studies required in different phases of pharmaceutical development

Part Four: Regulatory Considerations Regarding Product Quality

Chapter 12

Current Safety and Efficacy Concerns of the Regulatory Authorities

Frits Lekkerkerker MD, Former CHMP Member and Chairman, Medicines Evaluation Board, Netherlands, Member Advisory Board, NDA Regulatory Science Ltd

1. History

2. New regulatory guidance

3. Expectations of the regulatory authorities

3.1. The comparability exercise

3.2. Non-clinical studies

3.3. Clinical studies

3.4. Immunogenicity

3.5. Risk Management Plan

4. Where the industry tends to go wrong

4.1. The influence of manufacturing change on efficacy and especially safety are in general underestimated

4.2. Those responsible for quality assurance sometimes put too much trust in the reliability of quality testing procedures to show comparability after a change

4.3. Insufficient pre-change product for comparison

4.4. The timing of the change is important

4.5. Difficulties with immunogenicity assessment

4.6. Inadequate risk management plan

5. Will biologicals become harder to regulate?

Chapter 13

Requirements for an Effective CMC Regulatory Compliance Strategy

Steffen Gross, PhD, Laboratory Head and Scientific Assessor (Quality, Pre-clinic Section Monoclonal and Polyclonal Antibodies, Paul-Ehrlich-Institute, Germany

1. Introduction

2. CMC requirements for dossier filing

2.1. Manufacturing process

2.2. Characterisation and analysis

2.3. Stability

3. Development of a product - interaction with regulatory authorities

3.1. Clinical trial applications

3.2. Scientific Advice

Chapter 14

Regulatory Considerations in Performing Comparability Studies for Biotechnology Products: An Industry Perspective

Wassim Nashabeh Ph.D., Director, CMC Regulatory Affairs,

Ron Taticek Ph.D., Director, CMC Regulatory Affairs,

Reed J. Harris, BSc, Senior Director, Protein Analytical Chemistry

Genentech, Inc., USA

1. Introduction

2. Definitions and scope

3. General principles

3.1. Risk-based approach to comparability

3.2. Comparator lot selection

3.3. Product comparability strategy

3.4. Selection of chemical and biological/functional methods

3.5. Acceptance criteria for product comparability

3.6. Acceptance criteria for analytical profile comparisons

3.7. Process impurities

3.8. Stability

4. Reporting Requirements

Supplement: A QbD Approach to Biopharmaceutical Glycosylation

Dr Daryl Fernandes, Chief Executive, Ludger Ltd

Part 1 - Importance of glycosylation to developers and manufacturers of glycoprotein therapeutics

1. Introduction

1.1. The nature of biopharmaceutical glycosylation

2. Why measure quality of biopharmaceutical glycosylation?

2.1. Glycosylation can significantly influence biopharmaceutical efficacy

2.1.1. Erythropoietin (EPO)

2.1.2. Glycoprotein hormones

2.1.3. Antibody glycosylation can affect both Fab and Fc functions

2.2. Aberrant glycosylation can impact product safety

2.2.1. Alpha-Galactose

2.2.2. Non-human sialylation - NeuGc

2.2.3. Other non-human glycosylation

2.3. Glycosylation can enhance the product safety profile

2.4. Glycosylation affects product consistency

2.5. Increasing regulatory pressure and best practice guidelines for checking the quality of glycosylation

2.6. Glycosylation profiles can be used in patent protection of biopharmaceuticals

2.7. Glycosylation quality affects profitability and commercial competitiveness

3. Glycosylation and risk in biopharmaceutical production

4. Steps for setting up a glycosylation quality system

4.1. Understand glycosylation in the natural molecule

4.2. Determine glycoimportance in vivo

4.3. Consider glycosylation quality throughout the drug life cycle

4.4. Define glycosylation design and control spaces

4.4.1. Set molecular specifications using glycosylation critical quality attributes (GCQAs)

4.4.2. Set measurement specifications

Part 2 - Glycoprofiles and Glycoprofiling

1. Introduction

2. Monosaccharide profiling

2.1. Neutral monosaccharide profiling

2.2. Sialic acid profiling

3. Oligosaccharide profiling

3.1. Glycan release

3.2. Post-release purification

3.3. Labelling and derivatisation

3.4. HPLC

3.4.1. Amide HPLC

3.4.2. Reverse phase HPLC

3.4.3. HPAE-PAD and HPAE-FD

3.4.4. Anion Exchange (AEX) HPLC

3.4.5. EI (Electron Interaction) HPLC

3.4.6. Assignment of HPLC peaks

3.5. Oligosaccharide profiling by CE

3.6. Oligosaccharide profiling by MS and LC/MS

3.7. Exoglycosidase sequencing of oligosaccharides

3.8. Combining HPLC, CE and MS for detailed glycoprofiling

4. Glycosylation site profile

5. Glycoform profile

6. Glycoprofiling throughout the drug life cycle

6.1. Glycoprofiling in early stages of drug development

6.2. Glycoprofiling during process optimisation and scale up

6.3. Glycoprofiling for regulatory submissions

6.4. Glycoprofiling during production - PAT and lot release

6.5. Reviewing and improving your glycoprofiling quality system

7. Conclusions

About the Contributors

Abstract

• Critical quality attributes
• Manufacturing process parameters
• Process analytical technology
• Physicochemical analysis,
• Bioassays,
• Formulation and specifications
• Product- and process-related impurities
• Aggregation
• Non-clinical testing
• Clinical development,
• Post-marketing period
• Regulatory authority expectations
• Risk management
• Comparability concerns

• UCB
• UCB-Celltech
• Eli Lilly
• Amgen
• Roche
• Parexel Consulting
• Genentech

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