Manufacturing of Pharmaceutical Proteins E-Book

Stefan Behme

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 629

Veröffentlichungsjahr: 2015

Beschreibung

Structured like a textbook, the second edition of this reference covers all aspects of biopharmaceutical manufacturing, including legal and regulatory issues, production facility design, and quality assurance, with a focus on supply chain management and regulations in emerging markets and cost control. The author has longstanding industrial expertise in biopharmaceutical production and years of experience teaching at universities. As such, this practical book is ideal for use in academia as well as for internal training within companies.

Leseprobe

Table of Contents

Cover

Related Titles

Title Page

Copyright

Dedication

Preface

Preface to First Edition

List of Abbreviations

Part I: Introduction

Chapter 1: Biopharmaceutical Production: Value Creation, Product Types, and Biological Basics Introduction

1.1 Role of Production in Pharmaceutical Biotechnology

1.2 Product Groups

1.3 Basics of Biology

Part II: Technology

Chapter 2: Manufacturing Process

2.1 Role of the Manufacturing Process in Biotechnology

2.2 Process Schematic and Evaluation

2.3 Cell Bank

2.4 Fermentation

2.5 Purification

2.6 Formulation and Filling

2.7 Labeling and Packaging

Chapter 3: Analytics

3.1 Role of Analytics in Biotechnology

3.2 Product Analytics

3.3 Process Analytics

3.4 Environmental Monitoring

3.5 Raw Material Testing

3.6 Product Comparability

Part III: Pharmacy

Chapter 4: Pharmacology and Drug Safety

4.1 Action of Drugs in Humans

4.2 Routes and Forms of Administration

4.3 Drug Study

4.4 Path of the Drug from the Manufacturer to Patients

4.5 Drug Safety

Part IV: Quality Assurance

Chapter 5: Fundamentals of Quality Assurance

5.1 Basic Principles

5.2 Benefit of Quality Assurance Activities

5.3 Quality Management According to ISO 9000

5.4 Structure of Quality Management Systems

5.5 Quality Management System Components in the Pharmaceutical Area

5.6 Quality Assurance in Development

Chapter 6: Quality Assurance in Manufacturing

6.1 GMP

6.2 Operative Workflows under GMP Conditions

6.3 Production of Investigational Drugs

Appendix A: Case Study Part 4:Warning Letters by FDA

Part V: Pharmaceutical Law

Chapter 7: Pharmaceutical Law and Regulatory Authorities

7.1 Fields of Pharmaceutical Law

7.2 Bindingness of Regulations

7.3 Authorities, Institutions, and Their Regulations

7.4 Official Enforcement of Regulations

7.5 Drug Approval

Appendix B: Case Study Part 5: Clinical Trials for Protein Products

B.1 Mabthera®/Rituxan®

B.2 Enbrel®

B.3 Remicade® Infliximab

B.4 Humira® 40 mg

B.5 Lucentis®

B.6 Zaltrap®

Part VI: Production Facilities

Chapter 8: Facility Design

8.1 Basic Principles

8.2 GMP-Compliant Plant Design

8.3 Basic Concepts for Production Plants

8.4 Clean and Plant Utilities

8.5 Equipment Cleaning

8.6 Clean-Rooms

8.7 Automation

8.8 QC Laboratories

8.9 Location Factors

Chapter 9: Planning, Construction, and Commissioning of a Manufacturing Plant

9.1 Steps of the Engineering Project

9.2 Project Schedules

9.3 Cost Estimates

9.4 Organization of an Engineering Project

9.5 Successful Execution of an Engineering Project

9.6 Legal Aspects of Facility Engineering

Part VII: Economy

Chapter 10: Production Costs

10.1 Drug Life Cycle

10.2 Position of the Manufacturing Costs in the Overall Cost Framework

10.3 Basic Principles of Cost Calculation

10.4 Costs of Biotechnological Manufacturing Processes

10.5 Accounting Methods

Chapter 11: Investments

11.1 Basic Principles

11.2 Value–Benefit Analysis

11.3 Investment Appraisal

11.4 Dynamic Payback Time

Chapter 12: Production Concept

12.1 Capacity Planning

12.2 Dilemma of In-House Manufacturing

12.3 Aspects of Manufacturing Outsourcing

12.4 Make-or-Buy Analysis

12.5 Process Optimization after Market Launch

12.6 Supply-Chain Management

Appendix C: Examples Part 7: Manufacturing Cost Calculation

C.1 Introduction

C.2 Basic Assumptions for Both Production Processes

C.3 Step 1: Production of Product 1 in Dedicated Facility

C.4 Step 2: Addition of a Second Product

References

Index

End User License Agreement

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Guide

Cover

Table of Contents

Preface

Part I: Introduction

Begin Reading

List of Illustrations

Figure 1.1

Figure 1.2

Figure 1.3

Figure 1.4

Figure 1.5

Figure 1.6

Figure 1.7

Figure 1.8

Figure 1.9

Figure 1.10

Figure 1.11

Figure 1.12

Figure 1.13

Figure 1.14

Figure 1.15

Figure 1.16

Figure 1.17

Figure 2.1

Figure 2.2

Figure 2.3

Figure 2.4

Figure 2.5

Figure 2.6

Figure 2.7

Figure 2.8

Figure 2.9

Figure 2.10

Figure 2.11

Figure 2.12

Figure 2.13

Figure 2.14

Figure 2.15

Figure 2.16

Figure 2.17

Figure 2.18

Figure 2.19

Figure 2.20

Figure 2.21

Figure 2.22

Figure 2.23

Figure 2.24

Figure 2.25

Figure 2.26

Figure 2.27

Figure 2.28

Figure 2.29

Figure 2.30

Figure 2.31

Figure 32

Figure 2.33

Figure 2.34

Figure 2.35

Figure 3.1

Figure 3.2

Figure 3.3

Figure 3.4

Figure 3.5

Figure 3.6

Figure 3.7

Figure 3.8

Figure 3.9

Figure 3.10

Figure 3.11

Figure 3.12

Figure 3.13

Figure 3.14

Figure 3.15

Figure 3.16

Figure 3.17

Figure 3.18

Figure 3.19

Figure 4.1

Figure 4.2

Figure 4.3

Figure 4.4

Figure 4.5

Figure 4.6

Figure 4.7

Figure 4.8

Figure 5.1

Figure 5.2

Figure 5.3

Figure 5.4

Figure 6.1

Figure 6.2

Figure 6.3

Figure 6.4

Figure 6.5

Figure 6.6

Figure 6.7

Figure 7.1

Figure 7.2

Figure 8.1

Figure 8.2

Figure 8.3

Figure 8.4

Figure 8.6

Figure 8.5

Figure 8.7

Figure 8.8

Figure 8.9

Figure 8.10

Figure 8.11

Figure 8.12

Figure 8.13

Figure 8.14

Figure 8.15

Figure 8.16

Figure 8.17

Figure 9.1

Figure 9.2

Figure 9.3

Figure 10.1

Figure 10.2

Figure 10.3

Figure 10.4

Figure 10.5

Figure 10.6

Figure 10.7

Figure 10.8

Figure 10.9

Figure 10.10

Figure 10.11

Figure 11.1

Figure 11.2

Figure 11.3

Figure 11.4

Figure 11.5

Figure 12.3

Figure 12.4

Figure 12.1

Figure 12.2

Figure 12.5

Figure C.1

Figure C.2

List of Tables

Table 1.1

Table 2.1

Table 2.2

Table 2.3

Table 2.4

Table 3.1

Table 3.2

Table 3.3

Table 3.4

Table 4.1

Table 4.2

Table 5.1

Table 5.2

Table 5.3

Table 6.1

Table 6.2

Table 6.3

Table 6.4

Table 7.1

Table 7.2

Table 7.3

Table 7.4

Table 8.1

Table 8.2

Table 8.3

Table 8.4

Table 8.5

Table 8.6

Table 8.7

Table 9.1

Table 10.1

Table 10.2

Table 10.3

Table 10.4

Table 11.1

Table 11.2

Table 11.3

Table 12.1

Table 12.2

Table 12.3

Table 12.4

Table C.1

Table C.2

Table C.3

Table C.4

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Stefan Behme

Manufacturing of Pharmaceutical Proteins

From Technology to Economy

Second, revised and expanded Edition

Author

Dr.-Ing. Stefan Behme

Chlumer Str. 3

12203 Berlin

Germany

Cover

Photo production facility: © Peter

Ginter

Figure communication:

iStockphoto © Kuzma

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Medical disclaimer

The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting a specific method, diagnosis, or treatment by medical care providers for any particular patient. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation, any implied warranties of fitness for a particular purpose. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. Readers should consult with a specialist where appropriate. The fact that an organization or Website is referred to in this work as a citation and/or a potential source of further information does not mean that the author or the publisher endorses the information the organization or Website may provide or recommendations it may make. Further, readers should be aware that Internet Websites listed in this work may have changed or disappeared between when this work was written and when it is read. No warranty may be created or extended by any promotional statements of this work. Neither the publisher nor the author shall be liable for any damages arising herefrom.

Preface

Taking your own book in your hands a couple of years after publishing is an exciting experience. Despite having received a lot of positive feedback, doubts never really vanish whether you would write the same text in the same manner again today. Well – after my editor's request to launch a second edition, I went through the entire text and still found it pretty useful – yes, I would write it again. Of course, I stumbled over some topics that I slightly rephrased or cleaned up. I also added useful features, for example, a checklist for contractual supply agreements, and some aspects that have lately gained increased attention by drug manufacturers in the supply chain field. Instructive real-life examples on clinical studies, quality audits, and manufacturing cost calculations now ammend the text with even more tangible content. The original scheme of the book however – keep it simple and speak through pictures and examples – has not been compromised. The concept of strong simplification has obviously been well received by many readers. So I am very happy to present the second edition of this book now and thank my editor Wiley-VCH for the ongoing support.

Berlin, 17 December

Stefan Behme

Preface to First Edition

This book introduces the basic knowledge of industrial manufacturing of biopharmaceuticals. It is written for those wanting to understand the landscape, interfaces, and interactions between the different disciplines relevant for production as such; aspects of technology and analytics, pharmacy, quality assurance, regulatory affairs, facility technology, and economic efficiency are illustrated. The work shall serve as a textbook and reference at the same time, and is directed toward students as well as industry-experienced engineers, pharmacists, scientists, or economists wanting to acquire a basic knowledge of biotechnological production.

My daily industrial practice has inspired this book. Manufacturing advanced drugs under good manufacturing practice conditions can indeed be a critical factor for drug development and marketing. Being part of multidisciplinary teams, it became obvious to me that the technological and economic challenges of biopharmaceutical manufacturing and its interdependencies with adjacent disciplines are not understood everywhere. Decision making in interdisciplinary teams requires communication and appreciation of the constraints on the various counterparts in order to address them efficiently in the overall program. In contrast to this, particular disciplines become more and more specialized, using their language on a level difficult to understand for the counterparts foreign to the field, sometimes flavoring modern project work with a taste of the tale of the Tower of Babel.

Facilitating communication about manufacturing issues is the goal of this book. It does so by using numerous illustrations and simplifications, making the book easy to read. Correlations between disciplines are highlighted by cross-references, and a detailed keyword index facilitates the search for special topics. After having read this book, the reader should have a high-level understanding of the roles, correlations between terminologies of the different disciplines engaged in the production of biopharmaceutical proteins. For those wanting to dig deeper into the topics, literature recommendations and web links are provided for further reading.

I would like to thank Andrea Rothmaler and Andreas Janssen for their valuable input into the manuscript, my students at the Technical University of Dortmund for their instructive questions, and my company Bayer Schering Pharma AG for providing the opportunity to participate in exciting biotechnological projects.

I hope that my readers will enjoy reading this book as much as I have enjoyed writing it.

Berlin, October 2008

Stefan Behme

List of Abbreviations

AA

Amino Acid (= AS)

ADR

Adverse Drug Reaction

AE

Adverse Event

AIEX

Anion Exchanger

AMG

Arzneimittelgesetz

AMWHV

Drug and drug manufacturing Regulation

AP

Aqua Purificata

API

Active Pharmaceutical Ingredient

APR

Annual Product Review

AR

Adverse Reaction (= ADR)

AR

Annual Report

ATP

Adenosine Triphosphate

AUC

Area Under the Curve

AVP

Aqua Valde Purificata

BAS

Building Automation System

BDS

Bulk Drug Substance

BLA

Biological License Application

BOD

Basis of Design

BP

Basen Pair

BR

Batch Record

BRR

Batch Record Review

BSE

Bovine Spongiforme Encephalopathie

CAPA

Corrective Action Preventive Action

CBE30

Changes Being Effected in 30 days

CDW

Cell Dry Weight

CFR

Code of Federal Regulations

CFU

Colony Forming Unit

cGMP

Current Good Manufacturing Practice

CI

Chemical Ionization

CIEX

Cation Exchanger

CIP

Cleaning in Place

CJD

Creutzfeldt–Jakob Disease

CMC

Chemistry, Manufacturing, and Control

CMO

Contract Manufacturing Organization

CoA

Certificate of Analysis

CoC

Certificate of Compliance

COP

Cleaning out of Place

CRF

Case Report Form

CTA

Clinical Trials Authorization

CTD

Common Technical Document, Clinical Trials Directive

CVMP

Committee for Medicinal Products for Veterinary Use

DIN

Deutsches Institut für Normung

DNA

Desoxyribonucleic Acid

DQ

Design Qualification

DSC

Differential Scanning Calorimetry

EBR

Electronic Batch Record

ED

Effective Dose

EDQM

European Directorate for the Quality of Medicines

EIS

Electron Impact Spectroscopy

ELISA

Enzyme Linked Immunosorbent Assay

EMA

European Medicines Agency

EP

European Pharmacopoeia (PharmEur)

EPO

Erythropoietin

FAB

Fast Atom Bombardment

FBS

Fetal Bovine Serum

FCS

Fetal Calf Serum

FDA

Food and Drug Administration

FMEA

Failure Mode and Effect Analysis

FP

Final Product, Finished Product

GAMP

Good Automated Manufacturing Practice

GCP

Good Clinical Practice

G-CSF

Granulocyte Colony Stimulating Factor

GEP

Good Engineering Practice

GFC

Gel Filtration Chromatography

GLP

Good Laboratory Practice

GM-CSF

Granulocyte Macrophage Colony Stimulating Factor

GMO

Genetically Modified Organism

GMP

Good Manufacturing Practice

GPC

Gel Permeation Chromatography

GSP

Good Storage Practice

GSS

Gerstmann–Sträussler Syndrom

GTP

Good Tissue Practice

HCP

Host Cell Protein

HIC

Hydrophobic Interaction Chromatography

HIV

Human Immunodeficiency Virus

HPLC

High Pressure Liquid Chromatography (also High Performance LC)

HPMC

Hydroxypropylmethyl-cellulose

HSA

Human Serum-Albumin

HVAC

Heat Ventilation Air Conditioning

ICH

International Conference on Harmonization

IEF

Isoelectric Focusing

JEC

Jon Exchange Chromatography

IEX

Ion Exchanger

IF

Interferon

IGG

Immunoglobulin G

IL

Interleukin

IMP

Investigational Medicinal Product

IMPD

Investigational Medicinal Product Dossier

IND

Investigational New Drug

IOM

Investigations Operations Manual

IPC

In-Process Control

IQ

Installation Qualification

IR

Infrared

ISO

International Organization of Standardization

ISPE

International Society for Pharmaceutical Engineering

JP

Japanese Pharmacopoeia

KPI

Key Performance Indicator

LADME

Liberation, Absorption, Distribution, Metabolism, Excretion

LAL

Limulus Amebocyte Lysate

LD

Lethal Dose

LFH

Laminar Flow Hood

LIMS

Laboratory Information Management System

LOD

Limit of Detection

LOQ

Limit of Quantification

MALDI

Matrix Assisted Laser Desorption Ionization

MBR

Master Batch Record

MCB

Master Cell Bank

MCO

Molecular Cut Off (MWCO)

MF

Microfiltration

MHLW

Ministry of Health, Labor, and Welfare

MSA

Manufacturing and Supply Agreement

MTD

Maximal Tolerated Dose

MWCO

Molecular Weight Cut Off

NDA

New Drug Application

NPV

Net Present Value

OOS

Out of Specification (QC Context) or Out of Stock (Logistical Context)

OQ

Operational Qualification

PAB

Pharmaceutical Affairs Bureau

PAGE

Polyacrylamid Gel Elektrophoresis

PAS

Prior Approval Supplement

PCR

Polymerase Chain Reaction

PD

Pharmacodynamics

PD

Plasma Desorption

PDA

Parenteral Drug Association

PEG

Polyethylene glycol

PFBS

Pharmaceutical and Food Safety Bureau

PharmEur

European Pharmacopoeia

PIC/S

Pharmaceutical Inspection Convention/Scheme

PK

Pharmacokinetics

PM

Posttranslational Modification

PMDA

Pharmaceutical and Medical Devices Agency (KIKO)

PoC

Proof of Concept (PoP)

PoP

Proof of Principle (PoC)

PQR

Product Quality Review

QA

Quality Assurance

QAA

Quality Assurance Agreement

QC

Quality Control

QM

Quality Management

rFVIII

Recombinant Factor VIII

RNA

Ribonucleic Acid

ROI

Return on Investment

RPC

Reversed Phase Chromatography

RP-HPLC

Reversed Phase HPLC

RPM

Regulatory Procedures Manual

SDS

Sodiumdodecylsulfate

SEC

Size Exclusion Chromatography

SIP

Sterilization in Place (also Steaming in Place)

SKU

Stock Keeping Unit

SOP

Standard Operating Procedure

SPC

Statistical Process Control

SPC

Supplementary Protection Certificate

TEM

Transmission Electron Microskopy

TFF

Tangential Flow Filtration

TOC

Total Organic Carbon

TOF

Time of Flight

TSE

Transmissible Spongiform Encephalopathie

UF

Ultrafiltration

URS

User Requirements Specification

USP

United States Pharmacopoeia

UV

Ultra Violett

WCB

Working Cell Bank

WFI

Water for Injection

WHO

World Health Organization

ZLG

Zentralstelle fur Gesundheitsschutz bei

Arzneimitteln und Medizinprodukten

Part I

Introduction

1Biopharmaceutical Production: Value Creation, Product Types, and Biological Basics Introduction

1.1 Role of Production in Pharmaceutical Biotechnology

Over recent years pharmaceutical biotechnology has developed very dynamically. An important driver for this success has been the enormous increase of scientific know-how in the areas of genetics and immunology, which has created huge expectations for the development of innovative medicinal treatments.

The scientific pioneer spirit has been fueled by public and private sponsorship, resulting in a biotechnological landscape that has long been dominated by highly innovative, venture capital-based, small- and mid-size companies. However, before patients can benefit from scientific achievements it is necessary that the identified molecule is transformed into a medicine – fit for achieving the therapeutic target – and tested in comprehensive trials in the field. The production of such a medicine has to be carried out in officially licensed, often tailor-made technical manufacturing facilities.

This1 path from project to product usually lasts several years, and is associated with enormous costs and risks. On average, the development costs of a new compound are in the region of US$500–1000 million and only 10% of all projects that enter clinical trials find their way into the market.