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Herausgeber: John Wiley & Sons
Kategorie: Wissenschaft und neue Technologien
Sprache: Englisch

Beschreibung

Essential information for architects, designers, engineers, equipment suppliers, and other professionals who are working in or entering the biopharmaceutical manufacturing field Biomanufacturing facilities that are designed and built today are radically different than in the past. The vital information and knowledge needed to design and construct these increasingly sophisticated biopharmaceutical manufacturing facilities is difficult to find in published literature--and it's rarely taught in architecture or design schools. This is the first book for architects and designers that fills this void. Process Architecture in Biomanufacturing Facility Design provides information on design principles of biopharmaceutical manufacturing facilities that support emerging innovative processes and technologies, use state-of-the-art equipment, are energy efficient and sustainable, and meet regulatory requirements. Relying on their many years of hands-on design and operations experience, the authors emphasize concepts and practical approaches toward design, construction, and operation of biomanufacturing facilities, including product-process-facility relationships, closed systems and single use equipment, aseptic manufacturing considerations, design of biocontainment facility and process based laboratory, and sustainability considerations, as well as an outlook on the facility of the future. * Provides guidelines for meeting licensing and regulatory requirements for biomanufacturing facilities in the U.S.A and WHO--especially in emerging global markets in India, China, Latin America, and the Asia/Pacific regions * Focuses on innovative design and equipment, to speed construction and time to market, increase energy efficiency, and reduce footprint, construction and operational costs, as well as the financial risks associated with construction of a new facility prior to the approval of the manufactured products by regulatory agencies * Includes many diagrams that clarify the design approach Process Architecture in Biomanufacturing Facility Design is an ideal text for professionals involved in the design of facilities for manufacturing of biopharmaceuticals and vaccines, biotechnology, and life-science industry, including architects and designers of industrial facilities, construction, equipment vendors, and mechanical engineers. It is also recommended for university instructors, advanced undergraduates, and graduate students in architecture, industrial engineering, mechanical engineering, industrial design, and industrial interior design.

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Leseprobe

Cover

Title Page

Dedication

Contributors

Foreword

Preface: Why a Book on Process Architecture?

Chapter 1: Introduction to Biomanufacturing

1.1 Introduction

1.2 The Basic Constituents of Biopharmaceuticals

1.3 Enterprise Element #1—Manufacturing Processes

1.4 Enterprise Element #2—Manufacturing Facility

1.5 Enterprise Element #3—Manufacturing Infrastructure

1.6 Controlling the Manufacturing Enterprise

1.7 Summary

References

Chapter 2: Product–Process–Facility Relationship

2.1 Introduction

2.2 The Characteristics of Biological Therapeutic Products

2.3 Understanding the Attributes

2.4 Factors that Impact Facility Design

References

Chapter 3: Regulatory Considerations of Biomanufacturing Facilities

3.1 Introduction

3.2 Regulatory “Uncertainty,” A Two-Way Street

3.3 Design with the Patient in Mind: Assess the Patient, Product, Process, and Plant

3.4 Laws, Regulations, and Guidelines: Historical Background

3.5 Global Guidance Documents

3.6 Quality Systems and Risk Management

3.7 Product Changeover and Regulatory Assessment of Cleaning Validation

3.8 Control Strategy

3.9 Contract Manufacturing Organizations

3.10 FDA Inspections of Biopharm Facilities and Regulators' Priorities

3.11 Regulatory Meetings

3.12 Conclusion

References

Chapter 4: Biopharmaceutical Facility Design and Validation

4.1 Introduction

4.2 Designing for Compliance

4.3 Risk Management

4.4 Qualification/Verification

4.5 Process Validation

4.6 List of Abbreviations

References

Chapter 5: Closed Systems in Bioprocessing

5.1 Introduction

5.2 Definition of Closed Systems

5.3 Closed System Design

5.4 Impact on Facility Design

5.5 Impact on Operations

5.6 Summary

References

Chapter 6: Aseptic Manufacturing Considerations for Biomanufacturing Facility Design

6.1 Introduction

6.2 The Relationship to Biological Products

6.3 Process Attributes—Product Protection

6.4 Facility Design

6.5 Critical Area

References

Chapter 7: Facility Control of Microorganisms: Containment and Contamination

7.1 Introduction

7.2 Design Principles for Controlling Microorganisms

7.3 Controlling Viable Environmental Particulates

7.4 Reducing the Transport of Mold into the Bioprocess Facility

7.5 Reducing Mold Sources within the Bioprocess Facility

7.6 Biocontainment: An Overlay to Process Design

7.7 The Biocontainment Regulatory Environment

7.8 Principles of Biosafety

7.9 Principles of Biocontainment Facility Design

7.10 Design for the Entire Process

7.11 Conclusion

References

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Guide

Cover

Table of Contents

Foreword

Preface

Begin Reading

List of Illustrations

Chapter 1: Introduction to Biomanufacturing

Figure 1.1 The manufacturing enterprise is composed of three elements. Basically, the enterprise operates the process within the facility under the control of the infrastructure. The process and the facility are separate entities that can be run independently with the infrastructure providing the interface between the two. As shown in the side figure, the process is contained within the facility. The infrastructure element resides partially within the facility because the infrastructure is composed of both facility-specific and companywide, multifacility components.

Figure 1.2 Proteins are a polymer of the 20 amino acids listed in Figure 1.3. They are typically between 100 and 1500 amino acids in length. The term

peptide

refers to amino acid polymers of <25 amino acids.

Figure 1.3 While the Earth's natural environment contains hundreds of different amino acids, all life forms use only the 20 amino acids shown.

Figure 1.4 The central dogma describes the

replication

of DNA that allows the genetic information to be passed to future generations;

transcription

converts the DNA sequence code for the protein into RNA for transmission to the

translation

mechanism that converts the RNA sequence code into the amino acid sequence that determines the protein's primary structure.

Figure 1.5 All cells operate using catabolic metabolisms that generate energy for the cell by converting energy-containing raw materials into energy-depleted by-products. Anabolic metabolisms use the energy to convert other raw materials into complex molecules required to operate the cells metabolisms and support cell reproduction. The product protein is one of the complex molecules.

Figure 1.6 The process element of the manufacturing enterprise includes the unit operations required to make the product along with the equipment implementation of the process and the raw and in-process materials required to make the product.

Figure 1.7 A typical biopharmaceutical process is initiated from a cell bank containing cells whose DNA have been modified using recombinant technology into an inoculum train composed of a sequence of small bioreactors. After a sufficient number of cells are grown and the product produced in the main production bioreactor, the cells and product are separated in a harvest or recovery step. The product is then purified to an appropriate level for eventual formulation into a final dosage form for administration to the patient.

Figure 1.8 An overview of the mass and energy transfer required for the cell metabolisms to function correctly.

Figure 1.9 Upstream cell culture unit operation sequence, including initiation from a cell bank through to the final inoculum bioreactor. The inoculum train can vary widely depending on the sequence of small-scale bioreactors used to expand the culture. A key element of the inoculum train is to maintain the cell density above the minimum required for growth and below the maximum cell density supported by the bioreactor's mass transfer capabilities. Fermentation seed sequences are much simpler and faster because of the very rapid growth rate. No minimal cell density is required for propagating prokaryote cells.

Figure 1.10 The key features of a production bioreactor required for operating and managing the mass and energy balances of the cell metabolisms shown in Figure 1.5 and 1.8.

Figure 1.11 Typical monoclonal antibody (mAb) purification process. The mAb is selectively removed by the AC step. Protein A is usually the active ligand that captures the product mAb. The mAb is eluted in a low pH buffer that is then held under controlled conditions to inactivate viral contamination. The solution is then passed through an anion exchange (AEX) chromatography column to remove negatively charged contaminates, including any contaminating protein A from the affinity column. After viral filtration, the mAb is placed into the correct buffer for cryogenic storage in a sterile container. Additional steps may be added depending on the nature of the impurities and contaminates and the purity requirements of the final product.

Figure 1.12 Tangential flow filtration (TFF) process is a pressure-driven process. The TFF unit is supplied by a pump fed from the feed tank. The permeate contains the liquid and smaller particles or ion species that have passed through the membrane. The retentate, which can be removed or returned to the feed tank, contains the particles or ion species retained by the membrane.

Figure 1.13 Different types of membranes used in TFF provide a powerful tool for selecting particles or ion species in solution and can be used for a wide range of separations from harvesting cells from media to purifying sea water through reverse osmosis membranes capable of removing monovalent salts.

Figure 1.14 Chromatography process flow diagram—the column is fed through the required sensors from a bank of buffer feed tanks for preparing the column resin, loading the feed material, eluting the product from the column, and cleaning and washing the column after use. After passing through a detector that measures protein concentration, the outflow of the column is sent to a variety of vessels appropriate to receive the material. One of the vessels receives the eluted product depending on the time the product is scheduled and detected to elute from the resin bed.

Figure 1.15 Basic principle behind size exclusion chromatography (SEC). The larger species come out first because their large size limits them to a much shorter pathway through the resin. The small species have a longer effective path length because they can go through the numerous smaller channels in the resin and thus take longer to travel the bed's length. In the example shown, the product is the center peak while the first peak might be aggregates of the product and the last peak a product fragment caused by degradation of the product during upstream processing.

Figure 1.16 Illustrative example of the options for separating protein species in complex solutions using differences in reversible adsorption on a fixed resin chromatography bed. In this example, the column is loaded at time = 0 with four different protein species (A, B, C, and D). Protein species A passes through the column, whereas B, C, and D are bound. The buffer pH and/or counter-ion concentration flowing through the column is changed to form a gradient as shown. Weakly bound B is removed first, followed by C as the buffer concentration of one or more components increases. In this example, C is most likely the product. After C is eluted, the tightly bound D is removed using a high concentration cleaning or stripping buffer.

Figure 1.17 Summary of process inputs (parameters) and outputs (attributes), and how they are used to describe the process's performance in terms of CPRs and CPPs (COP, CMP, and CDP) to control the quality of the product as defined by the product's CQAs.

Figure 1.18 Cartoon showing the impact of skid-mounted SUSs on facility interdependencies. The enterprise elements shown in Figure 1.1 and 1.6 are integrated using the infrastructure element that coordinates and controls the performance of the process element within the facility element to assure a high quality product.

Figure 1.19 Expanding on Figure 1.1, the facility element is the facility's layout, environmental control features, utility systems, and facility controls required for providing the process with the necessary support and protection.

Figure 1.20 Basic in-process, personnel, and waste flows are required between unit operations, including supporting preparation areas.

Figure 1.21 Basic facility layout with flow control between areas. Processes located in the common areas would be commingled and separated by a segregation strategy based on closed equipment of the type provided by single use systems or highly automated SS systems. Note that media and buffer preparation operations in this layout would be carried out within the operating space.

Figure 1.22 The basic HVAC elements are shown. The air handling unit (AHU) pushes air into the rooms through appropriate filters. Clean rooms are supplied through in-line HEPA (high efficiency particulate air) filters in the ducts or terminal HEPAs in the duct outlets into the operating spaces. The air is removed from the room via air return duct to the AHU or vented outside the facility after appropriate filtration to remove possible process contaminates. For discussion purposes, the AHU shown supplies all four areas. In practice, the AHUs would be limited to supplying areas with common process separation requirements based on a well-defined segregation strategy.

Figure 1.23 Summary table of the most frequent clean room classifications according to the three most commonly used standards. The archaic, out of date Federal Standard 209E is still frequently used by many to identify the categories formally defined in the ISO 14644 and EUA-cGMP standards [33]. Although not an exact correlation, the three standards generally agree. Table also shows typical ranges for airflow velocities in the room and/or in laminar flow areas, room air change rates, and percent ceiling coverage for the classifications. Airflow velocities at the surface of HEPA filters is usually between 70 and 110 ft/min. Airflow rates above approximately 100 ft/min are turbulent.

Figure 1.24 Schematic of the utility systems relationship to the manufacturing core containing the process unit operations.

Figure 1.25 The infrastructure element of the manufacturing enterprise provides command and control of the entire manufacturing operation composed of the process and facility elements.

Figure 1.26 The enterprise elements are controlled by the practices defined in the infrastructure's practices defined in the policies and procedures. These practices are referred to as the

enterprise good manufacturing practices

(

GMPs

Figure 1.27 The second responsibility of the infrastructure is to provide “proof of control.”

Chapter 2: Product–Process–Facility Relationship

Figure 2.1 Protein manufacturing.

Figure 2.2 The product-process-facility continuum.

Figure 2.3 Basic biomanufacturing process steps.

Figure 2.4 (a) Extracellular product diagram. (b) Intracellular product diagram.

Figure 2.5 Cell culture growth curve

Figure 2.6 ADME components.

Chapter 4: Biopharmaceutical Facility Design and Validation

Figure 4.1 Block flow adjacency diagram.

Figure 4.2 Equipment flow diagram.

Figure 4.3 Personnel flow diagram.

Figure 4.4 Segregation diagram. [courtesy of International Society of Pharmaceutical Engineering.]

Figure 4.5 Facility layout adjacency diagram with flows.

Figure 4.6 Air lock configurations.

Figure 4.7 QbD approach steps.

Figure 4.8 Design space model.

Figure 4.9 Manufacturing control strategy.

Figure 4.10 Chart from ICH Q9.

Figure 4.11 Sample risk matrix.

Figure 4.12

Figure 4.13 Ishikawa diagram of CPPs for a production bioreactor.

Figure 4.14 Evolution of commissioning and qualification.

Figure 4.15 Good engineering practice.

Figure 4.16 Verification process flow.

Chapter 5: Closed Systems in Bioprocessing

Figure 5.1 Primary and secondary containment boundaries are defined by elements of the facility design, and include the use of closed systems to provide both product protection and environmental containment.

Figure 5.2 Closed system design example for in-process sampling.[Drawing courtesy of CRB Consulting Engineers, Kansas City, Missouri]

Figure 5.3 The NOVA septic NovaSeptum system with a presterilized component.[Photograph courtesy of NOVA Septic-Millipore, Gothenburg, Sweden]

Figure 5.4 Traditional approach to clean room design; large areas of classified space where closed systems were often not implemented.[Graphic courtesy of Flour Corporation, Greenville, South Carolina]

Figure 5.5 Implementing a predominately closed system approach: the layout of Figure 5.4 looks different, as the actual amount of classified space is dramatically reduced.[Graphic courtesy of Flour Corporation, Greenville, South Carolina]

Figure 5.6 The evolution of classified space design, from large open areas (Case 1) to current implementation of closed system design philosophy as defined by ICH Q7.[Graphic courtesy of ISPE, from the “Biopharmaceutical Facilities Baseline Guide, Volume 6.”]

Figure 5.7 Sample port locations inside a clean vestibule space sketch (a) and photograph (b). The creation of the vestibule allowed for sample collection inside a classified clean room space while reducing overall area of clean manufacturing space. [Sketch and photograph courtesy of Biogen, Research Triangle Park, North Carolina]

Figure 5.8 The RAFT (rapid aseptic fluid transfer) system, based on Biosafe Technology by Stedim, allows aseptic zone-to-zone transfer of fluids via closed transfer system and is used by many companies.[Photograph courtesy of Sartorius Stedim Biotech, Copenhagen]

Chapter 6: Aseptic Manufacturing Considerations for Biomanufacturing Facility Design

Figure 6.1 Closed system sequence.

Figure 6.2 A diagram of a closed process system boundary.

Figure 6.3 Kleenpak sterile connector courtesy of Pall Corporation.

Figure 6.4 HVAC pressure diagram (courtesy of IPS).

Figure 6.5 Example of flow diagrams for personnel, materials, and product as required by the FDA.

Figure 6.6 Facility segregation transitions zones.

Figure 6.7 System integrity capability to ensure sterility and product protection.

Figure 6.8 Schematic view of RABS unit (open RABS shown).

Figure 6.9 Schematic view of isolator unit.

Chapter 7: Facility Control of Microorganisms: Containment and Contamination

Figure 7.1 Anteroom/airlock airflow models.

Figure 7.2 Anteroom/airlock airflow model for combining clean and contained directional airflow. This model is balanced toward clean airflow and would not meet containment best practice for pathogen use of high risk.

Figure 7.3 Anteroom/airlock airflow model for combining clean and contained directional airflow. This model is balanced toward containment airflow and would not meet cGMP best practice for aseptic production of biopharmaceuticals.

Figure 7.4 Example of anteroom/airlock airflow model for combining clean and contained directional airflow. 1. Clean airlock to support classification and provide area for donning of gown and PPE. 2. Pass-through pressure bubble to maintain directional airflow. Potentially contaminated airlock for removal of outer gowning on exit, storage of any PPE remaining in containment, and storage of supplies for emergency cleanup protocols. Provide hand washing sink in 3. Figure shows two-way personnel flow. One-way personnel flows will be different.

Chapter 8: Process-Based Laboratory Design

Figure 8.1 R&D Bioreactor/Fermentation laboratory, customized design of vertical shafts with supplies and tables.

Figure 8.2 Laboratory planning and design value chain.

Figure 8.3 Cost savings versus design completion.

Figure 8.4 Traditional versus Frontloaded design method.

Figure 8.5 One-page strategy.

Figure 8.6 Example of typical day work flow and overall activity analysis.

Figure 8.7 Overview of a typical quality risk management process.

Figure 8.8 Diagram for addressing biorisk—risk characterization and risk evaluation.

Figure 8.9 Operational flow diagram, quality control laboratory.

Figure 8.10 Operational flow diagram,

in vivo

drug development laboratory.

Figure 8.11 Process flow for a quality laboratory.

Figure 8.12 Overall functional relation diagram example, indicating main functionalities with gray boxes and support/administrative functions as white boxes.

Figure 8.13 Room typology example—illustration of the first step of typology development.

Figure 8.14 Room typology examples—illustration of the second step of typology development.

Figure 8.21 Minimum recommended distance fume hood sash and table top.

Figure 8.22 Recommendation for distance between facing BSCs.

Figure 8.15 QC laboratory area distribution, gross square meter.

Figure 8.16 Laboratory concept evaluation example.

Figure 8.17 Using standard QC test time as basis for capacity planning.

Figure 8.18 Realized capacity numbers QC laboratory (confidential customer).

Figure 8.19 Example of a translated design driver of defined flexibility into a concept—with a requirement of changeability from laboratory setting to IVC animal holding (and vice versa) within 2–4 weeks.

Figure 8.20 Laboratory objectives diagram.

Figure 8.23 Section in laboratory building.

Figure 8.24 SHE areas to be considered during project initiation.

Chapter 10: Addressing Sustainability in Biomanufacturing Facility Design

Figure 10.1 Triple bottom line Venn diagram.

Figure 10.2 Commercial building energy consumption by end use.

Figure 10.3 Floor plan diagram illustrating a fixed 1000-L bioreactor space with the outline of two disposable suites, showing 50% more area available [28].

Figure 10.4 Airflow diagram in cell production suite [28].

Figure 10.5 Typical effect of load/ECWT-VFD drive. Red = 85F ECWT; Blue = 75F ECWT; and Green = 65F ECWT [42].

Figure 10.6 Compressed air diagram illustrating that only approximately 10% of the energy used by the compressed air system is embodied in the air delivered to the end user. The rest is lost in the form of heat, misuse, treatment, or distribution loses. Simple, cost-effective measures can be used to reduce losses resulting in energy savings of approximately 30% without major equipment replacement.

Figure 10.7 Phases of retro commissioning.

Figure 10.8 Five steps to best practice metering and submetering.

Figure 10.9 Understanding facility energy consumption.

Chapter 11: Technology's Impact on the Biomanufacturing Facility of the Future

Figure 11.1 Typical fixed SS bioreactor systems integrated with the facility. [Courtesy IPS.]

Figure 11.2 Portable single-use biomanufacturing system process flow diagram. [Courtesy of IPS.]

Figure 11.3 (a) The fixed SS process system is designed and connected to the facility and infrastructure as three highly integrated elements. (b) The single-use process systems are much less connected to the facility and infrastructure elements.

Figure 11.4 Using the new technologies, the facility elements are decoupled allowing them to be easily moved or modified to allow relocation, replication, or scale-out of manufacturing processes.

Figure 11.5 Modular clean room POD. [Courtesy of G-CON.]

Figure 11.6 Traditional biomanufacturing facility BFD. The solid arrows represent hard piped SS connections between the manufacturing and support systems.

Figure 11.7 SUS replace fixed stainless steel systems.

Figure 11.8 Reduced utility requirements.

Figure 11.9 SU, single operating area, and EBR-based facility solution provide complete control of all operations assuring and proving product quality.

Figure 11.10 Multiproduct commingled processes in common space. Unidirectional flow used to aid in procedural control of incoming materials and waste flows.

Figure 11.11 Carbon footprint reduction in pounds/batch. The use of disposable (DISP) systems is compared to stainless steel (SS) systems.

List of Tables

Chapter 2: Product–Process–Facility Relationship

Table 2.1 The Number of Amino Acids in Common Therapeutic Proteins

Table 2.2 Clinical Trial Phases

Table 2.3 Clinical Production

Table 2.4 Pilot Plant

Table 2.5 GMP Commercial Manufacturing

Chapter 4: Biopharmaceutical Facility Design and Validation

Table 4.1 QTPP Example

Table 4.2 Differences in Traditional Approach Versus Risk-Based Approach

Chapter 7: Facility Control of Microorganisms: Containment and Contamination

Table 7.1 Risk Groups for Pathogenic Organisms

Chapter 9: Case Study: Pharmaceutical Pilot Plant Design and Operation

Table 9.1 Types of Processing Equipment and Utilities Possibly Required for a Bioprocessing Pilot Plant

Table 9.2 Transfer Lines and Utility Piping Possibly Required for a Bioprocessing Pilot Plant

Table 9.3 Comparisons of Example Plant Steam and Clean Steam Achievable Quality

Table 9.4 Comparison of Example USP-Purified Water, Deionized Water, and Process Water Achievable Quality Attributes

Table 9.5 Comparisons of Example Controlled and Noncontrolled Area Achievable quality Based On Room Design in a Pilot Plant Facility

Table 9.6 Types of Testing (Sampling and Analysis) Possibly Required by On-Site or Off-Site Support Laboratories for a Bioprocessing Pilot Plant

Table 9.7 List of Example Types of Procedures that are Possibly Required for a Bioprocessing Pilot Plant

Chapter 10: Addressing Sustainability in Biomanufacturing Facility Design

Table 10.1 Annual Cost of Compressed Air System Leaks [50]

Process Architecture in Biomanufacturing Facility Design

Edited by

Jeffery Odum

NNE, Durham, North Carolina, USA

and

Michael C. Flickinger

Biomanufacturing Training and Education Center (BTEC),

North Carolina State University, Raleigh, North Carolina, USA

This edition first published 2018

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.

The right of Jeffery Odum and Michael C. Flickinger to be identified as the authors of the editorial material in this work has been asserted in accordance with law.

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This book is dedicated to our families, who tolerate and endure the consistently inconsistent nature of our schedules and timeline when developing this type of knowledge tool. Your patience is both appreciated and amazing.

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Contributors

Josh Capparella

Precis Engineering, Inc.

Ambler

Pennsylvania

USA

Samuel Colucci

Precis Engineering, Inc.

Ambler

Pennsylvania

USA

Daniel Conner

Precis Engineering, Inc.

Ambler

Pennsylvania

USA

Jonathan Crane

HDR, Inc.

Atlanta

Georgia

USA

Robert Dick

Precis Engineering, Inc.

Ambler

Pennsylvania

USA

Beth H. Junker

Bioprocess R&D

Merck Research Laboratories

Rahway

New Jersey

USA

Flemming K. Nielsen

NNE A/S

Gentofte

Denmark

Jeffery Odum

NNE

Durham

North Carolina

USA

Larry Pressley

IPS

Morrisville

North Carolina

USA

Kip Priesmeyer

Kip Priesmeyer & Associates, LLC

St. Louis

Missouri

USA

Hartmut Schaz

NNE

Frankfurt

Germany

Henriette Schubert

NNE A/S

Gentofte

Denmark

Amanda Weko

AGW Communications

Haddonfield

New Jersey

USA

Mark F. Witcher

NNE

Durham

North Carolina

USA

Foreword

Architecture evokes an interaction between fabricated space, form, and human activity. It can be a modest human-scale design or an awe-inspiring monumental work of art. Every architecture has both synergy and limitations. The synergy and limitations can be site, materials, artisanship, climate, government regulations, and certainly resources and budget.

Process Architecture in Biomanufacturing Facility Design is the first volume specifically written for architects, designers, and facility engineers to introduce the unique synergy between bioprocessing–biological medicines–people–facility and the limitations imposed by government regulatory requirements for the safe production of complex human biologics or vaccines by living cells.

Jeffery Odum has carefully assembled contributions into a unique and useful volume that explains the synergy of biopharmaceutical product, a carefully controlled process, equipment, GMPs, and facility design. This work explains how bioprocess architecture—the actual steps in the manufacturing process—affects the design of the manufacturing space and how people operating biological processes within this space produce, purify, formulate, and minimize contamination of potent human medicines.

Training a new generation of architects, designers, and engineers is particularly important now as the types and scale of biological medicines derived from living cells are rapidly expanding. Facilities to manufacture biological medicines for long-term care of chronic or degenerative human diseases are being built today. These new facilities will be capable of producing very large volumes of biologics (10,000 kg of active pharmaceutical ingredient or biologic per year) to meet the anticipated demand for treating hundreds of millions of patients over a long period. Examples of these large-scale biomanufacturing needs are facilities to produce biological medicines for treating diabetes, or Alzheimer's.

These facilities also need to be flexible. Many new facilities will be significantly smaller (reduced footprint, reduced construction costs, reduced utility, water, and solid waste requirements per kg product) to speed construction, reduce financial risk, and to meet requirements of new sites. Examples are new facilities to rapidly manufacture millions of doses of vaccines and adjuvants to meet global pandemics that have recently been built to improve regional vaccine quality. Vaccines can be complex multicomponent biologics manufactured by multistep processes. However, they must be manufactured as new products each year (often combining new antigens) seasonally. These facilities need to be operated efficiently with standardized automation for biologics to be compliant and cost effective.

In contrast, the emerging field of patient-specific biologics and cell therapy requires a completely different process architecture approach to facility design as each product may be derived from cells from a single patient destined to be immunologically or genetically altered and returned to that same patient. Product isolation and facility design to minimize product bioburden contamination are critical for these types of processes.

Process Architecture in Biomanufacturing Facility Design is an important new work to accelerate the design of a new generation of efficient, flexible, cost-effective, and compliant biomanufacturing facilities to deliver life-changing biologics and vaccines to patients worldwide.

Michael C. Flickinger, Professor, PhD

Preface: Why a Book on Process Architecture?

Process Architecture may not be a term that many people are familiar with in the context of this field. Most people relate this term to computer hardware and software design or business processes such as logistics or enterprise systems. The structure of a process system, or its architecture, is viewed as the hierarchy and relationship of a process system's components. But within the global biopharmaceutical industry, the term has a completely different meaning and holds a key strategic place in the list of activities necessary to develop a drug or biologic manufacturing facility design that meets regulatory compliance requirements.

For biopharmaceutical drug and vaccine manufacturing facilities, the relationship between product, process, and facility requires synergy across architecture and engineering disciplines, which is driven by a set of legally binding guidelines known as current good manufacturing practices, or the cGMPs.1 These strict regulatory guidelines are the foundation of current drug safety practice related to how these specialized facilities are licensed and operated. The critical first steps in developing concepts for proper operational effectiveness and regulatory compliance involve the execution of process architecture as presented for the first time in this book.

Biopharmaceutical process architecture involves the integration of process understanding and facility architecture concepts to create a design that meets the regulatory compliance guidelines for the manufacture of quality, safe drug, and biologic products. Product attributes, process parameters, and operational philosophy are defined and integrated via architectural programming activities that will define the solution(s) to an architectural problem, in this case, how best to provide a regulatory compliant manufacturing facility design.

This book focuses not only on the regulatory considerations driving facility design decisions but also on many of the different aspects of design specific to biomanufacturing pilot and production facilities for both biological therapeutics and vaccines. As the global biotech industry continues to grow into its fourth decade, more facility design companies will find themselves in a position to both understand and define facilities in a manner where the architectural program not only addresses function, form, economics, and time but also does so in a manner that will withstand regulatory scrutiny from different global agencies. Operational efficiency, flexibility, high-utilization rates, and a stringent focus on quality will take precedent over image. The practitioner leading the programming effort must not only establish the considerations, limits, and possibilities of the design but must also understand the product–process–facility relationship and be able to apply cGMP in all elements of the conceptual design.

The global biotechnology industry focused on drug and vaccine manufacturing will continue to grow; the execution of sound process architectural programming to define compliant facilities will be an essential part of this growth process. The authors contributing to this book are thought leaders within this industry and bring, along with their skills, a broad depth of experience in process engineering, architectural programming, regulatory compliance, facility operation, and aseptic manufacturing. Their willingness to contribute their time and energy to this project is not only greatly appreciated but is also a valuable and unique contribution to the expansion of the industry's body of knowledge.

Jeffery Odum, CPIP

Code of Federal Regulations, 21CFR, Part 211.

Chapter 1Introduction to Biomanufacturing

Mark F. Witcher

NNE, Durham, North Carolina, USA

1.1 Introduction

While the book covers designing biopharmaceutical and vaccine manufacturing facilities, this chapter is a brief introduction to biopharmaceutical manufacturing covering the essential elements of the overall biomanufacturing enterprise. Biomanufacturing is very complex and challenging. To be successful, the facility must be designed with a basic understanding of the overall manufacturing enterprise and how it functions. To simplify the discussion, vaccines will be combined with protein products for the purposes of this chapter.

The objective of this introduction is to:

Identify and describe a biopharmaceutical manufacturing enterprise's three basic elements (process, facility, and infrastructure);

Briefly describe the constituents used in biopharmaceutical manufacturing processes to appreciate the complexity and fundamental issues of operating the process's unit operations (UOs) within the facility;

Identify the basic process UOs typically used in biopharmaceutical manufacturing;

Provide a framework for describing, evaluating, and controlling the facility and process UOs, and;

Provide an understanding of how the overall manufacturing enterprise is operated and controlled.

In order to understand the challenges of biomanufacturing, we begin by looking at the overall manufacturing enterprise that surrounds and operates the manufacturing facility. As shown in Fig. 1.1, the manufacturing enterprise's myriad of components can be divided into three elements. The facility, process, and infrastructure are integrated and operated in concert to produce the product. As will be discussed, the three elements contain a wide variety of components required to achieve the overall objectives of the enterprise. Although the distribution used here provides structure to this introductory chapter, many variants or alternative distributions are possible.

In older enterprises, the facility and process are interdependent because the two were designed and constructed at the same time, usually for a specific product. In future enterprises, the process and facility will much less dependent on each other, with the multiproduct facility capable of running a wide variety of different processes. Because the process is not directly integrated with the facility, the processes can be moved in and out of a facility or moved to a different facility depending on manufacturing capacity or logistical requirements [1].

Manufacturing facilities are harder to run than they are to build. For the enterprise to be successful, the facility must be designed to be operated. All three elements must be carefully developed, so they can be integrated to assure the overall enterprise's success. They must work together in order to support and facilitate adequate control of all production activities to assure the efficient production of high quality product over the entire lifecycle of every product produced by the facility. This concept is emphasized by understanding that conformance lots or PPQ (process performance qualification) batches are more than just a test of the process [2]. Conformance lots are a test of the enterprise's ability to operate the process. Many conformance lot issues are encountered because the staff, part of the infrastructure, are not adequately trained and do not have the experience to execute the many tasks and activities required to successfully run the process and facility.

Starting from the beginning, the basic constituents of biopharmaceutical processes are cells, nucleic acids, and proteins.

1.2 The Basic Constituents of Biopharmaceuticals

Biopharmaceutical manufacturing uses relatively simple processes composed of UOs employing relatively simple pieces of equipment as compared to other industries, particularly those in the chemical and petrochemical industries. However, the constituents within the UOs are many orders of magnitude more complex. The purpose of this section is to provide a very brief introduction to the formidable challenges of managing and manipulating these constituents.

A defining element of biopharmaceuticals is the use of cells to produce the product. The product is most frequently a protein, but the product can be the cells themselves used for cellular therapies or in some cases the product can be genetic material manufactured in large quantities to modify or control genetic constructs and control mechanisms within the patient.

The cell is the largest and most complex element. The growth and characteristics of the cells are defined primarily by the genetic information stored in the cell's DNA. The machinery of the cells that use the genetic information is operated by proteins. The discussion will begin by describing the simplest element, proteins. Most pharmaceutical products are proteins manufacturing by the cell under the control of genetic constructs inserted into the cells using recombinant technology.

1.2.1 Proteins

Biopharmaceuticals are proteins. The product is created by cells in a complex environment of many complex biological molecules (carbohydrates, nucleic acids, lipids, and proteins) and cellular processes required for cell growth and product manufacturing. The discussion begins with an overview of proteins and their structure and behavior.

The fundamental structure of proteins is shown in Fig. 1.2. Proteins are polymers of 20 specific amino acids shown in Fig. 1.3 assembled by the cell according to the genetic code contained within the cell.

Figure 1.2 Proteins are a polymer of the 20 amino acids listed in Fig. 1.3. They are typically between 100 and 1500 amino acids in length. The term peptide refers to amino acid polymers of <25 amino acids.

Figure 1.3 While the Earth's natural environment contains hundreds of different amino acids, all life forms use only the 20 amino acids shown.

The sequence of amino acids forms the primary structure of the protein. Depending on many different structural and environmental factors, the amino acid chain is folded into higher order structures. These higher order structures can be defined as follows:

Primary

: the linear amino acid sequence of the polypeptide;

Secondary

: the localized folding of the primary structure into substructures sometimes called

helices

strands

, and

sheets

;

Tertiary

: the combining of the secondary spiral and flat elements to form larger three-dimensional structures;

Quaternary

: combining of tertiary structures to form a much larger complex three-dimensional structures.

The structures determine the protein's properties, including its safety and efficacy as a therapeutic product.

Additional protein complexity comes from post-translational modifications (PTMs) added to the protein during and after the four structural features described earlier are formed by the cell. PTMs change the behavior of the protein in solution and affect their therapeutic impact, safety, and efficacy in a wide variety of ways. The four structural features and PTMs along with the various altered product forms resulting from degradation, alternations, misincorporation, and aggregation combine with various impurities and contaminates from the manufacturing processes to determine the complex set of critical quality attributes (CQAs) that define the product's overall quality target product profile (QTPP) as defined in ICH Q8 (R2) [3]. The objective of the manufacturing process is to consistently produce a product described by the product's QTPP defined during development, tested in preclinical testing; and demonstrated to be safe and effective by clinical trials. For more details on the definition of biological products, ICH Q6B and ICH Q5E should be consulted [4, 5]. Biochemistry text books can be consulted for more information related to the structure, composition, and behavior of proteins [6–8].

All cells use thousands of proteins, called enzymes, to operate the machinery required to perform the myriad of internal maintenance functions, reproduce, and manufacture the product protein [9]. The production of proteins within the cell is carried out by complex metabolic pathways based on the genetic information contained within the cell. The genetic information is stored in the cell's DNA (deoxyribonucleic acid) formed by polymers of nucleic acids described later.

1.2.2 Nucleic Acids (DNA and RNA)

DNA provides a stable and efficient mechanism for storing and maintaining genetic information critical to the cell's ability to consistently and efficiently replicate without losing the ability to produce the target protein over many generations. DNA has a complex double helix spiral structure formed by two complimentary sequences of nucleic acids. The shape of the double helix can be found in many text books on the subject.

The management of DNA within the cell is a very complex and poorly understood sequence of internal processes. DNA has six different structural features much like the four structural features of proteins, but much more complex involving other supporting protein molecules to assist with storage, protein expression, and duplication. Further, DNA is subject to additional complex modifications involved in many cellular regulatory functions controlling how the DNA is used for cellular functions [10].

RNA or ribonucleic acid is a second nucleic acid very similar to DNA used by the cell for a variety of functions. The difference between RNA and DNA is the substitution of the nucleotide uracil for thymine in the sequence. While DNA is stable for information storage, RNA is more biologically active, less stable, and used in a number of important biological functions to transfer information and regulate protein production. RNA is also the basis for some biopharmaceuticals not covered in this introduction. However, the same basic concepts apply to manufacturing biologically active RNA therapeutics.

Nucleic acids and protein expression are connected by the central dogma that describes the three steps required to support cell reproduction and protein production. The central dogma is shown in Fig. 1.4 [11].

Figure 1.4 The central dogma describes the replication of DNA that allows the genetic information to be passed to future generations; transcription converts the DNA sequence code for the protein into RNA for transmission to the translation mechanism that converts the RNA sequence code into the amino acid sequence that determines the protein's primary structure.

Protein expression within the cell is controlled by a wide variety of feedback and feed forward control mechanisms based on the central dogma. Many of these control mechanisms have not yet been identified and much work remains by the scientific community to better understand the myriad of mechanisms used by the cell to control protein expression.

The use of living cells to manufacture the product is the primary distinguishing feature of biopharmaceuticals. While peptides can be manufactured by chemical synthesis, long amino acid sequences and the resulting structural forms and PTMs required for therapeutic safety and efficacy can only be achieved using living cells.

The history of cells goes back more than 3.5 billion years. The evolutionary history of cell development has resulted in extraordinary capabilities and complexity. The following is very brief introduction of the basic features required for the cells to make therapeutic proteins and vaccines.

1.2.3 Cells

In nature, there are virtually an unlimited number of different types of cells that possess a wide variety of capabilities, behaviors, and properties. The field of microbiology is very diverse and covered by many good books [12–14]. Biopharmaceutical manufacturing typically uses and manages one of two types of cells. For the purposes of understanding the fundamental principles associated with biomanufacturing, only two of the myriad of possible cells will be covered here.

The first cell type is prokaryotes, which are relatively simple cells and grow very rapidly. Many prokaryote cells double in number every 30–60 min [15, 16]. Escherichia coli is one of the types frequently used to make recombinant proteins. Prokaryotes are grown in fermenters designed to meet the requirements for supporting rapid growth.

The second type is eukaryote cells derived from plants, animals, and insects. The most frequently used eukaryote cells are mammalian cells [17]. Of the mammalian cells, Chinese hamster ovary (CHO) cells are frequently used for manufacturing therapeutic proteins. Eukaryotes have roughly a thousand times the internal volume of a prokaryote cell, although the sizes of both types of cells can vary over a wide range. Eukaryote cells are grown in cell culture bioreactors.

Both types of cells operate using metabolisms driven by a large number of specialized protein called enzymes necessary to make the myriad of required reactions work efficiently [9]. The metabolisms have evolved over billions of years and are extremely diverse and highly efficient in performing their functions. Taking a simplistic view, the metabolisms can be divided into two categories. Catabolic metabolisms shown in Fig. 1.5 on the left take energy containing raw materials and break them down to provide energy to the anabolic metabolisms on the right. Anabolic metabolisms take complex raw materials and produce the complex molecules required for cell functions and reproduction.

As will be explained, growing the cells and producing the product are determined by the manufacturing process's ability to manage the inputs and outputs of the two metabolisms. Adequate raw materials must be supplied to the cells along with the removal of by-product waste materials. An environment that supports the cell's metabolic enzymes with the correct operating temperature by removing or adding heat to the cell's environment is required. Thus, the necessary energy and mass transfer conditions and capabilities must be provided by the fermenter or bioreactor.

With the primary constituents identified, the discussion turns to the processes and equipment used to manage the cell's internal processes to grow the cells, produce the target protein, and then purify the product to provide a therapeutic product with the required purity, potency, and activity. The processes and equipment will be described in the context of the manufacturing enterprise are shown in Fig. 1.1.

1.3 Enterprise Element #1—Manufacturing Processes

Expanding Fig. 1.1, the components of the enterprise's process element are shown in Fig. 1.6.

1.3.1 Process—Unit Operations

The distinguishing feature of biomanufacturing is the growing of cells to produce the biopharmaceutical or vaccine. Biopharmaceutical processes or UOs use relatively simple equipment to manage and protect the complex constituents described previously. Some specific requirements of the cells and proteins in the process are poorly understood. The complexity of the cells, proteins, and other constituents contributes to the uncertainty and risk for managing the processes for manufacturing therapeutic products.

Biopharmaceutical processes generally follow a relatively straightforward sequence shown in Fig. 1.7.

Good manufacturing practices (GMPs) require that all process steps be separated from each other using an effective validated segregation strategy [1, 18, 19]. The segregation strategy must also keep all products and processes within the facility separated from each other.

As shown in Fig. 1.7, the process begins with breaking a vial from the cell bank to begin growing a sufficient number of cells required to manufacture the required amount of product. These initial processes are called the upstream processes.

1.3.2 Upstream Processes—Inoculum through Production Bioreactor

Most upstream processes fall into two categories: fermentation and cell culture. Rapidly growing, very hardy organisms such as prokaryotes and yeast require bioreactors that can support large energy and mass transfer requirements for growing the rapidly dividing organisms to high final cell densities. The second category is cell culture processes necessary to grow fragile, slow growing eukaryote organisms such as CHO cells. These two categories share many basic principles and characteristics, although the major differences between the two will be identified.

The following discussion will focus primarily on cell culture processes. Recent advances over the past 20 years have advanced cell culture to the point where it is used for many commercial biopharmaceutical produces because of inherent advantages over fermentation processes. The primary product difference between the two processes is that fermentation of prokaryotes cannot produce products with PTMs required for therapeutic activity. As will be explained later, PTMs may be critical to the safety and efficacy of the product. Cell culture processes not only provide the necessary PTMs to the product's structure but also excrete the product into the media greatly simplifying the separation of the cells from the therapeutic protein. Fermentation processes will remain important for manufacturing nonprotein products, large-scale commercial manufacturing of nontherapeutic proteins such as commercial enzymes, and making the few therapeutic proteins not requiring PTMs.

The overall internal cellular processes required to grow the cells are shown in Fig. 1.8. The metabolisms within the cells were summarized in Fig. 1.5. The upstream bioreactors must provide the correct operating environment to support adequate mass transfer of nutrients including oxygen into the cell and removal of waste products shown in Fig. 1.5 without damaging the cell's outside surface membrane owing to shear forces. In addition, the bioreactor must provide for the removal of energy generated by the cells to maintain the correct internal cell temperature for the metabolic enzymes to function properly. Energy removal for cell culture bioreactors is relatively small; however, in the case of fermentation, energy removal of heat from the cells and work added from agitation of the viscous, high cell density media is a significant issue.

Figure 1.8 An overview of the mass and energy transfer required for the cell metabolisms to function correctly.

The upstream processes are typically initiated by opening a 1-mL cryogenically preserved vial or ampule and aseptically placing roughly one million cells in a T-flask bioreactor for cell culture or a 1-L shake-flask for fermentation. The shake-flask is grown for approximately 12 h and then used to inoculate the production fermenter. Smaller intermediate seed fermenters are sometimes used to provide more efficient use of equipment by increasing the turnover rate of the high asset value production fermenter. In cell culture, the T-flask is grown a few days, and then the cells removed and placed into a slightly larger bioreactor. For cell culture, the cells must be maintained at a cell density between approximately 105 and 107 cells per milliliter for the culture to remain viable. Maintaining the necessary cell density range requires splitting the culture into successively larger bioreactors every few days to keep the cell density within the operating range while increasing the total number of cells. One possible inoculum sequence is shown in Fig. 1.9. Typical inoculum development sequences can take 3–5 weeks depending on the total volume of cells required to inoculate the production bioreactor.

Fermenters and production bioreactors support the growth of cells in a stirred tank reactor that provides agitation while adding raw materials and oxygen. The bioreactor must also provide various sensors, inoculum and media addition, and removal ports depending on the operating requirements and sequence of the culture. Specifics on fermenter design can be found in Stanbury [20] and cell culture bioreactor design can be found in Lubiniecki [21] and Ozturk and Hu [22]. The basic elements of a fermenter and bioreactor are shown in Fig. 1.10.

Figure 1.10 The key features of a production bioreactor required for operating and managing the mass and energy balances of the cell metabolisms shown in Figs. 1.5 and 1.8.

Cell culture bioreactors range from very small (<1 L) to up to 15,000 L for large stainless steel (SS) production bioreactors. Disposable plastic single use bioreactors (SUBs) range up to 2000 L, although functionally most SUBs are 500 L or less because of mass transfer and agitation limitations. SUBs are frequently used in inoculum trains for large SS bioreactors. Fermenters can be up to, and in some cases larger than, 100,000 L for large-scale production of enzymes and antibiotics.

After the final cell density is reached and the product protein produced to the final titer, the next step is to remove the product from the cells. For cell culture, the cells excrete the product protein into the media. The media also contains a wide variety of leftover media components, cell waste products, and some cell debris and metabolic enzymes from cells that have died and broken open. For fermentation, the product remains within the cell as insoluble inclusion bodies.

1.3.3 Upstream Processes—Harvest and Recovery

For cell culture processes, the cells and media containing the product protein are usually separated by some combination of normal filtration, tangential flow filtration (TFF), or centrifugation. Cell culture process can use all three types of UOs; however, fermentations typically are limited to centrifuges because of high cell densities and high solution viscosities from the fermenter. TFF is also widely used in protein purification for a number of different operations and will be covered in the purification section. The most important objective of harvest and recovery operations is to preserve as much active product as possible by minimizing degradation of the product.

1.3.3.1 Normal Filtration

Normal filtration consists of passing the solution containing suspended cells, proteins, or particles through a mesh that retains the larger particles or cells while allowing the solution and smaller particles or proteins to pass through. A wide assortment of filters with different pore sizes and filter material are available for the diverse filtration applications. Large surface area filter presses are available to remove the cells from large production bioreactors. Normal filtration is used in a wide variety of applications ranging from removing unknown and undetected viral threats by viral filtration to protect UOs from large particles that could interfere with the process's performance.

1.3.3.2 Centrifuge

Centrifugation is the accelerated settling of cells, proteins, or particles suspended in solution by high gravitational forces induced by rapid rotation of the solution. Centrifuges are used for separating cells from media and after protein precipitation in some large-scale processes. Disk stack and tubular centrifuges are the most common type used in manufacturing [23].

The primary advantage of centrifuges is that they do not add anything to the solutions and recently developed designs can be cleaned and sanitized effectively. Centrifuges come in a variety of sizes. Some disposable centrifuges have recently been developed and can be used for small- and medium-scale applications.

For cell culture processes, centrifuges can be used as cell separators to remove the cells from the media. The cells may be returned to the perfusion bioreactor, so they can continue to produce product or discarded in the case of cell harvesting in an operation similar to the normal filtration operation described earlier. After the cells are removed, the clarified solution containing the product is sent directly to purification or frozen for later purification.

In the case of fermentation, centrifuges are typically used to remove water from the media to produce a thick cell paste to assist with breaking the cells open to release the product (cell disruption).

1.3.3.3 Cell Disruption

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