Cover
Title Page
Copyright
Dedication
Contributors
Foreword
Preface: Why a Book on Process Architecture?
Chapter 1: Introduction to Biomanufacturing
1. 1.1 Introduction
2. 1.2 The Basic Constituents of Biopharmaceuticals
3. 1.3 Enterprise Element #1—Manufacturing Processes
4. 1.4 Enterprise Element #2—Manufacturing Facility
5. 1.5 Enterprise Element #3—Manufacturing Infrastructure
6. 1.6 Controlling the Manufacturing Enterprise
7. 1.7 Summary
8. References
Chapter 2: Product–Process–Facility Relationship
1. 2.1 Introduction
2. 2.2 The Characteristics of Biological Therapeutic Products
3. 2.3 Understanding the Attributes
4. 2.4 Factors that Impact Facility Design
5. References
Chapter 3: Regulatory Considerations of Biomanufacturing Facilities
1. 3.1 Introduction
2. 3.2 Regulatory “Uncertainty,” A Two-Way Street
3. 3.3 Design with the Patient in Mind: Assess the Patient, Product, Process, and Plant
4. 3.4 Laws, Regulations, and Guidelines: Historical Background
5. 3.5 Global Guidance Documents
6. 3.6 Quality Systems and Risk Management
7. 3.7 Product Changeover and Regulatory Assessment of Cleaning Validation
8. 3.8 Control Strategy
9. 3.9 Contract Manufacturing Organizations
10. 3.10 FDA Inspections of Biopharm Facilities and Regulators' Priorities
11. 3.11 Regulatory Meetings
12. 3.12 Conclusion
13. References
Chapter 4: Biopharmaceutical Facility Design and Validation
1. 4.1 Introduction
2. 4.2 Designing for Compliance
3. 4.3 Risk Management
4. 4.4 Qualification/Verification
5. 4.5 Process Validation
6. 4.6 List of Abbreviations
7. References
Chapter 5: Closed Systems in Bioprocessing
1. 5.1 Introduction
2. 5.2 Definition of Closed Systems
3. 5.3 Closed System Design
4. 5.4 Impact on Facility Design
5. 5.5 Impact on Operations
6. 5.6 Summary
7. References
Chapter 6: Aseptic Manufacturing Considerations for Biomanufacturing Facility Design
1. 6.1 Introduction
2. 6.2 The Relationship to Biological Products
3. 6.3 Process Attributes—Product Protection
4. 6.4 Facility Design
5. 6.5 Critical Area
6. References
Chapter 7: Facility Control of Microorganisms: Containment and Contamination
1. 7.1 Introduction
2. 7.2 Design Principles for Controlling Microorganisms
3. 7.3 Controlling Viable Environmental Particulates
4. 7.4 Reducing the Transport of Mold into the Bioprocess Facility
5. 7.5 Reducing Mold Sources within the Bioprocess Facility
6. 7.6 Biocontainment: An Overlay to Process Design
7. 7.7 The Biocontainment Regulatory Environment
8. 7.8 Principles of Biosafety
9. 7.9 Principles of Biocontainment Facility Design
10. 7.10 Design for the Entire Process
11. 7.11 Conclusion
12. References
13. Further Reading
Chapter 8: Process-Based Laboratory Design
1. 8.1 Introduction
2. 8.2 Areas of Application/Scope
3. 8.3 Translation of Process Elements into Laboratory Architecture
4. 8.4 Key Steps in Planning Approach and Methodology
5. 8.5 Laboratory Concept Development
6. 8.6 SHE Considerations
7. 8.7 Glossary
8. 8.8 List of Abbreviations
9. References
Chapter 9: Case Study: Pharmaceutical Pilot Plant Design and Operation
1. 9.1 Introduction
2. 9.2 Operational Concepts and Processing Requirements
3. 9.3 Design
4. 9.4 Operation
5. References
Chapter 10: Addressing Sustainability in Biomanufacturing Facility Design
1. 10.1 Introduction
2. 10.2 Process Architecture
3. 10.3 Water and Water Treatment
4. 10.4 Energy Efficiency
5. 10.5 Conclusion
6. Acknowledgments
7. References
Chapter 11: Technology's Impact on the Biomanufacturing Facility of the Future
1. 11.1 Introduction
2. 11.2 The Enabling Technologies
3. 11.3 Elements of a Biomanufacturing Enterprise
4. 11.4 Evolution of the Facility of the Future
5. 11.5 The Future—Summary and Conclusions
6. References
Glossary
Index
End User License Agreement

List of Illustrations

Chapter 1: Introduction to Biomanufacturing
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. Figure 1.8 An overview of the mass and energy transfer required for the cell metabolisms to function correctly.
9. 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.
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 Figure 1.5 and 1.8.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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.
18. 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.
19. 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.
20. Figure 1.20 Basic in-process, personnel, and waste flows are required between unit operations, including supporting preparation areas.
21. 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.
22. 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.
23. 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.
24. Figure 1.24 Schematic of the utility systems relationship to the manufacturing core containing the process unit operations.
25. 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.
26. 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).
27. Figure 1.27 The second responsibility of the infrastructure is to provide “proof of control.”
Chapter 2: Product–Process–Facility Relationship
1. Figure 2.1 Protein manufacturing.
2. Figure 2.2 The product-process-facility continuum.
3. Figure 2.3 Basic biomanufacturing process steps.
4. Figure 2.4 (a) Extracellular product diagram. (b) Intracellular product diagram.
5. Figure 2.5 Cell culture growth curve.
6. Figure 2.6 ADME components.
Chapter 4: Biopharmaceutical Facility Design and Validation
1. Figure 4.1 Block flow adjacency diagram.
2. Figure 4.2 Equipment flow diagram.
3. Figure 4.3 Personnel flow diagram.
4. Figure 4.4 Segregation diagram. [courtesy of International Society of Pharmaceutical Engineering.]
5. Figure 4.5 Facility layout adjacency diagram with flows.
6. Figure 4.6 Air lock configurations.
7. Figure 4.7 QbD approach steps.
8. Figure 4.8 Design space model.
9. Figure 4.9 Manufacturing control strategy.
10. Figure 4.10 Chart from ICH Q9.
11. Figure 4.11 Sample risk matrix.
12. Figure 4.12
13. Figure 4.13 Ishikawa diagram of CPPs for a production bioreactor.
14. Figure 4.14 Evolution of commissioning and qualification.
15. Figure 4.15 Good engineering practice.
16. Figure 4.16 Verification process flow.
Chapter 5: Closed Systems in Bioprocessing
1. 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.
2. Figure 5.2 Closed system design example for in-process sampling.[Drawing courtesy of CRB Consulting Engineers, Kansas City, Missouri]
3. Figure 5.3 The NOVA septic NovaSeptum system with a presterilized component.[Photograph courtesy of NOVA Septic-Millipore, Gothenburg, Sweden]
4. 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]
5. 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]
6. 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.”]
7. 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]
8. 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
1. Figure 6.1 Closed system sequence.
2. Figure 6.2 A diagram of a closed process system boundary.
3. Figure 6.3 Kleenpak sterile connector courtesy of Pall Corporation.
4. Figure 6.4 HVAC pressure diagram (courtesy of IPS).
5. Figure 6.5 Example of flow diagrams for personnel, materials, and product as required by the FDA.
6. Figure 6.6 Facility segregation transitions zones.
7. Figure 6.7 System integrity capability to ensure sterility and product protection.
8. Figure 6.8 Schematic view of RABS unit (open RABS shown).
9. Figure 6.9 Schematic view of isolator unit.
Chapter 7: Facility Control of Microorganisms: Containment and Contamination
1. Figure 7.1 Anteroom/airlock airflow models.
2. 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.
3. 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.
4. 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
1. Figure 8.1 R&D Bioreactor/Fermentation laboratory, customized design of vertical shafts with supplies and tables.
2. Figure 8.2 Laboratory planning and design value chain.
3. Figure 8.3 Cost savings versus design completion.
4. Figure 8.4 Traditional versus Frontloaded design method.
5. Figure 8.5 One-page strategy.
6. Figure 8.6 Example of typical day work flow and overall activity analysis.
7. Figure 8.7 Overview of a typical quality risk management process.
8. Figure 8.8 Diagram for addressing biorisk—risk characterization and risk evaluation.
9. Figure 8.9 Operational flow diagram, quality control laboratory.
10. Figure 8.10 Operational flow diagram, in vivo drug development laboratory.
11. Figure 8.11 Process flow for a quality laboratory.
12. Figure 8.12 Overall functional relation diagram example, indicating main functionalities with gray boxes and support/administrative functions as white boxes.
13. Figure 8.13 Room typology example—illustration of the first step of typology development.
14. Figure 8.14 Room typology examples—illustration of the second step of typology development.
15. Figure 8.21 Minimum recommended distance fume hood sash and table top.
16. Figure 8.22 Recommendation for distance between facing BSCs.
17. Figure 8.15 QC laboratory area distribution, gross square meter.
18. Figure 8.16 Laboratory concept evaluation example.
19. Figure 8.17 Using standard QC test time as basis for capacity planning.
20. Figure 8.18 Realized capacity numbers QC laboratory (confidential customer).
21. 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.
22. Figure 8.20 Laboratory objectives diagram.
23. Figure 8.23 Section in laboratory building.
24. Figure 8.24 SHE areas to be considered during project initiation.
Chapter 10: Addressing Sustainability in Biomanufacturing Facility Design
1. Figure 10.1 Triple bottom line Venn diagram.
2. Figure 10.2 Commercial building energy consumption by end use.
3. 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].
4. Figure 10.4 Airflow diagram in cell production suite [28].
5. Figure 10.5 Typical effect of load/ECWT-VFD drive. Red = 85F ECWT; Blue = 75F ECWT; and Green = 65F ECWT [42].
6. 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.
7. Figure 10.7 Phases of retro commissioning.
8. Figure 10.8 Five steps to best practice metering and submetering.
9. Figure 10.9 Understanding facility energy consumption.
Chapter 11: Technology's Impact on the Biomanufacturing Facility of the Future
1. Figure 11.1 Typical fixed SS bioreactor systems integrated with the facility. [Courtesy IPS.]
2. Figure 11.2 Portable single-use biomanufacturing system process flow diagram. [Courtesy of IPS.]
3. 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.
4. 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.
5. Figure 11.5 Modular clean room POD. [Courtesy of G-CON.]
6. Figure 11.6 Traditional biomanufacturing facility BFD. The solid arrows represent hard piped SS connections between the manufacturing and support systems.
7. Figure 11.7 SUS replace fixed stainless steel systems.
8. Figure 11.8 Reduced utility requirements.
9. Figure 11.9 SU, single operating area, and EBR-based facility solution provide complete control of all operations assuring and proving product quality.
10. Figure 11.10 Multiproduct commingled processes in common space. Unidirectional flow used to aid in procedural control of incoming materials and waste flows.
11. 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
1. Table 2.1 The Number of Amino Acids in Common Therapeutic Proteins
2. Table 2.2 Clinical Trial Phases
3. Table 2.3 Clinical Production
4. Table 2.4 Pilot Plant
5. Table 2.5 GMP Commercial Manufacturing
Chapter 4: Biopharmaceutical Facility Design and Validation
1. Table 4.1 QTPP Example
2. Table 4.2 Differences in Traditional Approach Versus Risk-Based Approach
Chapter 7: Facility Control of Microorganisms: Containment and Contamination
1. Table 7.1 Risk Groups for Pathogenic Organisms
Chapter 9: Case Study: Pharmaceutical Pilot Plant Design and Operation
1. Table 9.1 Types of Processing Equipment and Utilities Possibly Required for a Bioprocessing Pilot Plant
2. Table 9.2 Transfer Lines and Utility Piping Possibly Required for a Bioprocessing Pilot Plant
3. Table 9.3 Comparisons of Example Plant Steam and Clean Steam Achievable Quality
4. Table 9.4 Comparison of Example USP-Purified Water, Deionized Water, and Process Water Achievable Quality Attributes
5. Table 9.5 Comparisons of Example Controlled and Noncontrolled Area Achievable quality Based On Room Design in a Pilot Plant Facility
6. Table 9.6 Types of Testing (Sampling and Analysis) Possibly Required by On-Site or Off-Site Support Laboratories for a Bioprocessing Pilot Plant
7. 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
1. 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

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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.

Jeffery Odum and Michael C. Flickinger

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