Bioprocess Manufacturing Tool Preview: A First Look at ISPE's Baseline Guide for Biopharmaceuticals

With the biotechnology industry in the early phases of commercialization, many bioprocess companies are just beginning to build and operate commercial-scale production facilities. The commercialization of manufacturing processes has brought new challenges to the biotechnology industry. Designing, constructing, and operating production facilities are particularly challenging to an industry previously focused predominantly on researching and developing new products. Biopharmaceutical companies need guidance to make the transition to commercial scale biotechnology production. ISPE, the Society for Life Science Professionals, provides such guidance with its insight into the design and operation of bioprocess manufacturing.

Over the past several years, ISPE has developed a series of pharmaceutical industry guides that describe engineering and operational principles of various types of pharmaceutical manufacturing and support systems. The ISPE Baseline Pharmaceutical Engineering Guides are invaluable to industry, but none of them will have more impact than the soon-to-be-released sixth volume, which covers biopharmaceuticals.

Commercial manufacturing of biopharmaceutical products is still rapidly developing. Likewise, understanding of the processes and systems being designed is still evolving. At this point in biotechnology's evolution, there is a rapidly growing need for qualified people. The Biopharmaceuticals Baseline Guide provides insight from a variety of biotechnology industry experts. The guide, developed in cooperation with FDA, is specifically written to simplify complex concepts and highlight aspects critical to successful bioprocess operations. It is an excellent educational tool, covering subject matter of great importance to bioprocess manufacturers, regardless of their expertise or experience.

What Are the Baseline Guides?

This guide will help manufacturers focus on the issues that are most important to their ultimate success and give them more confidence in the approach they choose. Spending on noncritical components will be reduced. Ultimately, appropriate, simpler, less expensive, and easier to operate systems will be installed. The result will not only cut capital costs, but it also will reduce operating costs while improving or assuring product quality.

The Guide In Brief

The

Biopharmaceuticals Baseline Guide

, the newest volume in the ISPE Baseline Guide series, addresses aspects of biopharmaceutical manufacturing ranging from operations to facility and process designs to regulatory concepts. Although it's not a textbook, it provides substantial insight into key design considerations for bioprocess manufacturing - identifying alternative concepts and presenting the pros and cons of different approaches to various bioprocess operations and systems.

More than 100 industry professionals contributed to the development and review of this guide. The group included worldwide representatives from biotechnology manufacturing companies of varying sizes and interests. The team also included engineering equipment manufacturers and various industry service providers and FDA representatives. Regulators from other parts of the world contributed comments as well, and all regions of the world were invited to participate in the effort.

Chapters 1 and 2 of the guide are general and provide guidance and background in regulatory concepts significant to biopharmaceutical manufacturing operations. Although subsequent chapters address issues more specifically, the first and second chapters present concepts with a broader perspective. Emphasis is on product protection strategies that range from enclosed processing to facility systems to procedural methods. Principles of controlled bioburden processing and the contrast with conventional pharmaceutical aseptic processing are presented. Regulatory philosophy pertaining to concepts, such as multiproduct facilities, biological hazard containment, and open versus closed processes, are discussed. Segregation, cleanability, and area cleanliness classification concepts are introduced.

Figure 1. A typical guide figure illustrates one alternative conceptual product segregation approach.

Chapter 3 covers manufacturing operations and activities. It addresses the operational aspects of a biopharmaceutical facility - as opposed to the physical design of the facility itself - and addresses key regulatory issues and concepts defined in the second chapter. The impact of facility (and equipment) design decisions on manufacturing operations is addressed. This chapter also describes how operability and maintainability considerations should influence the design of a biopharmaceutical facility. Concerns and issues of production management, process operators, and other plant support personnel are included. Key concepts addressed include

• operational and procedural controls

• bioburden-controlled and endotoxin-controlled processing

• viral clearance (both reduction and inactivation)

• types of segregation

• multiproduct operations

• manufacturing at various product development stages.

Chapter commentary on multiproduct operations includes advice. For example:

In multiproduct operations, it is important to consider the tradeoff between cleaning costs (which include changeover, validation, routine cleaning activities and materials, and routine monitoring for cleaning effectiveness) and the cost of dedicated equipment. Typically, chromatography resins and filtration membranes should be dedicated to products, because they are notoriously difficult to clean. Similarly, gaskets, O-rings, valve diaphragms, and other "soft" components subject to product build-up are often replaced between campaigns.

Subsequent chapters address specific aspects of bioprocess manufacturing. Chapters 4, 5, and 6 examine process equipment and unit operations, support utilities, and facility considerations. Chapter 7 focuses on process controls, and Chapter 8 addresses qualification and commissioning. These chapters revolve around common recurring themes of multiple-product facilities, open and closed processing, and controlling the risks of contaminant exposure.

Manufacturing Baseline Guides

Chapter 4 explores the design of biopharmaceutical process equipment, associated piping, and instrumentation that contact a product or its components at a stage in the process where such contact could influence the quality, safety, purity, strength, or identity of the ultimate product. Concepts addressed include

• typical biopharmaceutical processes with simplified process flow diagrams (PFDs)

• parameters for controlling critical processes

• general and specific equipment design considerations

• equipment cleaning considerations.

The general, or broader, discussions in the equipment chapter cover equipment and system cleanability and piping and pumping system materials. A typical comment in this part of the guide reminds that electropolish is not a requirement, but may improve cleanability and corrosion resistance. Specific equipment design considerations are presented for each typical bioprocess unit operation. For example, the section covering harvest and recovery suggests that closed processing may not require deactivating the production organism before transferring it from the bioreactor - even during containment at biosafety level 3. Eliminating a deactivation step at this point in the process improves the efficiency of the harvest and recovery process.

Chapter 5 discusses process support utilities ranging from purified process water systems to centralized clean-in-place (CIP) and steam-in-place (SIP) systems. Specific guidance is provided for specialized aspects of bioprocess utilities, such as the challenges of critical temperature control for production of viable organisms. For example, in traditional parenteral drug manufacturing operations using U.S. Pharmacopeia (USP) standards, water for injection (WFI) is circulated hot - a practice that helps minimize microbial development in the water. However, bioprocesses often require waters at ambient or colder temperatures. This deviation from traditional drug manufacturing creates a number of design and operational challenges: Should ambient or cold WFI be circulated throughout the plant, or would point-of-use coolers be preferable? If you circulate ambient WFI, how do you control microbial growth in the recirculating water stream? The guide provides the pros and cons of each approach.

Chapter 6, the facility chapter, addresses all aspects of general facility design. Concepts covered range from material, people, and equipment flow patterns to facility layout and design considerations. Pros and cons of various facility layout concepts are discussed in detail. Considerations about the various needs of processing activity requirements and benefits of various vertical or horizontal process flow layouts are provided. This chapter also covers facility contaminant control issues. The impact of closed and open processing on area cleanliness classifications and other design considerations are discussed in detail. Input is provided to help define room environments and the impact of space classification on facility layout.

The facilities chapter provides significant advice on appropriate application of controlled not classified (CNC) production areas. CNC manufacturing spaces can be appropriate when operations in the space are closed or when subsequent processing and purification steps can be demonstrated to reliably control the quality of the product. Classified manufacturing spaces generally require strict compliance with performance requirements and access control including cleanroom gowning. If a process is closed and the product or product contact surfaces are never exposed, then such strict control may not be necessary. GMPs can be improved, while operating cost savings may be realized by placing high maintenance components together in CNC space, when possible (Figure 1).

Chapter 7, the process control chapter, identifies automation issues and provides guidance for setting the appropriate level of automation. The guide states that automation is not a GMP requirement. However, if properly applied, automation can help achieve GMP compliance. Excessive automation can introduce opportunities for failure, reducing the reliability of the operation. Some bioprocess sensors, such as pH or dissolved oxygen sensors in fermentation broth, may require redundant sensors. The high value of biopharmaceutical products can justify additional spending to improve reliability and reduce the risk of a failed batch.

Chapter 8. The chapter on qualification and commissioning is a supplement to the Commissioning and Qualification Baseline Guide and provides specific information on critical quality assurance (QA) and quality control (QC) processes.

The appendices provide definitions, references, and considerations for facilities not inspected by FDA; information on disposable equipment; NIH considerations; more detailed facility design information; and help in defining a product protection control strategy.

The Guide's effect on Industry

The guide covers such a spectrum of information that it is difficult to summarize the most important points. But a few concepts are integral to so many aspects of bioprocessing that they deserve mention.

The guide promotes the benefits of closed processing and suggests where and how it can be applied. Use of closed processing techniques wherever practical can improve GMPs of a bioprocess facility while reducing the cost of construction and operation.

Multiproduct manufacturing will become increasingly important to the biotech industry. Concepts critical to successful multiproduct manufacturing are covered throughout the guide. Two basic approaches to multiproduct operations are explained: campaigned and concurrent. Campaigned operations depend on cleaning and procedural controls. The guide suggests that concurrent multiproduct operations will typically require physical segregation. That segregation can be accomplished by using separate rooms, or by closed processing.

Cleaning is an integral part of bioprocess operations and is particularly important in multiproduct facilities. The guide provides extensive information on methods enhancing the quality of cleaning operations and procedures. Although CIP is not a GMP requirement, it is highly recommended by this guide for many bioprocess applications. Manual cleaning is possible but challenging for complex bioprocess unit operations. Humans are one of the greatest contamination risks in drug manufacturing. CIP may cost more initially, but it improves reliability and consistency of the cleaning operations while significantly reducing invasive operator contaminants. The guide provides advice on how to improve cleanability of equipment and vessels. It also addresses challenges of automating cleaning processes in existing operations. Relative benefits of portable and fixed cleaning systems are considered, as well as when and why clean-out-of-place (COP) should be considered.

Although the guide focuses on biopharmaceutical operations and FDA regulations, the operations and concepts presented apply to all bioprocessing. It is nonprescriptive, mostly providing pros and cons of the various alternative approaches available to each operating situation. That format enables manufacturers to define the best approach for specific situations. Manufacturers in highly competitive product lines can use the guide just as well as a manufacturer racing to market with a blockbuster drug.

As an international organization, ISPE is very sensitive to the need for the guides to address global regulatory requirements. To produce these guides in a timely manner, ISPE chose to focus on FDA because it has the most widely used and respected pharmaceutical regulations. With the guide's focus on fundamental principles, most technical recommendations in the guides are largely compliant with all regulators. Ultimately, the goal is to develop a tool that promotes harmonization among pharmaceutical regulators worldwide and to promote consistent and reliable production of safe, high-quality pharmaceutical products. If done properly, the cost of producing quality products is reduced while quality remains high or improves. Considerations for GMPs outside FDA's realm are covered in the appendix of the guide.

The Biopharmaceuticals Baseline Guide is currently under final legal review. Once that review is complete, it will be published and available for purchase from ISPE. It is anticipated the final version will be available in late 2003. The guide will be presented at a one-day seminar on 4 - 5 November at the 2003 ISPE annual meeting in New Orleans, LA. BPI