Manufacturing Management and Analytical Strategies

The need to streamline costs, shorten development timelines, and stretch valuable resources is driving biomanufacturers to seek innovative ways of enhancing manufacturing efficiency. Analytical methods for process development and validation as well as use of production technologies such as disposables and supply chain logistics can help companies establish facility flexibility.

Effective management of a good manufacturing practice (GMP) facility requires a keen eye on all those factors. The Enhancing Manufacturing and Development Efficiency track of the 2011 BioProcess International Conference and Exhibition will provide presentations, symposia, and workshops that discuss strategies for improving production flexibility and reducing risk so that bioprocessing companies can be ready for production changes while keeping costs at a minimum.

AUDIENCE: PROCESS DEVELOPMENT, MANUFACTURING, ANALYTICAL METHODS

KEYWORDS: PLATFORM PROCESSES, SINGLE-USE, SUPPLY CHAIN, FACILITY DESIGN, MONITORING, CHARACTERIZATION

TAKE-AWAY: LEARN THE LATEST RISK MITIGATION STRATEGIES FOR DRUG SUBSTANCE AND PRODUCT MANUFACTURE AS WELL AS STRATEGIES FOR FACILITY FLEXIBILITY AND SMOOTH OPERATION OF WORLDWIDE NETWORKS OF COLLABORATORS.

PROCESS PlATFORMS

Significant savings of cost, resources, and time can be achieved with the use of process platforms — leveraging baseline bioprocesses that support development by building upon a “common denominator” of well-characterized process steps and knowledge (1,2). For example, some antibodies can be expressed by the same expression vector using the same host cell line and a similar purification process. Advanced expression platform systems are already an integral part of many facilities, and the move toward platform purification is taking place at larger companies (3). At the 2011 BioProcess International Conference, Robert D. Kiss (director of late-stage cell culture at Genentech, Inc.) will report on how manufacturers need to balance implementation of future platforms with the need to continously improve processes and suppport new products, including the use of modified antibody frameworks (“BioProcess Platforms — Today’s Fad or a Future Necessity?” Wednesday, 8:15 AM).

Some biomanufacturers already understand the importance of that concept. Joost P. Quaadgras (director of strategic projects at Pfizer Inc.) will discuss his company’s approach to balancing process platforming with facility capabilities. He will present the key considerations that went into the company’s analyses and how those factors were addressed from development through commercial supply (“Getting the Most for your Development and Manufacturing Dollars” Tuesday, 8:15 AM).

MANUFACTURING NETWORKS

Network management requires the ability to understand and predict variations in product and process demand and assess how they can affect the efficiency of process streams. Some current strategies in clinical drug product manufacturing include use of process standardization, metric-driven interfaces, and disposables (4,5). Other approaches support process optimization during early phase development by improving selection methods and using ultra scale-down techniques to predict large-scale performance (6).

The 2011 BPI Conferences offers three sessions on Tuesday, 1 November 2011, that will describe the essential keys of successful network management. Gerry T. Boushelle (global master planner of biotherapeutics and vaccines at Pfizer) will provide unpublished data on the company’s approach toward increasing project predictability and site flexibility (“Managing Clinical Drug Product Manufacturing Networks,” 8:45 AM).

Amos M. Tsai, PhD (principal engineer of process development at Amgen) will also report on concepts in linking standardization with manufacturing efficiency. His presentation details how applying standardization can benefit late-phase drug development, CMC filing, and commercialization. His talk will present “high-level concepts” that demonstrate the value of standardization in managing changes in clinical and technology development as well as resource and asset availability leading up to final approval (“How Standardization Helps Manufacturing Networks Manage Through Constant Changes” 9:15 AM).

Enhancing Manufacturing and Development Efficiency Sessions

Enhancing Manufacturing and Development Efficiency Sessions ()

Finally, Curran Simpson (senior vice president of operations at Human Genome Sciences, Inc.) will describe a study in which a biopharmaceutical company successfully balanced contract production space and internal manufacturing capacity with minimal operations costs. The presentation addresses a problem many others are currently facing: how to handle the risk involved in investing in manufacturing before product approval while ensuring that resources will be ready to supply a launch once a product is approved (“Balancing Contract Management with Internal Programs at an Innovator Company” 10:15 AM).

SUPPLY CHAIN MANAGEMENT

The logistics required to plan, secure, and manage a network of suppliers are increasing in complexity as companies engage in more global outsourcing, offshoring, and multiple-company partnerships (7,8). Implementing riskmitigation strategies and taking advantage of flexible technologies such as single-use systems are effective tools in supply chain management and can also help support future production growth. In his presentation Myles Marcus (vice president of supply chain management at DendreonCorporation) will discuss the process steps used to support the company’s growth from no sales in 2009 to a planned $350-$400 million in 2011. “Typically, suppliers do not have idle or excess capacity to support significant growth, so early communication and commitments may have to be made,” says Marcus (“Supply Chain Planning in an Exponential Growth Environment” on Tuesday, 10:45 AM).

Risk mitigation strategies for commercial supply will also be the topic of Sushil J. Abraham’s (director of global process engineering, Amgen) case-study presentation. Abraham will provide information about his company’s strategies toward ensuring process and product comparability and licensure of a secondary manufacturing sit
e. Details include how the plan relates to multihost production, viral segregation requirements, current regulatory expectations, minimized process changes, and quick-response approaches to manage emergency scenarios (“Managing Product Supply Risks and Transferring Legacy Molecules,” Tuesday, 1:45 PM).

Disposables are a huge part of the bioprocessing industry, and a reliable and timely supply of disposable systems can make or break a production run. Minimizing risk in that supply chain is thus important for companies operating in both at local and global markets (9). Christopher P. Johnson (director of procurement at Pfizer) says, “Disposables replace a very standard and reliable option in our plants. Supply reliability, quality performance, and pricing (due to shift from capital to consumable) are critical to the long-term success of the technology within biotech manufacturing processes.” In his presentation, Johnson will discuss how Pfizer established design standardization and multisourcing to address those challenges (“Disposables Supply Risk and Cost Reduction — Creating Multi Sourcing as a Core Competency,” Tuesday, 2:15 PM).

Mauricio Barraza (senior manufacturing manager at Acceleron Pharma, Inc) will also discuss his company’s application of single-use technologies and its approach to ensuring a reliable and timely delivery of those systems. His discussion will emphasize the importance of leveraging systems that are supplier and product dependent as well as describe potential areas that would benefit from additional standardization (“Manufacturing and Quality Systems for Supply Chain Security with Single Use Technology,” Tuesday, 2:45 PM).

FACILITIESAND FLEXIBLE MANUFACTURING

Biomanufacturing for local distribution presents its own special challenges for companies (such as vaccine manufacturers) that set up production in emerging markets or developing countries. Regions may lack production capacity or sufficient infrastructure, and issues regarding intellectual property, government incentives, and availability of skilled labor must be considered (10,11,12). BPI editorial advisor Scott M. Wheelwright, PhD (president of Strategic Manufacturing Worldwide Inc.) will discuss many of these challenges in his presentation (“Developing Markets and Identifying Manufacturing Sites,” Tuesday,11:15 AM).

Facilities need to have flexibility in their capacity and technologies to meet changes in product demand and production scale. Several 2011 BPI Conference presenters will discuss approaches for addressing that need. Marisa Hewitt (process engineer II at BioMarin Pharmaceutical, Inc.) will describe a case study on process modeling analysis. Modeling is used to simulate various process scenarios that can help identify bottlenecks. The company used historical data on critical factors such as processing, equipment, labor, and resources to generate an equipment scope for a facility retrofit to process twice the bioreactor output (“Identifying Key Process Constraints in Retrofitting a Perfusion-Based Biotech Facility,” Wednesday, 8:45 AM).

Establishing a flexible facility and manufacturing process is the topic of a series of discussions at the BPI Conference this year. In her presentation, Elizabeth G. Kelly (associate director of manufacturing at Genentech, Inc.) will report on how one manufacturer implemented technology, optimized business process, and human resources to increase facility capacity. The company was also able to address the need to f luctuate between high and low run rates (“Increasing Capacity and Improving Flexibility in a Biomanufacturing Plant,” Wednesday, 9:15 AM).

Maintaining flexibility during process development can be a challenging task. Tools such as enterprise resource planning systems, manufacturing execution systems, and other modular data collection and management strategies can help find areas for improvement by linking the manufacturing f loor with corporate-wide information. Benjamin W. Drucker (senior supervisor of engineering, manufacturing science, and technology at Genentech Inc.) will discuss novel approaches for developing standard business modules and high-throughput technology transfer for rapid time to manufacture and commercialization (“Shortening the Lead Time: A Modular Approach to Accelerated Production,” Wednesday 10:30 AM).

Following that discussion, Stephen R. Hudd (director of global engineering at Biogen Idec) will describe how use of disposables affects the design of GMP facilities, including its influence on suite layout, construction, and operation. “The increased speed and reduced cost to install such facilities compared with traditional manufacturing facilities is extremely attractive,” says Hudd. The presentation will report on integrating a flexibile facility design to cope with continued development of single-use technologies and equipment (“Facility Design for Single-Use Technologies,” Wednesday, 11:00 AM).

On Thursday, 3 November, the 2011 BioProcess International Conference will present a strategy forum on flexible manufacturing methods (“Flexibility and Agility as Strategic Purpose, Time, and Cost Savers as a Tactical Means to Get There”). The forum will be moderated by Günter Jagschies, PhD (senior director of strategic customer relations at GE Healthcare Life Sciences) and will include panelists from Pfizer, Genentech, Abbott Bioresearch Center, and Genzyme Corp. Workshop topics include using “grouped” time savings to increase capacity, the link between cost dollars and revenue generation, hierarchy effects, workf lows, and tools for supporting flexibility while minimizing the investment risk.

ANALYTICAL TECHNOLOGIES

Evolving bioprocesses can benefit from high-throughput systems, disposables, automation, online analytical tools, and other sophisticated technologies that help establish state-of-the-art development pathways. Innovative analytics accelerate process timelines while ensuring that quality standards are maintained. The 2011 BPI Conference will include discussions on current analytical technologies to help manufacturers streamline all stages of development.

Process Development: The role of single-use components in process development is the topic of a Monday afternoon symposium, “Incorporating Single-Use in Process Development and Scale Up.” Six presentations report on real-world applications and challenges of disposables for media storage and handling, cell culture, and downstream processing as well as the scale-up and technology transfer of single-use bioreactor processes and in non-GMP and GMP environments.

A current trend in upstream processing is leveraging multiuse tools to handle both cell culture and microbial expression platforms. Rachel Bareither (biochemical engineer of bioprocess development at Merck & Co Inc.) will focus on improvements on upstream processing and how they can be carried into purification and analytics. The casestudy presentation will include unpublished data from evaluation of a novel small-scale, single-use prototype bioreactor (Technology Improvements to Accelerate Process Development of Biologics,” Tuesday, 8:15 AM).

Design of experiments (DoE) streamlines development by first defining the critical parameters of a process and then using those factors to optimize a design space. Well-defined process and product knowledge are the basis of this science-based approach (13). The symposium “Using DoE Effectively for Process Characterization Without Getting Lost in the Statistics” reviews the application of DoE as an essential instrument for process characterization, including information about when you should and should not apply DoE to develop and understand your production processes. The workshop will explain how to select the right DoE desig
n and introduce the concept of “experiments by design (EbD),” including how to effectively perform DoE. Presenters will report on how DoE applies to FDA guidelines on process validation and quality by design (QbD).

Quality by Design: QbD and process analytical technology (PAT) no longer need an introduction in the bioprocessing industry. Biomanufacturers are now seeking specific examples of how these FDA initiatives can be implemented effectively in real-world process applications and how they affect product quality and biopharmaceutical company bottom lines.

Stefan Steigmiller, PhD (head of PATBiotechnology projects at Bayer Technology Services GmbH) will present unpublished data about an innovative online analytics system for process control. BaychroMAT is a platform that fully automates analyzers and can be used with additional automation components to enable high operational availability. Steigmill will discuss its application for stainless steel bioreactors in pilot plants and process development and describe his company’s set-up of its closed-loop control for glucose, including an integrated PAT data management system (“BaychroMAT Bioplatform as an Analytical Key for Quality by Design,” Tuesday, 8:45 AM).

Traditionally, analytical method parameters have been evaluated one at a time, without much consideration of variable interactions. Moreover, the robustness of an analytical method is typically determined after method development is complete, so if method performance factors fail such testing, the method must be redeveloped. A QbD experimental approach takes into account variable interactions, which are detected during method screening and optimization and allows evaluation of method robustness during development. Anna Ip (senior associate scientist at Amgen Inc.) will discuss the application of QbD in her presentation that demonstrates high-performance liquid chromatography (HPLC) robustness testing and HPLC analytical method using the integrated QbD-based software Fusion AE from S-Matrix (“Application of QbD Concepts in Analytical Method Development,” Tuesday, 9:15 AM).

Cleaning Validation and Impurity Monitoring: Potent biopharmaceuticals such as antibody–drug conjugates pose unique production challenges, especially for multiproduct facilities. Many of those facilities use total organic carbon (TOC) methods to verify product clearance, but studies have shown that its use for potent biologics is limited. In her presentation, Rebecca Hill (staff scientist of analytical development at Fujifilm Diosynth Biotechnologies UK Ltd.) will report a case study on laboratory-based protein degradation and techniques that can be used to augment TOC data (“Challenges in Cleaning Validation Programs for Potent Biopharmaceuticals,” Tuesday, 10:15 AM).

Monitoring impurities such as leachables and residuals is a crucial task in bioprocessing to ensure safety and efficacy of finished products. Residuals are usually present at low levels in difficult sample matrices, making assay development and validation and ongoing testing complicated. Sample matrix types can vary greatly because impurity monitoring requires sampling at various process steps. Jon Kauffman (director of method development and validation at Lancaster Laboratories) will discuss those challenges, and the strategies for overcome them (“Analytical Strategies for Monitoring Impurities Encountered in Bioprocessing Regulatory,” Tuesday, 10:45 AM).

Characterization: The analytical characterization of complex biomolecules involves using complementary methods to precisely evaluate physical and chemical properties. Characterization of antibody–drug conjugates (ADCs) also takes into account the types of conjugation chemistry as well as the properties, number, and attachment sites of the cytotoxic drug-linker. AnnaMaria A. Hays Putnam (group leader of analytical and formulation development at Ambrx, Inc) will report unpublished data in her presentation that discusses methods to reduce the complexity of ADC characterization. “The ability to site-specifically attach toxins can substantially reduce the complexity allowing the conjugate to be identified, characterized, and impurity profiles to be accurately assessed,” she says. “In turn, this allows for the understanding and selection of molecules with optimal attributes” (“Analytical Characterization of Next Generation Antibody Drug Conjugates,” Tuesday, 11:15 AM).

About the Author

Author Details
Maribel Rios is managing editor of BioProcess International. Quotes not otherwise attributed are from presentation abstracts.

REFERENCES

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