Boosting manufacturing efficiency remains a key focus area as bioprocessing companies continue to leverage best-practice strategies for their operations. Multiproduct facilities especially are having to shift resources and maximize flexibility within narrow cost windows. Such flexibility may require reevaluation of facility layouts and design, implementation of new technologies including single-use systems, and renewed approaches toward technology transfer, operations schemes, and raw-material supply chain challenges.

Manufacturing Optimization

Manufacturers are increasingly seeking ways to increase process and personnel performance. Chris Pacheco of Amgen says activities toward achieving operational excellence should focus on team performance and process cycle time. His presentation will open the “manufacturing optimization” sessions on Tuesday. Pacheco will discuss strategies to help prevent and alleviate problems associated with production bottlenecks in the “critical path.” It also enables a facility to meet supply plan needs. As he observes, “Approaching improvements with a focus on learning from others coupled with the speed of sharing to accelerate learning is driving a positive transformational shift in the manufacturing facility’s culture.”

AUDIENCE: PROCESS DEVELOPMENT, OPERATIONS, MANUFACTURING, FACILITIES DESIGN
KEYWORDS: FLEXIBLE MANUFACTURING, SINGLE-USE, SUPPLY CHAIN, MONITORING AND CONTROL, RAW MATERIALS
TAKE-AWAY: IMPROVE MANUFACTURING EFFICIENCY AND DEVELOPMENT BY LEVERAGING OPTIMIZATION SOLUTIONS FOR MULTIPRODUCT FACILITIES, FLEXIBLE PROCESSES, AND MATERIALS MANAGEMENT.

Multiproduct facilities face additional optimization requirements associated with handling several approved products and drug substances at one site, including multiple technology transfers. Flexibility is vital for such companies. In his Tuesday presentation, Markus Wollenberg of Boehringer Ingelheim Pharma will describe how manufacturers deal with a wide range of processes (e.g., low-titer legacy and high-titer state of the art) and tech transfer projects. “Each project has its own set of priorities regarding speed, project cost, cost of goods, and risk,” he points out. His presentation will include examples of typical challenges found in multiproduct facilities and their corresponding solutions.

One well-recognized challenge in multiproduct facilities is minimizing or eliminating cross contamination. For that, industry and regulatory experts have advised manufacturers to take a risk-based approach. Such strategy can prove beneficial in flexible layouts in sites working with combinations of products, product classes, and host-cell types. In their presentation, Stephen Reich and Kristin Murray of Pfizer will share practices for selecting quality risk-management tools to identify and control cross contamination hazards across various facility designs and multiproduct operating schemes.

Paul Slaman of Shire Human Genetic Therapies will detail an example of a single-use/flexible approach to facility design. The approval of Shire’s new Lexington (MA) manufacturing facility earlier this year marked a milestone in the company’s implementation of single-use systems design. Slaman will provide an inside look at those systems and how the plant was designed to accommodate the growing variety of the company’s therapeutic proteins.

Rizwan Sharnez of Amgen will present a case study on cleaning validation, with a focus on using cleaning characterization to streamline new product launches (coauthors Michelle Monk, Laura Klewer, Chris Flint, and Arun Tholudur, all ofAmgen). Manufacturers need strategies for addressing cleaning validation challenges for bioprocesses. According to Sharnez, such strategies “are rooted in systematic and proactive approaches to cleaning.” Examples of such approaches include small-scale “cleanability studies” to minimize at-scale cleaning validation studies, master soils to streamline and provide flexibility for scheduling cleaning validation activities, and inactivation studies to obviate the need for product-specific assays and maximum allowable carryover (MAC) assessments.

Enhancing Manufacturing and Development Efficiency Sessions

Monday, 8 October 2012 1:00–5:00 PM Best Practices for Implementation Challenges with Single-Use Systems 1:00–5:00 PM Best Practices in Managing Variability of Raw Materials 1:00–5:00 PM Best Practices in Cleaning and Cleaning Validation Tuesday, 9 October 2012 8:00–11:45 AM Optimizing Manufacturing Operations 11:45 AM – 12:15 PM Concurrent Technology Workshops 1:30–3:15 pm Impact of Raw Material Variability and Reliability on Supply Chain and Development 4:15–5:45 PM Keynote Presentations on Manufacturing Partnerships Wednesday, 10 October 2012 8:00 AM – 12:30 PM Achieving Rapid Process Development and Novel Technology Implementation 12:00–12:30 PM Concurrent Technology Workshops 1:45–3:30 PM Plenary Session 4:00–6:00 PM Keynote Presentations

Tuesday morning’s sessions on manufacturing optimization concludes with a detailed look inside MedImmun’es manufacturing center in Frederick, MD. The site had to transition from a single-product facility to a fast-paced clinical and commercial multiproduct facility. Chad Briggs of MedImmune says senior leadership challenged the site to optimize changeover from an early cycle time of 28 days to 14 days or less. He will review the cross-functional work and operational excellence tools that successful
ly drove that changeover optimization.

Most bioprocesses are formatted on fed-batch, cell-culture methods of manufacturing. “The history of fed-batch as a method of producing proteins in CHO cells is remarkable with respect to the progress made in a relatively short period of time,” notes Peggy Lio of Life Technologies. “Within the past decade we have progressed from IgG titers in the milligram per liter range to current routine yields of multiple grams per liter.” Lio will lead a technology workshop on Tuesday that will explore the achievements of both sophisticated feeding strategies and cell line engineering. She will review recent improvements in fed-batch culture and explain how manufacturers can maintain flexibility in scale-up.

Following that workshop, EMD Millipore’s Richard Pearce presents the concept of “open sourcing” as a strategy for meeting challenges related to drug development and manufacturing. Addressing those issues during the many stages of processing at the clinical scale requires substantial knowledge, expertise, and resources. Pearce will introduce the concept of open sourcing, which as he explains, is “an alternative view of how such knowledge, expertise, and resources can be accessed and delivered to speed the journey to the clinic.” His presentation will highlight a case study about how a solutions-based approach facilitated the development of a clinical manufacturing process for a new drug along with the construction of a clinical manufacturing facility.

Raw Materials

An efficient raw-material supply chain is vital in maintaining ideal production. As Craig Malzahn of Human Genome Sciences points out, a raw-material supply issue can easily take down a supply chain. Consequently, he says, that situation could lead to lost production days, increased cost of goods, scrapped inventory, product recall, and in extreme situations having a product be unavailable for sale to the market. “How well do you understand your supply base and relative risks from one part and one supplier to the next, and what are you doing to mitigate this risk?” asks Malzahn. To assess risk, he encourages manufacturers to take a holistic approach to develop appropriate and feasible mitigations and dynamic monitoring of emerging risks.

Bob Repetto of Pfizer BioTherapeutics Pharmaceutical Sciences and chair of PDA’s Single- Use Systems Task Force will continue the discussion of supply chain challenges by focusing on process innovation and regulatory submission strategies. Such approaches can be implemented on both raw materials and single-use systems.

Process analytics have proven to be valuable tools in controlling raw material variation. “Challenges in identifying, monitoring, and control of raw material variability exist in the biopharmaceutical industry,” says Cenk Undey of Amgen. He will address strategies based on process analytics applied to raw materialsvariation monitoring and control, both for suppliers and manufacturers.

Single-Use Systems Symposium Monday, 8 October 2012

Symposium #2 Best Practices for Implementation Challenges with Single-Use Systems chaired by Robert Repetto (research fellow at Pfizer BioTherapeutics Pharmaceutical Sciences and chair of PDA’s Single-Use System Task Force)

The advantages of single-use systems have quickly made them vital components of many bioprocesses. Manufacturers are currently facing the challenge of proper and efficient implementation of these technologies, which requires assessing and understanding all potential risks. Andrew Sinclair (managing director of BioPharm Services) will present on the economics of single-use systems and loss risk. Other presenters will address implementation tasks toward developing successful control strategies of processes using single-use systems. They will discuss the challenges, risks, and potential approaches that can be leveraged throughout the supply chain, including understanding implementation risks, learning best implementation planning practices, building robustness, and evaluating single and dual sourcing.

Rapid Process Development and Novel Technologies

Issues surrounding process development and the implementation of new process tools are highlighted in Wednesday morning sessions sponsored by Pall Life Sciences. Kenneth D. Green of Pfizer and Simon Chalk of BioPhorum Operations Group will focus on the benefits and challenges in reducing levels of environmental controls for concurrent multiproduct manufacturing within a “ballroom facility” concept. Mitigating risk in such an environment requires solutions to specific design, operational, organizational, and testing problems. Mitigation includes quality risk management (QRM) approaches and assurance of closed processing by means of equipment-design integrity as well as procedural and operational controls. Consequently, benefits can extend to realizing facility capacity and reducing operational costs while maintaining product quality and operator safety.

QRM, process development, and day-to-day operations generate a vast amount of information. Sorting through that data to convert it to useful information can be a daunting task. Fernando Nuno Fialho of Amgen says an “electronic visual factory” is a means of finding innovative ways of making information available and useful. That information can be used not only to make better process and business decisions, he explains, but it can also help a company to “discover ways to improve process monitoring, achieve paperless manufacturing, enhance purposeful presence on-the-floor, and improve business communications and increase efficiency through mobile solutions.”

Gregory R. Naugle of Amgen points out that introduction of new processes into an established, high-run–rate commercial manufacturing facility can pose significant logistical and technical problems. “In addition to ensuring the success of the new product introduction, careful consideration is required to ensure that the fidelity of the existing process is maintained and the established plant capability and run rate are not disturbed.” Multiple processes with differing levels of process and scale-up experience can increase management complexity and create situations requiring simultaneous technology transfers. Naugle’s presentation will summarize these issues and the approaches taken to achieve successful technology transfers.

Raw-Materials Symposium Monday, 8 October 2012

Symposium #3 Best Practices in Managing Variability of Raw Materials introduced by Thomas M. Spitznagel (vice president of biopharmaceutical development at Human Genome Sciences, Inc)

Concern over managing raw material variability is becoming an increasingly important part of bioprocessing. Applying best practices within process development, clinical and commercial manufacturing, supply chain, and quality can help minimize the effects of raw material variability on process performance and product quality.

Spitznagel will first introduce an overview of current challenges in managing raw material variability using a case study example. “The impact of lot-to-lot variability of raw materials on process performance and product quality has gained increased attention,” he says. Spitznagel will review strategies to effectively manage that impact. Examples will include development approaches to minimize variability as well as data analysis and supply chain tools to manage variability.

Amgen’s Supplier Excellence program is another example of an industry approach toward ensuring raw material quality. Ran Zheng of Amgen will describe the company’s program in her presentation. The symposium will also include a joint presentation from David Radspinner of Thermo Fisher Scientific and an end user. The talk with focus on how industry and suppliers can work together to identify critical raw material attributes to ensure consistent and reliable oerf
ormance. The symposium concludes with an interactive panel discussion (sponsored by Thermo Scientific) discussing the potential for integration of suppliers’ and end-users’ quality systems, including product safety data, change control, and change control notification. Panelists include David Radspinner of Thermo Fisher Scientific and Ran Zheng.

Cleaning Symposium Monday, 8 October 2012

Symposium #5

Best Practices in Cleaning and Cleaning Validation (A Science-based and Integrated Approach for Biopharmaceuticals) presented by Rizwan Sharnez (Principal Engineer, Process Engineering, Amgen Inc.)

Bioprocess equipment used in multiproduct processing requires effective strategies for addressing challenges associated with cleaning and cleaning validation. Sharnez will review fundamental elements of robust cleaning programs and how each element is developed and integrated. He will discuss current regulatory expectations, acceptance limits for degraded or inactivated product, science-based cleaning characterization methods, and lifecycle approaches to cleaning validation and monitoring. Sharnez will also show how degradation/inactivation studies can be used to eliminate product-specific assays and describe the use of master soils to streamline and provide flexibility for scheduling cleaning validation activities.

Raw materials are associated with risks of contamination. Wednesday morning will include a thoughtleadership forum (sponsored by BD) on reducing those risks, including various strategies such as sourcing of animal-free or chemically defined components. Moderated by Barbara Potts of Potts and Nelson Consulting, a panel discussion will discuss the various interpretations of animal free (AF) and chemically defined (CD) media or supplements. The industry has yet to agree on definitions for both terms, which can have implications for risk mitigation and raw materials consistency in biopharmaceutical production. The panel will also address questions such as

• Is there a need for standard definitions of AF and CD across the industry?
• What are the key criteria for mitigating the risk of viral or other biological contaminants?
• What are the best practices for sourcing raw materials to mitigate the risk of a contamination event?
• What does the future hold for raw materials sourcing?

“Microbial contaminations are a reality for the biotech industry,” says Phil McDuff of Biogen Idec. “They are costly to an organization in many ways: financially, lost time in production, unplanned resource allocations, and elevated compliance risk.” He will lead an interactive discussion on the fundamentals of preventing microbial ingress into process equipment and processing environment. McDuff will look at facility design and operation, personnel, equipment design and operation, and material/process flows. He will present a case study using data analysis to identify areas where prevention measures significantly reduced contamination rates.

Diverse product pipelines, rapidly fluctuating market demands, and growing competition from biosimilars, have driven some biotechnology companies to develop innovative solutions for highly flexible and cost-effective manufacturing. To address these concerns, some manufacturers are considering the integration of continuous processing. Veena Warikoo of Genzyme (a Sanofi company) will present a case study demonstrating the application of innovative technologies to develop robust, disruptive solutions such as a continuous bioprocess platform. “A high-density perfusion cell culture and a directly coupled continuous capture step can be used as a universal biomanufacturing platform,” she explains.

Plenary Session

Viral contamination (by adventitious viruses and other microbial agents) of processes and products continues to be a top concern. Mark Z. Plavsic of Genzyme will present a case study detailing the steps taken to mitigate contamination risk. “Manufacturers typically control for this risk by careful raw material selection, vendor qualification, raw material and cell-bank testing, raw material treatment for viral clearance, and risk assessment,” he says. He will review Genzyme’s vesivirus case and discuss viral remediation approaches to lessen the risk due to adventitious agents.

Disposable technologies have become a mainstream part of bioprocessing. The development of closed-system designs, the achievements of high-titer yields, and increasing interest in personalized medicines have changed traditional mammalian cell culture processing and facility design toward more simple setups. Berthold Boedeker of Bayer Pharma will discuss a “manufacturing facility of the future” that incorporates those novel technologies for low cost-of-goods manufacturing of protein drugs. He will describe the design and operation of ballroom-like, low segregated, flexible facilities that use single-use bioreactors and will elaborate on the technical and regulatory requirements.

Keynote Presentation

In his keynote, Jörg Thömmes of Biogen Idec will review the achievements and challenges during the past 30 years. During this time, “the biopharmaceutical industry has had remarkable successes delivering tremendous value to our society,” he says. “The manufacturing side of our industry has also matured, driven by dramatic improvements in productivity over the past decade coupled with the development of robust platforms. We’ve seen an industrialization of biologics manufacturing, which makes manufacturing capacity a most valuable asset.” Innovation in manufacturing facilities, operation, and process understanding can significantly affect the industry’s ability to optimize manufacturing capacity. Boedeker will show how focused innovation can further improve manufacturing efficiency and turn biomanufacturing into a powerful value driver.

Author Details
Maribel Rios is managing editor of BioProcess International, mrios@bioprocessintl.com. Quotes not otherwise attributed are from presentation abstracts.