Smart management and maintainance of multiple production sites is essential for global manufacturers and suppliers to reach both existing and emerging markets. Optimal performance of these networks requires keen efficiency, due diligence, and cost reduction. Biomanufacturers are taking a close look at their facilities when developing strategies for reducing time to clinic and decreasing the cost of operations, including labor, energy, raw materials and supplies, and other resources. The Managing Manufacturing Networks track of the BioProcess International Conference and Exhibition will include sessions (see box below) highlighting the technology, innovation, and strategic business approaches to optimize performance of current operations and prepare new facilities to meet future technological challenges.

Modernizing Facilities with New Process Technologies

How much and when to invest in novel technology certainly depends on the unique needs of each company. Biomanufacturers should determine how the new technology will be compatible with existing systems. Traditionally, biomanufacturers ensured control over their products and processes by fully integrating production at one site. However, the business practice of outsourcing at least part of well characterized processes is now widespread, leaving companies to focus on developing new clinical and preclinical-phase products.

BPI CONFERENCE SESSIONS
Tuesday, 21 September 2010
7:55 AM–11:45 AM: Leveraging Your Assets: How Do We Reconcile the Installed Base with Current Technologies and Demand?

1:45 PM–3:30 PM: Smart Flexibility in Facilities

Wednesday, 22 September 2010
8:00 AM–11:30 AM: The Future of Manufacturing Networks and Facilities

At smaller scales, testing materials may be produced in environments based primarily on single-use systems. The flexibility and cost advantages of disposable components in upstream, downstream, and fill–finish operations are well known. However, implementation of small-footprint single-use systems has ushered in next-generation multiproduct facilities. These sites are beginning to take advantage of implementing not only single-use components, but entire unit operations. At the BioProcess International Conference, the design, operation, and qualification of such highly disposable facilities will be discussed as part of the Managing Manufacturing Networks track.

Innovation: A key element in keeping on top of the state of technology and keen strategic business models is knowing how to use current resources to your advantage. Günter Jagschies (senior director of strategic customer relations at GE Healthcare Life Sciences) will speak on “Leveraging Innovation to Achieve Successful Strategies for the Biotech Business” (Wednesday, 8:45 AM). He will review the technology, financial, and business resources that biomanufacturers can use to better manage their facilities.

Process Simulation: Process models (both real-time and batch-simulation models) provide a means of evaluating the various factors of a process and allow users to adjust a range of parameters according to the needs of a specific product. Process simulation is an effective tool for upgrading facilities to make high-titer processes and is often implemented during process development to establish correlations between process adjustments to cost and cycle time.

Interest in process simulation has grown thanks to the industry’s greater emphasis on efficiency, better understanding of process parameters, and application of process knowledge to reduce the likelihood of bottlenecks. Ian Gosling (principal at ChemSim LLC) will present a discussion titled “How Process Simulation is used in Biogen Idec to Optimize Manufacturing Processes” (Tuesday, 11:15 AM). He told me he has watched the industry’s adoption of process simulation change, especially during the past five years.

“I attended a BPI Conference in 2005 where process simulation was discussed,” says Gosling. “Although the conclusions about process simulation are still the same, because companies want to control costs and benefit from flexible approaches to manufacturing, simulation can help them get the most from their investment. People are looking at process simulation to get a better idea of how much protein they can get and how they can use facilities to get multiple products. That has been increasing slowly over the past five years.”

As Gosling observes, process simulation is used at different phases of product development. He says his initial work was optimizing clean-in-place skids to streamline their use. Recently, he used modeling for concept studies. For this application, one issue is the increasing titers of monoclonal antibodies (M Abs). Titers have become much higher, so now you can use smaller bioreactors, or — if you have a large bioreactor already — you can produce multiple products faster than you could in the past.

“In this case, process simulation is used to remove bottlenecks,” says Gosling. For example, a purification process with a capacity of 5 g/L can become problematic because it requires large buffer volumes. To help address this problem, people have discussed the use of buffer concentrates.
“My task then, is to apply process simulation to determine how we can incorporate buffer concentrates, what are the buffer tank sizes, and how we can use them most effectively for these high-titer processes,” says Gosling.

Implementing a process simulation model does come with its challenges, however. It may be relatively easy to build an initial model for many companies now. Most companies have initial process descriptions (which are the building blocks for these models). However, Gosling says there is always an iteration process after this first version is built, and it’s that process that can take some time. “It’s worth doing it if you want to get an accurate representation, but it does mean that initially management must have an understanding that some of these steps take a little while to develop before you’re actually going to see a return. That’s always a challenge.”

SPEAKER Q&A

Interview with Rick Johnston
Rick Johnston, codirector of the Center for Biopharmaceutical Operations at the University of California-Berkeley, will provide a presentation titled, “The Dinosaurs Reborn: Retrofitting Existing Facilities to Speed Technology Transfer and Support the Platform Process” (Tuesday, 10:45 AM).

BPI: Most of the industry is aware of the advantages of both stainless steel and single-use systems. Questions are now being asked about the implementation of disposables — where it makes more economic sense and how to incorporate it with existing systems. What are the current thoughts on addressing these issues?

RJ: Implementation of single-use seems to be widest in media and buffer preparation, especially for small volumes of less than 2,000 L. In these cases, implementation of single-use seems to make a lot of sense because the traditional s
tainless steel vessels in these areas are often facility bottlenecks. This can also be an area where piping manifolds or transfer panels are the most complex, and single-use systems can make a critical improvement. The benefit is less clear for fermentor vessels because the bag comes directly into contact with the product, but there are some good products — again, in the 100-L to 2,000-L range only. There doesn’t seem to be significant benefit in using single-use systems for recovery/ purification yet, because stainless steel columns are almost universally used.

BPI: What technologies are driving this need for a more flexible manufacturing management strategy?

RJ: As costs are driven down — particularly by generics, but also by low-cost vaccines — there will be an increasing need to take a closer look at the role of disposables and single-use systems in general. They do have the ability to lower costs and increase overall flexibility, when used judiciously.

His conference presentation will describe much of Gosling’s work with Biogen, which has been using this technology for quite a few years. The company is looking at these types of tools to improve facility-wide and company-wide operations. He will provide initial descriptions of process modeling that is used at Biogen as well as various case studies on debottlenecking and concept studies on design and operation.

New or Upgraded Facilities: Two presenters at this year’s BPI Conference and Exhibition will discuss their companies’ experience with building and qualifying a new facility that incorporates state-of-the-art technologies for streamlining processes. Jeff Johnson (engineering director of biovaccine process engineering, global engineering services, at Merck & Co.) will outline “ lessons learned ” in the design, commissioning, manufacture, qualification, and validation of a new biotech manufacturing site (“Manufacturing Aspects of a New Facility: Lessons Learned,” Tuesday, 8:45 AM). Part of his presentation will cover lessons in automation and process equipment. And Ken Hammer (vice president of facilities and engineering at Dendreon Corporation) will describe his company’s work in building a patient-specific product manufacturing plant (“Building the First Patient Specific Product Manufacturing Plants: Design and Construction of Dendreon Corporation’s Innovative Manufacturing Facilities,” Tuesday, 9:15 AM). His presentation will also summarize the design and construction of this unique facility.

Two other presenters at this year’s conference will talk about how their companies updated their facilities. Rich Meinel (associate director of global process engineering technology at Biogen Idec) will discuss the new product platform strategies and technologies for upgrading a manufacturing site (“Upgrading Current Facilities for Future High-Tier Processes,” Wednesday, 11:30 AM). These tools have the potential to instill flexibility in operations by increasing assest use, assisting in long-term capital planning for projects, and enabling cross-site facility consistency.

And Carol Basey (senior manufacturing technical specialist at Genentech) will present a case study titled “Enabling High-Throughput Production in an Existing Commercial Plant” (Tuesday, 10:15 AM). The discussion will detail how manufacturers can potentially lower the cost of goods by producing product at higher run rates. Basey will focus on how equipment and operational modifications can be identified and made and will reference historical performance data.

Supporting Single-Use and Stainless Steel Hybrid Systems

Modern biomanufacturing is beginning to transform into a hybrid system of stainless steel and single-use materials, which is what BPI Conference presenter Rick Johnston terms a bifurcation of biomanufacturing capacity. “Bifurcation is an emerging pattern in the industry, of disposables being increasingly used for small-scale plants but traditional stainless steel tank technologies still being built for larger plants,” explains Johnston.

This essentially creates two “types” of plants in the industry, with very different characteristics in terms of throughput, key bottleneck areas, flexibility, and overall cost. “Obviously, for smaller companies with lower production volumes, disposable technologies make a lot of sense. However, larger companies and contract manufacturers will need to continue to build stainless steel for the foreseeable future,” says Johnston.

Although using single-use systems can help lower cost and generally increase flexibility for smaller facilities, building two different types of facilities can be challenging for companies because there is less standardization. For a company managing a manufacturing net work of several facilties, these challenges include training, scale-up issues, and increased technology transfer times. Johnston will present “The Dinosaurs Reborn: Retrofitting Existing Facilities to Speed Tech Transfer and Support the Platform Process” on Tuesday, 10:45 AM.

Streamline Processing of Current Drug Products

Several case studies presented in the Managing Manufacturing Networks track focus on innovative solutions to streamline both upstream and downstream steps for specific therapeutic types.

Antibodies: Asha Radhamohan (engineer of bioprocess development at Genentech) will describe the company’s study of monoclonal antibodies involving a unique method of pH gradient elutions on protein A (“Design of a Protein A pH Gradient Elution Offers New Flexibility in MAb Processing, Tuesday 2:30 PM). Such elutions removed a greater number of process-and product-related impurities than could traditional step elution. Because of increased purity levels, the company was able to streamline membrane chromatography operations in place of downstream columns.

In some cases, high-dose concentrations (>100 mg/mL) of some MAb formulations enable subcutaneous delivery. Achieving these doses, however, takes considerable effort. Michael LaBarre (vice president of product development at Halozyme Therapeutics) will summarize the company’s Enhanze technology, which is designed to permit subcutaneous dosing of much greater than 1 mL/injection, thereby avoiding the challenges of high-concentration formulations (“Subcutaneous Protein Delivery: Challenges, Opportunities, and Key Lessons from a Drug Delivery Platform,” Wednesday, 10:30 AM).

DISPOSABLES-BASED FACILITIES

The Managing Manufacturing Networks track will include two sessions discussing two separate case studies of the large-scale implementation of single-use systems in a facility. Both sessions will take place Tuesday, starting at 2:00 PM.

Robert J. Steininger II (senior vice president of manufacturing at Acceleron Pharma) will describe his company’s use of single-use technology to increase flexibility, reduce cost, and ease operation. Acceleron is a small emerging biotech company that provides preclinical and clinical material.

Chris Brodeur (senior operations manager and commercial expansion head at BioMarin Pharmaceuticals) will discuss the company’s newly expanded and “highly disposable” commercial operations facility. The commissioning and qualification of the multiproduct site will be described.

Antibody drug conjugates (A DCs)deliver cytotoxic drugs through targeting moieties such as tumor cells using the specificity of a M Ab. An increasing number of A DCs are entering clinical trials in humans and undergoing FDA review. The FDA has developed specific guidelines to help companies ensure product safety and efficacy. Nonetheless, during the process development cycle and regulatory over view process, manufacturers can face significant challenges related to the chemistry, manufacturing, and controls (CMC) for each molecule. Jun Park (regulato
ry quality reviewer in the division of monoclonal andibodies, FDA’s Office of Biotechnology) will discuss CMC-related issues specific to A DCs in his presentation (“CMC-Related Regualtory Considerations for Development of Antibody-Drug Conjugates,” Wednesday, 8:15 AM).

Raxibacumab is a human MAb developed by HGS (Human Genome Sciences) to treat inhalation anthrax. In April 2009, the company delivered 20,000 doses of the drug to the US Strategic National Stockpile. Later that year, the company received an order for an additional 45,000. In a presentation titled “Biodefense: Human Genome Sciences’ Development and Manufacture of an Antibody for Treatment of Anthrax Delivered to the Strategic National Stockpile” (Wednesday, 11:00 AM), Craig Malzahn (director of supply chain and manufacturing operations for Human Genome Sciences) reviews the antibody program and the unique development process of this drug.

Recombinant Factor Product: Jens Vogel (global CMC development team leader and head of isolation and purification at Bayer Healthcare) will describe a simplified manufacturing process of the company’s rFVIII product (“Development and Implementation of a Next-Generation Manufacturing Process for a New rFVIII Product,” Wednesday, 9:15 AM). The presentation will review how the company’s CMC (chemistry, manufacturing, and controls) development team used innovative technologies to develop, scale up, and implement upstream and downsteam processes that now serves as platforms for manufacturing other biologics.

Author Details
Maribel Rios is managing editor of BioProcess International.

REFERENCES