June 15, 2009 (Vol. 29, No. 12)

Industry Veterans Offer Tips, Tools, and Strategies to Reduce Expenditures

There were several lessons for CMOs at the recent “BioProcess International Conference,” among them notification from Miriam Monge, vp of marketing and disposables implementation at Biopharm Services, that CMOs must significantly reduce development and manufacturing costs.

“The success of monoclonal antibodies is reflected in the major growth in manufacturing capacity,” said Monge. However, “high capital investment, coupled with high operating costs, and inflexible facilities have contributed to the high price of mAb-based treatments. 

“Starting in process development we have to develop efficient, robust processes more quickly,” Monge continued, “and with greater success. We then have to transfer the processes efficiently into flexible, low-cost manufacturing facilities.”

One of the speakers giving tips on how to improve technology transfer was Kristi Huntington, associate technical consultant at Eli Lilly and Co. Her presentation focused on how Lilly Ireland overcame the challenges it faced in transferring production of an inlicensed biologic to a facility that had never before made a biotech product. The production process was not well understood nor was it optimized. “We had limited information and data, and so we had to learn the nuances  of the process,” she explained.

First and foremost, she said, the tech transfer team needs to prepare a plan. “This insures up-front alignment of the key players with fewer surprises and a bigger chance of getting the process right the first time.” 

Owing to the accelerated project timeline, five teams worked on this tech transfer, although there was not a formal plan which, Huntington admitted, was not ideal. Despite facing significant technical challenges, two batches of API were made within a year. This success is a tribute to the positive attitude and commitment of those involved. “The learning from this tech transfer was priceless for Lilly Ireland,” she commented. “It really set the stage for our upcoming new biotech facility.”

Among the lessons learned was never to underestimate the need for experienced biotech operators, which “is absolutely key to the success of the process execution,” said Huntington. “We also underestimated the technical complexity of the molecule.”

CMOs can also speed up tech transfer by adopting new tools and technologies. Susanne Wallenborg, Ph.D., section manager of R&D, life sciences at GE Healthcare, described the role that high-throughput process development (HTPD) can play in tech transfer. Efficient process development is key to developing a robust and efficient manufacturing process, she said.

HTPD allows exploration of a larger experimental space and supports the definition of a well-established process design space where the critical process parameters that really need to be controlled and monitored are completely understood,” Dr. Wallenborg explained. 

Key to HTPD is the GE PreDictor™ plate, a 96-well plate product prefilled with chromatography media. The product can be used throughout downstream processing to screen for binding capacity, wash and elution conditions, adsorption isotherms, and CIP conditions, Dr. Wallenborg said.

Biovian is developing fed-batch and perfusion cultivation technologies to enhance process productivity in customer projects.

Operational Excellence

But it is not just innovative technology that is important to CMOs these days— organizational culture also plays a role. Fadel Hamed, Ph.D., head of operational excellence at Genentech, said that being “world class is a never-ending pursuit of perfection.” Companies aspiring to world-class status can use operational excellence (OE) to help them to deal with the challenges of the biopharmaceutical business. Dr. Hamed defined OE as the “routine delivery of exceptional performance through a systematic approach to continuous process improvement.”

OE has three stages. In the foundation phase, the infrastructure required to improve current operations is set up; in the incremental phase, operations are optimized to deliver a predictable performance; and the final and most difficult phase, which is known as transformation, sets a company well on the road to being world class. “Most companies will not reach the transformation stage,” Dr. Hamed claimed.

OE at Genentech is based upon a Lean/DMAIC (Define, Measure, Analyze, Improve, and Control) approach, which is a data-driven problem-solving methodology for delivering business results. Dr. Hamed explained that, “variation is the enemy, and we have to control it—Lean/DMAIC gives us a mechanism to do so.” 

“OE is about attitude and having a continuous improvement mindset,” he added. At Genentech, it is focused upon reliability, simplicity, and growth. However, one should beware of islands of excellence. What is needed is end-to-end OE throughout the whole organization to identify any weak areas. 

With a team of just 10 OE people, Genentech delivered $54 million in savings in 2008. Dr. Hamed explained that 30 different factors have been identified in the failure of OE, and the most important of these is leadership. “Leadership must be committed and accountable,” he concluded. 

Data Handling and Analysis

Justin Neway, Ph.D., evp and CSO at Aegis Analytical, addressed the data-management challenges that come with tech transfer. Aegis provides manufacturing intelligence solutions that drive a lean supply chain and accelerate revenue with a proven approach to data access, aggregation, analytics, and reporting, he explained.  

Dr. Neway believes the way forward is to create a collaborative, on-demand environment for handling data, rather than relying upon traditional methods (such as emailing spreadsheets), which involve a lot of work and often lead to loss of data and errors. The current data-collection landscape is not designed around flow and effective management of all the various types of data involved in biotech production. The most abundant type of data is real-time online data.

The people who need this data most for their work are not IT experts. “We need to translate the data world into one they can actually use and make it accessible in a context that’s meaningful to their needs,” said Dr. Neway. This involves the use of a dynamic mapping engine, which locates the data in its original source and preserves its batch, data type, and genealogy context for users to do their analysis. Although some companies have put together warehouses, data still needs to be pulled out of these on demand in a meaningful context.  All of these issues are important in both manufacturing and process development. 

Aegis has developed a software solution called Discoverant® which allows creation of this desirable collaborative setting for data handling and analysis, Dr. Neway said. The product leverages existing IT investments to enable on-demand and scheduled access to all manufacturing, quality and process development data for process performance analysis and visibility.

Discoverant has been used in a tech transfer situation between a sponsor in the U.S., and two of its CMOs in the U.S. and Asia, he noted. “The use of Discoverant gives better control of IP, processes, products, and the preparation of regulatory submissions in both internal and external tech transfer.”

He also remarked that “in tech transfer between clinical trials and commercialization, it has to be remembered that the role of the FDA and other regulatory bodies changes—they become more of an enforcement agency. Compliance stringency will be at its greatest in commercial operations, which means that earlier stages are the best to put innovation in place. Tech transfer must also go in the opposite direction, which is what is learned at the large scale is applied to the next molecule,” he concluded.

SynCo Bio Partners offers both clinical trial and commercial cGMP manufacturing. According to Joanne McCudden, sales and marketing director, biotech customers are taking a longer-term view and thinking about manufacturing even before Phase I—a trend that could benefit SynCo, while putting pressure on CMOs operating at a smaller scale. The company is also seeing more demand for cGMP manufacture of live microbial-based products like the Lactococcus delivery platform technology being developed by ActogeniX for GI disorders.

Biovian, a pure CMO, touts its ability to take a customer from gene sequence to finished vial of product. It offers both microbial and mammalian culture, mainly for clinical trial supplies but also at commercial scale for some niche markets and orphan drugs.

“We came to disposables very early because they mean shorter turnround time and line clearance between clients and no need for cleaning validation,” said Knut Ringbom, Ph.D., director, projects and marketing. He sees disposables entering the DSP and fill-and-finish side of production and promises that Biovian will be at the forefront of this. The company is also developing fed-batch and perfusion cultivation technologies to enhance process productivity in customer projects. 

CMC Biologics manufactures antibodies, recombinant proteins, and vaccines for customers from large pharma and small biotech and is gearing up to commercial scale as its customers push products through pipelines.  CHEF1® is an important new development for the company, reported Bernard Chan, business officer.

“It allows fast construction of a cell line to express the client’s protein,” he said. CHEF1 takes less time because it has no need for a gene amplification step. CMC’s large library of vectors allows insertion of multiple copies of a gene so that high levels of expression can also be achieved. Chan adds that the company is developing perfusion technology so that it can scale up without needing a much larger facility.

An emerging trend being seen at Cobra Biomanufacturing “is an increased requirement for biosimilars from our clients and not just for classical monoclonal antibodies, but for other products,” reported Daniel Smith, Ph.D., commercial scientific developments manager.

This demand has meant extra attention is needed on the analytical side to ensure the product is fully characterized for its similarity to the original. Cobra is working on a number of ongoing contracts involving biosimilars, though none is on the market yet. Increasingly, Cobra is relying on disposable single-use technologies, which are proving their worth in a multiproduct facility like theirs.

“There are so many developments in disposables in both fermentation and chromatography, but we do need to be careful of how they are used in a cGMP facility, which is why we work closely with manufacturers,” concluded Dr. Smith. 

SynCo Bio Partners reports that customers are taking a long-term view and thinking about manufacturing before Phase I studies begin, which is benefitting CMOs like SynCo that offer clinical- and commercial-scale manufacturing.

Susan Aldridge, Ph.D. ([email protected]), is a freelance science and medical writer.

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