June 1, 2006 (Vol. 26, No. 11)
Susan Aldridge, Ph.D.
New Emphasis Driven by Outsourcing Trend and Changes in Marketing and Strategy
If good science is to translate into new medicines, then effective technology tranfer is essential. At IIR’s recent Technology Transfer for Biopharmaceuticals meeting, the focus was on the latest developments and challengesfrom scale-up and process modeling to project and people management.
The highly complex process of technology transfer has become a fundamental aspect of the current biopharmaceutical environment, according to Andy Stephenson, senior consultant at Smarttech Consulting Services, who advises many companies on tech transfer.
It is, however, hard to define technology transfer because it is highly context-specific and encompasses so many different aspects, including in-house expertise, process definitions, manufacturing techniques and procedures, analytical methodology, and information packages.
Stephenson sees tech transfer as being driven by the trend toward outsourcing as well as changes in marketing requirements and company strategy, including takeovers and M&As. Good project management, with a dedicated manager and team, is essential to successful tech transfer, he explained, but deficiencies, such as insufficient resource allocation and insufficient time allowance and preparatory work, are often seen.
In particular, experts should be made more available to transfer recipients. Senior management buy-in is also important, he added. It is not uncommon to see projects without proper upward reporting.
Sunil Chhatre, research engineer at the department of biochemical engineering, University College, London, described some of the technologies being developed there to facilitate tech transfer.
Ultra-scale-down, which is the development of a small-scale version of an industrial process, has been found to give important insights and is usefully complemented by bioprocess and decisional modeling tools. Modeling is, said Chhatre, currently underutilized in biotech, and what is currently done often tends not to accurately reflect a real manufacturing process; his own research seeks to change this by using a more dynamic approach.
Chhatre has been able to apply these new tools in collaboration with Protherics (www.protherics.com) to improve yield and cost of goods in the manufacture of its rattlesnake antivenom product. Modeling allows rapid visualization of the impact of various process changes, he explained.
Early Biopharmaceutical Development
Some of the issues that are important in tech transfer at the earlier stages of development of a biopharmaceutical were explained by Richard Dennett, Ph.D., technology transfer manager at Eden Biodesign (www.edenbiodesign.com). Value can be added by understanding the needs of different kinds of donors or clients. For academic clients, tech transfer to a CMO may be their first contact with industry. These people are the powerhouses in generating ideas for new products, but they often don’t really know what tech transfer is, explained Dr. Dennett.
Such clients often have an unrealistic sense about the cost and time of bringing products to market and may also lack the traceable records that are needed to satisfy regulatory requirements. Eden works with these clients on areas such as training, due diligence, and filling in gaps to get products and process as watertight as possible.
The SME client, by contrast, has more knowledge and understanding in areas such as quality but may still tend to harbor unrealistic time/cost expectations; meanwhile, a big pharma client tends to know the rules but don’t always get the quality supporting package with protocols and standard operating procedures right, and it may be somewhat risk averse.
For these more advanced clients, it is still crucial to get a throrough understanding of the process and product. Common problems encountered in tech transfer with any type of client include incomplete information, quality issues, and lack of realistic timelinesand these can only be overcome by building good relationships from the start though effective project planning and scheduling of communications.
Corinna Sonderegger, Ph.D., group head of cell biology at Sandoz (www.sandoz.com), explained some of the tech transfer principles used at the company’s new cell culture facility at Schaftenau, Austria. These guidelines are especially relevant to Sandoz’ manufacture of generic biologics. The company’s version of human growth hormone, Omnitrope, recently become the first such product to be approved in Europe.
Tech transfer can be divided into three parts, said Dr. Sonderegger: materials transfer, process transfer, and analytics/QA. In materials transfer, cell banks, in particular, need a validated transport system in which planning ahead on who does what and when, with attention to documentation, has proved critical. For process transfer, co-location of development and pilot plants and production plants works well. The transfer would be divided into specific stages of which the first is a thorough understanding of the process.
Next comes scale-up of the upstream process from development to a 100-L pilot plant, followed by similar scale-up of downstream processing. The final step is the transfer to production, when the company likes to have the development personnel on-site for the critical steps.
At all stages, planning ahead is key to successlisting materials and methods to be transferred, defining QA responsibilities, and checking on traceability of exchanged documents such as databases and e-mails.
Nor should the human aspect be neglected. Try to understand and accept the other company’s procedures, said Dr. Sonderegger. Stay flexible and trust one another. Recently, the company has been involved in meeting a challenging timeline for tech transfer with a monoclonal antibody product. This was done by overlapping some activities at the source site with tech transfer at the receiving site instead of employing the usual sequential approach to operations. The fast-track approach is not without risk of course, but a high-quality product can be achieved in this way if the right expertise, commitment, and state-of-the-art equipment are employed.
Avecia Biotechnology (www.avecia.com) is another company with much experience in biopharmaceutical tech transfer. It has its own microbial fermentation capacity from 100 to 5,000 liters and transfers its full-scale mammalian manufacturing to CMOs.
Technology transfer usually involves a complex network of interfaces, especially for later-stage projects, explained Bo Kara, Ph.D., head of expression and cell sciences. The knowledge required tends to be in multiple organizations and locations and sometimes clients do not understand the nature of the information being transferred, perhaps because of a project’s history or personnel changes. Third parties may also be reluctant to release relevant information.
Effective tech transfer begins as soon as possible and requires the establishment of a program team with defined sub-groups with responsibility for aspects such as facilities and utilities. Dr. Kara also recommends a well-defined feasibility studytypically in a 100-liter pilot plantto get an idea of whether predefined and pre-agreed criteria for the tech transfer can actually be met. Because of time constraints, many operations must be carried out in parallel rather than sequentially. All tech-transfer projects have a different shape depending on their phaseat the early stage, a project will be dominated by R&D issues, at a later stage, by validation, manufacturing, and compliance.
A robust approach to risk management is also preferred by Avecia. It uses well-defined risk-assessment tools that look at the severity of impact, probability, and detectability of an occurrence, all of which is formally documented.
Risk analysis is a dynamic ongoing activity, said Dr. Kara. We have found it to be a powerful tool to set the cultural approach to tech transfer. Process modeling has also proven valuable in the simulation of manufacturing operationsit can help to pull out the less obvious risks in a process. For instance, in one project, a bottleneck in buffer supply was identified using this approach. By changing working patterns, we were then able to meet our requirements, he added.
Bram Bout, Ph.D., vp of protein production at Crucell (www.crucell.com), believes in designing manufacturability into a product at an early stage. Selection of the cell line for producing a protein is crucial, he said, and this means looking for scalability as well as productivity.
The company believes that the PER.C6 platform technology could provide a much-needed breakthrough in protein production, bringing down its current high cost. With 45 licensees and a planned expansion in the PER.C6 licensing program, tech transfer is naturally important to Crucell.
Finally, Peter Levison, Ph.D., technology development director for Pall Life Sciences (www.pall.com),spoke about tech transfer from the point of view of separation processes. Issues to be considered are the scalability of lab separations, supply, quality and cost of media, time constraints (capacity and flow rate), and what to do about procedures that are impractical or difficult to conduct in a GMP environment. There may also be regulatory difficulties when it comes to new chromatographic matrices.
The scale-up aspect of tech transfer often involves deciding between a column and a membrane to do a separation where trade-offs between resolution, capacity, and flow rate have to be considered.