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NIBRT's Ian Nelligan on what to expect when starting an upstream process, including the choice between single-use and stainless-steel bioreactors.
In this first part of a series of primers with training experts from the National Institute for Bioprocessing Research and Training (NIBRT), Ian Nelligan, Technical and Training Director, discusses upstream processing. NIBRT provides training, educational and research solutions for the international bioprocessing industry in state-of-the-art facilities. Located in South Dublin, it is based on an innovative collaboration between the University College Dublin, Trinity College Dublin, Dublin City University, and the Institute of Technology Sligo (see introduction to this series on "Training the Biopharma Industry").
BioPharm: Can you start by walking us through a brief description of what's involved in a typical upstream process for manufacturing a biologic-based product?
Nelligan: A typical process lasts approximately 40 days, so it's quite lengthy. The first 21 to 25 days involves growing the cells. Typically, each batch starts from cells stored in an ampoule. The cells are kept viable by being stored in liquid nitrogen in the laboratory. These cells are laid down by the research teams who first developed the cells and processes for later production. For commercial production purposes, one needs to use a vessel in a size ranging from a 1000 L to 10,000 L. This means the starter culture must be grown in a series of passages before inoculating these large production vessels.
Typically, the process begins with a few milliliters of cells in an ampoule growing up over 21 days to eventually inoculate a 1000-L or 2000-L production vessel. These cells last approximately 12 days in the production vessel, their metabolism being switched from growth to a production state by computer control of conditions. It is in this production stage that the cells make the targeted product (i.e., the drug substance) until it's ready to be harvested. At this point, one may have a few kilograms of monoclonal antibody (mAb), for example.
BioPharm: When scaling up from a laboratory process to a production process, as you've described here, what considerations does the manufacturer need to keep in mind when developing an overall biologic process? In other words, how can a team best prepare for the scale-up stage?
Nelligan: The process must be robust, first and foremost. Animal cells are very complex. The industry still struggles with identifying the areas of variability. Even though computer-controlled vessels are used to control the cells' metabolism very tightly, the quality of the product needs to be carefully checked before being dispositioned. One needs to keep in mind that mAbs are very powerful substances and over a thousand times more complex than the small-molecule chemical products produced by the pharmaceutical industry in the past. Sophisticated and state-of-the-art analytical techniques are therefore required to characterize such products. If the process is not robust and the drug substance product has not been fully characterized in the early development (or clinical trial) stages, undesired variability can arise when moving to large-scale manufacture.
BioPharm: With regard to equipment, there is a trend right now towards disposable, or single-use, bioreactors when performing an upstream process. In your experience, why is the industry changing this preference for material?
Nelligan: There are two aspects of this trend. One must keep in mind that biotechnology is a relatively new industry. We are approximately 10 years old, and technology is changing very quickly. The productivity of the cells has increased enormously over the past 10 years. With newer strains, the amount of drug substance has increased 10-fold compared with before. This increased productivity is leading to smaller and smaller manufacturing plants.
Ten years ago, production was taking place in 10,000-L vessels, and nowadays, it is taking place in 1000-L vessels or less. At this smaller scale, there is now the possibility of moving to a disposable plant. A 1000-L vessel is equivalent to a cubic meter, so new disposable vessels can literally sit on a laboratory countertop. Cells can therefore be cultured in disposable bags rather than in large stainless-steel bioreactors, which was norm a decade ago.
When using disposables, however, there are concerns regarding extractables in the plastic bags which can be transferred to the product. This problem does not occur in a stainless-steel environment, which is more robust. Plastics can also be quite friable. Disposable bags are limited in size because they cannot hold off pressure.
Despite these disadvantages, these bags are becoming the norm in industry. Although disposables are more expensive than perhaps the industry would like, companies are willing to pay the extra cost because the bags also come pre-validated and presterilized, which saves time and resources on commissioning and validation. As a result, plants can be established more quickly; a modern plant can be designed and up and running within three months when using disposable technology, rather than the two to three years that it may take when building a stainless-steel plant.
BioPharm: Looking ahead 10 or 20 years, what do you think will be the standard bioreactor of choice—a disposable, a stainless-steel, or perhaps a hybrid model?
Nelligan: We are already seeing hybrid models—partial disposable and partial stainless steel. People are gaining more confidence with disposable systems and favor the advantages they offer. For example, the first to market with a new product usually gets the lions share. If you have a new product that you want to get on the market quickly, the way to go is the disposable route.
The October issue of BioPharm International will feature a primer on downstream processing with Nelligan. The full interview with Nelligan on upstream processing can be listened to as a podcast on BioPharmInternational.com/BasicTraining
Ian Nelligan is the Technical and Training Director at the National Institute for Bioprocessing Research and Training (NIBRT) in Dublin.
Listen to the interview as a podcast on our Drug Development Basic Training web page.http://www.biopharminternational.com/biopharm/article/articleDetail.jsp?id=750474