Genetic Engineering & Biotechnology News

MAY1 2015

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30 | MAY 1, 2015 | GENengnews.com | Genetic Engineering & Biotechnology News Richard Grant One of the many challenges in cell therapy manufacturing is the thoughtful deployment of capital and technology in the set-up of a manu- facturing facility, which is dependent on factors that can differ radically from therapy to thera- py. Some of these factors are determined by the therapy type, some are dependent on individual processes, and others are based on the logistics model for incoming samples or the distribution and delivery model for fnal product. In this tutorial, the key differences be- tween allogeneic and autologous therapies are highlighted. These differences, which im- pact the planning and customization of fa- cilities, must be understood if manufacturing is to proceed effectively. As with all production facilities, planning seeks to balance goals in cost with essential requirements in optimizing throughput. Key to achieving this is to minimize the residence time of each procedural step. This is particu- larly true for those steps that utilize the more expensive pieces of equipment, as different unit processes demand various equipment solutions for manipulation or incubation of the cells. While the cost of building and then pro- ducing in clean manufacturing space can be a signifcant burden for the cell therapy in- dustry, planning should also consider moving production into sterile disposable sets capa- ble of being used in lower-class clean space. Allogeneic Therapy Scale Up For allogeneic therapies, where scale up can be performed by increasing batch size or a single facility's production capacity, balancing the batch size at every stage in the production process is essential to success. When allogeneic manufacturing processes are designed, critical questions arise. For example, it may become necessary to decide what constitutes a batch. Such questions are often hard to resolve. The answers to these questions drive many of the key decisions related to equipment and complementary disposable set design. For ex- ample, when large numbers of cells are to be expanded, process variability within the dis- posable set (i.e., multiple 2D cell culture ves- sels) can become an issue. If a process shows enough variability, production teams or regu- lators may determine that a run cannot be called a single batch. Moving a batch to the next process step also has the potential to present challenges if the determination of what defnes a batch is different for different unit processes. As a result, the need to match unit process capaci- ties can drive batch size down to the capacity of a single limiting process step. Surprisingly, different bottlenecks and blockers, often in- visible to the untrained eye, can become ap- parent at different scales of manufacture. For example, optical inspection for par- ticulates in the short time available before freezing may be a problem at full production volume, but it is unlikely to be an issue at manufacturing volumes appropriate for clin- ical trials, where the focus is not on driving batch size up and cost per batch down. Other examples include formulation. It is generally easy to formulate a large volume of cells into cryogenic storage media, but process- ing these into working cell bank bags or fnal dose vessels can present time limitations, and time spent in cryomedia at processing temper- atures is detrimental to cell viability. Process- ing the drug product in successive smaller vol- umes reduces the negative impact on viability and makes sense, but invites a question as to whether a batch is a batch. Another example is scalability. Process de- velopment ideally is done at small volumes to optimize batch cost, limit development time, and increase n numbers for credibility before the process is transitioned to production scale. But equipment currently available for many unit processes at research level is generally not scalable, so the transition to commercial scale can be both costly and time consuming in or- der to prove comparability. Larger batch size allogeneic processes can also suffer from another problem that is rare- ly obvious. If the match of scale of production and volume of product used means that only a few batches per year need to be produced with manufacturing performed in single-use disposable sets, this often results in major sup- ply chain challenges. Designing and qualifying disposable sets during development is a distinct need. But once the design is established and a program moves from development to ongoing manu- Manufacturing Methods for Cell Therapies BIOPROCESSING Appropriate Deployment of Processing Equipment Critical for Specifc Products Tutorial www.richter-helm.eu | Phone: +49 40 55 290 - 436 | t.rupp@richter-helm-biotec.eu Biopharmaceutical Develop ment and Manufacturing • recombinant proteins (e. g. cytokines, antibody fragments) • plasmid DNA • vaccines Manufacturing Capabilities • from strain development to GMP manufacturing • from lab scale up to commercial supply Partnering and Licensing • full development up to finished product • global in- and out-licensing of biopharmaceutical projects FDA and EMA GMP compliant Winner of CMO Leadership Awards 2015: Productivity | Quality | Innovation Meet us at: Bio International Convention 2015 Philadelphia, USA, June 15 –18, Booth # 3628 BioTalk Biological Manufacturing Excellence 2015 Berlin, Germany, September 24 – 25 Bio-Europe 2015 Munich, Germany, November 02 – 04 Experience for the Future Figure 1. The instrument shown here dispenses working cell bank material. A B Figure 2. System design accounted for the need to support increased production volume. "Support" is shown in terms of number of operators (A) and in terms of cleanroom area (B). "Production volume" is shown in terms of patients per year.

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