Genetic Engineering & Biotechnology News

MAY1 2015

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Genetic Engineering & Biotechnology News | GENengnews.com | MAY 1, 2015 | 31 facture, the volumes of disposable sets required for production can be as low as four per year. Even when we consider the set requirement for operator training and act to ensure consistency of manufacture and quality of supply, the total demand for disposable sets might be as low as 12. In this case, sourcing suppliers willing to in- vest the time and effort to develop and produce in low volumes becomes a challenge. Case Study 1 We recently provided cell expansion and for- mulation equipment for a client with an alloge- neic product with capacity to formulate batches up to 8 L. At this volume, the dispensing of working cell bank material for cryostorage re- quired up to 100 units in cryobags (Figure 1). Processing cryoformulated cells has critical time constraints (formulation to freezer) since, as noted, time spent in cryomedia at process- ing temperatures is detrimental to cell viability. To manage this constraint and facilitate accuracy within a closed-set environment, we developed a bag fller with 100-bag capacity. The system uses a functionally closed consum- able with bag-flling accuracy of ±10% and a total processing time less than 120 minutes. During the fll sequence, the cells in the source bag are maintained in uniform suspension. Without this fll capability, it would be neces- sary to formulate a series of smaller volumes as sub-batches and dispense. While this pres- ents a workable solution, the approach is also an example of process that can affect the claim of a single batch. Autologous Therapy Scale Out A different set of challenges confronts those dealing with autologous therapies. Scale out is the growth model here. Rather than upping batch size there is a need to replicate facilities and equipment logistically near patient processing centers. Each patient's cells constitute a batch. In addition to all processing costs, quality testing and documentation overhead applies to each patient. Also, each patient requires dedicated equipment. At full or even partial scale, the cost of capital required to set up an autologous cell therapy manufacturing facil- ity based on this model can be substantial. To reduce costs while achieving desired goals in production effciency, the design ef- fort must: •   Optimize the manufacturing process to achieve target goals in high process throughput (number of patient batches) on the more espensive pieces of equipment. •   Develop less expensive equipment for long duration process steps, potentially allowing bulk parallel processing of process steps such as incubation (which may take many days or even in some cases 5–10 weeks). •   Create multiple parallel balanced pods of manufacturing equipment in larger common spaces to process multiple patient batches within the same low grade clean space. •   Minimize Class A and B clean space requirements across facility. (Design high-throughput areas to allow incom- ing sample and time-critical reagents to be introduced to sterile disposable sets for sub- sequent processing in Class C or D space.) The need for separate disposable sets for each patient drives set volumes up compared to allogeneic cell therapy production. As a result, many disposable suppliers are keen to participate in this market. All related costs are associated with each patient's product. In the more complicated therapies, this can rapidly drive up the batch cost. Manufacturing must be designed to refne the process to be able to use simpler and less expensive disposable sets. In addition, signif- cant effort needs to be applied to refne dis- posable sets to be easy and less expensive to produce while supporting development of a robust and consistent product. They must also be easy to use and foolproof in production. Case Study 2 An analysis of a facility scale for an au- tologous process typically involves a com- parison between two approaches. The frst is a scale out, manual solution utilizing open material transfers within laminar fow hoods in Class B cleanrooms. The second is an au- tomated process using closed disposables for transfers in larger Class C spaces. Such a comparision was made during the development of manufacturing equipment to support the production of patient-specifc immunotherapies. Figure 2 compares opera- tor full-time equivalents and estimated facil- ity cleanroom areas (m 2 ). Both comparisons span a range of capacities. Conclusion A deep understanding of the process is critical to developing a manufacturing sys- tem and disposable processing sets that suit the individual therapy. Much of the equip- ment used to produce clinical trial product includes scientifc instruments that are not designed or suited to use as GMP manufac- turing equipment. A bespoke system is gener- ally necessary to provide a balanced fow and an optimum cost profle while delivering a robust stable manufacturing process and con- sistent product. BIOPROCESSING Tutorial Richard Grant (Richard.Grant@invetech.com. au) is global vice president of cell therapy at Invetech. Website: www.invetech.com.au.

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