May 1, 2015 (Vol. 35, No. 9)
Richard Grant Global VP of Cell Therapy Invetech
Appropriate Deployment of Processing Equipment Critical for Specific Products
One of the many challenges in cell therapy manufacturing is the thoughtful deployment of capital and technology in the set-up of a manufacturing facility, which is dependent on factors that can differ radically from therapy to therapy. 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 final product.
In this tutorial, the key differences between allogeneic and autologous therapies are highlighted. These differences, which impact the planning and customization of facilities, 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 particularly 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 producing in clean manufacturing space can be a significant burden for the cell therapy industry, planning should also consider moving production into sterile disposable sets capable 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 example, when large numbers of cells are to be expanded, process variability within the disposable set (i.e., multiple 2D cell culture vessels) can become an issue. If a process shows enough variability, production teams or regulators 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 defines a batch is different for different unit processes. As a result, the need to match unit process capacities can drive batch size down to the capacity of a single limiting process step. Surprisingly, different bottlenecks and blockers, often invisible to the untrained eye, can become apparent at different scales of manufacture.
For example, optical inspection for particulates 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 clinical 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 processing these into working cell bank bags or final dose vessels can present time limitations, and time spent in cryomedia at processing temperatures is detrimental to cell viability. Processing the drug product in successive smaller volumes 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 development 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 order to prove comparability.
Larger batch size allogeneic processes can also suffer from another problem that is rarely 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 supply 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 manufacture, 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 invest the time and effort to develop and produce in low volumes becomes a challenge.
Case Study 1
We recently provided cell expansion and formulation equipment for a client with an allogeneic product with capacity to formulate batches up to 8 L. At this volume, the dispensing of working cell bank material for cryostorage required 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 processing temperatures is detrimental to cell viability.
To manage this constraint and facilitate accuracy within a closed-set environment, we developed a bag filler with 100-bag capacity. The system uses a functionally closed consumable with bag-filling accuracy of ±10% and a total processing time less than 120 minutes. During the fill sequence, the cells in the source bag are maintained in uniform suspension. Without this fill capability, it would be necessary to formulate a series of smaller volumes as sub-batches and dispense. While this presents 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 facility based on this model can be substantial.
To reduce costs while achieving desired goals in production efficiency, the design effort 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 incoming sample and time-critical reagents to be introduced to sterile disposable sets for subsequent 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 refine the process to be able to use simpler and less expensive disposable sets. In addition, significant effort needs to be applied to refine disposable 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 autologous process typically involves a comparison between two approaches. The first is a scale out, manual solution utilizing open material transfers within laminar flow hoods in Class B cleanrooms. The second is an automated 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-specific immunotherapies. Figure 2 compares operator full-time equivalents and estimated facility cleanroom areas (m2). Both comparisons span a range of capacities.
A deep understanding of the process is critical to developing a manufacturing system and disposable processing sets that suit the individual therapy. Much of the equipment used to produce clinical trial product includes scientific instruments that are not designed or suited to use as GMP manufacturing equipment. A bespoke system is generally necessary to provide a balanced flow and an optimum cost profile while delivering a robust stable manufacturing process and consistent product.