Introduction
Cell and gene modified cell therapies hold tremendous opportunity to halt, reverse and even cure life threatening conditions. One of the many reasons for the success of these therapies is because of the personalized manufacturing approach that can be employed which is unique when compared to more traditional pharmaceutical processes. However, personalized cell therapies also present unique challenges relating to manufacturing infrastructure and production planning. Therapeutic developers strive to establish a robust process that is also operational and cost efficient. We will be discussing key considerations that can optimize production efficiency and operational excellence through a review of manufacturing infrastructure and strategies, facility consideration and production and forecast planning. These topics will be the foundation of future articles that specifically focus on product or facility specific production and forecast modeling, facility design considerations, and manufacturing staffing models.
Overview of Cell Therapy Types
Cell Types Most Commonly Used in Cell and Gene Modified Cell Therapies
Various cell sources have been adapted for therapeutic use, including pluripotent, multipotent, and immune cells. Pluripotent stem cells can self-renew and develop into all major cell types in the body, whereas multipotent stem cells only have capabilities to develop into limited cell types. Pluripotent stem cells traditionally fall into two major types; embryonic stem cells and induced pluripotent stem cells. Multipotent stem cells include such lineages as mesenchymal and hematopoietic stem cells. Immune cells encompass a wide range of cell types that play roles in the innate and adaptive immune response against infections by potential pathogens, Examples of this cell class are T-cells, natural killer (NK) cells, macrophages and B cells.
Major Product Classes for Cell and Gene Modified Cell Therapies
Cell therapy products can fall into two classes, non-gene modified cell therapies and gene modified cell therapies.
Non-gene modified cell therapies involve the collection of biological source tissue, isolation of a cell type of interest, followed in many cases by differentiation, activation and/or expansion of the target cell type prior to administration. These specific therapies can be mediated by various strategies including guided differentiation, selective depletion, and/or cytokine and chemokine stimulation.
Gene modified cell therapies are traditionally characterized by the introduction, removal and/or change in genetic material of the target cell type to enhance, add or remove a particular cellular function. Gene modification can be introduced into the cell by viral (e.g., retroviral, lentivirus, adenoviral, and adeno-associated viral vectors) or non-viral means (e.g. electroporation, sonoporation, chemical polymers, LNPs). Additionally, both viral and non-viral methods can be used to deliver both non-targeted genetic modifications or gene editing machinery such as CRISPR-Cas9 complex to instigate targeted gene modifications.
From here forward, we will refer to non-gene modified cell therapies and gene modified cell therapies jointly as “cell therapies”.
Autologous and Allogeneic Cell Therapy Definitions and Operational Considerations
Autologous cell therapies involve using an individual’s cells and/or tissues that are subsequently manipulated for a targeted indication and then administered back to the same patient. Because autologous cell therapies are manufactured from patient specific biological starting material which often has a short shelf life or requires a rapid turnaround to a severely ill patient, they often require the manufacturing facility to be in a constant operational state to ensure readiness to handle the starting material.
Alternatively, allogeneic cell therapy’s starting material is sourced from healthy donors. There are multiple paradigms for how allogeneic starting material may be sourced, collected, and subsequently utilized, depending on the nature of the cell therapy product. Some allogeneic cell therapies rely on unique donor material to support one or few manufacturing batches (e.g., allogeneic donor-derived Chimeric Antigen Receptor (CAR)-T cells, Mesenchymal Stem Cell therapies), while others are manufactured in perpetuity from a tiered cell banking system originating from a single donor (e.g. pluripotent stem cell derived cell therapies). Manufacturing of allogeneic cell therapies can be more predictable, enabling more efficient scheduling, production, and dosing.
Manufacturing Strategies
Regardless of autologous or allogeneic source, manufacturing of cell therapy products tends to be complex. Hurdles present themselves when scaling, troubleshooting technical complexities, and managing logistics. Often, early-phase therapeutic developers utilize an immature manufacturing process which can be open, manual, and labor intensive. While open and manual manufacturing processes can support small scale clinical demands typical at early phase, issues can arise when attempting to optimize or scale up or out, especially as a product advances towards late phase clinical trials and commercial production. Manual manufacturing processes inherently rely on operator technique and oftentimes can result in increased lot-to-lot variability, making process optimization difficult at best.
While there is not one single characteristic of cell therapy manufacturing that is holistically problematic, there are common features that present reoccurring trends. Mechanistically, a phase appropriate and forward compatible manufacturing approach should be informed by a thorough evaluation of each unit operation to aid in the identification of prospective risks. A phase appropriate manufacturing strategy is essential in creating a scalable and sustainable production line. This approach should be informed by inputs from process development, CMC, quality, analytics, and business operations. Gaining a predictive perspective of these process hurdles is critical when successfully ushering products from clinical to commercial scale.
Internal and External Manufacturing
Determination of a company’s strategy for internal versus external manufacturing should be completed early on to enable a scalable and sustainable operations model. Considerations should be given to available capital, technical capabilities, process maturity, time to clinic, supply chain, and regulatory experience to identify the best suited strategy to move forward. Building your own facility and creating internal manufacturing capabilities may seem like a prudent thing to do to control the manufacturing process, but it can be costly to build, maintain, equip, and staff, and can add significant additional lead time to getting manufacturing underway. Alternatively, external manufacturers (CDMOs) may initiate development and manufacturing sooner without as much upfront capital outlay, but the developer may sacrifice some level of control in the process and downstream timelines.
Dedicated and Shared Manufacturing Suites
As discussed above there are pros and cons with respect to internal and external manufacturing. Upon the determination of manufacturing location, another decision must be made in relation to suite model. While there are numerous derivatives of the suite model, dedicated versus shared suites are the baseline traditional framework. Operational readiness is one of the most influential factors when deciding what suite model is fit for the purpose of a specific manufacturing process.
A dedicated suite model is the reservation of an isolated, classified manufacturing space for a specific amount of time (e.g., 12 months). This model can enable maximum flexibility and control over operations. The level of optionality required is typically driven by high batch product requirements, a generally open aseptic manipulated process, donor dependent starting material, and short expiry starting material. Processes that require a dedicated suite model often have scale limitations. This model is often the costliest and makes the most sense for products that require high batch volumes and the utmost optionality, such as autologous products in late-stage manufacturing.
The alternative option is a shared suite model. In this approach, a portion of the classified manufacturing space is allocated for a process and/or client. The remainder of the classified manufacturing space can be assigned to a different process. This approach is commonly employed for early clinical phase products or rare diseases, due to their lower batch product requirement. Shared suites can also be utilized for high batch products; however, the process must be in a closed system (e.g., Miltenyi Prodigy) with a rather high level of automation. The introduction of increased automation and closed systems essentially eliminates the requirement for operator manipulations and equipment transitions optimizing space and process segregation.
Constant versus Campaign Operational Model
The final manufacturing strategy to be discussed is the constant versus campaign operational model. An operational model should not only be what is best suited for the facility but also the product type. A constant operational model suggests that the manufacturing facility and personnel are prepared to initiate manufacturing 24 hours, 7 days a week, allowing for maximum flexibility and capacity for manufacturing starts within a given facility. The alternative approach is defined as a campaign operational model, which leverages economies of scale to drive cost efficiency. The campaign model provides exclusive access or use of a portion of the manufacturing space for a specific amount of time. In this scenario, manufacturing is scheduled for a defined amount of time.
Each operational scenario has its pros and cons. A continuous operational model enables a batch to be started quickly upon receipt of starting material, staff is kept busy, and the facility remains in a constant state of readiness. This requires adequate staffing to ensure infrastructure is in a constant state of readiness and thus is the most expensive approach. However, costs can be controlled in this scenario if there is enough work to keep the facility and staff continuously manufacturing. In comparison, the campaign model is attractive when work is not continuous. Suites, equipment, and personnel can either be repurposed to another stream of work or transitioned into a state of shutdown to aid in containing cost and drive efficiencies. However, manufacturing facilities are typically characterized by high fixed costs, limiting the ability to manage costs through shutdowns.
Facility Considerations
There are a multitude of factors and scenarios that require evaluation before an appropriate manufacturing strategy can be determined. Regardless of the decision to internally or externally manufacturer there are general facility considerations that should be considered when deciding on the right production facility. A facility that has the ability to be flexible to accommodate existing technologies, and future manufacturing advances is always a value proposition. Manufacturing of cell therapies tends to vary between products, which results in cleanroom sizes, and equipment being extremely dependent on the process. A facility fit assessment is a great place to start when searching for a facility. This assessment is an analysis to ensure that cleanroom size and layout are appropriate for the intended process. It ensures that the cleanroom size, layout, flows, equipment, personnel, and cross contamination control strategy are appropriate. Major items evaluated in cross contamination control include physical (e.g., unidirectional flow, segregate cleanrooms), engineering (e.g., segregated HVAC, pressure cascades), and procedural (e.g., cross contamination, cleaning validation, sanitization) controls to mitigate the overall risk. These increased controls are an important part of any process.
When manufacturing is internal, the facility is often designed in a very product specific focal point or in some cases around a common product platform. The facility configuration is determined by predictive models that assess the nature, stage, and commercial capacity of the primary asset. Product specific facilities must optimize the capital spend while ensuring maximum throughput throughout the facility.
External manufacturing traditionally relies on a CDMO/CMO as the service provider. The majority of these providers will have facilities that have previously been commissioned and ready for use. They often manufacture a wide range of cell therapy modalities, thus having a facility design that is flexible and able to accommodate different types of manufacturing processes. CDMOs also require phase appropriate manufacturing settings to serve all types of products at different phases in the lifecycle. These strategies should include varying operational states, dedicated and share suites, and production and forecast planning.
Production and Forecast Modeling
As products progress towards late stage, oftentimes there is a requirement to optimize and scale, either up or out. These processes come with an increasingly complex supply chain, especially for processes that incorporate time sensitive, patient specific starting material. Scaling of manufacturing operations requires process specific variables which can be unique to each product and must be considered.
In order to scale manufacturing operations in an efficient manner, production and forecast modeling should be performed. Automation is one tool that can help drive an increased efficiency of manufacturing operations. Considerations for the addition of automation during early development will lead to an easier transition to late phase. Automation also can drive improvements when it comes to lean manufacturing operations.
Scheduling manufacturing batches has always been a challenge for both manufacturing operations and therapeutic developers as it requires a layered approach in order to drive efficiencies and reduce operational costs. An accurate production and forecast model are established because the inputs drive a clear understanding of capacity, forecast adherence and operational commonalties. Capacity is traditionally defined as the understanding of the facility’s production output specifically under full and maximum operation. Examining the transition from a traditional linear production line to concurrent or parallel production will increase throughput. Assessing how manufacturing will be undertaken, serial versus in parallel, is one step to help increase potential capacity and throughput but requires an in-depth examination of current and future production states. For example, assembling a model that evaluates how staff, manufacturing space and unit operations can be stacked, to produce a cyclic production rotation will result in a more efficient manner of personnel and equipment utilization which promotes increased productivity and throughput.
Forecast adherence, or the number of planned manufacturing starts that actually proceed to manufacturing within the slot allocated, present an additional area for careful analysis in optimizing manufacturing capacity. Autologous cell therapies rely on patient specific starting materials, which may unexpectedly not be available when anticipated, due to patient complications, shipping delays, or other unexpected developments. Examining the production forecast against the actual manufacturing starts will provide insight into the overall facility utilization and highlight areas or pockets of dormancy all while still being able to accommodate production variability. This modeling exercise will aide in defining the facility and manufacturing operational requirement in addition will identify areas for improvement related to incoming starting material shipping delays and material shelf life. Examining forecast adherence can also aide in the reduction of the gap between projected/potential and actual manufacturing starts, promoting efficiency which then leads to reduction of operational cost.
Operational excellence and lean manufacturing are gained by understanding manufacturing commonalities to enable cross utilization of staff, equipment, and manufacturing space.
Additionally, breaking down a manufacturing process into specific unit operations can enable understanding of opportunities for process overlap to maximize utilization of staff and facility resources, resulting in an overall reduction in operational expenses.
Conclusions
Cell therapies hold a tremendous opportunity to deliver life changing treatments, and cures, to patients with significant unmet medical need, however, the complex nature of the manufacturing processes for these products present many challenges.
Dark Horse Consulting can provide key support to ensure that the right partners are selected, informed plans and assessments are developed, and execution against timelines and milestone goals drives maximum efficiency. By deploying our unmatched Manufacturing, Quality, and Regulatory expertise, we leverage prior experiences to assist in product development throughout the Drug Product lifecycle to establish an environment for success on the path to approval Noting and acting upon the key considerations and variables identified in this article will positively impact the likelihood of clinical and ultimately commercial success.
