by Elena Meurer
Looking at drug development tendencies during the last decade, it becomes obvious that after a slow start ATMPs are pushing through to higher regulatory and public acceptance. Indeed, the potential of cell-based medicine is enormous as it employs the healing mechanisms of cells as worked out by nature combined with the most advanced technological solutions developed by mankind.
Yet, there are still many hurdles to overcome to make cell-based therapies robust, efficient and generally affordable. Whilst the complex biological nature of ATMPs offers many therapeutic opportunities, their complexity also makes them difficult to harness.
The affordability of ATMPs for the health care system and patients lies among the important aspects that clearly require further improvement. The overall high price of cell-based therapeutics, as known today, is driven by specific factors involved in development, manufacturing and clinical logistics.
Manufacturing costs are an essential contributor to high market price. Therefore, it is important to understand their major constituents and to distinguish between the objective factors arising from the specifics of manufacturing and those coming from a complex or suboptimal project setup. While the former parameters might need to be accepted, the impact of the latter can be minimized in order to optimize the overall costs.
Let us take a closer look which factors need to be considered for a cost-effective and efficient ATMP manufacturing process.
Many manual steps in a clean room. Manual processes are often unavoidable for cell-based therapeutics, at least at early clinical stages where an unknown therapeutic benefit does not yet justify the development of costly technological solutions. Manufacturing technology has yet to learn how to keep the pace with the multitude of ATMP manufacturing strategies. Thus, scale up or automation may not be available or would be very expensive.
However, it is important to remember that manual handling steps lead to increased clean room and personnel occupancy and consequently higher costs. An important strategic component is to evaluate the possibility of scaling up, scaling out or automated process solutions at the correct point of clinical development. For example, if the major goal of the planned clinical trial is a POC study with small patient numbers, manual processes may be the best solution. Furthermore, a potentially healing therapy with few alternative medical options could justify the high costs of manufacturing. At the same time, an expensive or outdated manufacturing technology may become a serious hurdle for product competitiveness on the market.
Elaborated and customized analytical methods. The testing strategy for ATMPs is, in general, rather extensive. Cell-based potency methods, especially, often require plenty of handling and customized performance with a long performance time. It is therefore not surprising that Quality Control departments at ATMP manufacturers are usually quite large. If not all QC methods can be performed at the manufacturing facility, costs of the outsourcing as well as controlled shipping at low temperatures significantly add to the overall price. It has to be part of the development strategy to identify complex QC assays and to develop appropriate alternatives early enough to offset such high costs. For example, introducing surrogate potency assays instead of cell-based assays is one of the possible approaches. However, such alternatives require good comprehension of the mode of action of the biological product.
Long processing times (days) with flexible duration of process steps. This situation is especially well known in the manufacturing of slow-growing cells with donor-specific growth characteristics. In R&D, the scientist will monitor the culture every couple of days for cell growth and density and decide on the day of further processing on short notice, at best two to three days beforehand. For clean room manufacturing it means that the two-to-three-day window needs to be considered in the planning for the clean room suite reservation, of which only one day will be used. Thus, the facility cannot be used at full capacity and the personnel must be available on a flexible basis. Therefore, the investment into the R&D to establish a robust process with timely fixed process steps or to develop a prediction method brings costs return at the manufacturing end.
Many customers prefer to use dedicated clean room suits. It is more advantageous in terms of planning as well as minimizing the risks of cross-contaminations and reducing activities for establishing the line clearance. It is clearly a costly solution since the manufacturer would not be able to use the dedicated suite for other purposes.
Autologous manufacturing with flexible patient enrollment dates. This situation is similar to the flexible process and requires the overall high responsiveness of the manufacturer with regards to clean room and personnel utilization planning.
Costs of starting materials and process equipment. In this respect, GMP manufacturing of plasmids and viral vectors requires special mentioning. This is a serious investment per se, due to complex manufacturing and characterization processes but also not least due to the use of patented / licensed technologies. In-licensing of proprietary plasmids and vectors is an essential COGs driver that is either reflected as initial high upfront payments, high milestones payments for GMP manufacturing or via licensing agreement, royalties from marketed products or co-development. Which strategy is more suitable is a case-by-case decision based on multiple factors, of which the company budget for early clinical phases plays a significant role.
These considerations are surely not restricted to the use of GMP vectors but also valid for most novel technologies, which are readily available for R&D use but may mean high COGs in the case of clinical manufacturing.
Costs of materials are also ultimately linked to manual process conduct. For instance, it requires large quantities of different single-use consumables. Single-use materials do have their advantages. They offer a straightforward and secure way of establishing aseptic manufacturing, not requiring additional infrastructure for equipment sterilization. They are perfectly suitable for the needs of diverse, unstandardized ATMP manufacturing processes. They have proved their worth during years of laboratory research. However, when used for producing large quantities of cells required for therapeutic application, they quickly become expensive. We have discussed the possibilities of automation or upscale above. But optimization of parameters of the manual process also offers room for more efficient use of disposables as well as cultivation components, such as media or vectors.
Large number of different materials used in the manufacturing process. Although it may not appear as such an essential cost factor as those mentioned above, each manufacturing material will require supplier and material qualification, establishment of specifications and maintenance in the quality assurance system, purchase and QC release. The overall extent and costs of these procedures are often underestimated. It is also advisable to assess the appropriateness of materials used throughout the complete process before the process transfer to the manufacturer. Change of materials in a GMP-compliant environment is subject to risk assessment and may need to be verified experimentally, resulting in a significant delay in the project timelines, especially if product characteristics are affected by the material change. It is worth noting that requirements for materials may change depending on the clinical phase. Also, it may be necessary to reconsider the quality requirements of materials in case of a transfer of manufacturing, e.g. from US to EU.
Stability and transport logistics. Finally, storage and distribution of ATMPs require special solutions, either due to their short shelf life or due to storage and transport at low controlled temperatures (e.g. in liquid nitrogen vapor after cryopreservation). When compared to small molecules or even biologics, this logistic is complex and costly.
Taken together, it is worth investing in optimizing process efficiency at different stages not only to deliver the best quality product but also to reduce the manufacturing costs and make the product more affordable to patients.
Although there are general rules for process optimization, no universal recipe can be applied. Each manufacturing process needs to be analyzed in detail to design an individual, more suitable optimization approach.
We at Biopharma Excellence can support you in further developing your ATMP manufacturing strategy. Do not hesitate to contact us for more information.