The 4 Essential Elements of a Successful ATMP Development Plan
Advanced Therapy Medicinal Products (ATMPs) are medicines for human use that are based on genes, tissues or cells. They represent a burgeoning growth area within the biotech/pharma industry – driven by the ground-breaking new opportunities they present for the treatment of disease and injury.
Oftentimes, these products originate in academic or hospital settings where the processes used to make small amounts of material for early-stage studies can be poorly defined, inconsistent and use exotic reagents and methodologies which are not compatible with later stage GMP manufacture.
Thus, some discussion is merited
on the essential overarching elements which should be included in the
development plan for any ATMP.
1. In-depth, data-driven risk assessment of the current process.
The use of certain exotic reagents and methodologies at an early
stage of development can often militate against later-stage GMP
manufacture. Thus, an assessment of
current raw materials is necessary to ensure that e.g. there are no materials
of animal origin, suppliers exist who will be in position to supply the
required materials at the scale, quality and price required over a 20 year
period. If alternative reagents are
required, it will need to be clearly demonstrated that they will lead to the
production of material with comparable CQA’s. A determination of the robustness of each process step is necessary
taking into consideration factors such as the sensitivities to variation in
methods of harvesting, storing and transportation and the impact on the
stability and quality of material.
2. In-depth, data-driven understanding and control of scaled-up process.
As the process scales from bench-scale equipment to larger scale vessels, differences in dynamic process parameters will manifest themselves. Often this will be as a result of physical effects such as mixing speed and reactor geometry. With this in mind, the use of Computational Fluid Dynamics to model different mixing regimes in different reactors can be an extremely powerful tool to rapidly undertake multiple experiments in silico and determine the optimal mixing conditions at scale. The CFD approach is especially critical for newer modalities where the manufacturing equipment is often bespoke (a wave bag for example) and not subject to the standard engineering calculations which govern scale-up. Biological factors (e.g. cell cultures in a different environment producing material of different quality or titer) may also come into play when scaling. Tools including Multi-Variate Data Analysis (MVDA) and Process Analytical technology (PAT) such as Raman Spectroscopy can be used for in-depth interrogation of cell culture operations in order to define optimal feeding and control strategies.
3. Comprehensive records detailing what decisions were made and why.
There are increasingly onerous requirements from the regulatory authorities on drug developers to demonstrate process understanding and to explain rationale which underpins the choice of manufacturing conditions. This underscores the importance of documenting every CMC decision on the medicine’s journey and which decisions were made when and, more importantly, which experiment, data point or insight informed that decision. The value of this however not only manifests itself at regulatory approval stage i.e. Market Authorization Application (MAA) or Biologics License Application (BLA) stage. Having such information to hand at as early as possible in the development journey, ensures that the tech transfer of the process can proceed smoothly between different parties with the transferee understanding the context to why certain decisions were made at earlier stages of development – thus avoiding unnecessary repeat experimentation and data collection, which can slow progress considerably.
4. Integration of development and manufacturing plans at the earliest possible juncture.
The specialized and complex nature of ATMP manufacture has seen an industry bottleneck develop in getting these medicines scaled-up and manufactured in a timely manner as ATMP developers compete for slots in the development and manufacturing schedule of competent CDMO’s. In the medium term this bottleneck will be ameliorated by additional specialist manufacturing capacity coming online, as a number of high profile global CDMO’s have begun to invest heavily in this niche. However, whilst it seems likely that the additional manufacturing capability will have an impact, it is too early to say with any degree of confidence that the investment in global ATMP manufacturing will be mirrored by the concomitant investment global process development capability necessary to define, scale and characterize the processes and ensure smooth tech transfer to the commercial manufacturing facility.
With this in mind, there is an increasing trend within the industry towards a business model which decouples process development from manufacture. This business model relies on outsourcing process development to specialist Contract Research or Contract Development Organizations who are tasked with developing robust, well characterized processes underpinned by an in-depth understanding of critical process parameters. In the climate of limited available resources within the manufacturing community, this enables proprietary ATMP developers to keep up momentum in terms of the CMC progress of their development candidates, whilst at the same time de-risking the future tech transfer to the commercial manufacturing facility. Furthermore, the use of specialist tools and modelling techniques like CFD enable a greater degree of flexibility in the design and development of a process for several different potential manufacturing locations – based upon an inherent understanding of behaviour of the process in different reactor sizes and geometries.
Notwithstanding, the advantages that this model presents, it is necessary to ensure that the development organization and the manufacturing organization work “hand in glove” to ensure seamless tech transfer and avoidance of unnecessary delays. With this in mind, making this connection between both organizations as early as possible is highly advisable and will enable both parties to be on the same page – with the ultimate manufacturing infrastructure and workflows helping inform the process design and scale-up activities.