Quality by Design as an aid to unlock full ATMP potential
Advanced therapy medicinal products (ATMP) are more and more becoming part of the present-day clinical reality. However, the complexity of their development and manufacturing requires novel approaches to guide the process in a robust and effective manner. To facilitate this, we put the Quality by Design (QbD) methodology at the center of our research philosophy.
QbD is a scientific, risk-based framework for process development. It focuses on the end-product profile to understand how this profile may be affected by the starting materials and variable parameters of the underlying process. QbD is an advanced Failure Mode and Effect Analysis (FMEA) which is used as quality control tool for manufacturing processes across regulated industries.
As explained in a previous post, realizing scalable manufacturing is one of the principal challenges faced by (ATMP) developers. The inherent variability of cells, which obviously are essential starting materials, may lead to increased risk and difficulties in delivering a robust product that is deemed safe and effective for patients by regulatory authorities. In this post, we explain how QbD provides a robust, risk-based framework for ATMP (process) development and how it guides R&D at Antleron.
Principles and components of QbD in an ATMP context
The term ‘Quality by Design’ was originally coined by Joseph M. Juran (1), who believed that quality could be achieved through planning for it. While QbD has originally been employed in other industries, such as the automotive industry, the methodology is equally relevant for ATMPs given the complexity associated with them. For over a decade, the FDA and EMA are advocating to implement QbD into pharmaceutical manufacturing process development i.e. by running a joint FDA-EMA pilot programme 2. To understand the methodology, a few key concepts are clarified below.
The ‘Quality Target Product Profile’ (QTPP) is the definition of the final product. Through Critical Quality Attributes (CQAs), the biological, chemical and physical attributes the product needs to meet in order to be safe and effective, and to fullfill the final release criteria, are quantified. These CQAs are, in turn, affected by Critical Process Parameters (CPPs) and Material Attributes (MAs). By defining the latter relationship in a quantitative way, a Design Space (DS) for the product can be developed, along with the Normal Operating Range (NOR), a range of process parameters settings combinations which ultimately ensure that the product meets the specified quality attributes.
The Design Space is constructed by using Design of Experiments (DoE), a data collection and analysis tool that enables to assess and quantify a number of factors (CPPs and MAs) that affect the outcome (CQAs). Multivariate process experimentation and analysis increases method understanding, accuracy and robustness. Such structured, knowledge-based approach allows for identifying interactions between factors that otherwise could go unnoticed in traditional experimentation.
ATMPs, above all when autologous, require process operations to be customized on a patient-to-patient basis. Since cells from different sources can behave differently, a lot of data must first be collected, analyzed and compiled to understand the CPPs and MAs and create the design space. Matching the process outcome with the therapy target profile, is only practically feasible in a QbD framework. Only in this way can we control and reduce the risks and facilitate clinical translation of advanced therapies.
Variability in cell material requires novel approaches to control CPPs and MAs. Typically, a process is mapped out in its smallest components – unit operations (UO). For each UO, a risk analysis is performed based on the current knowledge with the aim to assess the degree to which the UO’s CPPs and MAs affect the process CQAs. Consecutively, DoE can be applied to test the most critical parameters in order to construct the UO’s design space in a data-based manner. Ultimately, one wants to arrive at a more optimal and better-understood process, with an acceptable risk profile.
The intrinsic variability of starting material in most ATMP – cells – necessitates flexible and customizable process operations in general. Here, another key application of QbD, monitoring and control, comes into play. Process Analytical Technology (PAT), an approach to control processes by continuously measuring CPPs and CQAs, is put forth to keep parameters in spec throughout the process. Quantification of the ‘process state’ in this manner, also allows us to control the process and therefore increase its robustness.
QbD, through robust control and in-depth understanding of how various parameters impact CQAs of the final product, allows more flexibility to accommodate variability in a therapeutic product, given that the specs fall within the design space. In other words, by understanding from within which set of parameter settings will lead to a safe and effective product, one has the freedom to adjust an intrinsically variable cellular product within that specific parameter set. It provides a gateway to deliver personalized therapies, based on individual patients’ characteristics, in a safe way.
“… by Design” as a product and process development principle at Antleron
Every new R&D project is an adventure ‘by Design’.When working with various innovative ATMP-oriented technologies, Antleron employs QbD as a core tool to design technologies and process workflows that are instrumental in delivering breakthrough treatments to patients.The risk analysis performed at the beginning of each project facilitates identification of the most critical parameters.By applying this risk-based development methodology, and our innovation toolbox (ranging from design & simulation software, over additive manufacturing, bioreactors and soft sensors to commercial R&D solutions like BioScout® and Cell by Design®), to ATMP-related development projects, we can make data-driven, science-based decisions, resulting in optimal outcomes.Moreover, we hereby not only focus on the technical aspects of projects, but also take the economic and regulatory factors into consideration, as these can have an equally profound impact on a project’s success.
Conclusion
The QbD methodology is a process development tool that lets you build in quality from the very beginning. Concomitant with the shaping of your process, scalability is evolving along, as your therapeutic product moves through the development pipeline.
Cell by Design®
To facilitate the implementation of the QbD methodology into the ATMP field, two SMEs joined forces (Antleron and Quality by Design) and co-developed the Cell by Design® cloud-based software platform. Cell by Design® enables you to opt for a quality-focused ATMP development process by executing risk-based process assessments. The resulting insights guide science- and data-driven decisions to meet all predefined ATMP-critical quality attributes. Cell by Design® takes the manufacturability and scalability of your ATMP product into account, as well as the process itself, right from the start. Moreover, the cloud-based software facilitates regulatory dossier preparation later on.
Click here to find out more about Cell by Design®.