An analytical method needs to provide reliable results for its intended purpose, but developing a method that works under a defined set of conditions is not necessarily the same as understanding how that method behaves when those conditions change.
This distinction is central to the enhanced approach to analytical procedure development described in ICH Q14. The guideline, effective in the European Union since June 2024, provides a science and risk-based framework for developing and maintaining analytical procedures, complementing ICH Q2(R2), which addresses their validation.
Analytical Quality by Design (AQbD) is commonly used to describe the application of Quality by Design principles to analytical procedure development. Rather than focusing only on obtaining suitable analytical conditions, an AQbD-based approach intends to build a structured understanding of the factors that influence method performance and use that knowledge to support optimization, control and lifecycle management.
Note: Throughout this article, “analytical method” and “analytical procedure” are used interchangeably for readability, although ICH Q14 formally uses the term analytical procedure.
What is AQbD in Analytical Method Development?
ICH Q14 distinguishes between minimal and enhanced approaches to analytical procedure development. The minimal approach remains an accepted way of developing an analytical method. The enhanced approach adds elements that can provide greater understanding of the relationship between analytical procedure parameters and analytical performance.
This distinction is important. AQbD is not about replacing conventional analytical development, nor does ICH Q14 require every analytical procedure to be developed using an enhanced approach.
Instead, the enhanced approach provides a framework that can be applied according to the needs of the procedure, the available prior knowledge and the intended lifecycle strategy.
In practical terms, the focus shifts from simply asking:
“Does this method work?”
to also asking:
“What does this method need to achieve, what factors can affect its performance, and within which conditions can we demonstrate that it consistently meets its requirements?”
This additional understanding can then be used to establish appropriate operating ranges, support a control strategy and provide a stronger knowledge base for subsequent stages of the analytical procedure lifecycle.
Building a better understanding of method performance
An AQbD-based development starts by defining what the analytical procedure needs to achieve.
- Analytical Target Profile
The Analytical Target Profile (ATP) defines the intended purpose of the analytical procedure, the product attributes to be measured and the expected performance criteria.
It provides a basis for development by establishing the target against which development decisions can be evaluated.
- Knowledge and risk assessment
Once the intended performance is established, prior knowledge and risk assessment can be used to identify analytical procedure parameters that could affect performance.
These may relate to analytical conditions, materials, instrumentation or sample preparation, depending on the procedure.
The purpose is not simply to identify as many variables as possible, but to determine which parameters demand further investigation based on their potential impact on analytical performance.
- Preliminary development
Initial laboratory studies can then be used to establish suitable analytical conditions and develop a preliminary method.
This provides the starting point for more systematic investigation and optimization.
- Selectivity and forced degradation
For procedures where stability-indicating capability is required, appropriate forced degradation studies can be incorporated into development.
Stress studies can help evaluate selectivity and identify degradation-related separations that may require further optimization.
This is not a mandatory step for every analytical procedure. Its relevance depends on the intended purpose of the method and the characteristics of the product.
- Design of experiments and method optimization
One of the tools that can support the enhanced approach is Design of Experiments (DoE).
Instead of investigating one parameter at a time, appropriately designed experiments can be used to study the effects of relevant analytical procedure parameters and, where applicable, their interactions.
The resulting data can provide a more systematic basis for optimization and for understanding how different conditions influence analytical performance.
Importantly, ICH Q14 does not make DoE mandatory for every enhanced analytical procedure. It describes univariate or multivariate experimentation and modelling as elements that may be used as appropriate.
- Method Operable Design Region
The knowledge generated through experimentation can be used to establish appropriate parameter ranges.
Where applicable, this can include a Method Operable Design Region (MODR): a combination of ranges for relevant analytical procedure parameters within which the procedure is demonstrated to meet its predefined performance requirements.
- Analytical procedure control strategy
Development knowledge can then be translated into an analytical procedure control strategy, including appropriate parameter set-points or ranges and relevant system suitability criteria.
This connects the knowledge generated during development with the conditions that will be applied when the analytical procedure is used routinely.
- Documenting development knowledge
Finally, the development work needs to be documented in a way that captures not only the final method, but also the scientific rationale behind it.
A comprehensive development report can bring together development data, statistical evaluations, key technical decisions and the justification for the final analytical procedure and its operating conditions.
This is the structure Kymos has adopted in its internal AQbD development workflow. The resulting development package is intended to support subsequent validation, method transfer and lifecycle management.
ICH Q14 and the analytical procedure lifecycle
One of the key concepts in ICH Q14 is the analytical procedure lifecycle.
The guideline recognizes that analytical procedure development and lifecycle management are connected, and that the order and extent of individual activities can vary depending on the intended purpose and development approach. Several activities may also take place concurrently.
This means that the value of the development work is not limited to the point at which the final analytical conditions are established.
The knowledge generated during development can contribute to a better understanding of:
- Which parameters have the greatest impact on method performance
- How variations in those parameters affect the analytical procedure
- Which operating ranges can be scientifically justified
- Which controls are relevant during routine use
- How the procedure can be managed when changes are required
This compilation of knowledge can then provide a stronger foundation for the subsequent stages of the method lifecycle, including validation, transfer, routine use and lifecycle management.
AQbD and analytical method validation
AQbD does not replace analytical procedure validation.
ICH Q14 addresses analytical procedure development, while ICH Q2(R2) provides the framework for validation. The two guidelines are complementary.
At the same time, the data generated during development can contribute to the validation strategy. ICH Q14 notes that data generated during development, such as robustness data from a DoE study, may be used as part of the validation data for relevant analytical procedure performance characteristics, meaning that certain studies do not necessarily need to be repeated.
This creates a more connected process: the scientific understanding generated during development can inform the validation strategy rather than being left behind once the development phase is complete.
Supporting analytical procedure lifecycle management
A better understanding of analytical procedure parameters can also become valuable when changes are required later in the product lifecycle.
For example, an enhanced development approach may support the definition of scientifically justified operating ranges and the establishment of appropriate conditions for the analytical procedure. ICH Q14 links this enhanced understanding with greater flexibility in lifecycle management and with the management of certain post-approval changes.
This does not mean that an AQbD-developed method automatically eliminates regulatory requirements or avoids future changes. Rather, development knowledge and scientifically justified ranges can provide a stronger basis for assessing and managing those changes.
The same principle applies to analytical procedure transfer. A method whose relevant parameters, performance requirements and operating ranges are well understood provides a more complete knowledge base when the procedure needs to be implemented in another laboratory or under different operating conditions.
Building scientific understanding during development
The result of enhanced analytical development is a method supported by a deeper understanding of its performance. The development process can generate knowledge about why specific conditions were selected, which variables affect the method, how they interact and where the procedure can reliably operate.
This knowledge remains useful after development is complete. The analytical procedure needs to remain suitable for its intended purpose during validation, transfer and routine use, as well as when changes are introduced later in its lifecycle.
The risk assessment, experimental studies, statistical evaluation and definition of operating ranges carried out during development provide a scientific basis for managing the method throughout these stages. The resulting knowledge can also inform the control strategy and help assess changes when the analytical procedure needs to evolve.
For analytical procedures supporting pharmaceutical development and quality control, this lifecycle perspective is an important element of the enhanced approach described in ICH Q14.
Implementing AQbD at Kymos
At Kymos, the implementation of AQbD principles began with the study of the current analytical development framework, particularly ICH Q14 and ICH Q2(R2), together with relevant scientific and industry resources.
Our Lab Efficiency team at Kymos Italy then translated this knowledge into internal training material, and a proposed development workflow for the whole Group. To evaluate how the approach would work in practice, an existing method development project was selected as an internal pilot.
The purpose of this pilot was not to change the client’s project or deliver an additional AQbD package to the client. Instead, the method development was performed internally using AQbD principles to test the proposed approach, identify the activities involved and understand the additional development effort required. The resulting report was an internal development document that is the basis of this new approach.
This practical experience is now supporting Kymos’ broader implementation of AQbD-based analytical method development, adapted to the requirements of each project and the client’s needs.
AQbD provides a more structured approach to understanding method performance and the factors that affect it. The knowledge gained during development can help establish robust operating conditions, support method transfer and inform the management of changes throughout the analytical procedure lifecycle, where scientifically justified.
Kymos offers analytical method development using the approach best suited to each project. Clients can choose a conventional development strategy or an AQbD-based approach, which involves additional development activities and documentation to build a more detailed understanding of the method. The latter can be particularly valuable when robustness, transfer between laboratories or future lifecycle changes are important considerations.
Kymos can support pharmaceutical and biotech companies with analytical method development, validation and transfer for small molecules, biologics, oligonucleotides and peptides, and cell and gene therapies.
Want to discuss an analytical method development project? Contact our team at https://kymos.com/contact/ or commercial@kymos.com
