Design Space of Robust Analytical Methods in the Pharmaceutical Environment

Summary

In this white paper, we discuss the shift towards Quality by Design (QbD) in the pharmaceutical industry. This approach emphasizes understanding and controlling critical quality attributes (CQAs) and method parameters to ensure robust drug development and manufacturing processes. The QbD framework, endorsed by the FDA and ICH, integrates risk management and monitoring to optimize product quality. The article highlights the importance of the Method Operable Design Region (MODR) in defining a design space that ensures consistent performance. By adopting QbD principles, pharmaceutical teams can enhance process control, reduce variability, and improve regulatory compliance. The case study illustrates the application of QbD in developing a high-performance liquid chromatography (HPLC) method, showcasing the benefits of systematic method development and continuous improvement. This approach ultimately leads to better understanding, reduced risk, and more efficient manufacturing processes.

In the pharmaceutical industry, significant paradigm shifts are transforming the quality environment to support modern and innovative manufacturing. Regulators, industry leaders, and standards-setting organizations are increasingly emphasizing risk-based and Quality by Design (QbD) approaches over traditional compliance-driven and quality-by-testing methods[i]. This shift requires a deep understanding of products and processes, leading to changes in traditional validation practices. In this article, we will review the QbD principles applied to analytical methods, their advantages, especially for developing robust and optimized methods. Finally, to illustrate the benefits, a case study will be presented.

Introduction

The concept of analytical procedure validation is evolving towards a life cycle risk-based approach[ii]. Current validation practices often prioritize meeting regulatory requirements over understanding and controlling variability sources.

The quality risk management (QRM) process is what drives the design of optimum conditions, allowing the identification of conditions that optimize performance and minimize/avoid bias (reducing variability) to establish an operating range called “method operable design region” (MODR). The MODR is a multidimensional region where all study factors in combination provide suitable mean performance and robustness, ensuring procedure fitness for use. The MODR is equivalent to the term “Design Space” cited in the International Conference on Harmonisation (ICH) Q8 guidelines.

Within the quality environment, analytical methods are crucial throughout a drug’s lifecycle, requiring precision, accuracy, and reliability. Liquid chromatography (LC) techniques, like HPLC and UHPLC, are commonly used to separate analytes in samples. These methods are essential for analyzing active pharmaceutical ingredients (APIs) and their related substances.

In respect with ICH guidelines, especially ICH Q2(R2) and ICH Q14, the robustness of analytical procedure should be considered during method development phase and is defined as “a measure of its capacity to meet the expected performance requirements during normal use. Robustness is tested by deliberate variations of analytical procedure parameters.” [iii]

Traditional method development often uses a trial-and-error approach, called OFAT (one-factor-at-the -time), which can be time-consuming and less effective. Inconsistent method performance during routine use can lead to out-of-specification results, failure of the System Suitability Testing (SST) requiring redevelopment and regulatory approval, impacting cost and time.

Introducing the AQbD concept

In 2004, the U.S. Food and Drug Administration (FDA) introduced the concept of Quality by Design (QbD) as an essential tool to be used in developing new drug products and drug-product-related processes[iv]. Approved by the ICH in 2005, QbD emphasizes understanding products and processes based on science and quality risk management. Subsequent ICH guidelines (Q9, Q10, Q11) expanded on these principles, promoting innovation and continuous improvement[v].

QbD can also apply to analytical procedures, covering development, validation, transfer, and improvement. The FDA’s 2015 guidance recommends a systematic approach to method robustness, including risk assessment and multivariate experiments. The 2017 USP chapter ⟨1220⟩ further supports this lifecycle approach.

In 2018, the ICH began developing the Q14 guideline for analytical procedure development and validation, incorporating Analytical Quality by Design (AQbD) to ensure consistent, high-quality results
Since 2016, numerous publications have discussed AQbD in liquid chromatography (LC) method development, focusing on stability-indicating methods for degradation products and assays of active pharmaceutical ingredients (APIs). Some studies also address multiple assays for combined APIs and methods for determining preservatives in final dosage forms.

AQbD enhances method robustness by understanding relevant sources of variability of the method, reducing errors and out-of-specification results during routine use, leading to fewer post-approval changes and increased cost-effectiveness. It emphasizes systematic method development, risk assessment, and evaluation of method parameters to ensure optimal performance and robustness. This approach supports successful method validation and transfer. Within a complete Design Space (MODR) investigation, this can favor regulatory flexibility by allowing changes within the method’s robustness area without requiring revalidation.

Several reviews of AQbD have been published, detailing its theoretical background and summarizing scientific achievements using the AQbD concept[vi].

Download the white paper below to learn more about Quality by Design and discover its benefits in a case study

References :
[i] J. Weitzel, et al., AAPS J. 23:112 (2021). https://doi.org/10.1208/s12248-021-00634-5.
[ii] ICH, ICH Guideline Q2(R2) Validation of Analytical Procedures (ICH 2024).
[iii] FDA, Pharmaceutical cGMPs for the 21st Century – A Risk Based Approach, 2004
[iv] FDA. Guidance for Industry, Process Validation: General Principles and Practices (2011).
[v] ICH, Q8(R2) Pharmaceutical Development (ICH, 2009).
[vi] T. Tome et al., Development and Optimization of Liquid Chromatography Analytical Methods by Using AQbD Principles: Overview and Recent Advances Org. Process Res. Dev. 2019, 23, 1784−1802.