Beyond SOPs

A decade ago, the introduction of standard operating procedures was groundbreaking, but new understanding now helps bring the rigor of QbD to analytical method development.

By Paul Davies and Paul Kippax, Malvern Instruments

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As the philosophy and techniques enshrined in Quality by Design (QbD) become second nature to the pharmaceutical industry, their application is spreading. Analytical method development is a current area of focus. The process of developing, validating and deploying analytical methods closely parallels product development and can similarly benefit from the systematic and scientific approach that QbD promotes. The dependence of pharmaceutical development and manufacture on robust analytical data intensifies the need for rigor in analytical method development and increasingly a QbD approach — Analytical QbD (AQbD) — is seen as the way forward.

In analytical method development the goal is to develop, validate and deploy a method for making an analysis that will deliver the information required, in all the instances that it is required to do so. The starting point is to identify exactly why the measurement is being made; in the same way that the starting point for conventional QbD is to identify clinical performance targets for the product. Once this is established, the process is one of understanding and learning to control those aspects of the measurement method that define critical elements of analytical performance. This closely mirrors the QbD model of working toward a fully scoped design space.

A useful starting point for examining AQbD is to return to the generally accepted definition of QbD, which was originally presented in International Conference on Harmonization document Q8(R2). This states that QbD is:

“A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management …”

Figure 1 shows the QbD workflow that represents this systematic approach. The first step is to identify the Quality Target Product Profile (QTPP), the definition of what the product must deliver. The subsequent steps of QbD involve identification of the variables that must be controlled to deliver the defined product performance, and the best way of implementing that control.

Determination of performance-defining Critical Quality Attributes (CQAs), and the Critical Process Parameters (CPPs) and Critical Material Properties (CMAs) that control them, comes first. Definition of the design space follows. The design space is the operating envelope for the process. It encompasses the defined ranges for the CPPs and CMAs that ensure the CQAs will be achieved consistently. Defining the control strategies needed to maintain operation within the design space is the final step, but the entire workflow is wrapped within a process of continuous improvement across the lifecycle of the drug. Indeed, a major attraction of QbD is that its application permits ongoing optimization within the design space without requiring further regulatory approval.

ICHQ8 (R2) does not specifically mention analytical method development. However, the underlined phrases in the original QbD definition (above) have direct resonance when looking to apply a structured, rigorous approach to developing analytical methods. This resonance has prompted the evolution of Analytical Quality by Design (AQbD).

FDA guidance on the application of AQbD [1] highlights the potential benefits of transferring QbD to analytical method development. The proposal is that AQbD will lead to the development of a robust method that will be applicable throughout the lifecycle of the product. Just as with QbD, being able to demonstrate adherence to AQbD will be associated with a certain degree of regulatory flexibility, providing the freedom to change method parameters within a method’s design space, referred to as the Method Operable Design Region (MODR). 

The starting point for AQbD is an Analytical Target Profile, or ATP, which is directly analogous to a QTPP (Figure 1). The ATP defines the goal of the analytical method development process, linking the output of the method to the overall QTPP. Identifying why the analytical information is required, what it will be used for and when, helps to formulate the ATP. Supplementary targets for performance characteristics, such as precision and reproducibility, stem from a more detailed analysis of these needs. 

The next step is to identify a suitable analytical technique. This must be done with reference to the needs defined in the ATP. Once the technique is identified, AQbD focuses on method development and includes detailed assessment of the risks associated with variability associated with:

• Analyst methods
• Instrument configuration and maintenance
• Measurement and method parameters
• Material characteristics
• Environmental conditions

This assessment identifies the CQAs, the parameters that impact the ATP. A Design of Experiments (DOE) approach is then adopted to define the MODR. This is the operating range for the CQAs that produces results that consistently meet the goals set out in the ATP. Once this is defined, appropriate method controls can be put in place and method validation carried out following the guidance in ICH Q2.

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