A Systematic Method Development Strategy for Determination of Pharmaceutical Genotoxic Impurities

Abstract

Trace level genotoxic impurities (GTIs) in pharmaceutical products require precise, accurate, and robust analytical methodologies for their analysis and control. The need to control most genotoxic impurities to the low ppm level in combination with the very often reactive and labile nature of genotoxic impurities presents significant analytical challenges. This article reports a systematic GTI method development strategy (MDS) based on our successful experiences in GTI analysis in recent years and quality by design (QbD) principles emphasizing the expected method performance being built into the method. It starts with a predefined method goal, followed by method understanding and a risk control strategy. Due to the nature of the GTI analysis, sophisticated analytical methodologies such as chemical derivatization and mass spectrometry detection are often developed, especially in the research and development (R&D) phase of drug development. Such methods usually consist of more variables than conventional methods in pharmaceutical analysis. Therefore, sound scientific understanding and risk control strategies are of great importance to ensure the method performance for trace GTI analysis. For methods to be implemented in manufacturing quality control laboratories that are lacking sophisticated instrumentation and skilled analysts, method simplicity, robustness, and ruggedness become more prominent in addition to method accuracy. This article describes QbD approaches for developing such methods using real world case studies including dimethyl sulfate analysis of a recently approved drug, pazopanib HCl (Votrient).

Development of Quality-By-Design Analytical Methods

“…In light of the variety of analytical methods that can potentially benefit from QbD approaches, a structured approach to analytical method development that transcends the technique used is necessary, such as the MDS approach. [8][9][10][11][12] The structured steps utilized in the MDS approach are shown in Figure 1 and begin with the definition of a goal for the method and collection of background information, systematic scouting and evaluation of alternative methods, selection of a promising method that meets the goal, assessment of the method for risks using structured tools, and finally development of a control strategy to ensure method performance. The MDS approach emphasizes the use of scientific understanding and QbD principles during each step in method development, rather that testing quality into an already-developed method.…”

“…A number of factors, such as patient safety, product efficacy, and quality requirements, as well as prior knowledge of similar drug compounds on the market, must be taken into consideration for the development of a method goal. [8][9][10][11][12] The operational intent of the method and end user requirements must also be considered, including instrumentation capabilities at future testing laboratories, geographical location and climate of the laboratories, and potential constraints on access to chemical reagents. [8][9][10][11][12] The method goal concept can be illustrated using HPLC as an example.…”

“…[8][9][10][11][12] The operational intent of the method and end user requirements must also be considered, including instrumentation capabilities at future testing laboratories, geographical location and climate of the laboratories, and potential constraints on access to chemical reagents. [8][9][10][11][12] The method goal concept can be illustrated using HPLC as an example. 8,13 The goal of an HPLC method for API is generally to separate and quantify the main compound and the critical quality attribute (CQA) impurities that may impact the quality of the drug product.…”

“…7 The QbD concept can be extended to analytical methods. [8][9][10][11][12][13][14][15][16][17][18][19] This paper summarizes the current state of QbD as applied to the development of analytical methods small-molecule pharmaceutical process development, including synthesis of the active pharmaceutical ingredient (API) and formulation, and biopharmaceutical process development. In this section, we introduce the principles of QbD and briefly review the overall status of QbD in the pharmaceutical industry to illustrate the position that analytical QbD occupies in this paradigm.…”

Implementation of Quality by Design for the Development and Validation of Pioglitazone Hydrochloride by RP-UPLC with Application to Formulated Forms

“…It has become an important paradigm in the pharmaceutical industry since its introduction by the US Food and Drug Administration [3][4][5][6][7]. The QbD concept can be extended to analytical methods [8][9][10][11][12][13][14][15]. The analytical methods used for the analysis of active pharmaceutical ingredients (API) and drug products are an integral part of the QbD.…”