Analytical control of process impurities in Pazopanib hydrochloride by impurity fate mapping
Introduction
Active pharmaceutical ingredients (APIs) are manufactured by scale-up of synthetic chemical processes. Development of synthetic chemical process can lead to the generation of unwanted organic impurities. These usually include the un-reacted starting materials (SMs), impurities originating from the SMs, un-reacted intermediates (IMs), reaction by-products, and degradation products [1], [2], [3]. These undesired impurities usually provide no benefit to patients and can pose risks to patient safety or drug efficacy [4], [5]. Thus, the detection, identification, quantification, and control of such impurities originating in the manufacturing process have become an important element of drug development in order to ensure product quality and ultimately patient safety [6], [7], [8]. Regulatory agencies also explicitly regulate the control criteria for these drug related substances in APIs and subsequent drug products by providing guidance for the pharmaceutical industry [1], [9].
In the traditional framework, product quality is ensured predominantly by restricting flexibility in the manufacturing process and end product testing (so called quality-by-testing, QbT) [10]. Under QbT, process impurities are usually tested against specifications set using the observed data from a number of batches. However, this places little or no emphasis on the process understanding and the design of an effective and efficient impurity control strategy. In light of the recent quality by design (QbD) initiative by the U.S. Food and Drug Administration (FDA) [11], increasing attention has been drawn to the application of the QbD principles [12], [13] to impurity investigation and control, emphasizing process understanding based on sound science and risk management [10], [14], [15]. Under the new QbD paradigm, impurities should not only be tested in the final API, but rather be proactively controlled in the manufacturing process. By developing a product with this goal in mind, end product testing would be solely used for the confirmation of product quality since the process understanding and/or process control provides sufficient evidence that batches will meet the specification if tested [10]. However, only a handful of discussions with regard to a systematic approach to the investigation and control of process impurities have been made available over the past few years [7], [8], [16], [17], [18]. Particularly, the development of a comprehensive QbD approach to impurity investigation in order to actively seek out drug quality is not widely discussed in the literature.
A comprehensive and systematic approach to analytical control of process impurities by impurity fate mapping (IFM) is reported in this paper. This approach is taken to actively search for possible impurities in an API process, obtain intrinsic knowledge of the origin, formation pathway, fate, and process purgeability of impurities, design risk mitigation steps to reduce those impurities during reactions, and finally derive a comprehensive and scientifically justified control strategy for the overall process [19], [20]. A general outline of such an IFM framework is provided in Fig. 1, which is a joint effort from a cross-functional team involving analytical scientists, synthetic chemists, and process engineers. This report highlights the analytical perspective of the IFM process.
To successfully support IFM activities, the application of various complementary analytical techniques for impurity detection, structural identification, separation/isolation, and quantification are essential [21]. For instance, liquid chromatography (LC) with UV detection is an essential tool for separation and determination of impurities in drugs [2], [22] which is backed up with gas chromatography (GC) when impurities are not amenable to LC, whereas the orthogonal techniques, LC–mass spectrometry (LC–MS) and GC–MS are universal tools for impurity tracking and identification [23], [24], [25]. When definitive structures are required, isolation by preparative chromatography followed by nuclear magnetic resonance spectroscopy (NMR) analyses is a powerful technique for characterization of impurity structures [6], [21]. The use of these orthogonal techniques as appropriate helps to maximize the impurities that can be detected and the structures that can be confirmed. Typically IFM commences at the late development stage when the final route of synthesis and an optimal process are finalized where a comprehensive impurity control strategy is needed. This means that analytical methods used for impurity testing at the early development stage may not be suitable for IFM, because of changes in impurity profiles caused by changes in the synthetic route from early to late development stages as well as the greater number of impurities identified through IFM itself. Therefore, evolution of analytical methods becomes a key aspect of IFM, which can pose significant challenges to the analytical method development. Furthermore, analytical control strategy of process impurities can be derived based on the knowledge gained throughout the IFM. As part of the overall control strategy (including the effective and efficient control of quality process parameters and analytical control of impurities), the analytical control is usually comprised of three key aspects as shown in Fig. 1: (1) designation of specified impurities, (2) setting of scientifically justified specifications, where IFM can make significant contributions, and (3) development of simple, robust and rugged analytical control methods for use over the product lifecycle.
By emphasizing process understanding and risk management, the IFM approach outlined in Fig. 1 has been successfully applied to the understanding and control of process impurities in Pazopanib hydrochloride (GW786034B in Scheme 1), a VEGFR tyrosine kinase inhibitor approved recently by the U.S. FDA for treatment of renal cell carcinoma [26]. The work presented in this paper illustrates how QbD concepts are applied to the analytical control of process impurities in API. The analytical support to the IFM of Pazopanib hydrochloride and analytical challenges encountered during this process are addressed in this article.
Section snippets
Materials
Drug substances, intermediates, and impurities were synthesized or isolated by preparative chromatography in house at GlaxoSmithKline. The starting materials (SMs) were obtained from various vendors: three vendors V1a, V1b and V1c for SM1; two vendors V2a and V2b for SM2; and three vendors V3a, V3b and V3c for SM3. Trifluoroacetic acid (TFA), formic acid, ammonium acetate, and HPLC grade acetonitrile were all from J.T. Baker (Phillipsburg, NJ, USA). De-ionized water was obtained from a Milli-Q
Process evaluation
A thorough process evaluation was first conducted at the beginning of the IFM of Pazopanib hydrochloride. This assessment was used to provide initial input of known and potential impurities that may be generated in the process, and help the planning of further experiments. This was mainly a paper exercise including an analytical evaluation and a chemistry assessment. Close collaboration between the two disciplines is essential to the initiation of the IFM.
The purpose of the analytical
Conclusion
A comprehensive approach to analytical control of process impurities by IFM has been established and successfully applied to the understanding and control of impurities in the manufacturing process of Pazopanib hydrochloride. The ultimate goal of IFM is to design a comprehensive impurity control strategy to ensure that product quality (impurity levels in this case) is built into the manufacturing process. This approach aligns well with the FDA's QbD initiative by emphasizing process
Acknowledgements
The authors would like to thank Drs. Sarah Chen, Li Liu, Alan Freyer, Mingjiang Sun, Hyunjung Kim, and Fred Vogt, and Mr. Sheng Tang, Mr. Jack Dougherty, and Mr. Lin Bai of Chemical Development, GlaxoSmithKline, for their contributions to the experiments and discussions described in this paper. The authors are grateful to Drs. Ted Chen, Tom Roper, and Chris Brook of Chemical Development, GlaxoSmithKline, for their support of this work.
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