Fenghe Qiu

Identification of Pharmaceutical Impurities

Abstract Identification of pharmaceutical impurities is a critical analytical activity in the drug development process whose goal is to fully elucidate the chemical structures of unknown pharmaceutical impurities present in either drug substances or drug products above a particular threshold. Knowledge of the chemical structure of an impurity is essential to assess its toxicological implications and to gain an understanding of its formation mechanism. Knowledge of the formation mechanism is critical for improving the synthetic chemical processes and optimizing the drug formulation to reduce or eliminate the impurity. This article reviews the current regulatory requirements for impurity identification and the chemical origins of various impurities, particularly those derived from degradation of drugs. Strategies for identification of pharmaceutical impurities are discussed followed by an overview of the critical steps and the roles of various analytical techniques, such as HPLC‐DAD, LC‐MS, LC‐NMR, GC‐MS, and NMR, in pharmaceutical impurity identification, with an emphasis on applications of mass spectrometry based hyphenated techniques. Carefully selected examples are included to demonstrate key points in impurity formation and the appropriate application of various analytical techniques.

Genotoxic Impurities : A Quantitative Approach

Abstract Starting materials, intermediates and by-products are often found as impurities in active pharmaceutical ingredients (APIs). Some of these known impurities are potential mutagens or carcinogens but can be difficult or impossible to eliminate completely from the synthetic scheme. Based on current regulatory guidances for genotoxic impurities, analytical methods should be developed to meet the required limit of 1.5 µg/day daily intake of each individual impurity for new drug substances. During the early clinical development stages the Pharma Task group proposed a staged TTC concept, where greater daily intake can be allowed. The allowable daily intake thus calculated would then provide a basis for estimating the quantitation limit (QL) required for the development of an analytical method for determining genotoxic impurity levels. The approach for choosing an analytical technique will depend on many factors including availability of the instrumentation and physical and chemical properties of the analyte. Although UV absorbance is normally the first choice detection technique for HPLC analysis, many genotoxic impurities lack a UV chromophore and consequently are not suitable for quantitation via UV detection. The examples described in this report show different approaches for quantitation on a case-by-case basis using various detection techniques such as UV, ELSD, CAD and MS. Although in one case the required alert level of 30 ppm was easily achieved using standard UV detection, other examples highlight the need for using alternatives such as an LC-MS/MS method. The latter methodology was necessary to achieve a required QL level of 57 ppm for one particular impurity. Validation of this method as per ICH guidelines with respect to specificity, linearity, accuracy and QL is also discussed.

Identification of a process impurity formed during synthesis of a nevirapine analogue HIV NNRT inhibitor using LC/MS and forced degradation studies

Impurities in pharmaceutical products do not enhance the desired therapeutic effect and may, of course, have adverse effects. Impurities must therefore be limited or controlled for quality and safety considerations. Structural identification of an impurity is the first step in understanding the chemistry of its formation and subsequently controlling the impurity. In this article, the chemical structure of an unknown by-product formed during the synthesis of a nevirapine analogue HIV NNRT inhibitor was identified using a combination of low resolution, high resolution and H/D exchange LC/MS and LC/MS/MS. The origin of the impurity was investigated through a series of photo- and oxidative stress studies. It was concluded that this impurity is formed via a side-reaction of the last intermediate with the oxidant used in the synthesis.

Identification of Drug Meglumine Interaction Products Using LC/MS and Forced Degradation Studies

Abstract In this work we report the identification of unknown degradation products observed during the accelerated stability studies of a Hepatitis C Virus inhibitor drug product by using LC/MS and forced degradation studies. These degradation products are formed through chemical interaction between the Active Pharmaceutical Ingredient (API) and meglumine, an excipient in the drug formulation.

ASAP Application: Unstable Drug Candidate in Early Development

Abstract ICH and WHO stability guidelines require minimum 6–12 months of stability data at recommended long-term and accelerated conditions to support the expiry dating for registration. This approach is problematic in early clinical development because of the lengthy duration of the stability studies. This is particularly true for a drug candidate that is considered very unstable, as in this case the stability of the candidate drug would be a critical issue and must be assessed routinely and quickly during early development. Recently, Accelerated Stability Assessment Program (ASAP) (Waterman et al., 2007) has been demonstrated to be a useful tool for prediction of drug chemical stability in a short period of time with reliable accuracy and precision. In this chapter, ASAP was applied to predict the stability of an unstable active pharmaceutical ingredient (API), which was eventually confirmed by long-term stability data, and to conduct comparative stability predictions of various prototype formulations to enable quick selection of stable formulations for early clinical studies. These quick predictions not only provided the insight into the possible retest period of the API, but also served as a quick decision-making tool during process and formulation development of the unstable candidate drug.

Monitoring the chemical and physical stability for tromethamine excipient in a lipid based formulation by HPLC coupled with ELSD

Tromethamine, a UV-transparent amine base excipient, was used in the liquid phase of a self-emulsifying drug delivery system-soft gelatin capsule (SEDDS-SGC) formulation as an emulsification agent and to improve solubilization of the active drug. The level of this excipient was found to be decreasing in aged and stressed drug product capsules. The decrease could potentially affect oral bioavailability of the drug; should the amount of solubilizer decrease enough to lead to precipitation of the active drug from the formulation. Therefore, further investigation was warranted. HPLC coupled with evaporative light scattering detection (ELSD) was used to monitor the physical and chemical stability of tromethamine in the SEDDS-SGC formulation. Confirmation of the tromethamine interaction products was done by LC-MS.