Analytical Method Development Articles

Purpose. A sensitive, robust, and selective liquid chromatographic – tandem mass spectrometric method (LC-MS/MS) was developed and validated for paroxetine quantification in human EDTA plasma. Methods. Sample preparation was based on liquid-liquid extraction using a mixture of ethyl acetate/hexane (50/50; v/v) to extract the drug and internal standard from plasma. Chromatography was performed on a C-18 analytical column and the retention times were 1.6 and 1.7 for paroxetine and fluoxetine (IS), respectively.

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Reproducibility? Ruggedness? Robustness? To many people, all of these terms mean the same thing. But in reality, in the words of a popular children's program, "one of these things is not like the other." An earlier "Validation Viewpoint" column (1) touched briefly on this topic, but this column will explore the topic in a little more detail. So, for the purposes of this discussion, the "R-word" we are most interested in is robustness. However, first we need a few clarifications.

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This article is the second of a series of articles detailing the development of near-infrared (NIR) methods for solid dosage-form analysis. Experiments were conducted at the Duquesne University Center for Pharmaceutical Technology to demonstrate a method for developing and validating NIR models for the analysis of active pharmaceutical ingredient (API) content and hardness of a solid dosage form.

R.D. McDowall

When you write up your observations and notes in a traditional laboratory notebook, there are a number of features that help to ensure data integrity. The notebook pages are numbered sequentially and they are bound together. Therefore, if a page is removed, it is obvious immediately. When recording observations in the notebook, the order of the write-up is important and is enforced by the sequential or linear pagination of the notebook. The author signs and dates the recorded information and this is witnessed by a second person, who signs and also dates when they reviewed the work. Note that it is not usual to time and date signatures in a laboratory notebook.

Working in an Electronic Environment

Many industry professionals know that analytical testing for biopharmaceuticals for all raw materials, production in-process stages, and final containers must be validated, and they generally understand how this can be achieved. Many of us even understand the basic concepts of laboratory compliance and production process quality. However, how exactly are analytical test method performance and process robustness related and how do they depend on each other? Furthermore, how do we monitor and maintain the accuracy and reliability of analytical methods long after validation completion to ensure the suitability of these methods for measuring process quality?

During pharmaceutical development and postapproval, it is often necessary to change analytical methods to ensure they remain stability-indicating, take advantage of improved analytical technology, monitor new related substances as a result of changes in synthetic or formulation processes, and improve analytical effeciency (e.g.,through automation).

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This article describes a software solution for automating the chromatographic method validation process starting from experimental planning, data acquisition and processing, through final report generation in a seamless manner. All experimental planning and calculations are accomplished within the chromatography data software and, thus, are structurally validated, secure, and audit trailed. Highlights of the software are provided, including benefits to the analyst. The analysis of important method validation characteristics such as linearity, accuracy, and precision is automated. These characteristics and their acceptance criteria can be captured in a method template, which adheres to the company's standard operating procedure. This template method can then be used repeatedly by other scientists in the organization, hence, eliminating the need to create a new experimental plan each time a new validation is conducted

This article provides guidance for minimally acceptable method validation practices and a foundation for assessing the risks and benefits associated with method validation programs.

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The chromatographic analytical method validation process involves a series of activities that are currently conducted in separate “technology islands” using tools that exist for each activity.This article describes a software program that provides an overarching automation technology for analytical method validation and brings together the individual activities under one integrated-technology platform that is adapted to multiple instruments and data systems.

Dissolution testing of poorly soluble compounds in immediate- release
(IR) solid dosage forms poses many challenges. These challenges include
developing and validating the test method, ensuring that the method is
appropriately discriminatory, and addressing the potential for an in
vivo–in vitro relationship (IVIVR) or correlation (IVIVC). The
objectives of dissolution testing, in general, vary during the life
cycle of a dosage form. The primary objective during Phases
0 and I is to develop a method to clearly establish the mechanism of in
vitro drug release and solubilization.During Phases II and III, the
objective shifts to identifying a test method that can provide an
IVIVR, IVIVC, or other biorelevant information. At registration and
beyond, the
goal is to identify a quality control (QC) dissolution test method to verify process and product consistency.