Requirements of The Method

In developing HPLC methodology, these validation requirements stipulate that stability-indicating impurity methods be designed and validated to  

Simultaneously separate, identify, and quantitate degradates/impurities from the active drug substance 

Be free from interference from the excipient materials 

In summary, many of the requirements of a method development project are being dictated through regulation and internationally accepted guidelines, as well as a knowledge of current good practice accepted in the pharmaceutical industry. 

The methods provided in official monographs have been validated by the laboratory submitting the monograph and/or other laboratories designated by the USP. This validation has been performed with material produced or used by the laboratory and on equipment contained in the laboratory. It is important for all compendia methods that each individual laboratory performs a scaled-back validation of the method or verification of the method s suitability in its laboratory. 

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In the first phase, the performance of the instrumentation used for the method is demonstrated. Based on the analysis of standards, results from the participating laboratory should meet the system suitability requirements of the method. Successful completion of this phase will qualify the analyst, his or her equipment, and the laboratory for the trial. Failure in the first phase does not usually cause a method to fail the trial. However, it can slow the process. When a procedure fails during the first phase of a trial, the sponsor may need to write a cautionary note in the SOP discussing recommended or inadequate types of instruments. To correct the problem, the participating laboratory analyst can substitute equipment that gives adequate performance alternatively, the sponsor must find a different laboratory to participate in the trial. 

Several safety analysis methods have been developed already. Some of them are internationally known and proved, some have been used and developed more or less inside companies. Information requirements of the methods are different, also the results produced vary. Thus different safety methods are suitable for different stages of process development, design and operation (Fig. 3). Some safety analysis methods are discussed below in more detail. 

The FSA undertakes surveillance exercises, the data for which are acquired from analytical determinations. The Agency will take measures to ensure that the analytical data produced by contractors are sufficient with respect to analytical quality, i.e. that the results obtained meet predetermined analytical quality requirements such as fitness-for-purpose, accuracy and reliability. Thus when inviting tenders FSA will ask potential contractors to provide information regarding the performance requirements of the methods to be used in the exercise, e.g. limit of detection, accuracy, precision etc., and the quality assurance measures used in their laboratories. When presenting tenders, laboratories should confirm how they comply with these specifications and give the principles of the methods to be used. These requirements extend both to the laboratory as a whole and to the specific analytical determinations being required in the surveillance exercise. The requirements are described in three parts, namely ... 

Several strategies have been described for the preconcentration of sample components present at low concentrations. These techniques include zone sharpening,28-29 on-line packed columns,30 and transient capillary isotachophoresis (cITP).31-32 Other standard laboratory techniques are often used, including solid-phase extraction, protein precipitation, ultrafiltration, etc. Two important points to keep in mind when selecting a concentration protocol are the sample requirements of the method and the potential selectivity on relative concentrations of sample components. The latter point applies to purity and concentration analysis. 

Performance specifications of the method It is important to recall the previously-stated requirements of the method, which could be expressed in terms of accuracy, precision, repeatability, up-time, and/or other attributes. It s also quite possible that these specifications have changed since the method was first put into service. 

In addition to the ICH levels repeatability and intermediate precision, the system precision, i.e., repeated injections/determinations of a single sample solution (also referred to as injection repeatability or injection precision), provides valuable information. Evaluation of these data will help us to show that the chosen equipment is suitable for its intended use. Injection precision will also become part of the system suitability requirements of the method and an acceptance... 

Some comment should be made concerning the levels of precision and accuracy required of the methods. When we are concerned merely with determining the rough outlines of the oceanic distribution of organic... 

Planning. Planning encompasses the user requirements of the method. Planning includes the following major items ... 

An advantage of surface-plasmon microscopy is that great contrast between layers of different thicknesses that can be obtained in very thin films without the use of the probe molecules. It is a requirement of the method, however, that there be an underlying coating of a conductor such as silver that carries that surface plasmon field. There is a possibility that images can be obtained from the water/monolayer film that adheres to a vertical slide that has been partially drawn through the air-water interface. ... 

The answer to question 1 is of vital importance because it determines how much time and care will he needed for the analysis The answers to questions 2 and determine how sensitive the method must be and how wide a range of concentrations must be accommodated. rhe aii.swer to question 4 determines the selectivity required of the method. I hc answers to question 5 are important because some analytical methods in Table I-l arc applicable to solutions (usually aqueous) of the analyte. Other methods aie more easily applied l< gaseous samples, and still other frietlu ds are suited to (he direct analysis of solids. 

We summarize in Table 4.A.1 the computational requirements of the methods considered to determine the sensitivity coefficients for n concentrations to m parameters. 

Method validation should not be considered as an isolated event. Method validation essentially begins once we develop or select a method for use. The first question to be answered is whether the method has been suitably validated by another analyst or laboratory as fit for purpose. As discussed earlier, the fitness-for-purpose statement used for this determination should include identification of the analytes and matrices to which the method is to be applied, legal limits or other concentrations that define the concentration range required of the method, plus any other considerations such as required accuracy, precision, or measurement uncertainty (MU). When suitable documentation of such validation work is available, then the method may be used by other analysts or laboratories once they have demonstrated that they can routinely attain the performance standards established in the initial validation. If evidence of such validation is not available, then experiments should be conducted to validate the method before implementation. 

This is a very important aspect for this work, as the methodology can be applied in different companies and coimtries worldwide, and the easier the approach, the better it will run. The only requirement of the method is to select the strongest component or category, and uses it as the basis for comparisons with all others, as it... 

The dialyzer unit employed in FIA is formed by two plates of inert material (methacrylate) that are screwed to each other through a crescent bore in each. To decrease dispersion, the channels are often packed with inert glass beads. In this way, the sample is injected into the donor stream, crosses the dialyzer, and is brought into contact with a membrane that is crossed by the analyte. The dialyzer can be nesting at virtually any point in the flow assembly, according to the requirements of the method, and planar spiral arrangements have been proved to be the most efficient. 

The effects of spectral shifts on an analysis are also readily anticipated if both UV cutoff and complete spectral curve information are considered. In most cases, the analytical effects of a spectral shift can be virtually eliminated if the analysis is run at a wavelength more than 20 nm higher than the reported UV cutoff. In instances where such considerations carmot be met, specifically designated solvent specifications should be communicated to the manufacturer so that solvent lots are supplied that meet the requirements of the method. 

The accuracy of any method depends to a large degree upon the skills and experience of those who not only collect the samples but also those who analyze the samples. Even for methods that are collaboratively tested, some laboratories are closer to the true values than others. Some laboratories may meet the precision and accuracy requirements of the method others may consistently far exceed them for the same method. 

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