Analytical Method Development in Pharmaceuticals and Validation Steps

By July 5, 2021 EstiData
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Analytical methods are rigorously validated because they provide critical data for ensuring consumer health and safety. 

Validation is required for any analytical method used on a pharmaceutical product by Current Good Manufacturing Practices (cGMPs). In addition, before use, must validate the methods used to generate data supporting the production of pharmaceuticals or regulatory filing (with the FDA, for example).

Validated analytical methods aid in the characterization of a drug, quality control, and manufacturing batch records. This analytical test method validation provides a documented process that demonstrates that the test procedure is appropriate for its intended purpose, includes evidence of method performance, and ensures the quality and reliability of results.

Data Quality

A test method validation can be viewed as one component of a more extensive process of producing consistent and reliable quality data (Figure 1). Process analytical Instrument Qualification, a collection of documented evidence that the instruments used in the method perform suitably for their intended purpose, is the first key component that forms the foundation for generating quality data.

Before method validation, any equipment, software, or database must be qualified using Installation, Operational, and Performance Qualifications (IQ, OQ, and PQ).

Using a validated procedure with qualified instruments ensures that the design will produce valid data of acceptable quality. System Suitability Tests verify the performance of the test by the criteria set in the process and confirm acceptance of this performance at the time of the test; they are based on the principle that the equipment, electronics, analytical operations and samples to be analyzed from an integral test system.

System suitability tests, in conjunction with Quality Control, Check samples, which provide ongoing assurance of the test’s performance, ensure that the validated method will work under the specific conditions. System suitability testing includes verification, initial testing, and product-specific validation.

Method Development

Every year, a more significant number of drugs are introduced into the market. These drugs could be entirely new or a partial structural modification of an existing one. There is frequently a time lag between the date a drug is introduced and the date it is included in pharmacopeias process analytical. This is due to potential uncertainties in the continued and expanded use of these drugs, reports of new toxicities (resulting in their withdrawal from the market), the development of patient resistance, and the introduction of better drugs by competitors. Standards and analytical procedures for these drugs may not be available in pharmacopeia under these conditions. It becomes necessary, therefore, to develop newer analytical methods for such medications.

Essential criteria for developing new drug analysis methodsMethod Development

  • Any pharmacopeias may not recognize the drug or drug combination process analytical.
  • Due to patent regulations, a proper analytical procedure for the drug may not be available in the literature.
  • Due to the interference caused by the formulation excipients, analytical methods for the drug in the form of a formulation may not be available.
  • There are probably no analytical methods for measuring the medication in bodily fluids.
  • Analytical procedures for medicine in combination with other medications may not be accessible.
  • Existing analytical procedures may necessitate the use of costly reagents and solvents. It may also necessitate time-consuming extraction and separation procedures, which may or may not be reliable.

Guidelines and requirements

Although method validation is required for all pharma test methods, the validation process itself can vary greatly depending on the regulatory bodies governing drug development, production, and the method’s purpose. Because government regulations do not specify the scientific approach to method validation in detail, pharmaceutical companies and contract analytical testing laboratories rely on guidelines to meet compliance and scientific soundness expectations of the method in use.

Regulatory and government bodies, such as the ICH or FDA, provide non-binding guidelines that conform to regulatory requirements and industry standards for safe pharmaceutical product development, as well as a set of official references for method validation. Here are some examples of available guidance documents:

  • Validation of Analytical Procedures: Text and Methodology Q2(R1), ICH 2005
  • Guidance for Industry: Analytical Procedures and Methods Validation for Drugs and Biologics, FDA 2015
  • Guidance for Industry: Bioanalytical Method Validation (Draft Guidance), FDA 2013
    • Validation of Compendial Procedures, USP 39
    • Verification of Compendial Procedures
    • Analytical Instrument Qualification.

Regulatory bodies’ guidance documents describe several characteristics or performance elements that must define during the method validation process. The nature of the test procedure determines the specific combination of factors to be evaluated during the validation process; assay validation parameters can vary significantly between methods, depending on the essay’s purpose or the compound of interest.

As a result, validation will demonstrate, through specific laboratory examinations, that the method’s performance characteristics are reliable and appropriate for the intended use. The criteria for validating the acceptability of analytical data must be defined early in the process, along with the method’s scope.

According to Validation of Analytical Procedures: Text and Methodology Q2(R1), two these characteristics are: 

  • Accuracy – is the method’s ability to produce test results close to the actual value, either accepted as an authentic traditional or reference value. Using reference standards or calculating the percentage of recovery of a known added amount of analyte in a sample is frequently used to evaluate accuracy. Because the analytical method is expected to be accurate throughout its expected range of values, it Should evaluate the accuracy throughout the method’s desired range of values.
  • Precision – the degree of agreement between a series of measurements taken from multiple samples of the same homogeneous sample under strictly defined experimental conditions. It should represent the repeatability and reproducibility of the method. As with accuracy determination, must evaluate it across the expected range of measurements.
  • Specificity – The ability to assess the analysis in category presence of components predicted to occur, such as contaminants, degraded products and matrix; in the presence of large concentrations of other similar but not identical items, the item will be detected in a specific technique, even at low quantities. Again, determining the specificity of a procedure must be done across the expected range of values and under strictly defined conditions.
  • The detection limits – The smallest amount of analyte in a sample that can be detected but not necessarily quantitated as an exact value under defined experimental conditions is the minimum amount of analyte in a model that can be seen but not necessarily quantitated actual value. The smallest amount of tested material contained within the sample produces a signal above the noise.
  • Quantitation limit –  The smallest analyte in a sample that can quantify with appropriate precision and accuracy under specific experimental circumstances is the lowest quantity of analyte in a model that can quantify with appropriate precision and accuracy. The established quantitation limit will illustrate the method’s lowest point in its range.
  • Linearity – The ability of an analytical method to produce test results that are proportional to the concentration of the analyte in the sample, either directly or through a well-defined mathematical transformation within a given range. If linearity is not possible, a non-linear model can be used. Any quantitative method must show a clear quantitative relationship between the assay measurement and the amount of material of interest in the tested sample. An analytical procedure’s range is the interval between the upper and lower analyte levels in the model (including these levels). It has been demonstrated that the analytical method process analytical has adequate precision, accuracy, and linearity.

The robustness – of an analytical method measures its ability to remain unaffected by minor but deliberate variations in method parameters and indicates its dependability under normal conditions.

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