Analytical Method Development

For a successful pharmaceutical development program, Analytical Method Development, Validation and Transfer are essential elements. Analytical method development activities will focus on technical aspects as applied to drug products, including activities which are considered routine and paid little attention, but may impact the developmental time and cost. These each activity are interrelated and should be considered with utmost care during development activities. Some of these activities may occur concurrently or require retuning at different stages of the development. The changes occur during development may require modification to existing analytical methods. These modifications to the analytical methods, may require additional validation or transfer activities.

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Analytical method development requires following focus:

Analytical method development is the process of selecting an accurate assay method to determine the composition of drug product. It is the process of confirming that an analytical method is acceptable for use in laboratory to measure the concentration of routine samples. Analytical methods should be used within GMP and GLP environments and must be developed using the protocols and acceptance criteria set out in the ICH guidelines Q2(R1).

 

The prerequisite for method development are as follows:

– Qualified and calibrated instruments

– Documented methods

– Reliable reference standards

– Qualified analysts

– Sample selection and integrity

– Change control

 

The common steps followed in the method development are as follows:

– Standard analyte characterization

– Method requirements

– Literature search

– Selecting the method

– Instrumental setup and preliminary studies

– Optimization of parameters

– Documentation of analytical figure

– Evaluation of the method development with the sample

– Determination of percent recovery of the sample

– Demonstration of quantitative sample analysis

 

Analytical methods need to be validated or revalidated

– before their introduction into routine use;

– whenever the conditions change for which the method has been validated (e.g., an instrument with different characteristics or samples with a different matrix); and

– whenever the method is changed and the change is outside the original scope of the method.

 

The USP has published specific guidelines for method validation for compound evaluation. USP defines eight steps for validation:

– Accuracy

– Precision

– Specificity

– Limit of detection

– Limit of quantitation

– Linearity and range

– Ruggedness

– Robustness

 

Strategy for the Method Validation

Method validation should be demonstrated in laboratory experiments using samples or standards that are similar to unknown samples to be analyzed routinely. The preparation and execution follow a validation protocol to execute a test procedure, and executed as per the instruction. This procedure assumes that the instruments were selected and methods were developed. It will have acceptance criteria which has to meet during the method validation activities.

 

The strategy for method validation may be outlined as below:

– Develop a validation protocol, an operating procedure or a validation master plan for the validation

– For a specific validation project define owners and responsibilities

– Develop a validation project plan

– Define the application, purpose and scope of the method

– Define the performance parameters and acceptance criteria

– Define validation experiments

– Verify relevant performance characteristics of equipment

– Qualify materials, e.g. standards and reagents for purity, accurate amounts and sufficient stability

– Perform pre-validation experiments

– Adjust method parameters or/and acceptance criteria if necessary

– Perform full internal (and external) validation experiments

– Develop SOPs for executing the method in the routine

– Define criteria for revalidation

– Define type and frequency of system suitability tests and/or analytical quality control (AQC) checks for the routine

– Document validation experiments and results in the validation report

 

Method Transfer

Method transfer between two laboratories at the same or different sites when contract laboratories offer services for routine analysis in different areas or when products are manufactured in different areas. When validated routine methods are transferred between laboratories and sites, their validated state should be maintained to ensure the same reliable results in the receiving laboratory. This means the competence of the receiving laboratory to use the method should be demonstrated through tests, for example, repeat critical method validation experiments and run samples in parallel in the transferring and receiving laboratories. The transfer should be controlled by a procedure, The recommended steps are:

– Develop a transfer plan

– Define transfer tests and acceptance criteria

– Describe rational for tests

– Train receiving lab operators in transferring lab on equipment, method, critical parameters and troubleshooting

– Repeat 2 critical method validation tests in routine lab

– Analyze at least three samples in transferring and receiving lab

– Document transfer results