(4) Validation

• Validation


  Rectification or confirmation
• Validation (in pharmaceutical analysis)

  A procedure that demonstrates that a process under standard conditions is capable of consistently producing a product that meets the established product specifications
• Types of Validation


  • Analytical Method Validation
  • Equipment Validation
  • Cleaning Validation
  • Process Validation
• Analytical Method Validation


  • Must prove that the analytical method used for a specific test is suitable for which it is to be carried out
  • Methods should be validated when they are to be established for routine use
  • When the method is to be changed due to change in conditions
  • Whenever the equivalence between new method and the standard are demonstrated
• Procedures to be validated for Analytical Method Validation

  • Accuracy
  • Precision
  • Repeatability
  • Intermediate Precision
  • Reproducibility
  • Specificity
  • Linearity
  • Quantitation Limit
  • Robustness
  • Range
  • Detection Limit
• Accuracy


  The closeness of agreement between the observed value and the value which is either conventionally a true one or reference one
• Precision


  The closeness of values obtained from a series of tests
• Repeatability


  When the same sample is estimated repeatedly by the same analyst using same analytical method within the same laboratory using same instrument and performed within a short period of time
• Intermediate Precision


  When the test is repeated on different days by different persons or using different instruments within the same laboratory, the variation is expressed in terms of intermediate precision
• Reproducibility


  When a method is standardized, the test is carried out in different laboratories using the same method, the precision between the laboratories is referred to as reproducibility
• Specificity


  The ability of a test method to measure the analyte explicitly in the presence of other components
• Linearity


  The ability of an analytical method to measure a specific component within a range
• Quantitation Limit


  The lowest amount of analyte in a sample which can be quantitatively determined with suitable precision and accuracy
• Robustness


  A measure of its capacity to remain unaffected by small, but deliberate variations in method parameters and provides an indication of its reliability during normal usage
• Range


  The interval between the upper and lower concentration (amounts) of analyte in the sample
• Limit of Detection (LOD)


  The lowest concentration of an analyte that can be reliably distinguished from the background noise with a certain level of confidence
• Limit of Quantification (LOQ)

  The lowest concentration of an analyte that can be reliably detected and quantified with acceptable accuracy and precision
• Types of Equipment Validation

  • Installation Qualification (IQ)
  • Operational Qualification (OQ)
  • Design Qualification (DQ)
  • Performance Qualification (PQ)
• Installation Qualification (IQ)


  • Ensures that all major processing and packing equipment and ancillary systems are in conformity with installation specification, equipment manuals, schematics
  • Considers calibration, preventive maintenance, safety features, software documentation, equipment design features
• Operational Qualification (OQ)


  • Provides a high degree of assurance that the equipment functions as intended
  • Conducted in 2 stages - component operational qualification & system operational qualification
  • Considers software procedures, raw material specification, process operation procedures, material handling requirements
• Design Qualification (DQ)


  • A documented review of the design, at an appropriate stage in the project, for conformance to operational and regulatory expectation
  • Considers GMP's and regulatory requirements, reliability and efficiency, safety and environment impact, constructability and installation of equipment
• Performance Qualification (PQ)


  • A documented verification that all aspects of a facility, utility or equipment perform as intended in meeting pre-determined acceptance criteria
  • Considers actual product & process parameters, acceptability of the product, process repeatability, long term process stability
• Cleaning Validation


  Ensures that there is no cross contamination in a multi-product manufacturing plant and also prevents microbial contamination
• Types of Contamination to be considered in Cleaning Validation

  • Cross contamination
  • Microbial contamination
  • Contamination by cleaning or sanitizing agent
  • Contamination by other agents
• Types of Process Validation

  • Prospective Validation
  • Concurrent Validation
  • Retrospective Validation
  • Process Re-Validation
• Prospective Validation


  • Conducted prior to the distribution of either a new product or a product made under a modified production process, where the modifications are significant & may affect the product characteristics
  • Includes initial stages of formulation development & process development, setting of process sampling plans, designing of batch records, defining raw material specifications, transfer of technology from scale up to commercial size batches, environmental controls
• Concurrent Validation


  • A process where current production batches are used to monitor processing parameters
  • Gives of the present batch being studied, and offers limited assurance regarding consistency of quality from batch to batch
  • Examples include when a previous validated process is being transferred to a third party contract manufacturer or to another site, the number of batches produced are limited, process with low production volume per batch and market demand, the product is a different strength of a previously validated product with the same ratio of active or inactive ingredients
• Retrospective Validation


  • Conducted for a product already being marketed and is based on extensive data accumulated over several lots and over time
  • Only acceptable for well established detailed processes and will be inappropriate when there have recent changes in the formulation of the products, operating procedures, equipment & facility
  • Essential elements include batches manufactured for a definite period, number of lots released per year, master manufacturing/packaging documents, list of process deviations, corrective actions & changes to manufacturing documents, data for stability testing for several batches
• Process Re-Validation


  • Required when there is a change in any of the critical process parameters, formulation, primary packaging components, major equipment or premises
  • Examples include changes in raw materials, changes in source of active raw material manufacturer, changes in packaging material, changes in the process, changes in the equipment, changes in the plant/facility