APR September/October 2020 - 76

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MANUFACTURING

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Operating Parameters

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Reagents/Standards

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Sample Preparation

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Standards Solution Preparation

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Procedure

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System Suitability

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Calculations

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Data Reporting

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Reference Standards and Materials

due to the frequent changes in the drug substance manufacturing
process and the drug product formulation. Therefore, analytical
methods are frequently being updated and re-validated to ensure the
suitability of the method for its intended use. In addition, the number
of testing samples is small and performed by a few analysts in a single
lab. Therefore, limited validation may be appropriate in the early
phases. As the manufacturing process and formulation are decided in
late development, complete method validation is required. Figure 2
lists a typical flow of validation parameters to be studied based on the
phase of product development.14

Reference Standards and Materials
Reference standards play a critical role in any analysis. In HPLC analyses,
reference standards are used for identification and quantitation. Each
company must have an SOP to guide the qualification, distribution,
and maintenance of reference standards. Reference standards must be
fully characterized, and the impurities profiles must be determined and
tracked using appropriate testing. Companies can use commercially
available reference standards or qualify their secondary standards for
volume testing.

Performance of the
Chromatographic Method
Typically, the system suitability is established according to USP General
Chapter <621>. Validation data are used to establish the acceptance
criteria for the system suitability test (SST). It is recommended that
system suitability should be designed with commercially available
reagents, solvents, or standards.
When the method is transferred to a Quality Control (QC) or a contract
lab, the critical parameters of the methods must be well studied to
understand the performance of the method at the receiving lab. It
is recommended that SST data be evaluated and trended to detect
potential deviations prior to system failure.13

Validation by Phases
Several global guidelines require that full validation be completed for
the analytical method prior to the testing of the first registration batch.
Method validation is also expected during drug development. However,
the expectation at the early phase of method qualification is more
relaxed than in the later phases (IIb or III) or when the first registration
batch is manufactured. These phase-appropriate expectations are
appropriate because the analytical method is evolving and based on
the risk involved. Critical parameters should be studied to ensure that
the test is suitable to release and monitor clinical supplies. The current
trend of validation activities is a risk-based approach to determine the
critical validation parameters at each phase of development. In the
early development phases, the sample matrix is frequently changing

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Figure 2. Analytical Method Validation by
Phases of Development

Changes to the Analytical Methods
Many regulatory guidance documents indicate that validation is
a process, which makes the validation report a living document. It
is important to understand that the analytical procedure used for a
specific test must be proven suitable for its intended purpose and
demonstrated through validation. The validity of a specific method
must be demonstrated in the laboratories; therefore, method
validation must be fully completed prior to being used routinely in the
Quality Control laboratories for release or stability testing. Whenever
the method or the test sample is changed outside of the original scope
of the method, validation must be reviewed to ensure the procedure
continues to function as intended. Different method validation
parameters may be reevaluated to accommodate the change. These
changes are tracked with a change control program and properly
characterized. Table 2 lists some specific changes that may cause
method revalidation.12,15
Table 2. Reasons for changes to an Analytical Procedure
1. Synthetic process change
2. Formulation change
3. Out-of-Specification investigation
4. Specificity problem (e.g., new impurity)
5. Ruggedness issue
6. Post-approval changes (e.g., site change)
7. Improving method performance
8. Modification of method parameters to improve robustness

| September/October 2020

10/2/20 11:45 AM
APR September/October 2020

Table of Contents for the Digital Edition of APR September/October 2020
