For Pharmaceuticals:

The Food and Drug Administration (FDA), International Organization for Standardization (ISO), European and other regulatory authorities have requirements and expectations regarding the performance and documentation of an analytical method validation.

Method validations are required when a new method is developed, an existing method is significantly modified (optimized) or an existing, validated method is applied to a different sample matrix. These methods may include HPLC, GC, GC/MS, UV-Visible, FTIR, titration, etc. Additionally, many wet chemistry (non-instrumental) methods require some level of verification or validation.

There must be assurance that "the accuracy, sensitivity, specificity, and reproducibility of test methods employed by the firm are established and documented." (CFR Title 21-Part 211).

The FDA and other regulatory authorities have cited organizations for not providing assurance that their test methods have been appropriately validated or verified. Many firms use USP methodology for routine analyses but fail to verify that the methods are "suitable for their intended use." A few examples of key regulatory findings include:

• Company A - Failure to have laboratory controls which establish scientifically sound and appropriate specifications, standards, and test procedures to assure product identity, strength, purity, and quality.
  • What does this mean?
    • There was no "proof" that the test methods used for product disposition decisions had been properly validated.

• Company B - "The test methods performed for Product A have not been verified to ensure suitability under actual conditions of use."
  • What does this mean?
    • The firm was using USP methodology without any verification of suitability.

Executing validation activities is not a one-step process. Considerations must be made prior to execution. There are key points to consider prior to, during, and after completion of a validation including the following:

• a. Understand the requirements (i.e., the validation characteristics required for the sample matrix).
  • i. Understanding the expectation is key to a successful validation.

• a. Test method is "ready" for validation.
  • i. Method development should not occur at this time. If there is a need for continued method optimization, your method is NOT ready for validation.
• b. Analyst must be qualified, has demonstrated proficiency and clearly understand how to perform a method validation.
• c. Instruments/Equipment is in a "qualified state."

• a. When is verification applicable and when is a validation required?
  • i. Not all validation characteristics are required for verification of a validated test method or USP compendial procedure.
  • ii. An assessment must be made to determine if a validation is required.
• b. Many firms struggle with determining when a re-validation is or is not required after optimization/modification of a test method.
  • i. Method Modification - "Any adjustment to operating conditions outside of the test method and operating parameters identified as a result of the test method validation."
  • ii. Re-validation is required when the:
    • 1. Change/new parameter is outside of the operating range.
    • 2. Sample matrix has changed.
    • 3. Instrument type has changed.
      • a. VWD versus DAD
      • b. NPD versus FID

• a. Quantitation of major components (Category I)
• b. Determination of impurities in bulk drug substances (Category II)
• c. Determination of performance characteristics (dissolution) (Category III)
• d. Identification Tests (Category IV)

• a. Accuracy
• b. Precision
  • i. Reproducibility
  • ii. Repeatability
  • iii. Intermediate Precision (Ruggedness)
  • iv. Instrument Precision
• c. Specificity
• d. Selectivity
• e. Limit of Detection
• f. Limit of Quantitation
• g. Linearity
• h. Range
• i. Robustness
• j. Ruggedness

• a. System Suitability - Used to verify that the resolution and reproducibility of the chromatographic system are adequate for the analyses performed.
• b. Solution Stability - Determines the stability of the solution after preparation in accordance with the test method.
  • i. Consideration must also be given to reagents, chemicals, mobile phase, etc.
• c. Stress Testing - Demonstrates the specificity of the assay and analytical procedures for impurities. We need to ensure that "no interference with quantitation is evident from impurities and degradants from the active ingredient and excipients."

• a. Key elements:
  • i. Introduction
  • ii. Scope
  • iii. Summary of Results
  • iv. Pre-validation activity (pre-requisites)
  • v. Detail of all relevant materials, chemicals, reagents, etc.
    • 1. Mfr. Lot#, Purity, Expiry, etc.
  • vi. Listing of all instruments/equipment
  • vii. Reference Standards
    • 1. Sample and Blank Preparations
  • viii. Test Method Detail (may also be an attachment)
  • ix. Detail of each Validation Characteristic
  • 1. Data Presentation (Table Format)
  • x. Protocol Exceptions (if applicable)
  • xi. Copies of key representation plots, chromatograms, etc.
  • xii. Representative Calculations
  • xiii. Approvals
  • xiv. Protocol (Attachment)

In summary, there are many things to consider prior to executing a method validation.

A method validation protocol must be in place with the appropriate Quality and Management approvals.

All validation activities and results should be documented in a Method Validation Summary Report and approved by Quality and Management.

Remember the requirements:

• "The accuracy, sensitivity, specificity and reproducibility of test methods employed by the firm shall be established and documented." (CFR 21-Part 211)
• "The method developed shall have been validated appropriately before use." (ANS/ISO/IEC 17025:2005(E))

Michele H. Piepoli has more than 35 years experience in the pharmaceutical industry, including 20 years in management. She currently serves as Managing Director of MHP Consultants, LLC, a consulting organization with emphasis in the Pharmaceutical and Medical Device Industry. Michele has led domestic and international projects ensuring completion of regulatory commitments. Her areas of expertise include quality/compliance, laboratory excellence and process improvement. She regularly presents compliance training seminars, conducts facility audits and plays a key role in the development and implementation of quality systems. Michele has been instrumental in making successful recommendations for remediation of critical health authority findings.

A certified instructor for Agilent Technologies, her technical depth includes: High Pressure and Gas Chromatography, Fourier Transform Infrared and UV-Visible Spectroscopy, Analytical Method Development/Validation and Instrumentation Validation. Michele has been instrumental in leading efforts to improve the quality of Laboratory and Manufacturing Investigations resulting in significant deviation reduction.Contact Michele Piepoli at 770-587-0743 or at solutions@mhpconsultants.com.

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