FDA Publishes New Near Infrared (NIR) Guidance

Near infrared (NIR) analytical procedures are widely used in the pharmaceutical industry for identification testing and assay measurements performed on pharmaceutical starting materials, intermediates, and finished products, and for monitoring and controlling manufacturing processes. In this context, the U.S. Food and Drug Administration (FDA) has published a new Guidance for Industry entitled Development and Submission of Near Infrared Analytical Procedures.

According to the FDA, "the guidance provides recommendations to applicants to aid the development, validation, and use of near infrared (NIR)-based analytical procedures in evaluating the identity, strength, quality, purity, and potency of drug substances and drug products. The recommendations apply to new drug applications (NDAs), abbreviated new drug applications (ANDAs), and supplemental NDAs and ANDAs for small molecule drugs. The principles in this guidance also apply to drug substances and drug products covered in Type II drug master files." It is noted that the document "pertains only to the development and validation of NIR analytical procedures and does not provide recommendations concerning the setup, qualification, maintenance, or calibration of NIR instruments."

The 25-page document is divided into an introduction, a description of the background, six main chapters (Chapter III., IV., V., VI., VII., and VIII.), and a glossary.

The PDF document of the final guidance is available on the FDA's website.

General Modes of Measurement for NIR Implementation

Chapter III. of the document deals with modes of measurement commonly used for process understanding, monitoring, and control:

  • Off-line (the sample is analyzed away from the process stream or reactor)
  • At-line (the sample is removed, isolated from, and analyzed in close proximity to the process stream or reactor)
  • On-line (the sample is diverted to a side stream off the main manufacturing process and may be returned to the process stream or reactor)
  • In-line (the sample is not removed from the process stream or reactor)

In this regard, the guidance describes some specific features that applicants should consider during development when selecting the appropriate mode of measurement for NIR implementation.

Development of NIR Models

The following chapter (Chapter IV.) names and explains the steps that the development of a NIR model should include:

  • Construction of a calibration set
  • Presentation of samples
  • Development of chemometric models
  • Internal validation of identification libraries
  • Internal validation of quantitative calibration models
  • Development of rate-of-change models

External Validation of NIR Analytical Procedures

In Chapter V., it is pointed out that "applicants should perform validation after their chemometric models are developed. This validation is sometimes referred to as external validation. Internal validation of the chemometric model is not considered a substitute for external validation."

These introductory remarks are followed by explanations of how qualitative analytical, quantitative analytical, and rate-of-change procedures should be validated.

Implementing and Maintaining NIR Analytical Procedures

As a general rule, "applicants must ensure that NIR analytical procedures are appropriately followed, maintained, and updated as needed throughout the drug product's life cycle in accordance with CGMP requirements." According to the information given in Chapter VI., this requires that drug product manufacturers establish procedures to

  • Appropriately maintain hardware
  • Monitor calibration model predictions and model diagnostics to detect changes, including trends and shifts
  • Recognize circumstances that may warrant revision of the calibration model
  • Revise and revalidate the calibration model

Information Submitted in an Application

For NIR analytical procedures, applicants should provide information concerning

  • The purpose of the procedure
  • The analyzer and software specifications
  • The steps for the sample's analysis

Chapter VII. of the guidance also lists which information should be provided for the development of NIR analytical procedures concerning

  • Calibration and internal validation sets
  • Chemometric models
  • In-line or on-line methods
  • On-line and in-line methods for blending or mixing

For the validation of NIR analytical procedures, FDA expects at least the following information:

  • The external validation set
  • The specificity, linearity, accuracy, precision, and robustness of the quantitative procedures used
  • A validation of the qualitative method used, including testing for specificity of that method
  • The reference analytical procedure and its standard error
  • Data that demonstrate that the model is valid at commercial scale
  • The procedure's maintenance over the drug product's life cycle

Life Cycle Management

Chapter VIII. finally provides recommendations for the life cycle management, especially of how the potential impact of a change to the NIR procedure and the appropriate corresponding reporting mechanism can be evaluated.

A distinction is made between the following types of postapproval changes:

  • Major changes
  • Moderate changes
  • Minor changes
  • Other minimal changes

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