The IQ requirements provide evidence that the hardware and software are properly installed in the desired location.

Because the majority of mid-IR spectra are measured with Fourier-transform IR (FTIR) spectrophotometers, only these instruments will be discussed. [Note—No recommended values for signal-to-noise ratio or 100% line stability are included in this chapter because these vary with manufacturer, model, and age of the instrument. ]

The purpose of performance qualification (PQ) is to determine that the instrument is capable of meeting the user's requirements for all the parameters that may affect the quality of the measurement.

Certain powdered alkali halides such as potassium bromide, potassium chloride, and caesium iodide coalesce under high pressure and can be formed into self-supporting disks that are transparent to mid-IR radiation. The alkali halide most commonly used is powdered, dry, highly pure potassium bromide, which is transparent to mid-IR radiation above 400 cm1.

Commercial presses and dies in a range of diameters are available for the preparation of alkali halide and similar disks.

A typical procedure to prepare a mull is to place 10–20 mg of the sample into an agate mortar, and then grind the sample to a fine particle-size powder using a vigorous rotary motion of the pestle. A small drop of the mulling agent is added to the mortar. Rotary motion of the pestle is used to mix the components into a uniform paste, which is transferred to the center of a clean IR-transparent window (e.g., potassium bromide, sodium chloride, silver bromide, or caesium iodide). A second matching window is placed on top of the mull, and the mull is squeezed to form a thin, translucent film that is free from bubbles.

The most widely used mulling agent for the mid-IR region is a saturated hydrocarbon mineral oil (liquid paraffin, Nujol).

The mid-IR transmission spectrum of many polymers used as packaging materials is at times recorded from samples prepared as thin self-supporting films using hot compression molding or microtoming.

Nonvolatile liquids can be examined neat in the form of a thin layer sandwiched between two matching windows that are transparent to mid-IR radiation. The liquid layer must be free of bubbles and must completely cover the diameter of the IR beam focused on the sample.

For the examination of liquid and solution samples, transmission cell assemblies that comprise a window pair, spacer, filling ports, and a holder are available commercially in both macro- and micro-sample configurations.

For laboratory applications, spacers typically are formed from lead, poly(tetrafluoroethylene), or poly(ethylene terephthalate) and can be supplied, depending on spacer materials, in standard thickness path lengths from approximately 6 µm to 1 mm or larger.

Mid-IR transmission cells for static or flow-through gas and vapor sampling are available in a wide range of materials to suit the application, from laboratory to process scale. In the laboratory, the traditional gas cell has been a 10 cm long cylinder made from borosilicate glass or stainless steel with an approximately 40-mm aperture at each end. Each open end is covered with an end cap that contains one of a pair of mid-IR–transparent windows constructed from, e.g., potassium bromide, zinc selenium, or calcium fluoride.

Attenuated total reflectance spectroscopy relies on the optical phenomenon of radiation passing through a medium of high refractive index at a certain angle of incidence entirely reflected internally at a boundary in contact with a material of lower refractive index. The medium of high refractive index is also known as the internal reflection element (IRE).

The sample under examination should be placed in close contact with the IRE such as diamond, germanium, zinc selenide, or another suitable material of high refractive index. Ensure close and uniform contact between the substance and the whole crystal surface by applying pressure in the case of solid samples or by dissolving the substance in an appropriate solvent and then covering the IRE with the solution and evaporating to dryness.

The most important and commonly used form of sample preparation for diffuse reflection is to dilute the sample by intimately mixing it with 90%–99% of nonabsorbing diluents such as finely powdered potassium bromide or potassium chloride. The sample dilution has the added benefit of reducing absorption band intensities to an appropriate level.

Coupling a light microscope with a mid-IR spectrophotometer allows spectra to be obtained from very small samples. Generally applied in transmittance or reflectance modes, it provides, for example, a powerful tool for obtaining spectroscopic data of contaminants in pharmaceutical samples.

Validation is required when an IR method is intended for use as an alternative to the official procedure for testing an official article.

The objective of an IR method validation is to demonstrate that the measurement is suitable for its intended purpose including: quantitative determination of the main component in a drug substance or a drug product (Category I assays), quantitative determination of impurities or limit tests (Category II), and identification tests (Category IV, see Table 2 in Validation of Compendial Procedures 1225). Depending on the category of the test, the validation process for IR may require the testing of linearity, range, accuracy, specificity, precision, detection limit, quantitation limit, and robustness. If the IR procedure employs a chemometrics model calculated against the response of another analytical technology (e.g., HPLC), then the principles of Near-Infrared Spectroscopy 1119, specifically the Method Validation section, is to be applied.

Chapter 1225 provides definitions and general guidance on analytical procedures validation without indicating specific validation for each characteristic. The following sections are intended to provide the user with specific validation criteria that represent the minimum expectations for this technology. For each particular application, tighter criteria may be needed in order to demonstrate suitability for the intended use.

U.S. Current Good Manufacturing Practices regulations [21 CFR 211.194(a)(2)] indicate that users of analytical procedures described in USP–NF are not required to validate these procedures if provided in a monograph. Instead, they must simply verify their suitability under actual conditions of use.

The objective of an IR procedure verification is to demonstrate that the method, as prescribed in specific monographs, is being executed with suitable accuracy, sensitivity, and precision. Verification of Compendial Procedures 1226 notes that if the verification of the compendial procedure, according to the monograph, is not successful, the procedure is not suitable for use with the article under test. It may be necessary to develop and validate an alternative procedure as allowed in General Notices and Requirements 6.30.

Although complete revalidation of a compendial procedure is not required, verification of the compendial Mid-IR procedure includes the execution of certain critical parameters. When the method being verified is for identification purposes, specificity is the only parameter required. For quantitative applications, additional validation parameters are studied. Typically these include accuracy, precision, and quantitation limit, as indicated in Validation.USP38