Paul Smith is EMEAI laboratory compliance productivity specialist at Agilent Technologies UK Ltd, 610 Wharefedale Road, IQ Winnersh, Wokingham, Berkshire RG41 5TP, United Kingdom, paul_smith@agilent.com

Paul Smith

Some parts of the United States Food and Drug Administration’s new draft guidance entitled “Development and Submission of Near Infrared (NIR) Analytical Procedures” are reviewed and critiqued here. What’s in it for spectroscopists?

	Near infrared (NIR) spectrometry as an analytical technique has been used in the pharmaceutical industry for a variety of analytical tasks during the past 25-30 years. Historically, NIR applications may have been based on filter-based instruments and the chemometric modeling technique of choice was multiple linear regression. The skill and time was in choosing the wavelengths to include in the regression model. This generally resulted in applications that were slow to develop, but which were relatively robust. Increased computerization power linked to the easy-to-use application of more-powerful chemometric models in the NIR software resulted in faster development of NIR applications, but like many other analytical techniques, does a user know what is happening inside the instrument and within the software?

	NIR is used within the pharmaceutical industry for the following purposes:

		 identification of raw materials using spectral libraries that are built in-house after the instrument has been  qualified and the software validated for intended use

		 off-line in laboratories or near-line in warehouses or other production areas

		 on-line or in-line production with process analytical technology (PAT) methods.

	Using classical infrared (IR) spectroscopy for sample identification, a sample would be taken and sent to the laboratory, then prepared for analysis. Historically, this involved preparing a Nujol mull, compressing the sample with potassium bromide to form a disk, or preparing a thin film. The sample is then presented to the instrument and a transmission IR spectrum is obtained. More recently, high-pressure attenuated total internal reflection (ATR) has become the sample preparation method of choice for IR identification (1) because it can significantly reduce variation in the IR spectrum caused by sample preparation (Nujol mulls and KBr disks are dependent on the user’s skill). ATR simplifies sample preparation, but it still requires an experienced analyst or spectroscopist to manually perform the comparison of the sample spectrum with the approved reference spectrum for the material. One important aspect of this approach is the need to interpret the sample results and the significance of any differences between the test and reference spectra. Additionally, pharmacopeia wording for identification by IR needs to be understood, because the wording typically implies that differences might be caused by the presence of an undetected polymorph in the test sample. Compare this approach to the use of a NIR system with an optic probe where a nonscientist may be working in a sampling booth in a warehouse. They insert a probe into a drum of material and within seconds the “computer says yes” and the identity is confirmed. All the science is now incorporated into the NIR library and with the spectroscopists who built and validated it for operational use.

	NIR analysis is fast when compared with IR, but there is the nonscientist operator versus the trained and experienced scientist to consider as well. At the heart of the discussion is the contrast between an organization investing in training analytical scientists to perform IR analysis versus investing in the NIR application software, selecting a model, and determining how a library has been built.

	NIR can be used in both qualitative and quantitative modes for identification and measurement of materials, respectively. Usually qualitative methods are deployed before quantitative ones because the former are easier to develop and validate.

	In March 2015, the United States Food and Drug Administration (FDA) issued a draft guidance for industry entitled “Development and Submission of NIR Analytical Procedures” (2). At 21 pages, the draft guidance is quite detailed and in this column, we will review and comment on some the contents of the document. Before we begin we just need to consider terminology-often we talk about analytical methods, but the guidance and the 

) refer to analytical procedure. Are they the same? No, is the short answer. An analytical procedure covers the whole process from sampling to calculating the reportable result, and the analytical method only refers to the instrumental analysis within the overall procedure.

	The draft guidance (2) covers the development, validation, submission, and maintenance of NIR analytical procedures. The document includes the following sections:

		Modes of measurement that could be implemented

		External validation of NIR analytical procedures

		Implementing and maintaining NIR procedures

		Information submitted in an application

					Figure 1: Diagram of the scope of the draft FDA guidance on NIR analytical procedures.

	The scope of the draft guidance is shown diagrammatically in Figure 1. As can be seen, the guidance divides into two main sections covering different ways of using NIR analytical procedures. There are off-line and at-line as well as process control and PAT procedures. The four terms are defined as follows:

: The sample is analyzed away from the process as in, for example, identity testing of raw material samples by NIR in the quality control (QC) laboratory or warehouse.

: The sample is removed from, isolated from, and analyzed in close proximity to the process stream or reactor. An example is measurement of tablet assay or content uniformity by NIR, where the NIR analyzer is located next to the tablet press and samples are fed manually or automatically to the instrument.

: The sample is diverted to a side stream off the main manufacturing process and may be returned to the process stream or reactor. An example is the measurement of cell density in an anaerobic fermentation process using a flow-through cell.

: The sample is not removed from the process stream or reactor. An example is in-line monitoring of blend uniformity by NIR, where the NIR analyzer is interfaced with the blender through a window and takes continuous spectral measurements.

	For the purposes of this column, we are restricting our discussion of the draft guidance to off-line or at-line analytical procedures because those are the main applications of NIR used in the pharmaceutical industry. Although NIR can be used quantitatively, we are focusing specifically on NIR used for the qualitative identification of materials, typically incoming raw materials such as active pharmaceutical ingredients (APIs) and excipients. In this situation, the spectrum of the material under test is compared to a composite spectrum of the same material generated over time. This requires that

		Sufficient numbers of reference materials and hence spectra are used to generate the composite spectrum that will be used to ensure positive identification.

		If one material is used from more than one supplier, then sufficient samples from each supplier need to be used to generate the reference spectra and allow for inter-supplier differences. From a spectroscopic perspective, it is better to have a single supplier of each material because the library build is simpler.

		If an organization holds retained samples, the question is which samples can be used to build a library because the storage conditions for retention samples are different than those for reference standards. Therefore, when do retained samples become too old to be useful to generate the reference spectra? There needs to be a process in place for identifying and using these samples to generate reference spectra.

	The guidance explicitly excludes any discussion of how to set up or qualify the instrument itself including any accessories that may be used such as an autosampler or a fiber-optic probe, but it does state the requirement to implement both instrument maintenance and the NIR procedure (for example, the calibration model). This aspect will come under the authority of 

 <1058> on analytical instrument qualification (AIQ) (3) for the approach and the individual chapters in the 

) for the details. The draft guidance also does not discuss which mode of measurement is best, such as transmission or reflectance, because measurement mode is in the domain of the developer of the analytical procedure. 

	Currently, there are general chapters for NIR in both the 

 <1119>, entitled “Near Infrared Spectrometry,” (4) covers a general introduction to the technique and then discusses the following aspects:

		Measurement modes-transmission and reflectance

		Instrumentation: equipment, NIR reference spectra, qualification of the instrument

		Method validation: validation parameters, on-going method evaluation and method transfer

 <1119> is currently an informational general chapter rather than a mandatory one. When revised, <1119> will be split into two general chapters: one that will be mandatory (

 <856>) and one that is best practice that is informational (

 <1856>) (6). The new mandatory chapter will contain the instrument parameters and tolerances for qualification and the process will be contained in the updated general chapter <1058>.

 2.2.40, strangely enough also entitled “Near-Infrared Spectrometry” (5), has the following sections:

		Qualitative analysis (identification and characterization)

	Although the chapter is only six pages long, it contains a lot of information that requires careful reading and interpretation.

	To keep the discussion to a reasonable length we have excluded publications on NIR from the Therapeutic Goods Administration (TGA), World Health Organization (WHO), and Japanese Pharmacopoeia (JP). As Smith and Sellors (1) note for Fourier transform infrared (FT-IR) spectroscopy, training is essential to ensure compliance with pharmacopeial requirements and that differences between monographs and regulatory agency guidance are taken into account when developing analytical procedures. The same is also true for NIR methods.

Qualification, Validation, and Verification

	Fitness for intended use is a mandatory requirement of any instrument and associated software (7). The first part of this process is the qualification of the instrument coupled with the integrated validation of the associated software and is shown as the bottom two layers in Figure 2. However, these steps are only part of the overall process for fitness of purpose when using NIR for identification. The second, and most important, part is building, validating, and maintaining the spectral libraries used for the identification of materials. This process is shown in the top section of Figure 2 with the selection of the calibration model to be used and the discrimination required (what is the number and structure of compounds to be included in the library and how close are they in structure?). From these two elements of information, the number of libraries that would be required can be deduced. Additional factors are the number of suppliers of each material coupled with batch consistency: only one supplier producing a consistent product is easier to handle than multiple suppliers of the same product where different manufacturing processes produce differences in NIR spectra. Validation of the library is discussed later in this column.

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