Leaning on NIR in Pisa

The utilization of near-infrared (NIR) spectroscopy for quality control (QC) of pharmaceutical tablets has become increasingly widespread over the past decade. This is due in part to stricter regulatory control of QC in drug manufacturing, but also the increasing realization that it may no longer be practical to use a wide range of testing methods within one plant.

Chapter 5.30 of the Good Manufacturing Practice (GMP) guidelines specifies that a pharmaceutical company must “…provide suitable procedures or measures to guarantee the identification of the material contained in each recipient.” [1] Traditionally, companies used a number of different analysis methods for raw materials testing, as suggested in early versions of Pharmacopoeia methods. However, regulatory guidelines now advocate that nearinfrared spectroscopy may be the best universal method for raw material testing.

Characterizing Raw Materials

Raw material analysis is an essential process in any pharmaceutical manufacturing laboratory. According to Annex 8, EU GMP:

“…the identity of a complete batch of starting materials can normally only be ensured if individual samples are taken from all the containers and an identity test performed on each sample…It is permissible to sample only a proportion of the containers where a validated procedure has been established to ensure that no single container of starting material has been incorrectly labeled …” [2]

In compliance with GMP guidelines, identification of the raw materials must be executed on each API and excipient. Since most pharmaceutical manufacturing laboratories receive many raw materials and the number is only getting bigger, this can be a difficult job in terms of time and cost.

Regulatory Guidance

Prior to the European Pharmacopoeia 5th edition (2002), there was no universal method recommended by pharmaceutical guidelines relating to raw materials analysis. Different methods were specified for each raw material to be identified — a time-consuming process. It also was costly, not only the outlay for different instruments, reagents and other chemicals, but also the decreased productivity of laboratory instruments and personnel.

Traditionally, raw material identification was performed on a statistical basis, where only a certain percentage of each batch would be analyzed. However, regulations now require the identification of every single container of each batch of raw materials, regardless of whether they are actives or excipients. The only exceptions to this requirement are sucrose, talc and sodium chloride.

Additionally, when using traditional Pharmacopoeia methods for raw material analysis, more than one test may be mandated. For example, when analyzing lactose, it may be necessary to use IR (infrared) spectroscopy, thin layer chromatography and melting point analysis.

It is evident that where there are many raw materials to be analyzed, using multiple analytical methods isn’t practical. There are three possible solutions: mandating that suppliers provide larger sized containers, validating suppliers or finding an alternative method of analysis.

NIR Spectroscopy

Several recently revised sets of guidelines advocate NIR spectroscopy as a universal method for the identification of raw materials:

• European Pharmacopoeia 5 (2005), p. 59
• EMEA – CPMP/QWP/3309/01 and EMEA/CVMP/961/ 01: Note for Guidance on the use of near-infrared spectroscopy by the pharmaceutical industry and the data requirements for new submissions and variations, EMEA, London, 2003.
• USP 29 (2006), p. 2979. “…NIR spectroscopy is a well established technique in the food, chemical . . . and petrochemical industry, and has now also been used for many years in the pharmaceutical industry. The technique appears to be useful for the identification and assay of pharmaceutical substances, the identification and assay of such substances in the finished products, as well as for in-process control and for monitoring purposes.” [3] —EMEA, Note for Guidance

Identifying a substance with NIR spectroscopy is based on a comparison between the spectral data of the substance being analyzed and the spectral data of multiple samples of batches in a reference library. Chemometrics should be used to compare the data and derive conclusions.

For raw material characterization, NIR spectroscopy has been found to have some unique benefits. It enables analysis of the starting material in the original packaging without opening the primary container, reducing the risk of cross-contamination and abolishing the need to conduct the analysis within a designated area. NIR spectroscopy reduces the time down to roughly two minutes for each analysis and can be used from pilot- to production-scale blenders in order to follow the development of a pharmaceutical product.

The method can be used to collect high-quality reflectance spectra of both the active ingredient and excipients, and is sensitive to both the chemical and physical properties of the powder blend. It can also be beneficial within pharmaceutical manufacturing, as it is non-contact and non-destructive, highly reproducible, rapid and does not require any sample preparation.

Within a pharmaceutical plant, NIR spectroscopy can be carried out at multiple stages in the manufacturing process — in the raw materials warehouse, the dispensing area or the QC lab. When using NIR spectroscopy, each company must choose its own “best place” to locate the analyzer.

If the analysis is carried out in the warehouse (Figure 2, p. 42), no sampling is required by GMP guidelines, so the time for analysis is reduced. In addition, because raw materials analyzed in the warehouse do not have to be transported for analysis, workflow is improved.