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NIR spectroscopy: a 21 CFR Part 11 compliant tool for QC and product screening

NIR spectroscopy: a 21 CFR Part 11 compliant tool for QC and product screening

Pharmacology: a brief history

Our search for medicines is nearly as old as humanity itself. Medicinal ingredients from plant, mineral, and animal sources were used for healing purposes since the earliest of advanced civilizations. Herbal remedies from China date back to a couple of thousand years ago, while indigenous populations have been relying on environmental sources for healing for several millennia. Systematic descriptions of medicines have been handed down to us from the ancient Greeks and the Roman Empire, laying a foundation for contemporary pharmacology. It was not until the 16th century that the science began its departure from the models passed down from antiquity.

The path to developing synthetic drugs began with the emergence of organic chemistry at the beginning of the 19th century. Although drug therapies had been limited to naturally occurring substances and inorganic compounds up to that point, this changed with the targeted production of organic synthetic drugs based on substances isolated from medicinal plants. Within a very short period, this led to a vast number of synthesized active pharmaceutical ingredients (APIs). Researchers had finally come to understand the relationship linking the action of these substances to their chemical structures.

Pharmaceutical analysis provides information about the identity, purity, content, and stability of starting materials, excipients, and APIs. Medicinal products come in various forms (e.g., ointments, tinctures, pills, lotions, suppositories, infusions, sprays, etc.) and consist of the active substance and at least one pharmaceutical excipient. Impurities are mainly introduced during the synthesis of the active ingredients.
According to the World Health Organization (WHO), specifications and test methods for commonly used active ingredients and excipients are outlined in detail in monographs contained in the national pharmacopoeias of more than 38 countries. The pharmacopoeias are official compendia containing statutory requirements pertaining to identity, content, quality, purity, packaging, storage, and labeling of active pharmaceutical ingredients and other products used for therapeutic purposes. They are essential for anyone seeking to produce, test, or market medicinal products.

Near-infrared spectroscopy—a 21 CFR Part 11 compliant tool to assess the quality of pharmaceuticals

Near-infrared spectroscopy (NIRS) has been an established method for fast and reliable quality control within the petrochemical industry for more than 30 years. However, many companies still do not consistently consider the implementation of NIRS in their QA/QC labs. The reasons could be either limited experience regarding application possibilities or a general hesitation about implementing new methods.

However, the advantages of NIRS are numerous, such as the ability to measure multiple parameters in just 30 seconds with no sample preparation! The non-invasive light-matter interaction used by NIRS, influenced by physical as well as chemical sample properties, makes it an excellent method for the determination of both property types.

In the remainder of this post, we will indicate where NIRS technology can be used in the pharmaceutical production process and what parameters can be analyzed. Furthermore, we present proven applications developed according the NIRS implementation guidelines of ASTM E1655 (quantitative method development) and ASTM E1790 (qualitative method development).

For more detailed information about NIRS as a secondary technique and NIRS as a QC tool for pharmaceuticals, please read our previous blog posts.

NIRS compliance with international pharmacopoeias

As a secondary test method, NIRS is recommended in all the key pharmacopoeias – European (Ph. Eur. 2.2.40) as well as American (USP<856/1856>) and Japanese pharmacopoeias (Chapter 6, since 2007).

All Metrohm NIRS instruments are fully compliant with USP <856/1856> and all the other key pharmacopoeias. Furthermore, all Metrohm NIRS instruments meet the standards for wavelength precision, reproducibility, and photometric noise. Numerous reference standards and user-friendly software make it easy to check the instrument requirements specified in the pharmacopoeias. The pharmaceutical version of the Vision Air software is fully validated and compliant with 21 CFR Part 11.

Find out more about Metrohm NIRS instruments for laboratory and process analysis below.

Where can NIRS be used in pharmaceutical manufacturing processes and what parameters can be analyzed?

NIRS is an indispensable analysis technique that can be used along the entire production chain: from checking the incoming materials to the production line, even to the quality control of finished products. A typical pharmaceutical tablet production process is shown in Figure 1 with markers noting where NIRS can be implemented.

Figure 1. Illustration of a pharmaceutical tablet production plant with NIRS used all along the process.
Typical NIRS applications at the different stages of the pharmaceutical production process are outlined in Figure 2.
Figure 2. NIRS analysis can be used at several points in the pharmaceutical manufacturing process for many types of applications.
Relevant application notes can be found on the Metrohm website.

Applications and parameters for NIRS in pharmaceutical production

NIR spectroscopy is the fast solution for determining myriad parameters simultaneously in almost any sample matrix. In addition, this technique requires no sample preparation, and it is non-destructive. Table 1 contains a list of different administered forms of medications given with commonly measured parameters and related materials to download for more information.

Table 1. NIRS can be used to determine several parameters in many kinds of administered forms of pharmaceuticals.
Substance form Parameter Conventional method Related NIRS Application Notes
Powders or granulates API, Moisture HPLC / GC / KF titration AN-NIR-018

AN-NIR-014

Tablets and capsules API, Content uniformity, Moisture content, Dissolution profile HPLC / GC / KF titration AN-NIR-073

AN-NIR-066

AN-NIR-063

AN-NIR-017

Creams or gels API, Moisture content HPLC / GC / KF titration AN-NIR-020
Solutions or suspensions API HPLC / GC AN-NIR-088

AN-NIR-076

Injectables API HPLC / GC AN-NIR-042
Lyophilized products Moisture content KF titration AN-NIR-078
Following are a few examples of successfully implemented NIRS applications at numerous pharmaceutical companies worldwide.
Incoming (raw) material inspection

Raw material identification and qualification, shown in Figure 3, is one of the most mature applications in the pharmaceutical industry. Good manufacturing practice requirements demand that every single package unit that arrives in the warehouse needs to be checked.  Therefore, a rapid analytical technology as NIR spectroscopy is needed to measure many samples in a short period of time. NIRS is a general accepted alternative method by the USP.

Figure 3. Raw material inspection by NIR spectroscopy.
NIRS is an ideal analytical method for raw material inspection:

  • identify tests of APIs, excipients, packaging
  • quantitative control of materials (e.g., moisture)
  • GMP Requirement to test 100% of raw materials
  • quality control of materials (e.g., supplier, particle size, dyes)
Blending

Blending of APIs and excipients can be easily monitored without sample destruction by NIRS (Figure 4). This application focuses on the standard deviation between consecutive spectra. As the blending proceeds, the differences between consecutive spectra will become smaller and smaller, approaching unity. This parameter indicates when the blend is homogeneous. This information is important for operators to optimize the blending time and consequently increase the blending capacity of a facility.

Figure 4. Blending of APIs and excipients is easier to monitor with NIRS.
NIRS is an ideal analytical method for blending processes:

  • determination of blend homogeneity
  • sample spectra statistically compared to library of well blended material
  • optimized blending for improved operation of next production steps
Learn more about the Metrohm NIRS DS2500 Analyzer here.
Lyophilized products

Moisture determination in lyophilized products is an ideal application for NIRS (Figure 5). Typical water content of lyophilizates is somewhere between 0.5% and 3.0%. For many pharmaceutical lyophilized products, this value must be lower than 2.0%. Water is a strong NIR absorber, so detection limits are low and the demands of the pharmaceutical industry can be easily met.

Primary methods like loss on drying (LOD) or Karl Fischer titration are typically time-consuming, especially compared to NIRS (data in seconds). These samples have a relatively high value combined with a low moisture content. NIRS analysis only illuminates the sample so the same sample can be used for compendial analysis without any damage. This application has a quick return on investment (ROI) due to the high sample frequency.

Figure 5. Moisture determination in lyophilized products with NIRS is fast and cost-effective compared to other techniques.
NIRS is an ideal analytical method for measuring moisture in lyophilized products:

  • samples can be easily altered to provide calibration sets with varying amounts of moisture
  • complete analysis takes less than one minute and is non-destructive
Tablet analysis

When analyzing intact tablets with a NIR spectrometer, it is important to measure them in diffuse transmission mode. This illuminates a larger sample big portion and investigates the inner composition of the tablet (Figure 6). Measuring the same tablet in reflectance mode will gather the information from the outside coating of the tablet due to the low penetration depth. Content uniformity parameters are measured within a minute, and the tablet trays allow unattended measurement of up to 30 tablets.

Figure 6. NIRS allows fast determination of API content in intact tablets.
Learn more about the differences in NIRS measurement modes in our previous blog post.

Summary

Near-infrared spectroscopy has long been one of the most important and versatile analytical techniques in the pharmaceutical industry. The biggest benefit of using NIRS is the possibility of obtaining reliable analysis results in just seconds without any sample preparation or reagents required.

The pharmaceutical version of Vision Air software from Metrohm is 21 CFR Part 11 compliant and compatible with third party method development software like Unscrambler.

For more information

About spectroscopy solutions provided by Metrohm, visit our website!

We offer NIRS for lab, NIRS for process, as well as Raman solutions

Post written by Wim Guns, International Sales Support Spectroscopy at Metrohm International Headquarters, Herisau, Switzerland.
Five myths about online dispersive NIR spectroscopy, FT-NIR, and FT-IR – Part 1

Five myths about online dispersive NIR spectroscopy, FT-NIR, and FT-IR – Part 1

Spectroscopy is not just spectroscopy—or is it?

When talking with our project partners and customers, the topic of near-infrared (NIR) spectroscopy is often automatically associated with FT-NIR spectroscopy. So, why isn’t it just called NIR? What is the difference between IR and NIR? Some of you might even wonder: “Can I replace an old IR analyzer with NIR hardware?” And additionally: “Why should I replace the IR with a NIR process analyzer?”

This two-part series aims to explain the differences between these techniques and dispel some myths.

Click below to jump directly to a section:

A brief historical overview

Wavelengths

The NIR wavelength range has a long history. As early as the 1880s, organic components were investigated in the NIR range and the strong –OH band relating to the presence of water was discovered as a very important piece of information. Shortly after, measurement of oils from the agricultural industry and investigations into various polymers followed. Some of the first industrial applications of dispersive NIR spectrometers were in the food and agricultural industries. In such applications, parameters including moisture, protein content, and fat content were analyzed quantitatively.

On the other hand, some strong advantages came from using the infrared (IR) wavelength range—high structural sensitivity and specificity—making it possible to obtain precise fingerprints for structural identification.

Figure 1. Historical punch card for assigning various spectral features to acetyl chloride in the infrared wavelength region [1]. (Click to enlarge image)
For more information about the differences between IR and NIR spectroscopy, read our previous blog posts.
Hardware

The hardware for NIR and IR analysis was fundamentally different. At that time, even though the evaluation of NIR spectra seemed to be too difficult and ambiguous due to the broad overlapping peaks, there was one major advantage: robust and cheap materials could be used for NIRS (e.g., PbS detectors, tungsten lamps, and simple glass materials for the optics). Since the NIR-bands were broad and overlapped, users were limited to only the essential information and therefore did not need higher resolution, so simple dispersive gratings (monochromator gratings) were sufficient.

For IR, Fourier transform infrared spectrometers (FT-IR) were used which operated based on Michelson interferometers. This was necessary to obtain the spectral resolution needed for structural interpretation (e.g., distinguishing the isomers 1-propanol and 2-propanol at about 2700 nm for the first time). These spectrometers were introduced to the market in the 1960s. Due to the high costs for interferometers, special optics, and lasers, they were mainly used for research purposes.

Software

Significant progress has been made in the field of spectroscopy due to the development of more powerful computers in the 1980s and 1990s in combination with chemometrics. While IR spectroscopy, due to its high data point density, was still far behind in the application of computer-based chemometric methods, NIR spectrometers were already able to benefit from fast evaluation methods.

Chemometric tools combined with the hardware benefits of NIR technology led many manufacturers to transfer their existing FT-IR measurement technology to the NIR range. And other companies? They just used and improved their already existing measurement technology to achieve perfect synergy between spectrometer and chemometrics.

Now that some of the background has been laid out, it’s time to answer some myths about NIR, FT-NIR, and FT-IR spectroscopy.

Myth 1: NIR spectroscopy always means FT-NIR

This is a persistent myth that you could easily miss unless you look closely. What exactly does the «FT» mean and why doesn’t everyone use it to describe NIR spectroscopy?

When using a FT-NIR spectrometer, first an interferogram is generated—not a spectrum in that sense. The conversion of the interferogram into a spectrum is done by applying a mathematical operation, the Fourier transform (FT). This transforms the path-dependent information (e.g., relative mirror position of two mirrors in the spectrometer) into a frequency-dependent function. This means FT-NIR is nothing more than the methodology of generating the spectrum in the NIR wavelength range.

As before, it is NIR spectroscopy that provides the same information as dispersive NIR spectroscopy or diode array spectroscopy. FT-NIR uses the interferences produced by an interferometer to extract single wavelengths from white light (halogen lamp), while dispersive spectrometers use gratings. Gratings are produced by very modern lithographic techniques and offer the highest precision (of wavelength accuracy).

Table 1. Comparison of FT-NIR and dispersive NIR spectroscopy

Parameter FT-NIR NIR
Wavelength splitting Mathematical calculation (Fourier transformation) from the phase shift of two incident light beams (interferogram) Diffraction or dispersion, movement by a digital encoder
Resolution depends on… Setting the maximum offset of the moving mirror Number of lines of the monochromator grid, slit width, encoder quality
Moving elements Yes (motor of the interference mirror) Yes (motor of the grid)
Wavelength range 12500 cm-1–4000 cm-1

(800–2500 nm)

800–2500 nm

(expandable to 400 nm)

Noise Depending on the resolution, higher than dispersive NIR with comparable setup Depending on the resolution, lower than FT-NIR with comparable setup
Method transferability (i.e., to other spectrometers) Yes Yes (due to the Metrohm calibration concept)

 

Consumables Laser source, halogen lamp, and desiccant Halogen lamp
Compared to a dispersive analyzer, a FT-NIR spectrometer uses a laser to control the position of the interferometer mirror. This laser must be changed periodically, however this task is generally not done by the end-user themselves compared to halogen lamp, which is easily replaceable.

Looking a little bit deeper into the details of Table 1, it is clear that dispersive spectroscopic instruments are more suitable for industrial process applications. Why? A low acquisition time is critical for real-time measurements with the least time loss. Compared to a FT-NIR instrument, the acquisition time is lower for a dispersive analyzer (leading to faster results) at the same resolution.

If you have ever wondered why you might need to calculate a Fourier transform, you will know after the next myth is answered.

Myth 2: Method transfer is only possible with FT-NIR spectrometers and not with dispersive spectrometers

Where does this myth originate?

Visualize the internal structure of an interferometer. A He-Ne laser is used as the reference measurement for the precise determination of the mirror position and thus also obtains an exact spectrum with high wavelength reproducibility at the same spatial coordinate by the Fourier transformation.

What is different about the dispersive spectrum?

In this case, the spectrum is not calculated in a mathematically complex way but is recorded directly via the dispersing element (the monochromator) on the detector. Here, a high-resolution state of the art grating and an accurate digital encoder that is precisely matched with the detector play an important role. NIRS XDS Process Analyzers from Metrohm Process Analytics (Figure 2) use wavelength standards to achieve both high wavelength precision and reproducibility and to ensure the transferability of the developed method.

Figure 2. The NIRS XDS Process Analyzer from Metrohm Process Analytics. 
Wavelength Precision <0.015 nm Valid
975.880 nm 0.0012 nm Yes
1221.342 nm 0.0005 nm Yes
1678.040 nm 0.0012 nm Yes
Figure 3. Results of the wavelength reproducibility test of a NIRS XDS Process Analyzer during a performance test. The precision meets the very narrowly defined testing specifications.
By using a wavelength and reference standard built into the spectrometer, additional diagnostics can be carried out at routine intervals (either as part of maintenance or automated within regular process operation) to check the wavelength accuracy and precision.

Due to the standardization concept with reference standards and wavelength standards, methods can be transferred without much effort even when changing or adjusting accessories (e.g., longer optical fibers, partially changed probes).

To summarize: a good standardization concept with NIST certified reference and wavelength standards as well as internally installed standards allow robust method transfers to other spectrometers and excellent long-term stability in the production process.

Myth 3: Many applications cannot be measured with dispersive NIRS, but require well-resolved FT-NIR spectroscopy

The Michelson interferometer and the monochromator grating were both developed in the 1800s. Both of these technologies have been used industrially since the advancement of computer technology and utilize the same light sources, detectors, optical fibers, and probes.

Monochromator gratings now consist of, e.g., a holographic concave diffraction grating with an optimized image plane to avoid aberrations and stray light. Holographic gratings are created by etching interference lines via laser into a photoresist layer. An advantage of this is very high spectral resolution, which together with a detailed adjustable encoder (and other components of the monochromator), provides very good resolution with the NIR spectrometer. For example, the NIRS XDS Process Analyzer (Figure 2) has a real resolution of 8.75 nm.

In comparison, higher resolutions can be achieved with interferometers, but this can also decrease the signal-to-noise (S/N) ratio. Usually, resolutions of approximately 8 cm-1 or 16 cm-1 are used, which corresponds to 10–25 nm at 2500 nm.

Parameter FT-NIR Dispersive NIR (Metrohm)
Wavelength range (nm) 800–2200

(12,500–4545 cm-1)

800–2200

400–2200 (optional)

Wavelength precision (nm) ~0.01 ~0.005
Wavelength accuracy (nm) ~0.05–0.2 ~0.05
Figure 4. Noise spectra recorded with a Metrohm dispersive NIRS analyzer and a typical FT-NIR spectrometer.
Higher resolutions are usually not required for the majority of applications since harmonics/overtones and combination bands of pure substances in the NIR wavelength range have a broad bandwidth. The absorption peak with the smallest bandwidth currently known in the NIR region is talc at slightly more than 10 nm.

Very similar overlapping information (e.g., –OH bands or –COOH bands) are separated by using chemometric methods and are evaluated individually and specifically.

Another example that shows how powerful dispersive NIR spectroscopy is compared to FT techniques and IR spectroscopy can be seen in the separation of xylene isomers in a mixture of several aromatics/hydrocarbons (Figure 5).

Figure 5. Xylene isomers present in a mixture of aromatics and other hydrocarbons. (L) Raw spectra of all components from 800–2200 nm. (R) Raw spectra of xylene isomers show significant molecular vibration variations in the –CH region from 1700–1850 nm.
Figure 5 shows that the three xylene isomers can be clearly distinguished spectroscopically. Applying chemometrics elaborates the information even more and ultimately all six components can be determined individually and quantitatively. In a production process, the real-time reaction monitoring can be performed for all six components (Figure 6).
Figure 6. Graph showing real-time monitoring during a feed separation process of a mixture including three xylene isomers.
The application shown in Figures 5 and 6 has often been implemented with IR photometers in the past. We have now shown that the application can not only be transferred to the NIR wavelength range, but that even minimal structural differences between the functional groups of molecules can be detected by dispersive NIR spectroscopy.

To summarize: dispersive spectrometers have very good spectral resolution—in some cases better than FT-NIR spectrometers—and can even distinguish between different isomers in complex mixtures, or between very similar components like –OH and –COOH functional groups.

Summary

In the first part of this series, we went more into detail about the practical differences between FT-NIR and dispersive NIR spectroscopy. Three myths were discussed: that NIR spectroscopy always means FT-NIR—False, method transfer is only possible with FT-NIR spectrometers and not with dispersive spectrometers—False, and many applications cannot be measured with dispersive NIRS, but require well-resolved FT-NIR spectroscopy—False.

Some myths should no longer be kept alive because they are not facts!

We have also compared FT-NIR spectrometers to dispersive spectrometers when used in a process environment. Some critical points to remember: the dispersive analyzer is less sensitive to vibrations; less maintenance is necessary, and the grating is post-dispersive and therefore less prone to pollution due to lower ambient light.

To prove those arguments, Part 2 will show that, contrary to some expectations, it is possible to replace IR measurement techniques in industrial processes with easy-to-implement NIR measurement techniques. We will dispel some more myths and go into detail of an extremely low water content measurement in a process with the support of our primary analysis methods.

Reference

[1] Baker, A. W.; Wright, N.; Opler, A. Automatic Infrared Punched Card Identification of Mixtures. Anal. Chem. 1953, 25 (10), 1457–1460. doi:10.1021/ac60082a011

Find your process application

Our Applications Book contains hundreds of sold process applications from our more than 10,000 installed analyzers over several industries!

Post written by Sabrina Hakelberg, Product Manager NIRS Process Analyzers, Deutsche Metrohm Prozessanalytik (Germany).

NIR spectroscopy in the petrochemical and refinery industry: The ASTM compliant tool for QC and product screening – Part 5

NIR spectroscopy in the petrochemical and refinery industry: The ASTM compliant tool for QC and product screening – Part 5

History of ASTM International

The American Society for Testing and Materials (ASTM) is an organization that currently provides over 12,500 international standards. Its roots date back to 1898, when ASTM was formed by a group of scientists and engineers to address the frequent rail breaks affecting the fast-growing railroad industry. The group developed a standard for the steel used to fabricate rails.

Originally, this organization was called the «American Society for Testing Materials» (1902) and was changed to the «American Society for Testing and Materials» in 1961. In 2001, ASTM officially changed its name to «ASTM International» and added the tagline «Standards Worldwide». This tagline was modified in 2014 to «Helping our world work better». Now, aside from the US, ASTM International also has offices in Belgium, Canada, China, and Peru.

ASTM International aims to ensure that quality and standard requirements are met when using materials for engineering projects. Therefore, they had to agree upon a single language for engineers and technicians to enhance compatibility, and ultimately developed a system grouped according to industries in the form of letters A–G. Currently, there are over 12,500 ASTM standards used by about 150 countries. This has increased trade in different markets by instilling and strengthening consumer confidence.

ASTM Committee D02 on Petroleum Products, Liquid Fuels, and Lubricants

Formed in 1904, ASTM Committee D02 currently meets twice per year for five days of technical meetings, attended by approximately 1000 members (out of around 2500). D02 has jurisdiction over 814 standards with a prominent role in all aspects relating to the standardization of petroleum products and lubricants, which are published in the Annual Book of ASTM Standards (Volumes 05.01 through 05.06).

Near-infrared spectroscopy—an ASTM compliant tool to assess the quality of petrochemical products

Near-infrared spectroscopy (NIRS) has been an established method for fast and reliable quality control within the petrochemical industry for more than 30 years. However, many companies still do not consistently consider the implementation of NIRS in their QA/QC labs. The reasons could be either limited experience regarding application possibilities or a general hesitation about implementing NIRS as an alternative technology.

Many companies are not aware that now there are many ASTM standards about how to implement NIR spectroscopy as an alternative to conventional methods. Several NIRS-related ASTM guidelines are shown in Figure 1.

ASTM E1655 (method development quantitative NIR analysis) and ASTM E1790 (method development qualitative NIR analysis) are applicable for all industries (e.g., polymer, chemical, petrochemical, etc.).

ASTM D6122 (method validation), ASTM D8321 (development and validation of multivariate analysis), and ASTM D8340 (performance qualification) are dedicated for the petrochemical industry. These three standards were released recently in 2020, and ASTM D8340 was updated at the end of 2021.

Figure 1. Overview of NIRS-related ASTM guidelines.

Method development

ASTM E1655: Standard Practices for Infrared Multivariate Quantitative Analysis

«These practices cover a guide for the multivariate calibration of infrared spectrometers used in determining the physical or chemical characteristics of materials. These practices are applicable to analyses conducted in the near infrared (NIR) spectral region (roughly 780 to 2500 nm).»

ASTM E1790: Standard Practice for Near Infrared Qualitative Analysis

«This practice covers the use of near-infrared (NIR) spectroscopy for the qualitative analysis of liquids and solids. The practice is written under the assumption that most NIR qualitative analyses will be performed with instruments designed specifically for this purpose and equipped with computerized data handling algorithms.»

Method validation

ASTM D6122: Standard Practice for Validation of the Performance of Multivariate Online, At-Line, Field and Laboratory Infrared Spectrophotometer, and Raman Spectrometer Based Analyzer Systems

«This practice covers requirements for the validation of measurements made by laboratory, field, or process (online or at-line) infrared (near- or mid-infrared analyzers, or both), and Raman analyzers, used in the calculation of physical, chemical, or quality parameters (that is, properties) of liquid petroleum products and fuels.»

These requirements include the following topics:

  • Analyzer calibration
  • Correlation of NIRS vs. lab method (treated and untreated samples)
  • Probationary validation
  • General & Continual validation

Results validation

ASTM D8321: Standard Practice for Development and Validation of Multivariate Analyses for Use in Predicting Properties of Petroleum Products, Liquid Fuels, and Lubricants based on Spectroscopic Measurements

«This practice covers a guide for the multivariate calibration of infrared (IR) spectrophotometers and Raman spectrometers used in determining the physical, chemical, and performance properties of petroleum products, liquid fuels including biofuels, and lubricants. This practice is applicable to analyses conducted in the near infrared (NIR) spectral region (roughly 780 nm to 2500 nm).»

The main purpose for this standard is to establish the validity of test results during calibration.

ASTM D8340: Standard Practice for Performance-Based Qualification of Spectroscopic Analyzer Systems

«This practice covers requirements for establishing performance-based qualification of vibrational spectroscopic analyzer systems intended to be used to predict the test result of a material that would be produced by a Primary Test Method (PTM) if the same material is tested by the PTM.»

Furthermore, it includes the prescriptive requirements regarding multivariate models, including Multi Linear Regression (MLR), Partial Least Square (PLS), Principal Component Regression (PCR), Cross validation, and Outlier statistics, as well as instrument considerations.

Regarding the required accuracy of the NIRS method the expected agreement and user requirements is that the Standard Error of Prediction for the NIRS value should be equal to or smaller than the laboratory method reproducibility.

ASTM D8340 compliance with the NIRS DS2500 Petro Analyzer and Vision Air

Temperature stability, section 5.4:

There are prescriptive requirements included in this norm regarding temperature stability of the NIRS Analyzer. Section 5.4 requires sample temperature to be carefully controlled in the analyzer system hardware or that effects of temperature change be compensated in the modeling or software. Metrohm’s solution to this issue for the NIRS DS2500 Petro Analyzer is shown in Figure 2.

Figure 2. Temperature stability for the NIRS DS2500 Petro Analyzer.
Learn more about the possibilities of petrochemical analysis with Metrohm NIRS DS2500 Petro Analyzers in our free brochure.
Analyzer wavelength accuracy and precision, section 6.3:

Section 6.3 requires that the analyzer shall include a means of demonstrating that it is operating within the vendor’s specification. Therefore, the analyzer shall incorporate instrument performance tests to demonstrate that it is operating within historically expected limits. Furthermore, the analyzer shall have a means of validating wavelength/frequency precision and accuracy. Also, the wavelength precision must be sufficient to allow spectra to be collected and used in creating a multivariate model that meets or exceeds user’s specifications. The wavelength precision of the analyzer used for calibration and the analyzer-to-analyzer wavelength accuracy and reproducibility must be sufficient to allow analyzers to be validated by Practice D6122. Metrohm’s solution to this is the Vision Air software shown in Figure 3.

Figure 3. Analyzer wavelength accuracy and precision for ASTM D8340 section 6.3 (click to enlarge image).
Vendor created global multivariate model, section 8.2.2:

The multivariate model can be that of a standardized test method, a user/vendor-created global multivariate model, or a user-created site-specific multivariate model. A global multivariate model is one developed by use of samples and data that may represent materials produced at multiple facilities or locations. Some locations may start with a global model and add site-specific sample to it. Metrohm offers several pre-calibrations for the NIRS DS2500 Petro Analyzer, listed in Figure 4.

Figure 4. Available NIRS pre-calibrations for the petrochemical industry.
Discover our selection of NIRS pre-calibrations available for the petrochemical industry in our free brochure.
Outlier statistics, sections 9.3, 9.4, and 9.5:

The requirements of outlier handling are described in these sections. Identification and handling of outliers is important to the success of meeting this performance-based practice. It is permissible for the identification and handling of outliers to be performed by the same or separate software used for generating predictions from spectra. For analysis of a sample for the purposes of determining property values, the software shall indicate whether the spectrum is identified as an outlier, based on the criteria set by the user. The sample analysis may indicate that expected performance is not reached for a sample identified as an outlier.

Vision Air is Metrohm’s universal software for Vis-NIR spectroscopy. Vision Air accounts for the unique needs of each type of instrument user. It offers specific interfaces optimized for the most common tasks – simplifying routine measurement, method development, outlier handling, and both data and instrument management. Vision Air is also compatible with third-party software like Unscrambler (Figure 5).

Figure 5Vision Air—Metrohm’s universal software for lab Vis-NIR spectroscopy.

Summary

In the petrochemical industry, typical requirements from management are usually that quality control should be quick, operating costs should be low, feedback should be fast, and operation should be safe.

Typical requirements from the user are that the analysis should be accurate and precise, and the instrumentation should be easy to use, fast, and safe.

NIR spectroscopy is compliant with all of these requirements, and as shown in this blog series, the technology is supported by several ASTM guidelines for method development, method validation, and results validation.

By utilizing NIRS in the petrochemical industry, manufacturers not only improve the efficiency of screening and quality control of petrochemical products, but also fully adhere to internationally accepted standards.

For more information

About spectroscopy solutions provided by Metrohm, visit our website!

We offer NIRS for lab, NIRS for process, as well as Raman solutions

Post written by Wim Guns, International Sales Support Spectroscopy at Metrohm International Headquarters, Herisau, Switzerland.
NIR spectroscopy in the petrochemical and refinery industry: The ASTM compliant tool for QC and product screening – Part 4

NIR spectroscopy in the petrochemical and refinery industry: The ASTM compliant tool for QC and product screening – Part 4

What is a lubricant?

A lubricant is defined as a petroleum-derived product used to control and reduce the friction and wear of moving machinery parts (e.g., in engines and turbines). The main purpose of lubricants  is to help protect and prolong the lifetime of the equipment.

Machinery and lubricants go hand in hand, as shown here.
These goals are accomplished in the following ways:

Lubrication by reducing friction and wear. The lubricant forms a film between the mechanical moving parts of the equipment. In this way the metal-to-metal contact and, thus, the wear is reduced.

Cooling by acting as a heat sink. This causes the heat to dissipate away from critical parts of the equipment so that deformation due to increased temperature is prevented.

Protection by building a film. This film is unaffected by oxygen or corrosive substances and therefore prevents metal damage and oxidation (rust) and therefore also prevents wear.

Types of lubricants

For the most part, lubricants consist of oils to which additives and other chemical substances are added. There are two common types of lubricants which are based on the origin of the oil:

1. Lubricants based on mineral oils (Figure 1a) are the most commonly used type. They are comprised of petroleum products (base stock) to which synthetic additives are added. These types of lubricants are used in applications where there are no high temperature requirements. Typical areas where mineral oil-based lubricants are used include: engines, hydraulics, gears, and bearings.
2. Lubricants based on synthetic oils (Figure 1b) are artificially developed substitutes for mineral oils. They are less common and more expensive. Synthetic oils are specifically developed to create lubricants with superior properties to mineral oils. For example, heat-resistant synthetic oils are used in high performance machinery operating at high temperatures.
a)
b)
Figure 1. Difference in the molecular structure found in lubricants: a) mineral oil and b) synthetic oil.
In the following table, different lubricant types with sub-classes are listed.
Table 1. Different lubricating oil types.

Lubricant type

Sub-classes

Automotive oil Engine oil

Gear oil

Transmission fluids

Industrial oil Hydraulic oil

Turbine oil

Greases
Metal working fluids Forming fluids

Cutting fluids

The physical properties of a lubricant (such as viscosity and density) mostly depend on the oil base stock, whereas the additives fine-tune the chemical properties, e.g., the acid number or base number. For each application, the oil is typically formulated to meet the physical and chemical properties required by the customer. Therefore, various types of oil exist (Table 1).

Near-infrared spectroscopy—an ASTM compliant tool to assess the quality of lubricants

Near-infrared spectroscopy (NIRS) has been an established method for fast and reliable quality control within the petrochemical industry for more than 30 years. However, many companies still do not consistently consider the implementation of NIRS in their QA/QC labs. The reasons could be either limited experience regarding application possibilities or a general hesitation about implementing new methods.

There are several advantages of using NIRS over other conventional analytical technologies. For one, NIRS is able to measure multiple parameters in just 30 seconds without any sample preparation! The non-invasive light matter interaction used by NIRS, influenced by physical as well as chemical sample properties, makes it an excellent method for the determination of both property types.

In the remainder of this post, available solutions for lubricants are discussed which have been developed according the NIRS implementation guidelines of ASTM E1655 (method development), ASTM D6122 (method validation), and ASTM D8340 (results validation).

Did you miss the first parts in this series about NIRS as a QC tool for the petrochemical industry? Find them all below!

Read our previous blog posts to learn more about NIRS as a secondary technique.

Applications and parameters for lubricant analysis with NIRS

The main NIRS application for lubricants is to easily monitor the oil condition, i.e., checking if the oil is still of suitable quality for proper lubrication of the equipment. Reducing unnecessary oil changes means significant cost savings. On the other hand, changing the oil too infrequently can result in possible damage of the equipment, leading to costly repairs. Therefore optimizing the usage of the lubricating oil is very important.

The following parameters can be correlated between NIRS and the values from a primary method: kinematic viscosity, viscosity index, color, density, water content, TAN (total acid number), and TBN (total base number). A large set of samples provided by several different companies was used to develop working NIRS models of these parameters, including hydraulic oil, gear oil, and others. In some cases, it was not clear for what application the lubricant was used, so the exact identity of the oil was unknown.

The most relevant application notes for NIRS analysis of lubricants are listed below in Table 2.

Table 2. Metrohm’s NIRS solutions for lubricants including application details and benefits.
Parameter Reference method Norm NIRS Application Notes NIRS benefits
Acid number Titration ASTM D664 AN-NIR-071

AN-NIR-041

All parameters are measured simultaneously within a minute, without requiring any sample preparation or chemical reagents.
Kinematic viscosity at 40 °C Viscosimeter ASTM D445
Kinematic viscosity at 100 °C Viscosimeter ASTM D445
Viscosity index Calculation ASTM D2270
Color number Colorimeter ASTM D1500
Moisture content Karl Fischer titration ASTM D6304
Base number Titration ASTM D2896
Density Density meter ASTM D4052

 

Solutions by means of starter models—expedite and simplify quality control of lubricants

Lubricants keep our modern lives running smoothly. During use, the oil needs to be monitored to check if it still of good enough quality or whether it needs to be exchanged.

The data obtained here indicate that lubricants vary per application and per supplier. This means that there is still not sufficient information for each oil type and subtype to prepare a model robust enough to transform into a pre-calibration. However, if a partner provides the samples, a feasibility study can quickly indicate if the NIR spectra are able to be correlated to the primary method values.

Typically, several key parameters such as the acid and base numbers (AN and BN), viscosity, moisture content, color, and density are determined in the laboratory by various chemical and physical methods. These methods not only incur high running costs, they are also quite time consuming to perform.

NIRS on the other hand requires neither chemicals nor sample preparation, and provides results in less than a minute. This spectroscopic technique is also easy enough to be used by non-chemists. Furthermore, multiple chemical and physical parameters can be determined simultaneously. The combined benefits of this technology make NIRS the ideal solution for many daily QA/QC measurements or ad-hoc atline analysis.

Application example: starter model for lubricants with the NIRS DS2500 Liquid Analyzer

For lubricant analysis, determination of the acid number (ASTM D664), viscosity (ASTM D445), moisture content (ASTM D6304), and color number (ASTM D1500) require the use of multiple analytical technologies and, in part, large volumes of chemicals. The time to result can therefore be quite a long and costly process.

In this example, different lubricant samples were measured with a Metrohm NIRS DS2500 Liquid Analyzer in transmission mode over the full wavelength range (400–2500 nm). The built-in temperature controlled sample chamber was set to 40 °C to provide a stable sample environment. For convenience reasons, disposable vials with a pathlength of 8 mm were used, which made a cleaning procedure obsolete.

Learn more about the possibilities of petrochemical analysis with Metrohm NIRS DS2500 Analyzers in our free brochure.
Figure 2. Quality control of lubricants as performed by the Metrohm NIRS DS2500 Liquid Analyzer.
The obtained Vis-NIR spectra (Figure 2) were used to create prediction models for the determination of key lubricant parameters (such as those in Table 2). The quality of the prediction models was evaluated using correlation diagrams, which display the correlation between the Vis-NIR prediction and primary method values. The respective figures of merit (FOM) display the expected precision of a prediction during routine analysis (Figure 3).
Figure 3. Correlation plots and figures of merit (FOM) for different parameters measured in lubricants.
This solution demonstrates that NIR spectroscopy is excellently suited for the analysis of multiple parameters in lubricants in less than one minute without sample preparation or using any chemical reagents.

In case a large series of samples must be analyzed, there is also the possibility to measure lubricant samples in a fully automated way, as detailed in our free Application Note below.

Here, the samples were measured in transmission mode over the full wavelength range (400–2500 nm) using a NIRS XDS RapidLiquid Analyzer in combination with an 815 Robotic USB Sample Processor, which can carry a total of 141 samples (Figure 4).
Figure 4. Metrohm NIRS XDS RapidLiquid Analyzer equipped with a with 5.0 mm flow cell (left) and the 815 Sample Processor (right).

Summary

Near-infrared spectroscopy is very well suited for lubricant analysis. Available starter models are developed and validated in accordance with the ASTM guidelines. Positive aspects of using NIRS as an alternative technology to primary methods are the short time to result (less than one minute), no chemicals or other expensive equipment needed, and ease of handling so that even shift workers and non-chemists can perform these analyses in a safe manner.

Future installments in this series

This blog article was dedicated to the topic of lubricants and how NIR spectroscopy can be used as the ideal QC tool for the petrochemical / refinery industry. The final installment will be dedicated to:

 

For more information

About spectroscopy solutions provided by Metrohm, visit our website!

We offer NIRS for lab, NIRS for process, as well as Raman solutions

Post written by Wim Guns, International Sales Support Spectroscopy at Metrohm International Headquarters, Herisau, Switzerland.
Ph. Eur. 2.2.48 Raman Spectroscopy: How Raman instruments from Metrohm comply with the 2022 update

Ph. Eur. 2.2.48 Raman Spectroscopy: How Raman instruments from Metrohm comply with the 2022 update

The European Pharmacopoeia (Ph. Eur.) is a single reference work for the quality control of medicines. Ph. Eur. contains norms, suggests analytical methods, and lists many properties that define quality control (QC) during the production of medicines, the raw materials used, and the instruments required to perform such tests. These official standards are legally binding in several countries – not only in Europe, but worldwide.

Raman spectrometers—especially handheld and portable instruments—are increasingly used for QC of medicines and raw materials (RMID). Instrument interfaces are user-friendly, requiring little technical expertise, and they provide flexible sampling options for most sample types with rapid, non-destructive measurements.

Metrohm’s Raman systems exhibit great flexibility—from see-through to standoff to immersion sampling.
An excerpt from the Ph. Eur. 2.2.48 Raman Spectroscopy chapter says:
«Raman spectroscopy is commonly used for qualitative and quantitative applications and can be applied to solid, liquid, and gaseous samples. Raman spectroscopy is a rapid and non-invasive analytical method and can be performed off-line, at-line, on-line, or in-line[…] Raman spectrometers can be situated far from the point of measurement using long-distance optical fibres to collect the Raman signal.»

Technological developments and their increasing adoption in the pharmaceutical industry prompted a revision of Ph. Eur. 2.2.48 which ensures the reliability of Raman results. The updated chapter 2.2.48 was published in the Ph. Eur. Supplement 10.7 (October 2021) and will ultimately take effect in April 2022.

While much of the Ph. Eur. 2.2.48 chapter has remained the same, the latest revision features:

  • new requirements for spectral resolution for qualitative Raman analysis using a suitable reference material
  • updated requirements for the Raman response-intensity scale
  • detailed procedures for the comparison of spectra

We will address these new requirements across our Raman spectroscopy product lines in the rest of this article.

Spectral Resolution

«Spectral resolution is the ability of a spectroscopic system to separate adjacent bands, which makes it possible to characterise complex samples (e.g., brand analysis, crystallinity, polymorphism).

[…] For identity tests, unless otherwise prescribed in a monograph, the spectral resolution must be less than or equal to 15cm-1 (measured in the wavenumber range between 1000cm-1 and 1100cm-1).

The spectral resolution is verified using a suitable reference material. The instrument parameters used for the test, such as laser, slit-width and grating for dispersive instruments and circular aperture […] for FT-instruments, must be the same as those applied for sample measurements. For example record the Raman spectrum of calcium carbonate for equipment qualification CRS, and determine the full width at half height (W1085) of the band located at 1085 cm-1. The spectral resolution (R) using calcium carbonate is then given by the following relation:»

Handheld Raman instruments: MIRA P and NanoRam

All MIRA P and NanoRam devices (including both NanoRam and NanoRam-1064) for the pharmaceutical industry are designed and tested to meet stringent resolution requirements. During QC, the resolution of each instrument is tested to be less than 15 cm-1 against a secondary USP (US Pharmacopeia) reference standard of calcium carbonate according to ASTM E2529, which is the same procedure recommended in this newly released Ph. Eur. chapter.

The measured spectral resolution value for each instrument, along with its identifying serial number, is included in the instrument final test report. A certificate or final test report is packaged with the device and sent to the customer (starting in April 2022 for MIRA P). This resolution is fixed by the optical design of the instrument and is stable over time.

Portable Raman instruments: i-Raman series, QTRam, STRam, and PTRam

The instrument resolution for all of Metrohm’s portable Raman instruments from B&W Tek are factory-tested with calcium carbonate and displayed on final instrument test reports. The spectral resolution is dependent on the instrument design and defined for each specific instrument configuration. Depending on the instrument model, the spectral resolution is between 3.5–11 cm-1. Additionally, the instrument control softwares Vision and BWAnalyst have the performance test function that verifies spectral resolution using the 1001.4 cm-1 peak of polystyrene.

Handheld and portable Raman instruments from B&W Tek.

Response-Intensity Scale

«The verification of the response-intensity scale is principally performed for quantitative methods.

Appropriate acceptance criteria will vary with the application. A maximum variation of ± 10 per cent in band intensities compared to the previous instrument qualification is achievable in most cases. Response calibration may involve the use of white-light standards or luminescent glass (e.g., NIST SRM 2241).»

Handheld Raman instruments: MIRA P, MIRA M-3, and NanoRam series

MIRA P, MIRA M-3, and NanoRam systems are designed for qualitative analysis, not for quantitative purposes. Therefore, this criterion is not a strict requirement for handheld Raman products.

However, the relative intensity response of MIRA P and NanoRam series instruments is calibrated with a NIST standard SRM calibration material (SRM 2241, SRM 2242) or NIST SRM 2241-traceable calibration standard to achieve better uniformity from instrument-to-instrument.

The NanoRam series instruments have an acceptance criterion for relative intensity response in the instrument performance validation in alignment with Ph. Eur. 2.2.48 and USP<858>. To pass the performance validation, <10% relative intensity error is required using the factory-supplied polystyrene cap.

Portable Raman instruments: i-Raman series, QTRam, STRam, and PTRam

The relative intensity response of these portable Raman instruments is calibrated using a proper NIST standard SRM calibration material to achieve better uniformity from instrument-to-instrument. Additionally, the Vision instrument control software includes the performance test function that verifies the intensities of several Raman peaks of polystyrene relative to its 1001.4 cm-1 peak, to a maximum variation of ±10% compared to the previous instrument qualification.

Comparison Procedures

For qualitative methods, additional information for identification has been defined.

«Several comparison procedures may be used, and the analyst must document and justify the method used and the specific acceptance criteria that allow a conclusion for identification. The spectra can be compared by either overlaying the spectra (in the whole spectral range or in the region of interest specified in the monograph) or by using mathematical calculations of the software. It is possible for example to perform:

  • visual comparison based on band positions and relative intensities unless otherwise specified[…]
  • a statistical determination of the similarity between the spectra of the material to be examined and the reference standard[…]
  • evaluation by chemometric methods[…]»

While an experienced Raman spectroscopist can certainly compare spectra visually and assess sample validity based on peak location, fluorescence, saturation, and signal-to-noise ratio, the widespread implementation of Raman in the real world means that complex analysis must be done by the device and not the user. Statistical comparison methods are used primarily for identification of unknowns through correlation of a sample spectrum with library spectra. The software performs library searches and returns a Hit Quality Index (HQI) value indicating the level of correlation as defined by a user-defined threshold.

Chemometric methods rely on dimensionality-reduction methods that are performed by the software, such as Principal Component Analysis (PCA), where new sample data is compared within a multivariate model created from representative samples. This permits highly accurate verification of known materials according to how well a spectrum fits into the model limits, which are determined by a confidence interval. In the analysis of medicines and raw materials, chemometric methods are used to distinguish the quality and consistency of a material. MIRA P (and its dedicated software, MIRA Cal P) and NanoRam instruments use both statistical and chemometric methods for sample identification and verification based on the needs of the end-user.

For more information, download our free technical and application notes as well as a White Paper below.

Wavenumber accuracy requirements of Ph. Eur. 2.2.48

«Verify the wavenumber scale for Raman shifts using a suitable standard that has characteristic maxima at the wavenumbers under investigation, for example an organic substance such as polystyrene, paracetamol or cyclohexane[..]

A minimum of 3 wavenumbers covering the working range of the instrument intended for measurements should be selected.[…]»

This chapter maintains the same requirements for Raman wavenumber accuracy and is consistent with the USP <858> and JP 2.26. All of Metrohm’s handheld Raman instruments meet these requirements. Users are recommended to run performance validation tests at regular intervals using polystyrene or another ASTM Raman shift calibration material.

Download our free White Paper below to learn more about instrument calibration, system verification, and performance validation.

The Calibrate/Verify Attachment (CVA) shown here is a dual-ended accessory containing a toluene/acetonitrile ASTM standard for calibration/verification of the wavenumber axis and polystyrene for a second wavenumber verification according to Ph. Eur. 2.2.48.
Performance tests for Raman wavenumber accuracy are included the Vision and BWAnalyst softwares for the i-Raman series and other portable Raman products (STRam, QTRam, PTRam), with acceptance criteria in accordance with the pharmacopeial requirements.

Metrohm’s unique way of compliance with Ph. Eur. 2.2.48

Better representation of the material

«When using Raman spectroscopy[…] care must be taken to ensure that the measurement is representative. This can be achieved by, for example rotation of the sample, performing multiple measurements on different preparations of the sample, using orbital raster scanning (ORS), increasing the area of illumination by reducing the magnification, by demagnification of the laser beam or by changing the focal length between measurements to scan at different depths.»

ORS™ is Metrohm Raman’s proprietary method for moving the excitation laser in a pattern over a sample in order to collect more representative data from a larger area of the sample, especially on heterogeneous samples. All MIRA and MISA instruments are equipped with ORS.
Learn more about ORS by downloading the related Application Note.
For more details about how we comply, please check the U.S. Pharmacopeia Raman Chapters Updates page on the B&W Tek website. For more general information, download this General Compliance Statement for MIRA handheld Raman systems
For a more comprehensive look at raw material identification and verification in the pharmaceutical industry, there is a significant amount of information on this topic in our related blog post.

Post written by Dr. Melissa Gelwicks (Technical Writer at Metrohm Raman, Laramie, Wyoming), and Dr. Xiangyu (Max) Ma (Handheld Raman Product Manager) and Dr. Jun Zhao (R&D Director) at B&W Tek, Plainsboro, New Jersey.