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Cell culture media identification: Handheld Raman devices help speed quality and efficiency in biopharm products.

The production of biopharmaceuticals is an area of rapid growth within the pharmaceutical industry and cell culture media plays an important role in the quality and efficiency of biopharmaceutical products. The raw materials and culture media used in cell cultures represent a complex analytical challenge and existing techniques for analysis are often time-consuming, costly and not suited to screening high volumes of materials in containers. Rapid, reliable and robust analytical methods that are non-destructive are crucial to ensuring high quality control processes for the production of biopharmaceutical products.

Another important consideration in biopharmaceutical production is the requirement for 100 percent inspection of incoming raw materials in most countries by the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-Operation Scheme. Handheld Raman can help to optimize the raw material identification process (RM1D) to ensure quality control and compliance with these industry regulations.

Advances in Raman Spectroscopy

Raman spectroscopy is a popular analytical technique for RMID in pharmaceutical applications due to its sensitivity, specificity and ease of use. Raman spectroscopy focuses a laser on a sample. The light scattered from the sample is measured to provide highly detailed chemical information. The specificity of Raman comes from the fact that it is a vibrational technique and measures any chemical or physical changes that will affect molecular vibrations and alter the Raman spectrum.

Smaller and more reliable spectrometers have been developed through improvements in components such as the laser, detector and electronics. These spectrometers are enabling fast sample analysis at the point of need, eliminating the need for expensive and time consuming lab analysis.

Recognized by the United States Pharmacopeia (USP) and the European Pharmacopoeia (EP) as a viable technique for compendial identification, Raman spectroscopy is a non-destructive, reliable, efficient and cost effective method for the analysis of complex cell culture media. Some biopharmaceutical materials, such as cell culture media, are susceptible to fluorescence when being analyzed which can make it impossible to obtain reliable and specific information about the sample. The choice of excitation wavelengths used in Raman spectroscopy has had a significant impact on the extent to which material analysis is affected by fluorescence.

Raman devices traditionally use visible excitation wavelengths such as 532nm and 785nm. Although these shorter excitation wavelengths have a strong Raman scattering, they are also affected by fluorescence interference which increases background intensity. Strong fluorescence decreases the dynamic range of the detector, limiting the signal-to-noise ratio and consequently the identification ability of the device.

Due to the fact that fewer materials fluoresce at longer excitation wavelengths, wavelengths like 1064nm allow for a more comprehensive range of materials to be analyzed, particularly within biopharm applications. A new generation in handheld Raman spectrometers that utilize a 1064nm excitation laser (such as the Progeny(tm) from Rigaku) will enable more valuable and colored materials, such as cell culture media, to be identified.

Cell Culture Analysis with 1064

Small changes in the composition of cell culture media can have a dramatic effect on the health and validity of cell lines so it is therefore crucial that it undergoes accurate, precise analysis. The advantages of using a I064nm analyzer for cell culture media analysis, compared to a 785nm analyzer can be clearly demonstrated, as seen in Figure 1.

The spectra shown in Figure 1 are from a Minimum Essential Medium formulated by Harry Eagle, which is one of the most commonly used synthetic cell culture media. The Raman spectra collected at 785nm and 1064nm excitation are also shown in Figure 1. The 785nm spectrum is dominated by fluorescence making it impossible to obtain reliable and specific information about the sample. In contrast, the 1064nm spectra show clear Raman peaks that can be used to reliably identify the media.

Figure 2 shows the Raman spectra using a 1064nm laser from two cell culture media, both of which are versions of a minimum essential medium developed by Harry Eagle, that have only small differences in their components. Clear differences can be seen in these Raman spectra and when a correlation analysis was performed these two media could be accurately and reliably distinguished.

Spectra affected by fluorescence do not reveal detailed information about specific compositional differences or changes in the sample being measured. However, 1064 provides much clearer results. When using 1064nm excitation laser, most cell culture media materials do not fluoresce and can therefore be quickly and reliably identified using handheld Raman spectroscopy. This development in handheld Raman technology means that closely related materials can be distinguished with higher quality data.

Improving QC and Efficiency with Raman

With this drive towards 100 percent inspection and lean manufacturing, handheld Raman optimizes the RM1D process in a number of ways. Handheld Raman devices provide the ability to analyze, identify and qualify materials against specific criteria on the spot.

This removes the delay in waiting for lab results, improving cycle time, optimizing material movement, and the need for quarantine. Handheld Raman instruments can also identify substances through bags and other types of packaging, thus eliminating the risk of compromising the integrity of the contained materials. All these factors result in an improved workflow, reduction in space and inventory, as well as time and cost savings.

Ease of use is a key consideration for the new generation of handheld devices, and the Progeny has been engineered to be quickly and easily implemented into customized RMID workflows. Features include a touchscreen user interface inspired by modern smartphone, one-handed operation and an angled display. This means that the device can quite literally 'point and shoot' at the container being analyzed while the user simultaneously checks the measurements on screen.

In order to ensure accurate data entry tracking and compliance, Progeny has an integrated digital camera and 21 CFR Part 11 compliant electronic signature capabilities. By introducing the new generation of handheld Raman technology into the RMID workflow, companies can work towards overcoming these challenges and achieve leaner manufacturing processes, lower costs per analysis and increased inspection rates without compromising quality.


Raman spectroscopy is a non-destructive, reliable, efficient and cost effective method for raw material identification. With a minimal need for sample preparation, the availability of handheld instrumentation, and the ability to measure samples through containers, the Raman technique offers significant advantages for biopharmaceutical applications. The next generation in handheld Raman spectroscopy could enable the rapid characterization and quality control of complex cell culture media.

In the past, users of handheld Raman devices with 785nm or 532nm visible range extraction lasers were unable to identify colored substances, materials through colored containers or samples with high fluorescence interference.

The Progeny's 1064nm excitation laser enables users to broaden their analysis range thanks to minimal fluorescence. The combination of longer excitation wavelengths with a portable handheld device is set to revolutionize raw material identification by allowing analysis to take place quickly and efficiently on site, while simultaneously generating more accurate, reliable results.

These advances in quality control allow those involved in the manufacturing process to have increased control over the quality of cell culture media.

By Claire Dentinger, Ph. D., Sr. Applications Scientist, Rigaku Raman Technologies
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Title Annotation:BIOPHARM
Author:Dentinger, Claire
Publication:Pharmaceutical Processing
Date:Jan 1, 2015
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