At-line and In-process Monitoring in Pharmaceutical Manufacturing

Process optimization using field-proven technology

The use of online Process Analytical Technology (PAT) has recently become a high-profile endeavor in the pharmaceutical and biotechnology industry. Fermentation scientists have been utilizing process mass spectrometry since the early 1980s to reliably monitor the composition of gas streams into and out of fermentors and bioreactors. These measurements enable pre-screening for possible contamination as well as real-time information regarding culture respiration and the availability of nutrients. 

More advanced gas analysis technology platforms are now available that encompass the latest design techniques for fault-tolerant operation, ensuring high reliability for closed-loop control in harsh industrial environments.

As part of cGMP many pharmaceutical manufacturers are adopting Process Analytical Technologies (PAT), Quality by Design (QbD), or Process Validation (PV). cGMP and associated process monitoring necessitates continuous process verification and analysis. Analytical instruments such as Near-infrared and Raman spectroscopy and chemometric modeling software may be used for at-line monitoring to bring the technology to the sample. This offers more efficient testing that can speed up the analysis process and enable customers to be more flexible due to a smaller footprint.

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Popular products for at-line and in-process monitoring

The FDA’s Process Analytical Technology (PAT) initiative promotes improved process understanding by defining Critical Process Parameters (CPP) and monitoring these CPPs, either in-line, on-line, or at-line. Controlling manufacturing by testing and measuring during the processing of critical quality and performance attributes of raw and in-process materials helps ensure final product quality. Real time off gas monitoring provides metabolism data without the need for offline tests and without compromising the sterile environment. With advanced process mass spectrometers, pharmaceutical manufacturers can monitor and control multiple fermentors in real-time to ensure that each progresses according to the design of experiment and produces optimum outcomes.

Technology that Enables Point of Use Measurements

Handheld Raman and NIR instruments provide the ability to build quantitative methods for complex material analysis such as multiple component discrimination, API content quantification and solvent quantitation. TruScan RM with TruTools and MicroPHAZIR RX allow users to bring rugged analytical instrumentation to the pharmaceutical/ biopharmaceutical manufacturing floor for quick release of in-process materials without the significant costs associated with fixed installations.  Handheld technology enables customers to be more efficient, reduce lab testing time, and provide results in minutes with little to no instrument maintenance.

Biologic Drug Identification at Fill and Finish

In pharmaceutical manufacturing of chemical compounds, handheld Raman analyzers are widely accepted for material verification of excipients and APIs. For many years the pharmaceutical industry has used TruScan RM’s embedded multivariate residual analysis decision engine to identify most raw materials. Moreover, TruScan RM’s characteristics of non-contact, nondestructive testing, little or no sample preparation, high molecular specificity, and the ability to measure aqueous solutions make it suitable for larger molecule biologics testing. With the addition of TruTools on-board chemometrics, complex biological molecules can be discriminated. This can dramatically reduce the amount of time, technical resources, and expense required to conduct protein product ID tests.

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Gas Analysis Mass Spectrometer Applications in Fermentation and Cell Culture Process

Many fermentations are characterized by small changes in oxygen and carbon dioxide concentrations at critical phases of the fermentation, for example, during the lag phase when the micro-organisms exist in equilibrium with the nutrients. It is vital that the method used for measuring off gas is capable of fast, precise analysis. The speed of MS makes it ideal for the fermentation application but speed must not be at the expense of precision. It is equally important that precise data is acquired; otherwise small changes in concentration will be lost. Magnetic sector mass spectrometers have demonstrated the highest levels of precision for fermentation off-gas analysis and have been successfully monitoring fermentor off-gas at many of the world’s leading biotechnology and pharmaceutical companies for many years. By combining high speed with excellent stability, the magnetic sector analyzer lends itself ideally to this demanding application.

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Near infrared spectroscopy (NIR) has been used effectively and reliably to measure moisture in a wide variety of samples. Due to the large overtone band for water in NIR, levels of accuracy tend to be high and limits of detection are lower than for most materials measured by NIR. In this feasibility study the performance of a portable NIR instrument was evaluated to monitor moisture levels within a protein sample, as proof of concept to monitor lyophilized samples in a pharmaceutical process.

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Process Mass Spectrometry in Biotechnology

Read about the versatile Prima PRO Process Mass Spectrometer that enables optimization of a number of biotechnology processes to improve overall product quality as well as increase product yield. From bench to pilot to full-scale production, it facilitates every stage of the scale-up process and minimizes the risks associated with the complex manufacturing of biomaterials, biomass, food additives, vitamins, and pharmaceuticals, including prophylactics, vaccines, growth factors, monoclonal antibodies, hormones, fusion proteins, cytokines, antibiotics, insulin, and thrombolytics.

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By law, pharmaceutical manufacturers must identify and verify all incoming materials. Current Good Manufacturing Processes (cGMP) require that not only incoming raw materials but all in-process materials be tested for identity, strength, quality, and purity throughout the manufacturing process. 

Make sure your QA/QC program is compliant. Download the free eBook, What You Need to Know About Field-Based Material Identification and Authentication for Pharmaceuticals.

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