How to implement PAT to efficiently remove solvents in pharmaceutical processes.

Process Analytical Technology (PAT) has been successfully employed in many biopharmaceutical processes. In the case of gas analysis mass spectrometry, its most notable application is for the online monitoring of bioreactors for determination of control parameters, including oxygen uptake rate (OUR), CO₂ evolution rate (CER), and respiratory quotient (RQ).

Historically, labs confirmed successful solvent removal from downstream product vessels such as vacuum, tray, or rotary dryers by testing a sample at the end of the process. The test, known as loss on drying (LOD), measured the amount of residual solvent in the sample, and a failing result meant that the lab must repeat the drying process—a costly and disruptive rework.

Effective implementation of a process mass spectrometer capable of the simultaneous analysis of multiple solvents with a high degree of selectivity over wide sample pressure ranges can reduce drying times, minimize or eliminate offline testing, improve product quality, and increase productivity.

Implementation of Process Mass Spectrometry

Following the launch in 2004 of the Federal Drug Administration’s PAT initiative, many pharmaceutical companies studied the benefits of implementing process analytical techniques to improve process understanding in the pharmaceutical industries. The drying process was an obvious candidate for investigation and PAT teams began the search for suitable techniques for continuous process analysis.

Mass spectrometers have many attractive features for this measurement: they are non-intrusive; they sample only from the exhaust lines of the drying vessels; no interruption to the drying processes is necessary; and, by measuring the byproducts of solvent evaporation in the headspace above the drying material, they can provide an accurate determination of the solvent content as a whole—thus eliminating problems associated with heterogeneity in the drying product.

A key feature of a mass spectrometer is its ability to measure multiple species with excellent selectivity over very short cycle times (typically just a few seconds per sample point). An effective calibration system, which takes into account the overlapping spectrum from the various solvents, can allow one mass spectrometer to monitor several dryers each with different analytical methods.

The fragmentation of the molecules from each solvent in the sample yields often complex mass spectra as observed in the example of ethanol in figure 1. The selection of the preferred peak(s) used for calibration and subsequent measurement of concentrations should take into account the presence of peaks from other solvents at the same or adjacent mass numbers. It is observed that the molecular ion of ethanol (mass 46) is in fact not the most significant peak and typically mass 31 (the CH2OH⁺ fragment ion) is selected as the base peak for ethanol calibration. Other solvents will have their own unique mass spectra, often referred to as a “fingerprint” which can enable measurement with a high degree of selectivity.

Figures 2 and 3 demonstrate the selectivity of the mass spectrometer where dryer 1 contains ethanol, methanol, tetrahydrofuran, cyclohexane, and ethyl acetate, while dryer 2 contains only ethanol. Note that in Dryer 2 all of the solvent readings except ethanol remain at zero, indicating no cross interference as a result of a successful multi-component calibration.

Conventionally, mass spectrometers are calibrated against certified gas mixtures in cylinders. This is still a method that can be employed in solvent drying applications, but where calibration mixtures are unavailable or cost-prohibitive (particularly when many different solvents are to be calibrated). The implementation of liquid calibration standards can be very advantageous since the pure solvents are readily available at the pharmaceutical manufacturing facility. A simple method of introducing a vial of solvent in liquid phase, where the solvent vaporizes into the low pressure region upstream of the mass spectrometer ion source, enables calibration at the high concentrations typically encountered at the start of the drying process. This provides an inexpensive calibration method for the user.

Dryer End Point Determination

The successful implementation of a PAT initiative may result in a more predictable process operation, reduced material costs, time savings, or more consistent product quality. The use of mass spectrometry for online solvent dryer monitoring is designed to fulfill all of these objectives. The ability to observe in near real time the rate at which solvents are being removed from the API provides the basis for online control of the dryer endpoint. A method for controlling this function reliably is to use the slope average or rate of change of slope in the reducing concentrations of solvents measured; the mass spectrometer software is equipped with derived values which interpret the raw data to provide these parameters.

Benefits of Magnetic Sector Technology

Magnetic sector MS has many inherent characteristics of benefit to the user, including resistance to contamination, long intervals between calibrations, and a high degree of precision and accuracy. Depending on the complexity of the gas mixture being analyzed, magnetic sector MS offers analytical precision between two and 10 times better than that of quadrupole analyzers, which have also been used for this measurement.

Beyond the inherent value of the technology, several design improvements can increase the performance of a magnetic sector MS system even further. Systems with laminated magnets, for example, can scan at speeds equal to those of quadrupole analyzers, offering both rapid analysis and low maintenance. Enclosed ion sources can also improve magnetic sector MS performance by increasing sensitivity, minimizing background interference, and maximizing contamination resistance.

Figure 6 shows a schematic of the magnetic sector contained within the Thermo Scientific Prima PRO process mass spectrometer analyzer. The broad flat-topped peaks that characterize this technique are optimized for long-term stability. Magnetic sector mass spectrometers have a proven track record of monitoring high percent-level concentrations of organic compounds without experiencing drift or contamination.

Vacuum Drying Sampling

The fact that magnetic sector MS analyzers operate at high vacuum makes them ideal for monitoring vacuum drying processes, but this is only true if technicians follow procedures correctly. It is vitally important that the pressure in the MS remains constant as the process pressure falls down to the vacuum levels required to dry the product. Poor control can cause the MS signals to rise and fall with sample pressure, which makes the collected data inaccurate.

Early magnetic sector MS vacuum drying systems struggled with this, especially when the vacuum process was complex. Many used only a single control valve—typically a voltage sensitive orifice (VSO) valve linked to a gauge monitoring the sample pressure. This worked well for simple processes: the VSO valve would open and close in response to sample pressure changes, keeping the pressure within the MS constant. Unfortunately, this technique suffered valve malfunctions and loss of control at pressures below 10 millibars. Further, the control valve was not suited to the rapid changes in pressure that occur frequently in multiple dryer setups.

This problem can be easily solved with the addition of a second control valve that works in opposition to the first—as one closes, the other opens. Together in a variable pressure inlet, a dual valve system allows an MS analyzer to handle sample pressures as low as 0.3 mbar.

Applying Quality by Design Concepts to Instrument Installation

Process instruments, no matter how capable and well-designed, are only effective when they are installed and calibrated correctly. Meeting the demanding standards of the pharmaceutical industry requires particularly rigorous testing. For MS systems, this testing is typically carried out at the production facility by connecting the new MS to the pharmaceutical company’s vacuum dryers. Testing on the production line obviously has a negative effect on throughput, which in turn can cause the testing process to be rushed. The end result includes inadequate testing, post-installation problems, and damaged products. Understandably, going through this process has caused many companies to lose confidence in MS systems.

To solve this problem, many producers of process magnetic sector MS analyzers are applying a widely used concept in the pharmaceutical industry: quality by design (QbD). Instead of testing the quality and capabilities of an MS system post-installation, as is traditional, producers ensure quality pre-installation by improving analyzer designs and performing more rigorous offsite testing.

Testing designs in-house—rather than on customer product lines—allows manufacturers to assess MS designs over a much wider range of sample pressures, solvent combinations, and solvent concentrations. Difficult challenges that push the limits of a magnetic sector MS—for example, switching between a dryer at the start of its drying run with high pressure and solvent concentrations and another reaching the end of its drying run, with opposite conditions—are much easier to test at a solvent drying test facility than on an actual pharmaceutical production line. 

Offsite testing also allows engineers to change the design of an instrument, if necessary, based on observations from testing. Using a practical process improvement (PPI) approach, engineers can use test facility data to further ensure that quality is designed into the instrument. Most important, a combined QbD/PPI methodology helps ensure that finished magnetic sector MS analyzers can be installed in production lines with minimal process interruption.

Implementation of PAT solutions in pharmaceutical manufacturing processes is an effective means to maintain product quality while reducing operating costs. Magnetic sector mass spectrometry is ideally suited to the online monitoring and control of solvent drying processes as it provides real time, precise, and highly-selective measurement of the solvent content in the dryer headspace. The use of mass spectrometry does not interrupt the drying process, it can reduce or eliminate offline LOD tests and cut overall drying times while avoiding rework or the downstream problems associated with over-drying.

About Daniel Merriman

Daniel Merriman has worked in the field of process analyzers for more than 25 years. During this time, he has gained experience with many different mass spectrometry technologies applied in industries including bioprocessing, petrochemicals, and iron and steel. He is based at the Thermo Fisher Scientific process analyzer factory in the UK and holds the position of product manager.

This article can also be found in the January/February 2016 edition. 

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