Lyophilization

Process Analytical Technology (PAT) for Lyophilization: LYOPLUS®

The LYOPLUS® mass spectrometer provides essential data from within the freeze dryer itself, including the ability to detect very small silicone oil leaks and monitor the moisture content.

By analyzing the gas mix situated inside the freeze dryer the system is able to distinguish substances that are common in the freeze drying environment, such as water or other solvents, nitrogen, oxygen and helium. The comprehensible data representation allows easy implementations of primary and secondary drying endpoint detection and convenient chamber leak testing.

LYOPLUS mounted to freeze dryer

The purity of pharmaceutical products such as parenterals is an absolute prerequisite. Production processes such as freeze drying pose an inherent risk of contamination with process fluids. This should not happen during routine production; but, in the event of a malfunction, small amounts of these fluids may contaminate the drug product and invalidate the safety of an entire batch.

The GEA LYOPLUS® mass spectrometer improves the safety, quality and productivity of freeze-drying applications. Being able to prevent product contamination by detecting trace concentrations of silicone oil or other known contamination sources, the multipurpose device can also be used to monitor the moisture content in the product chamber during freeze drying cycles. 

As a result of the monitoring, recipe-dependent moisture profiles can be derived, making it possible to define endpoints for primary and secondary drying. 

Originally developed to detect very small traces of silicone oil inside freeze dryers, the LYOPLUS® mass spectrometer is fitted with advanced software that facilitates the collection and evaluation of measurement data that wouldn’t be possible with ordinary equipment. 

The system can be implemented into any existing automation environment by using industrial standard interfaces or can be operated alongside any legacy control system as a standalone unit without interfering with any qualified process. The full integration into the freeze dryer’s control system can also be realized. 

Silicone Oil Detection

Silicone oil is used to transfer heat energy to the product. After years of operation, the harsh conditions in the dryer can lead to small leaks and, as a consequence, product contamination. 

Eventually, as the leak increases, silicone oil is detected during end product testing in quality control. But how many batches have been contaminated? With LYOPLUS®, it is possible to detect even small traces of silicone oil during the operating cycle. No additional product is at put risk as the leak is detected immediately. 

Moisture Content

At the start of the drying process, the chamber fills with product-derived water vapor. During the later stages, however, the moisture level decreases significantly. The LYOPLUS® system returns a quantitative characterization of this drop and makes it possible to correlate the data with the average product moisture levels in the vials. 

This information can be used to refine drying recipes, avoid any unnecessary drying time and predict product-drying curves based on the chamber’s moisture content.

Chamber Leak Tests

To prevent leak-based contamination, it is mandatory to perform a leak test after each critical process. In cases the leak test failed, helium leak tests can begin instantly, as the LYOPLUS® is permanently connected to the freeze dryer. Due to its high sensitivity, detection time is decreased and the freeze dryer can return to production much faster.

The LYOPLUS® combines all these three use cases in one single system, improving the freeze dryer’s integrity, enhancing productivity and providing better understanding on the freeze drying process with respect to business needs and demands in the GMP environment.

System details

  • High-performance quadrupole mass spectrometer system with Faraday and Secondary Electron Multiplier detectors
  • Detection limit down to 1 ppm of non-interfering species
  • High-conductance inlet system
  • Tri-clamp connection by default or customer demand (<3d)
  • GEA LYOPLUS® SCADA application compliant to 21 CFR Part 11 with User log, Audit trail and Batch reports
  • Alarms & messages, e.g. for high silicone oil concentration
  • Multilingual graphical user interface
  • Diverse interfaces and functions to forward or export data
  • Additional advanced data collection and control software for maintenance and diagnostic purposes
  • Technical design and support documents 
  • System’s validation executed with IQ / OQ documentation and test procedures for prove of detectability (Spike Test)
  • Training for operators and engineering staff
Table with LYOPLUS® types

Benefits at a glance

  • Detection of impurities possible before problems arise
  • Provides valuable information for recipe development, scale-up and product transfers 
  • Fully automated system for use in pharmaceutical production environment with interfaces to existing freeze dryer automation 
  • Integrated interlocks and fault procedures to ensure sterility and machine availability
  • Easy to retrofit

Detection of silicone oil leakages in freeze dryers with LYOPLUS™

Lyophil_LYOVAC_Shelf_down_w

As a small leakage from the silicone oil tubes in pharmaceutical freeze dryers may go undetected for several cycles it is a major threat both to product safety as well as to the economic performance of such an installation. A properly mounted mass spectrometer offers a non-invasive way to detect amounts of silicone oil down to 1 ppm. Additionally the system allows for improved leak testing procedures and also the use as a PAT tool for improved process control.

Introduction

Freeze drying has been used for many years in the production of parenterals to stabilize thermo labile molecules. With the continually rising number of large molecules the use of freeze drying will further increase as it offers the gentlest way of converting a liquid formulation into a more stable solid.

From an engineering point of view the typical process is very rough and demanding on the hardware. After washing every part of the entire dryer potentially in contact with the product, it is exposed to saturated steam at 127°C which relates to an overpressure of ~1,5barg. After loading the vials the dryer is evacuated down to 0,05mbar while the shelves and ice condenser are cooled down to temperatures typically in the range of -85°C. Various types of silicone oils are used to transfer the required heat energy in and out of the dryer. As a result of these rough conditions, and after many cycles, small leaks can occur in the silicone oil circulation system. This article identifies the most critical areas for the occurrence of leaks and introduces a system for the detection of small amounts of silicone oil in the system. It will also introduce new and improved state-of-the-art designs that minimize the risk of leakage.

Silicone oil is brought to the required temperature in the heat exchangers in the technical zone and then pumped into the system. Most important is the even heating/cooling of the shelves. From an engineering point of view, building the shelves to be as light weight as possible while ensuring an even surface temperature and a plan surface of all shelves is a challenge. The shelves are moved up and down during the loading, unloading and when closing of the vials at the end of the drying cycle. This means that the tubes supplying the silicone oil to the shelves need to be constructed and guided in a way that reduces bending that could increase the risk of cracks in the tubes.

Freeze dryers of older design tend to get small cracks generated through numerous cycles. It is through these cracks that silicone oil can escape into the drying chamber. To begin with these leaks are relatively small and will not cause malfunctions of the system. This means there is the risk that several batches could be produced before, by chance, QC may pick up the problem analyzing vials produced. That batch would most likely have to be destroyed but there is little guarantee that there hadn’t already been unacceptable amounts of silicone oil present in previous batches. For these reasons it would be helpful to have a method allowing the detection of traces of silicone oil from the moment the first leak occurs.

Feasibility Trials: The Detection of Silicone Oil Traces

Mass spectroscopy was chosen as a method of detection because of its sensitivity. Quadrupole mass spectrometer systems are widely used for the monitoring of critical processes and the detection of residual contamination. The principle of the operation is based on electron impact ionization, the separation of the formed ions in an electromagnetic field, and their detection. Early trials proved the principle of the method and determined the sensitivity to be evaluated. An MKS Vision 2000-P mass spectrometer, as shown in picture 2, was connected via a standard flange with an LYOVAC™ FCM-2 freeze dryer installed in the test centre at GEA Lyophil in Hürth (Germany).

When silicone oil is introduced into the mass spectrometer the molecule is broken into several fragments. By detecting the characteristics of the fragments, traces of silicone oil can be found. During the tests different types of silicone oils were used. As KT5 (Bayer AG) has the lowest vapor pressure it was used for all measurements. After the first trials a characteristic peak at 73 AMU was found. Additionally other types of silicone oil which may be present in a freeze dryer were tested. While the oil typically used for the siliconization of stoppers gave a characteristic peak at 56 AMU, silicone oil-based maintenance spray- typically used for lubrication of moving parts in loading and unloading systems- gave a characteristic peak at 58AMU.

As the characteristic peak at the mass of 73 AMU represents the type of oils used in the temperature circles of a freeze dryer this signal was used for the further measurements.

As a next step an amount of 2 mg of silicone was introduced into a vial which was closed by a stopper and held by the upper shelf in position. After the desired vacuum level was reached the upper shelf was lifted. As a result the stopper popped off and the oil evaporated into the freeze dryer. After just seconds a signal was detected.

During a further simulation 100mg KT5 was introduced over a small buffer volume into the drying chamber with a shelf size of 40m². This test confirmed again the characteristic signal pattern of silicon oil.

Measurements at Production Units

LYOVAC™ Freeze Dryer with Automatic Loading- and Unloading System ALUS™
The detection system was mounted onto production size freeze driers.
UnitShelfarea m³ChamberVolume m³mg
LYOVAC™ FCM 20,10,080,4
LYOVAC™ GT 100,80,211
LYOVAC™ GT 300-D24,89,145
LYOVAC™ FCM 400-D206,130
LYOVAC™ FCM 500-D4412,260

While two of these LYOVAC™ freeze dryers were installed at GEA the other two are manufacturing units installed at European production sites of two multi-national pharmaceutical companies.

Dynamic effects have to be taken into consideration as a result of the larger dimensions of production scale driers. To achieve an enhanced sensitivity the measurement is done when the mushroom valve between dryer and condenser is closed.

For the determination of sensitivity it was decided that the signal would be measured after the chamber was contaminated with a known amount of silicone oil that should be at least 5 times higher than the average background noise level detected. After 12 hours of evacuation the noise level was slightly below 0,2 ppm resulting in the ability to safely detect silicone oil contamination down to 1 ppm.

Evaluation of further possibilities

Performing a leak test is a standard procedure when assuring the integrity of a freeze drying chamber. The test requires the chamber to be evacuated to a pre-defined pressure, all valves closed and the rise in pressure monitored. To assure a meaningful measurement this is often done for between two and four hours. A mounted mass spectrometer offers a much faster way. Before evacuation the chamber is flushed with nitrogen. After the desired vacuum level has been reached all valves are closed and the composition of the remaining gas (> 99% Nitrogen) is monitored. As a result of small leaks- present in every industrial scale freeze dryer- air flows into the chamber which can be detected by monitoring the rise in concentration of oxygen.

Outlook

A model for the quantitative analysis of the oxygen signals has been developed. Due to the sensitivity and fast response of the instrument it can additionally be used to determine the location of leaks in the chamber.

In addition the spectrometer can also detect the concentration of water in the freeze drying chamber. This means that it can be used as a PAT tool for monitoring the drying cycle and the safe and non- invasive detection of the end points of primary and secondary drying.

The system is currently retrofitted to two production scale freeze driers owned by multinational pharmaceutical companies with more companies evaluating the potential of the method.

References

1. Handbook of Vaccuum Technology, Karl Jousten, Wiley-VCH Verlag GmbH & Co. KGaA; Etition: 1. (17. September 2008)   
2. NIST Chemistry WebBook, NIST (National Institute of Standards and Technology) Standard Reference Database Number 69, http://webbook.nist.gov/chemistry by Uwe Meissner, MKS, Munich, Germany, Dr. Harald Stahl, Senior Pharmaceutical Technologist for GEA and Daniel Steinkellner, Process Engineer, GEA Group.

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