NMR gives on-line weight control

Jos Corver at BOC Edwards Pharmaceutical Systems explains how process control can be improved through NMR-based non-contact checkweighing

Earlier this year BOC Edwards Pharmaceutical Systems announced a strategic collaboration with Bruker BioSpin.The partnership was formed to further develop the use of time-domain nuclear magnetic resonance (TD-NMR) technology in pharmaceutical packaging equipment.

The objective of the project was to combine research technology and innovative process control equipment to create first-of-its-kind equipment that can help companies meet the process analytical technology (PAT) initiative set up by the US FDA. The result of this partnership has been the development of a non-contact check-weighing (NCCW) system for one of the world's largest pharmaceutical manufacturers.

The PAT initiative, launched by the FDA in 2002, has opened the door to the use of new technologies in drug production. In the past, companies were hesitant to trial new processes or technologies, not knowing what the regulatory implications might be and fearful of costly down-time or effects on end-product. PAT, whose principle is that 'quality cannot be tested into products; it should be built-in or created by design', is actively encouraging manufacturers to move away from data-related validation and look to new ways to enable greater efficiency and quality.

As a result of this change, new technologies - often based on proven techniques from other industries - have emerged. One area that has witnessed significant advances is the weighing systems that form part of the 'in process control' (IPC) systems.

At present, most IPC systems used in the high-speed aseptic filling of liquids and powders employ balances to weigh vials during production.

Balances are sensitive to vibration, static electricity, air-flow and pressure fluctuations, all of which impact on the accuracy that can be achieved. Balances also require the same vial to be weighed empty and filled in order to establish net weight, meaning the vial is removed twice from the mainstream.

non-invasive

By developing a non-invasive measurement technique BOC Edwards Pharmaceutical Systems and Bruker BioSpin realised that critical parameters could be monitored continuously without disturbing the process or compromising quality of product. As a result, companies could benefit from a quicker and more reliable production process. To achieve this, a joint collaboration was initiated with the result being a non-contact check weigher (NCCW) based on nuclear magnetic resonance (NMR) technology.

NMR is already a proven analytical technology in pharmaceutical and academic research in the areas of drug discovery and structural biology, for example Magnetic Resonance Imaging (MRI) and analysis of blood. It can also be found in quality control applications used in other industries, such as chemical, petro-chemical, food and agriculture.

The working principle of NMR is as follows: protons in the nuclei of certain elements can be thought of as small magnets. When brought into a strong magnetic field, these protons align themselves with this field - like compass needles align with the earth's magnetic field. By applying an additional variable magnetic field these aligned 'needles' can be driven out of their equilibrium position. A special antenna or probe emits this radio frequency field. When the additional field is removed, the protons re-align and while doing so emit a signal detected by the same antenna. This signal is called free induction decay (FID).

calibration

The amplitude of the FID signal is dependent upon the number of magnetic 'needles' present in the measurement zone. Since this relation is linear, a straightforward calibration against known weights can be used to determine the relationship between the measured signal and the amount of product in the measurement area.

The NCCW, which can be used both in a stand-alone set up or in combination with a filling line, is specifically tuned to the frequency of the protons in hydrogen, since virtually all pharmaceutical products contain hydrogen atoms, enabling the calculation to be made.

The integration of NMR technology into a high-speed production line presented the BOC Edwards/Bruker team with a number of technical challenges.

Firstly, the NMR effect is temperature dependent. In a bench-top instrument, close temperature control is relatively straightforward, but in a moving production line it is more complex. The new system uses a combination of insulation, temperature stabilisation and regulation to maintain a constant temperature for measurement.

Then there is the issue of the line itself and the materials it is made from. Although most filling lines use stainless steel vial conveyors with polymer belts, the NCCW is built using specific high quality steel to avoid interference with the magnetic field. Metals in moving parts, such as pulleys, have also been removed.

In order to negate any undesired signals, which can be generated by other parts in the filling line or preceding and following vials, techniques for signal separation have been developed for the NCCW. These techniques investigate the spacing of each vial (spatial separation) to restrict the area of the magnetic RF-field to the sample and analysis of the characteristics of each sample (temporal separation). Various calibration techniques can also be incorporated if required.

And finally, there is the problem that magnetisation of the product decreases with increasing vial speed. There are various ways to overcome this, but basically the solution lies in ensuring constant speed of the line and precision engineering of the detection system to minimise the effect.

in-line measure

This combination of NMR method-ology and process control equipment has resulted in the first 100% in-line weight measurement for pharmaceutical manufacturers. Coupled with the ability to operate at speeds of up to 600 vials per minute, it provides a faster yet more controlled process. Three other key benefits are:

• Any problems on the production line can be identified more quickly and corrected via process feedback to the equipment. As a result, manufacturers can reduce costs associated with out-of-specification (OOS) product and downtime.

• One hundred percent sampling ensures that all vials are filled to within the required weight limits and provides identical product 'experiences', key elements of a well controlled and predictable process.

• The NCCW eliminates the need for 'destructive sampling' (the testing of a set number of vials in the production line). This reduces costs (such as labour and equipment) associated with this testing process.

The NCCW system is the most significant innovation in check-weighing for more than 50 years and yet its full potential is still to be realised. Insensitive to container characteristics, NMR could potentially be deployed to weigh other packaging forms, such as carpoules and syringes. It can also separate signals from liquid and solid components, which could be used to determine moisture content in solids - for example as a quality check for freeze-dried products.