With water contributing the largest component of pharmaceutical products, especially injected products, control of the quality of water in both systems and finished product is paramount. The particulate burden of finished product is a Pharmacopoeia regulation in the major standards documents, USP<788>1 and USP<789>2, EP<2.9.19>3, and JP<6.07>4.
It should be noted that particle counting is not a method for determining the distribution of particles in a suspension, as here the particle burden would saturate the optics of most commonly used particle counters employed in contamination controls; there is an expectation that the liquids being tested are “essentially free” from contamination and the particle counter is looking for particles possibly caused by events in the handling and management of the water supply that has caused an out of control condition.
There are two primary methods for measuring the particle contamination of liquids: light obscuration and light scattering.
Light obscuration particle counting is where a beam of light (laser) is directed through a narrow capillary tube with a flowing stream of liquid; any particle passing through the laser beam blocks a certain amount of light and casts a shadow across the photo-detector. The amount of light blocked is equivalent to the size of the particle in the liquid; accurate sizing of the detected particles can be determined by calibrating the particle counter with particles of known sizes suspended in clean water.
This method of light obscuration is ideal for measuring particles that are relatively large, 1.5 microns (1.5 µm) up to over 150 microns (150 µm); particles greater than 150 µm are typically within the range of those particles that are potentially visible.
For smaller particles than the 1.5 µm lower limits of light obscuration, light scattering is used.
Light scattering is where the laser beam is directed through a narrow capillary tube with a flowing stream of liquid. When a particle within that stream passes through the laser beam light is scattered off the particle by several different interactions with the particle’s surface (reflection, diffraction, and refraction), this scattered light is then collected using a series of mirrors and focused onto a photodetector for analysis. The amount of light scattered off a particle is equivalent to its size; i.e. the bigger the particle the more light is scattered, and accurate sizing of particles within a liquid can be determined by the calibration of a particle counter against known size standards.
This method of particle counting using scattering is used for volumetric instruments down to 0.2 µm and is effective up to above 20 µm. Below the 0.2 µm threshold volumetric sensors tend to give way to non-volumetric instruments where only a small fraction of the total liquid flow is monitored.
There are two primary applications for particle counters in production environments: the primary one being the testing of finished products to those standards identified above and a second one of monitoring the quality of the water for injection (WFI).
Testing of finished products to the Pharmacopoeia standards is performed against a strict test requirement. Test samples comprise of either a pooled sample of small injectable products, sufficient to perform testing. A minimum of 10 pooled containers should be used, or where large production volumes are manufactured a portion of several individual containers can be used. These differences are based upon the finished products’ normal supplied volume being less than or greater than 100ml. The sample is drawn using a syringe sampler through a light obscuration particle counter and the number of particles measured are reported as either particles per container volume, or particles per ml. The current limits for maximum allowable concentrations are given in the table below.
Instruments used for performing these tests must be validated to meet the requirements of “suitably calibrated” and the regional requirements for count standard accuracy.
The second application for particle counters is for demonstrating control over the particle burden of the WFI system. There are no current regulations that require monitoring be performed; however, several facilities that have employed particle counters on the WFI loop have been able to notice when filters are beginning to degrade as there is a shift in the distribution of particles remaining in the water. When filters begin to blind and the smaller pores block, two thing occur: a rise on pressure across the filter, and a shift in the distribution of particles where the smaller sized particles increase relative to the overall population. It is common to change filters based upon either a maintenance schedule of time, or an increase in the pressure drop across the filter, where particle counters have been employed; however, filter life can be extended as the distribution shift is monitoring, or shortened as increases in overall levels of particles is witnessed in the clean supply.
It also allows for the identification of when a recirculation problem may exist within a filling tank; if the recirculation pumps on the system begin to fade, the filters become less efficient (overall volume filtered) and so a recovery of the system can be identified.
1. USP <788>. Particulate Matter in Injections, United States Pharmacopoeia 37-NF 32, May 1, 2014
2. USP <789>. Particulate Matter in Ophthalmic Solutions, United States Pharmacopoeia 37-NF 32, May 1, 2014
3. EP <2.9.19>. Particulate Contamination: Sub-Visible Particles, European Pharmacopoeia 5.0, January 2005.
4. JP <6.07>. Insoluble Particulate Matter Test for Injections, The Japanese Pharmacopoeia 16, March 2011
Mark Hallworth, Market Manager for the Life Sciences Division of Particle Measuring Systems in Boulder, Colo., has spent over 17 years with the company. He has over 25 years’ experience in particles, including their transportation and measurement in many industrial and scientific applications. He has designed several instruments for the measurement of particles, including extreme environmental conditions and fully integrated controls systems, which has led to software products that meet the demands of a regulated industry. firstname.lastname@example.org; www.pmeasuring.com
This article appeared in the October 2014 issue of Controlled Environments.