Why is particulate matter testing crucial for injectable medicines, and what does it entail?

The USP’s requirements for injectable particle matter testing are in line with those of the European and Japanese Pharmacopeias. In injectable solutions, undissolved particles (apart from gas bubbles) are referred to as particulate matter. The parenteral formulation does not purposefully contain these particle materials. Unintentional, non-biological particles are controlled in injectable formulations to prevent undesirable toxicity, disease, or side effects, much like unintended microorganisms are avoided and controlled in injectables to prevent patient illness. The USP 788 particle matter regulation standards are not applicable to persons making parenteral medications for veterinary use, solutions for irrigation only, or radiopharmaceutical preparations. Your injectable product might be free from particulate matter regulations if it filters before being administered to patients, as long as there is scientific evidence to support the exemption. Please take note that injectable and parenteral will be used interchangeably in this text. Therefore, the words “small-volume injection” and “small-volume parenteral” are interchangeable.

There are two methods for detecting particulate matter: the tiny particle count test and the light-obscuration particle count test. For the detection of subvisible particles, light-obscuration particle count measurement is recommended. Microscopic particle count tests should be used to evaluate parenteral preparations that have higher viscosity or decreased clarity, such as emulsions, colloids, and liposomal formulations. Products that frequently create air or gas bubbles during sampling can also benefit from microscopic particle count testing. In certain situations, confirming subvisible particle counts will require the use of both particulate matter test methods. Additionally, many injectable formulations could be challenging to evaluate using both conventional particle matter testing techniques. In these specific situations, which frequently occur when the test preparation’s viscosity is high, a quantitative dilution with the proper diluent may be done to reduce viscosity as needed to enable the particle analysis.

How is testing for tiny particle counts done?

A binocular microscope, a filter assembly for collecting particulate matter, and a membrane filter for sample analysis are used in microscopic particle count testing. The ocular micrometer of the microscope will have a graticule (reproduced from Figure 1 of USP 788 below). A stage micrometer that has been approved by a national or international standard organization is used to calibrate the ocular micrometer. The microscope assembly also requires two illuminators, one external and one internal.

Figure 1 shows a graticule with a circular diameter. The graticule field of view (GFOV) is the huge circle that has been divided into quadrants by crosshairs. For particle size, transparent and black circles with widths of 10 μm and 25 μm are offered as comparative scales.

All glassware and testing apparatus are cleaned with particle-free water before use. Following equipment setup, particle-free water samples are examined to ensure that no more than 20 particles measuring 10 μm or larger are detected in triplicate particle-free controls. The testing apparatus will be cleaned and recalibrated prior to sample testing if more particles are found.

Slow inversion is used to mix the contents of each sample for testing. The contents of 10 or more units are mixed in a sanitized container to provide a volume of at least 25 milliliters (mL) for small-volume parenterals (less than 25 mL in volume). To guarantee test accuracy, a parenterally administered powder is reconstituted using either particle-free water or a suitable particle-free solvent. Individual testing is not required for injectables with a volume of 25 mL or more. All things considered, there must be a sufficient number of samples (pooled or not) to produce a statistically sound evaluation.

Following the preparation of the injectable samples, particle-free water is used to moisten the filter holder. The filtration funnel receives the entire volume of an injected sample or pooled sample. After then, a vacuum is used until there is no more liquid on the membrane filter’s surface. The membrane filter is then put in a Petri dish and left to dry naturally. The membrane filter is examined under a microscope in its entirety once it has dried. Both the number of particles equal to or greater than 25 μm and the total number of particles on the membrane filter that are equal to or greater than 10 μm are tallied. By comparing the particle’s equivalent diameter to the 10 μm and 25 μm reference circles on the graticule, the particle’s size is estimated.

Amorphous, semiliquid, or other unclear materials that appear as a stain or discoloration on the membrane filter cannot be sized in microscopic particle count measurements. These substances appear to be gelatinous or film-like. Use the light-obscuration particle count test on a sample of the solution if thick or film-like materials start to show up.

Determine the sample’s mean particle count once the particles have been counted. Two test criteria apply to microscopic particle count tests. The first test criterion is applicable to sample preparations that have a volume greater than 100 mL. The second test criterion is applied to samples that have a volume of less than 100 mL. If the average number of particles in the sample is less than 12 particles per milliliter (mL) equal to or greater than 10 μm and less than 2 particles per milliliter (mL) equal to or greater than 25 μm, the sample satisfies the first test criterion for the particle count test.

If the average number of particles in the units tested is less than 3000 per container, which is equal to or greater than 10 μm, and less than 300 per container, which is equal to or greater than 25 μm, the sample satisfies the second test criterion.

In Brief

articulate matter testing is a crucial injectable microbiological test. Injectable formulations control unintended, non-biological particles to avoid unintended toxicity, disease, or adverse consequences in patients after therapy. Particulate matter testing can be done using two different methods: microscopic particle count testing and light-obscuration particle count testing. When preparations are too viscous or hazy for light obscuration particle count techniques, microscopic particle count testing is employed. All things considered, when creating your injectable product, make sure you pick a contract testing company that can help you with the right microbiology testing for your particular product or medical device requirements.