Our laboratory is dedicated to the measurement of FPM from OINDP. With our experience we ensure a smooth operation and traceability of our results. In the following we describe all the steps that are necessary to ensure the correct assessment of foreign particulates from a delivered dose of an inhaler.

How we control FPM in OINDP:

Collect the delivered dose in a collection tube designed for low blank values

We collect the samples and delivered doses a controlled clean environment in order to minimize environmental background. The inhaler is discharged into rap.IDs Foreign Particle Collection Tube (FPCT). This dose apparatus collection tube was specially designed to collect particles (2-10 µm) reliably and be easy to clean and therefore maintain a low blank value. This collection tube is mounted in a controlled class 100 clean bench, Biosafe, Hereaus.

A second collection tube is placed outside the clean bench to collect the waste actuations. In order to guarantee a tight fit to the mouthpiece, the seals, mouthpiece adaptors, tube fittings are manufactured by rap.ID. An additional design feature is the tube’s ability to maintain a flow rate that generates a controlled pressure drop. A flow controller (Copley Scientific, Nottingham, UK) is used to ensure the systems flow and pressure drop characteristics.

Dissolve active and excipient particles and filtration

Samples were suspended in a solvent mixture. The solution is filtered through rap.ID 0.8 µm gold coated Polycarbonate membranes (filtr.AID) on an Effective Filtration Area (EFA) of 4 mm in diameter. Prior to each measurement, a blind sample is prepared and visually evaluated with a video microscope to ensure the cleanliness of the analysis equipment, the environment (clean bench), as well as solvents and materials used in the sample preparation.

Enumerate the particles isolated on a filtr.AID patch with the Single Particle Explorer

Microscopic images of the entire membrane surface, covered with particles, are automatically recorded and evaluated. The automated imaging system takes 100 individual images of the membrane. Automated focusing provides sharpness without user interaction. Particles appear bright, while the membrane remains dark gray to black. The image is binarized and the particles are recognized. The automated thresholding algorithm determines the grayscale threshold, making the result free of subjective judgment . Using this procedure, particle position, length, and width can be determined down to the sub-micrometer. The entire particle-loaded area is scanned, a montage is obtained, and particles overlapping multiple fields are combined and merged with a special algorithm.

Particle Counting Result

Method: Membrane Particle Counting

Automatically identify hundreds of the FPM with the Single Particle Explorer

Selection criteria for spectroscopy are set prior or during the measurement. Thus particles meeting a certain size criteria are chosen automatically for the analysis. Other shape parameters like elongation or rectangularity can also be used to preselect particles for to undergo fully automated analysis. determine for the automated Raman microprobe measurement of the particles. Movement of the membrane is controlled and the motorized stage is able to work with 50 nm steps. This is necessary to align the laser for the Raman analysis with an accuracy of 200 nm, enabling the automated spectroscopy of 500 nm particles such as sub micron particles.

Document the status of FPM numbers and composition in an OINDP

The device carries out Raman spectroscopic examinations on the selected particles. The resulting spectra are automatically identified on the basis of the pharmaceutical and customer-specific database created with Raman chemical fingerprint of material samples. The system therefore has great recognition of mixed materials, such as rubber stoppers or dyed polymers, due to their characteristic chemical fingerprint. An automatically created 21 CFR Part 11 compliant report provides the size, shape and best-matched identification and spectrum quality for each individual particle in the form of hypertext protocol.

Automatically Particle Size + Chemical Composition

The analysis of thousands of particles enables the user to locate the major source(s) of contamination in various manufacturing processes. Over a longer period of time, the comparability of analytical results enables the user to detect trends more easily and install a more intelligent means of quality management accordingly. The routine method enables the user to employ lasting supervision and optimization.