QUALITY CONTROL OF STERILE PRODUCTS (2)

CLARITY TESTING (DETECTION OF PARTICULATE MATTER)

Particulate matter can be detected in parenteral product by two methods, including visual inspection and electronic particulate counting.

A) Visual methods

1) Visual inspection by naked eye

In visual inspection, each injectable is inspected visually against white and black backgrounds. The white background aids in diction of dark colored particles. The light or reflective particles will appear against the black back ground. Some visual-enhancing aids can increase the efficiency. A magnifying lens at 2.5 × magnification set at the eye level facilitates the inspection. Microscopic examination enhances detection of particulate matter in injectables. Visual inspection gives the qualitative estimation of the particulate matter. Acceptance Standards is that each container checked must not contain any visible particulate matter.

II) Automated visual inspection

The automatic systems are also called as the electron particles counter. The electronic particles counter evaluates the particles in injectables automatically. However, this method requires destruction of the ampoule/container for the particle examination.

Electronic particles counting may be based on any one of the following principles: a) change in electrical resistance, b) light blockages principle and c) light scattering. Some of the automated systems for visual particle inspection include Autoskan, Eisai Ampoule inspection machine, Schering PDS/A-V system, etc. Autoskan System.

The Autoskan system is based on light scattering principle whereby the particle in the path of a light source causes the scattering of light. The scattered light is measured and provides the corresponding information regarding the presence of particulate in the sample. This is a non-destructive test.

EISAI AMPOULE MACHINE SYSTEM

The Eisai ampoule machine (AIM) system is based on the light blockage principle. The particle size dimensions are determined with the shadow created by the particle under light source. Assessment of the shadow is the indication of the presence of particulate matter. This is also a non-destructive test.

Schering PDS/A-V system

The Schering PDS/A-V System is based on light scattering by particle if present in the sample. This is also a non-destructive test.

B) PARTICLE COUNT METHODS

Particle count methods are the USP specified microscopic methods, which require the use of optical microscope and automatic microscope.

I) Optical Microscopic Method

The optical microscopic method requires magnification of 100 k.10x. One eyepiece must

be equipped with graticule. A graticule have a series of circles of different diameters,

usually in a “under root 2 progression”. The graticule is in circular diameter used to size

the particulate. The micrometer is graduated in 10 micro meter increments.

A circular diameter graticule

Ii) Automated Particle Counters

The automated particle counters are based on the light obscuration, light scattering method and the electrical resistance methods. Coulter Counter counts the particles in a sample based on the change in the electrical resistance. Particle size detection limit in this instrument is from 0.1 to 1000 micrometer.

The powder sample requires pretreatment such as dispersion in an electrolyte to form a very dilute suspension. The Suspension is usually subjected to ultrasonic agitation to avoid particle agglomerates. A dispersant may also be added to aid particle deagglomeration. Passage of particle causes the change in electrical resistance in between the electrodes which is proportional to the volume of particle. The change in resistance is converted into voltage pulse which is amplified and processed electronically and split into the particle size distribution into many different size-range.

Glass Tube

Orifice

Principle of coulter counter

This is a destructive test and large errors in measuring flakes and fibers are expected.

This test is not recommended by FDA for parenterals.

Illustration for a coulter counter

High Accuracy (HIAC) Instrument

High Accuracy (HIAC) Instrument is based on light blockage principle. The test is highly effective for counting the both solid and liquid suspended particles. The instrument is calibrated easily and the test is recommended by USP. This is destructive test method and is expensive.

P Light source

Digital

Value

Principle of light blockage

Met-One Climet Particle Counter

Met-One Climet Particle Counter is based on light scattering principle. The particles are assessed and counted in the sample based on the principle of light scattering. The instrument measures 6 particles sizes at a time and has the excellent ability for the detection of large particle. The test is destructive.

Depending on the instrument used, the sample may be presented as the liquid as suspension or air suspension. The light emitted by a helium-neon laser is incident on the sample particle. Light-particle interaction results in scattering of light. The photo detector converts the signals corresponding area/volume diameter of the particle.

Instrument based on light scatter principle