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Particulate Matter Testing

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What is particulate matter and why is testing performed?

Particulate matter is unwanted solid material in solutions for injection. Particle counts that exceed USP limits in intravenous drug products could block blood flow inside the patient’s body causing paralysis or death.  

Particulate matter testing is a good indicator of the quality of a manufacturing process and the containers used. If the containers are not particle free on the inside, this will introduce particulates into the drug product. If the instrumentation used is not clean, unwanted solid matter could end up in a final drug product and cause patient harm.

Where does particulate matter come from?

Particulate matter comes from three sources:

  • Intrinsic stems from the internal manufacturing process. This can be introduced in the drug formulation, packaging or container, and poor cleaning systems. Examples include glass from inside containers, stainless steel from container closure systems, or rubber from the stoppers.
  • Extrinsic stems from the external production environment and human error. This can be introduced during improper gowning in a cleanroom and other external behavior. Examples include clothing, hair, metal, plastic, or paint that fall into sample containers.
  • Inherent stems from a product’s characteristic that may contain a small level of unintended particulate matter, even after careful formulation

How is particulate matter tested?

United States Pharmacopeia has three main chapters that describe testing methods and specifications for particulate matter:

  • USP <787> Subvisible Particulate Matter in Therapeutic Protein Injections
  • USP <788> Particulate Matter in Injections
  • USP <789> Particulate Matter in Ophthalmic Solutions

USP also has chapters that give broader information and relate to the test methodology:

  • USP <771> Ophthalmic Products – Quality Tests
  • USP <1788> Methods for the Determination of Subvisible Particulate Matter
  • USP <1788.1> Light Obscuration Method for the Determination of Subvisible Particulate Matter
  • USP <1788.2> Membrane Microscope Method for the Determination of Subvisible Particulate Matter

ARL Bio Pharma uses validated methodology to test particulate matter samples. Our laboratory uses two methods to test for particulate matter: Method 1 and Method 2. There are advantages and disadvantages to each method. ARL determines which method to use based on sample type. 

Method 1 uses a light obscuration particle counter to test the sample. A probe goes into the sample container. The sample travels up through the laser’s path and particles are counted. When testing is complete, the sample is discarded out of the system to a waste container

Method 2 uses a microscope, and an analyst counts the particles. The particles present in a sample are collected on a membrane filter and then viewed under a microscope for counting. The analyst uses a graticule inside the microscope lens to determine the size and count of the particles based on USP criteria.

Method 1Method 2
Appearance
  • Objective – particle count is performed with a laser and is calibrated regularly
  • Results are repeatable and reproducible
  • Fast processing time
  • Sample thickness and color does not affect the test
  • Only particles are counted
  • Particles are retained on the filter so they can be analyzed later
Appearance
  • Sample properties may preclude testing (color, texture, and thickness)
  • Bubbles may be created during testing and the laser cannot distinguish between bubbles and particle counts. This may give a false count.
  • Sample tested cannot be used for additional analysis
  • Subjective – depends on analyst’s eyesight and size judgement
  • Longer processing time

What are the USP Particle Size Limits for Light Obscuration and Microscopy?

USP <787> Subvisible Particulate Matter in Therapeutic Protein Injections

Sample Volume≥10 µm≥25 µm
≤100 mL6000 per container600 per container
100 mL25 per mL AND 6000 per container3 per mL AND 600 per container

USP <788> Particulate Matter in Injections

MethodSample Volume≥10 µm≥25 µm
1-a>100 mLNMT 25 particles/mLNMT 3 particles/mL
1-b≤100 mLNMT 6000 particles/containerNMT 6000 particles/container
2-a>100 mLNMT 12 particles/mLNMT 2 particles/mL
2-b≤100 mLNMT 3000 particles/containerNMT 300 particles/container

USP <789> Particulate Matter in Ophthalmic Solutions

Method≥10 µm≥25 µm≥50 µm
1NMT 50 particles/mLNMT 5 particles/mLNMT 2 particles/mL
2NMT 50 particles/mLNMT 5 particles/mLNMT 2 particles/mL

For more information on particulate matter testing, contact (800) 393-1595 or info@arlok.com 

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