Ph. Eur. 2.9.19. Particulate Contamination: Sub-visible Particles

This harmonized chapter recognized as interchangeable under ICH Q4B Annex 3(R1), provided the chapter is applied in full, establishes official methods and acceptance criteria for controlling sub-visible particulate matter in parenteral injections and infusions. Sub-visible particles (≥ 10 µm and ≥ 25 µm) are not visible to the naked eye but can cause emboli, inflammation, or other adverse effects if injected. The limits protect patient safety by ensuring that particulate levels are maintained below internationally agreed thresholds.

Applies to small- and large-volume parenterals, numeric limits do not apply to products that inherently contain particles (e.g., emulsions, liposomes, suspensions). However, such products require alternative, validated methods to confirm absence of extraneous particulates.

• Tests are performed on the final product in its container, or after reconstitution if supplied as a powder; handling must avoid bubble formation or extraneous particulates that could bias results.

  Test Methods

  1. Light Obscuration Particle Count Test – Preferred method

     • Measures light blockage pulses as particles pass through a laser beam.

     • Objective, rapid, and suitable for clear, low-viscosity liquids.

  2. Microscopic Particle Count Test – Alternative method

     • Filters a known volume through a ~0.45 µm membrane.

     • Particles are sized and counted microscopically.

Used when light obscuration is unsuitable (colored, viscous, or bubble-forming products).

Light obscuration is the compendial method of choice; microscopy is permitted only when light obscuration cannot be applied.

Harmonized Acceptance Criteria

• Harmonized acceptance criteria (per EP 2.9.19/USP <788>/JP) per mL of product tested, based on the measured sample.
  • Small-volume parenterals (≤100 mL): not more than 6 000 particles ≥10 µm and not more than 600 particles ≥25 µm per container.
  • Large-volume parenterals (>100 mL): not more than 25 particles ≥10 µm and not more than 3 particles ≥25 µm per mL.