USP 788 Particulate Matter in Injectables
Parenteral drug infusions for intramuscular, subcutaneous or intravenous (IV) injection should be virtually free of subvisible particles that can be harmful when introduced to the bloodstream. To ensure these products meet or exceed standards, particles are detected and measured using light obscuration analysis or microscopic inspection after capturing the particles on a filter.
USP <788> Particulate Matter in Injections. The USP <788> Particulate Matter in Injections.general chapter is used to determine the count and size of undissolved particles in injection solutions ≥ 10 and ≥ 25 µm. This general chapter provides an overview for the use of two procedures; Method 1, Light Obscuration Particle Count Test, and Method II, Microscopic Particle Count Test. Chapter <788> of the United States Pharmacopeia (USP) is harmonized with Chapter 2.9.19 of the European Pharmacopoeia, and Japanese Pharmacopoeia. These standards apply to most small- and large-volume parenteral products.
USP <789> Particulate Matter in Ophthalmic Solutions. Ophthalmic solutions are used in the treatment of eye conditions and the determination of foreign particles in these products is of obvious importance to prevent irritation and possible damage to a patient’s vision in extreme cases. This general chapter is closely related to USP <788> in that the same analytical techniques are used, however a ≥ 50 µm size criterion is added to the product acceptance criteria.
USP <787>, Subvisible Particulate Matter in Therapeutic Protein Injections. Investigating protein aggregation phenomenon is required to evaluate shelf life, stability and efficacy just as a few examples. USP Chapter 787 outlines testing of more sensitive therapeutic protein formulations and allows a smaller sample volume testing framework to address proteinaceous particles in samples with small volume dosage forms. Protein injections are often only available in single milliliter dosages, so their testing requires modified USP 788 testing procedures.
METHOD 1
Light Obscuration Particle Count Test is used to examine injections and parenteral infusions for subvisible particles, other than gas bubbles, unintentionally present in the product. A vial or a pooled sample of vials from the product are sampled by the instrument in a clean environment. The instrument measures the number and size of particles in the injectable formulation and the results compared to USP requirements. PTL’s instrument is performance verified on a routine basis to ensure counting and sizing accuracy specifically for this important test.
In some cases, it may be necessary to further test some products by the Microscopic Particle Count Test to prove conformance to requirements. For example, products that produce air or gas bubbles when drawn into the sensor, are of high viscosity, or are optically opaque may require microscopic particle count testing. The Microscopic Particle Count test is also used to reach a conclusion on conformance to the requirements if an unexpected result is obtained from the Light Obscuration test.
METHOD 2
Microscopic Particle Count Test is conducted by retaining particulate on a membrane filter for examination under a microscope. The filter is then scanned visually by a trained chemist using a microscope with proper illumination capabilities. The observed particles are compared against a USP defined reticle to determine if they are ≥ 10 and ≥ 25 µm. The microscopy count test is used for unique products which are not appropriate for Method 1 or as a secondary check for unexpected results from the Light Obscuration Test. Should a sample have reduced clarity or increased viscosity, such as in emulsions, colloids, or liposomal preparations for example, Method 2 should be utilized rather than Method 1.
Advantages
- High Accuracy - each particle is measured directly (Method 1)
- Syringe pump pulls accurate and precise sample volumes (Method 1
- Easily adapted for FDA requested “cleanliness testing” of medical devices
Considerations
- For medical devices, a discussion on the size of the device, complexity and type of proposed simulated use system would determine if PTL could assist with the testing
- The USP chapter does not provide guidance for medical devices; therefore, PTL depends on our clients to determine how many devices would need to be included into a sampling plan
Sample Requirements
For small volume vials, 10 or more units should be pooled, totaling no less than 25 mL total.
Vials with volume of 25 mL or more can be tested individually.
Detection Range
The AccuSizer A7000/780SIS has a nominal detection range of 2 µm to 400 µm.
Data Reported
Count of particles ≥ 10 µm and ≥ 25 µm. For USP <789> a count of particles ≥ 50 µm.
Instrumentation
The instrument used at Particle Technology Labs for Method 1 is the Entegris / Particle Sizing Systems AccuSizer model A7000/780SIS. For Method 2 a Nikon Eclipse Ci polarizing microscope is used.
AccuSizer Model A7000/780SIS
