Contaminants may be identified by microscopical examination of their morphological characteristics; their shapes and forms are extremely important features in their analysis and tracing their origins. AMRI recognizes that every pharmaceutical, nutritional, and food product has the inherent risk to contain unknown particulates and that rapidly characterizing these contaminants provides our clients with important information to help investigate and resolve the issue. These unknown particles or foreign particulate matter can be visually distinguished from the raw materials, materials in intermediate process steps, or the final product. In our experience, particulate matter can appear from four major sources of contamination: raw materials such as packaging, the working environment, processing steps, and instability of the container or product. Though most relevant scholarly articles focus on visible and sub-visible particulates in injectables, unknown particulates can occur in any liquid, semisolid or solid dosage form or food. The United States Food and Drug Administration (FDA) classify a pharmaceutical with unknown particulates or foreign particulate matter as adulterated, meaning that the product differs from the standard of strength, quality, or purity.  Food products are similarly classified as adulterated when unknown particulates exceed the maximum level of defect allowed by the FDA.

Upon discovering unknown particulates or foreign particulate matter, the particles must be identified, and their source(s) investigated and confirmed. For pharmaceuticals, corrective and preventive actions (CAPA) must be established according to ICH Q10 Guidance for Industry: Pharmaceutical Quality System with a thorough evaluation of the potential risk as defined in ICH Q9 Guidance for Industry: Quality Risk Management. Since unknown particulates have many possible sources and their physical size is usually quite small, their identification can be both technically interesting and challenging.  Gaining an understanding of where the particulates first appear and the extent to which they appear can help to determine which analytical techniques are most appropriate. Most often, light microscopy is the first step to start the identification and sometimes positively identify materials such as fibers and human hair, for example. IR microscopy is another tool used as it often can provide absolute identification of many materials including polymers, organic compounds such as drugs, vitamins, or excipients/food additives, and sometimes inorganic metals, to name only a few. Subsequent testing is based on these initial techniques and is used to either confirm the material’s identity or provide additional data to make an identification. To enable root cause analysis, it is best to compare results with a clean sample, as well as a sample of the suspected source of contamination, such as a piece of filter or screen, ink that might have rubbed off a packaging material, lubricating grease used on a packaging line, etc.  The use of qualified instrumentation maintained under current Good Manufacturing Processes (cGMP) and data handling systems provides confidence in the results and subsequent conclusions made by our team of highly-skilled microscopists and microspectroscopists.

Unknown Particulate Testing Services

AMRI offers the following microscopy and microanalytical techniques relevant to the characterization of unknown particulates:

  • Contaminant Analysis Services, USP <788> and <789>
  • FEI Quanta 200 ESEM
  • Energy Dispersive X-ray (EDX)
  • Leica DMLP Compound Polarized Light Microscope
  • Leica Stereomicroscope, MZ6, MZ12.5 and M80
  • Leica Polarized Light Stereomicroscope, DMLP
  • Linkam Hot/Cold Stage (–196 to +350 °C)
  • Linkam Lyophilization Stage (freeze drying, –196 to +100 °C)
  • Nikon Optiphot-pol Compound Polarized Light Microscope
  • Zeiss Imager.A2m Polarized Light Microscope
  • Wagner & Munz Kofler Hot Stage and Hot Bar
  • Continuµm Fourier Transform Infrared (FT-IR) Microscope with Fluorescence illumination capabilities
  • Raman Microspectrometer

USP <788> and <789> Testing

As a keystone to the support services required for characterization of unknown particulates or foreign particulate matter, AMRI is able to provide expert services to support contaminant analysis specifically for injectable products. The Particle Sizing Systems AccuSizer 780 SIS is a Single Particle Optical Sensing (SPOS) system, also known as light obscuration, used to count and size particles between  0.5 to 400 micrometers. The system is operated in a HEPA-filtered laminar flow hood designed to create a Class 100/ISO 5 work environment and uses a syringe pump to pull accurate and precise aliquots of liquid samples through a light obscuration sensor. This technique allows skilled our microscopists to conduct USP <788> (Particulate Matter in Injections) and USP <789> (Particulate Matter in Ophthalmic Solutions) to characterize extraneous, undissolved sub-visible particles unintentionally present in the solutions using light obscuration and microscopic particle counting (Methods 1 and 2). For both USP <788> and <789>, Method 2 is also available for microscopic counting of particles collected on a membrane filter or for liquid samples that exceed the particle count parameters as stated in Method 1 for either General Chapter.