Significance and Use
4.1 The presence of extraneous solid and insoluble particulate matter in a final parenteral drug product is a potential hazard that may cause harm to the patient receiving the drug product in addition to potentially reducing drug product quality, efficacy, and availability.
4.2 This guide provides guidance on the development of AMM test methods designed to count and size particulate matter present in the manufacturing of parenteral pharmaceuticals. An AMM test method consists of four steps: a test liquid preparation procedure, a filtration procedure, an image acquisition process, and an image analysis process.
4.3 Test liquids such as process fluids, drug substances, or drug products sampled from pharmaceutical manufacturing processes may be directly filtered through a membrane filter to create an analysis membrane. Test liquids of interest may also include liquid extracts obtained by extraction (rinsing, washing, and flushing) of the surfaces of process equipment, drug containers, delivery devices, and components thereof. Particles dispersed over sometimes large surface areas are collected in the liquid extract and, upon filtering through a membrane filter, become concentrated onto the relatively small surface area of an analysis membrane.
4.4 In the image acquisition process, the analysis membrane is scanned by an optical microscope and digital camera creating multiple images of the analysis membrane surface. The image analysis process stitches together the multiple images and determines which pixels are associated with individual particles and which pixels are associated with the membrane filter background. Analysis of the resulting segmented image determines the particle count and particle sizes of the particles present on the surface of the analysis membrane.
4.5 Development of test methods applying AMM to the counting and sizing of the wide variety of particulate matter potentially present in parenteral pharmaceutical manufacturing presents significant challenges. Particles composed of different materials, varying in size and morphology, may be found in the various stages of parenteral pharmaceutical manufacturing. Although definitions vary, “intrinsic” typically describes a class of particles originating from formulation ingredients and the materials of construction of processing equipment, final containers, and drug delivery devices. “Extrinsic” typically describes a class of particles originating from human operators and the environment surrounding the manufacturing process. Solid and insoluble particulate matter may include, but is not limited to, textile fibers, hair fibers, paper fibers, plastic and elastomeric particles, metal and ceramic particles, skin flakes, dust, insect parts, and other organic matter. Semi-solid particles (for example, protein aggregates) or liquid droplets (for example, silicone oils) may partially or completely penetrate membrane filters and, thus, are not usually measurable by an AMM test method. An AMM test method may be useful for the measurement of particulate matter inherent to drug products, vaccine adjuvants, and cells in cell and gene therapies. However, the development of AMM test methods for inherent particles is out of the scope of this guide.
4.6 This guide is applicable to the development of AMM test methods for measurement of particles in both the commonly defined size categories of subvisible (<100 µm) and visible (≥100 µm) particles as described in the pharmacopoeias. This guide recommends use of the maximum Feret diameter as a characteristic particle size parameter. Determination of other particle morphology parameters is out of the scope of this guide.
Scope
1.1 This guide provides guidance on the development of test methods that apply automated membrane microscopy (AMM) to the measurement of extraneous solid insoluble particulate matter present in parenteral pharmaceutical manufacturing processes and drug products. For the validation requirements for AMM test methods, see Practice E3411.
1.2 In an AMM test method, a test liquid containing suspended particles is filtered through a membrane filter, the particles are retained on the surface of the membrane filter, the membrane filter surface is imaged with an optical microscope and digital camera, and application of image analysis software determines particle count and particle sizes.
1.3 AMM test methods may be applied to the measurement of the commonly defined size categories of subvisible (<100 µm) or visible (≥100 µm) or both particulate matter present during any stage of the manufacturing of parenteral pharmaceuticals.
1.4 The test liquid characterized by an AMM test method may be a process fluid, drug substance or drug product, or liquid extracts from the surfaces of processing equipment, drug containers, delivery devices, and components thereof.
1.5 This guide does not apply to the characterization of particles inherent to parenteral suspensions (for example, cells, protein aggregates, or vaccine adjuvants) or the characterization of liquid droplets (for example, silicone oil).
1.6 Units—The values stated in SI units are to be regarded as standard. No other units of measurement are included in this standard.
1.7 This standard does not purport to address all of the safety concerns, if any, associated with its use. It is the responsibility of the user of this standard to establish appropriate safety, health, and environmental practices and determine the applicability of regulatory limitations prior to use.
1.8 This international standard was developed in accordance with internationally recognized principles on standardization established in the Decision on Principles for the Development of International Standards, Guides and Recommendations issued by the World Trade Organization Technical Barriers to Trade (TBT) Committee.
