Significance and Use
4.1 From a quality risk management perspective (ICH Q9), 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. Minimization of the probability of occurrence of particulate matter in a drug product depends upon conformance to current good manufacturing practices (CGMPs) along the entire pharmaceutical manufacturing process from starting ingredients to final drug product. Good detectability of particulate matter in parenteral drug products results from the required combination of 100 % visual inspection, along with sampling and destructive testing of final drug products for subvisible (<100 µm) particulate matter as described in USP <788> and related USP and equivalent harmonized European (EP 2.9.19) and Japanese (JP 6.07) monographs.
4.2 In the USP <788> Method 2 microscopic particle count test, particles suspended in liquid are filtered onto a membrane filter, and under controlled illumination conditions, the particles collected on the membrane filter are manually counted and size classified under a microscope using a reticule consisting of a defined inspection field and reference circles (graticules) of 10 µm and 25 µm diameter. The number of particles found ≥10 µm and ≥25 µm are reported. Method 2 is labor intensive and susceptible to human error since each particle is individually size classified and counted manually by the human analyst.
4.3 The pharmacopoeial chapters also describe automated methods for the measurement of particulate matter suspended in liquid. In the USP <788> Method 1 light obscuration particle count test, a particle suspended in liquid is drawn into a tube, passes through a light beam detector, and the particle is counted when the light beam is attenuated because of scattering or absorption or both of light by the particle. The light attenuated by the particle is related to a particle size via comparison with a calibration obtained with spherical particle size standards. Thus, the output of USP <788> Method 1 is an equivalent circular diameter. Note that USP <1788.1> indicates that light obscuration is useful for an approximate particle size range from 1 µm to 300 µm depending upon instrument and configuration. Alternately, USP <1788>, <1788.3>, and Guide E3060 describe flow imaging, in which the detector is an imaging system, and image analysis determines particle size. Measurement techniques specifically applicable to therapeutic protein injections are described in USP <1787>.
4.4 In addition, “automated approaches” to the measurement of particulate matter on the surface of a membrane filter are discussed in Section 6 of USP <1788.2>. In USP <1788.2>, it is noted that, with automation, “there is increased potential for objective accuracy and precision versus subjective human decision and tabulation” required in the manual size classification of particles as per USP <788> Method 2.
4.5 This practice describes the requirements for validation of automated membrane microscopy (AMM) test methods designed to count and size particulate matter present in the manufacturing of parenteral pharmaceuticals. 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.
4.6 Significant challenges arise in the validation of test methods applying AMM to the counting and sizing of the wide variety of particulate matter potentially present in parenteral pharmaceutical manufacturing. Particles composed of different materials, varying in size and morphology, may be found in the various stages of parenteral pharmaceutical manufacturing. 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 and validation of AMM test methods for inherent particles is out of the scope of this practice.
4.7 Particulate matter may be carried into the final drug product from formulation ingredients and processing equipment. Particulate matter may also be carried into the final drug product via final containers and drug delivery devices, along with components thereof (for example, glass containers, elastomeric closures, syringe assemblies, and infusion bags). Various guidance and standards documents describe methods for generation of test liquids suitable for AMM test methods via liquid extraction of the surfaces of single-use process equipment (Practice E3230), final container materials (ISO 8871),10 and drug delivery devices (VDI 2083 Part 21), along with procedures for the analysis of particulate matter in “difficult to inspect” drug products.11
4.8 This practice is applicable to the validation 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. In this practice, the use of the maximum Feret diameter as a characteristic particle size parameter is recommended. Determination of other particle morphology parameters is out of the scope of this practice.
Scope
1.1 This practice covers the requirements for validation 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 extensive guidance on the development of AMM test methods see Guide E3425.
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 practice 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.
