Visible Particulates for Injectable Drugs
Visible particulates refer to insoluble substances present in injections, ophthalmic liquid drugs and sterile raw materials that can be visually observed under specified conditions, and their particle size or length is usually greater than 50μm.
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Advantages
Compliance
FDA、EMA、WHO、PIC/S、NMPA（CDE）
Marketing Proven
Cooperation with top global clients, such as Apptech, Hengrui Pharma
Customization
Wide ranges of options to meet your demands.
Applications
01
Set-up a defect library
02
Verification of light inspection machine
03
Knapp human-machine comparison
04
Operators Training
Technical Specifications
| Defect Type | Glass, metal, fibers, black specks, white specks, hair, rubber particles, white plastic, colored specks, clumps, sub-visible particles, fill volume variation, glass crack, aluminum seal defect, and other customized defects. |
| Partical Size | 50um-2000um |
| Qty | 1-3、5-10、≥10 |
| Volume | 1mL、2mL、5mL、20mL |
| Liquid Carrier | Water, Liquid of drugs |
| Packaging Type | Ampoules, vials, cartridges, PFS, and others |
Regulatory agencies worldwide explicitly require the use of visible particulates.
7.5 These qualified defects standard units are then assembled into test sets, which may be used to specifically challenge the particle detection technique of human inspectors, used as part of a defect test set (including container-closure defects) for human qualification or for comparison during automated equipment qualification and validation. When possible, the test set should be prepared with duplicate product units per particle type and size to ensure that backup units are available in the event that a standard container is broken or the particle is trapped or lost within the container.
TS1 What are the differences between qualification, particle (Knapp test) and function test set?
The function test set serves for a sort of system suitability test, i.e. this test is used to test before and after each batch whether the cameras are functioning correctly. Usually, no challenging samples are used for this, but rather unities with particles having a detection rate of 100% such as particles with a size of 1000 µm, vials with missing stoppers.
Qualification test set: the qualification test set consists of product specific containers containing the product and having all known "static" defects (scratches, wrong flip-off, missing stopper,...). Usually, about 10-20% of the containers of the set have a defect. New failures or defects are added to the qualification test set.
Particle test set (Knapp-Test): Sets that contain only particles. These are particles having the size from 50µm to 1000µm and consisting of different materials (plastic, the material stoppers are made of, glass, metal). Hence, they are "non-static", i.e. the defect is in the container or in the drug solution. Particle test sets are part of the qualification test set at the same time.
TS2 Should all these test sets be prepared artificially? Should this be done, for instance, by an external laboratory with defined failures?
We prepare the static defects in-house and a part of the non-static defects (particle defects) are produced externally. But it is also possible to have everything produced externally. But the static defects should be the same that are generated in the worst case by your production machines. Therefore, I advise to make these in-house and get the release from QA. In this way you would have representative bad samples from your process. In the best case you take bad samples from your process but it is not possible to do this for all samples.
8.30 A defect library should be generated and maintained which captures all known classes of defects. The defect library should be used for the training of production and quality assurance personnel. Critical defects should not be identified during any subsequent sampling and inspection of acceptable containers.
8.31 The qualification should be undertaken using appropriate samples from the manufacturer's defect library sets.
8.32 Where automated methods of inspection are used, the process should be validated to detect known defects (which may impact product quality or safety) and be equal to, or better than, manual inspection methods. The performance of the equipment should be challenged using representative defects prior to start up and at regular intervals throughout the batch.
Visible particulates are defined as insoluble matter that can be observed by the unaided eye under specified conditions, with particle size or length typically greater than 50 μm.
Two primary methods are available for the inspection of visible particulates: the visual inspection method and the light scattering method. The visual inspection method is generally the most commonly used approach. For products for which the visual inspection method is not suitable—such as those packaged in dark transparent containers or those with deeply colored liquids (generally darker than Standard Color Solution No. 7)—the light scattering method may be employed as an alternative.
Manufacturers shall use risk assessment tools to identify potential defect types for the product, taking into account product characteristics, manufacturing processes, primary packaging materials, and historical defect data. Defect types shall be classified into severity levels-typically critical, major, and minor-based primarily on the impact on patient safety. Probability of Detection (PoD) criteria shall be rationally established for each defect type.
Defect samples shall be prepared for use in manual inspection qualification or for comparison with alternative (automated) methods. To ensure that the prepared defective samples are representative, they may be obtained from the following two sources:
More Information
How does ECA stipulate about visible particulates for injectable drugs?
4.3 What aspects should be considered when assessing artificially created test kits, and how should their suitability be justified?
Artificially created test kits are often used when representative production samples are unavailable, technically unsuitable, or cannot be obtained in sufficient quantity for qualification, training, or evaluation purposes.
Their suitability should be assessed based on the inspection technology used and the required level of representativeness. Artificially created defects and conforming units should exhibit optical, physical, and mechanical characteristics comparable to those of the real product under routine inspection conditions.
For AI-based inspection systems, higher requirements regarding representativeness may apply, as these systems often utilize very subtle features and characteristics to distinguish between acceptable and defective units. For example, a genuine lyophilized cake with crystalline reflective properties can generally be distinguished from a matte plaster-based imitation if these differences are visible in the image data.
If artificially created defects differ in relevant characteristics—such as texture, reflectivity, contrast, size, movement behaviour, or other optical or physical properties—there is a risk that the neural network learns features introduced by the artificial manufacturing process rather than the actual defect itself. Likewise, particle detection may be influenced by factors such as viscosity, turbidity, fill height particle size, or particle contrast. These factors should therefore be considered when assessing the suitability of artificially created test kits and may also affect the performance of conventional rule-based inspection systems.
Conventional rule-based systems are generally less susceptible to such effects because they evaluate predefined image features rather than learning complex representations. Although these approaches are often less selective and may be less suitable for highly challenging inspection tasks, they typically demonstrate greater robustness against variations or realism drifts within artificially created test kits.
Consequently, the suitability of artificially created test kits should always be justified and documented with regard to the inspection technology and the intended application. The decisive criterion is not whether defects are artificially created or taken from routine production, but whether the test kit reliably reproduces the behaviour of the final drug product under the selected inspection strategy.
Can one instrument test different package sizes?
Yes. Different package sizes and shapes can be tested by changing the test chamber, fixture or sample holder.
Can the system test pharmaceutical vials?
Yes. Vacuum decay testing can be configured for vials containing powder, lyophilized products or medicinal liquids. A package-specific chamber is normally required.
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