Manual Visual Inspection is an important step in pharmaceutical manufacturing which aids in the detection of various formulation defects. The defects are observed in the all types of formulations viz. tablets, capsules, injectables etc. To effectively observe the defects there are many requirements w.r.t. trained and qualified operators, Inspection belt, lighting, background etc.

In this series on pharmaceutical product inspection, we shall be discussing various aspects of manual visual inspection serially. Previously, we had already discussed about the “Lighting requirements for Manual Visual Inspection of Pharmaceuticals”, “Inspection Rate for Manual Visual Inspection of Pharmaceuticals”, “Container Handling during Manual Visual Inspection of Pharmaceuticals” and “Qualification and Validation of Visual Inspectors and Inspection Processes”.

Accordingly, this article shall provide information on product and container considerations for manual visual inspection of pharmaceuticals.

Unique Products:

  1. Lyophilized Product: All the vials of lyophilized products shall be inspected after the freeze-drying step has been completed and each unit has been sealed. The major concern with inspecting the lyophilized product is lack of visibility of particles in the solid matrix of the lyophilized cake. The visible cake surface accounts only for a very small fraction of the cake volume.

Due to these challenges, a small portion of the total manufactured vials are reconstituted and inspected for visible particles. This is in addition to the 100% inspection of the remaining lyophilized vials. Reconstitution shall be done with utmost care to avoid contamination that can lead to false-positive results. Sample preparation should be done in a clean environment with appropriate particle-control measures. Reconstituted samples should be inspected using the same conditions as those for visible particles. The destructive nature of this test limits the size of the sample.

Sampling plans for this type of test may be referred to special sampling plans S-3 and S-4 in ANSI/ASQ Z1.4. The S-plans offer a practical compromise between sample size and statistical power. For most batch sizes between 3,201 and 150,000 it suggest a sample size of 20 with an accept number of 0 (based on an AQL of 0.65%). Alternative plans are acceptable, but care should be taken to examine the UQL of such plans to assess their sensitivity.

Once inspection of these reconstituted samples has been performed, they may be used for other required testing, such as that for subvisible particles, potency, impurities, or other specified tests. If particles are detected in this relatively small sample, additional units may be reconstituted as part of an investigation and to assess the compliance of the entire batch.

  1. Powder Product: Sterile powders are difficult to inspect for particles due to powder flow and the occlusion of white or light-colored particles by the drug product itself. Sterile powders should be reconstituted and inspected for visible foreign particles using an approach similar to that for lyophilized products, as discussed.
  2. Emulsion and Suspension Product: The manufacturer may allow inherent particles if the product is an emulsion or suspension. It is recommended to carryout test involving dissolving of the suspension or disruption of the emulsion for suspension products. This aids in detection of extrinsic and intrinsic particles. This destructive supplemental testing of a small sample shall be carried out as described above for lyophilized products.
  3. Combination Products: When inspecting the unlabeled primary drug container for a combination product, the inspection considerations should be the same as those specified for a conventional drug product in a vial or syringe. This inspection should be performed before assembly into the device. Where there are critical attributes that are only visible after assembly (such as alignment with a fill-level window), a second inspection after assembly may also be required.

 Containers:

  1. Amber Containers: Inspecting amber containers is challenging. This is because selected elements have been added to mask UV light penetration into the Type I glass container. Light transmission is blocked below 500 nm. Hence, increased light intensity (e.g., 8,000–10,000 lux) may be required to observe visible particles during inspection. Directional lighting from behind the container may also be beneficial.
  2. Translucent Plastic Containers: Plastic or translucent containers are chosen for break resistance or other properties that glass cannot offer. For example, injection molding into shapes that minimize hold-up volume or for use in a combination product. Plastic containers may have optical properties that require significantly more light (e.g., 8,000–10,000 lux) to illuminate any visible particles against black and white backgrounds. Directional lighting from behind the container may also be beneficial.
  3. Large Volume Containers: Large-volume containers (>100 mL) may require additional time to complete a thorough inspection. The flexible bags are made of semi-transparent PVC film. Hence, these containers may require the use of additional light intensity to enhance the visibility of particles. Directional lighting from behind the container may also be beneficial.