How to use semi-automatic inspection of pharmaceutical vials and syringes for regulatory compliance.

Semi-automatic (or Semi-automated) inspection machines for the pharmaceutical industry are intended for easy and effective examination of vials, ampoules, cartridges, and syringes carrying injectable liquids, powders, or freeze-dried products. This is the step up from a manual inspection approach which would typically be done by a trained inspector by rotating the vial in front of a black and white background for the analyses of certain defects, particles and particulates. The semi-automatic approach allows for higher volumes of pharmaceutical products to be inspected at greater speeds.

In simple terms, “Semi-Automatic” means the ability to rotate the product and present it with the correct lighting LUX level on a black and white background for the purpose of an operator to visually identify defects in the container or contents. This is typically in the form of a stand-alone semi-automated machine or part of an in-feed or in-line production system. Therefore, this shouldn’t be confused with fully automated visual inspection systems.

The key documents relating to the inspection of pharmaceutical vials and ampoules for contamination are driven by the United States Pharmacopeia (USP) Chapter 1 Injections and Implanted Drug Products (Parenterals). Product Quality Tests states that injectable drug preparations should be designed to exclude particulate matter as defined in USP Chapters “787” Subvisible Particulate Matter in Therapeutic Protein Injections, “788” Particulate Matter in Injections, and “789” Particulate Matter in Ophthalmic Solutions. Each final container should be inspected for particulate matter, as defined in Chapter “790” Visible Particulates in Injections. Containers that show the presence of visible particulates must be rejected.

Particulates can take all forms, from contamination and debris particulates, coating fragments, air bubbles or inconsistencies, visual defects in primary containers, polymer particles through to glass & metallic particles and microscopic cracks or inclusions in the glass or polymer. All these levels of defects need to be identified and rejected.

Every product needs to undergo a visual inspection to determine whether or not it contains any particle matter. It is possible to automate, manually perform, or partially automate the initial 100% check. The subsequent inspection to ensure that the acceptable quality level (AQL) has been met must be carried out manually. The presumed value for the lower limit of the visible range is 100µm; however, this value can shift based on the product container, the nature of the drug product, and the qualities of the particulate matter (shape, colour, refractive index etc.).

The sample in its primary container (vial, prefilled syringe, and glass cartridge) is rotated under standardised conditions for semi-automated visual inspection (roughly above 50-100 µm). The liquid in the spinning and/or subsequently stopped container can then be viewed to confirm compliance to quality levels. This is the way to reach regulatory compliance by applying semi-automatic inspection.

Although the regulation of particulate matter in pharmaceutical products is as detailed above, there is no regulatory guidance on either the limits of particulate matter in principal packaging components. Instead, the specifications are determined through collaboration between the customers and the providers. To lessen the amount of particulate matter in finished drug products, pharmaceutical manufacturers and packaging suppliers must work together to achieve this goal. In particular, this can be accomplished by making use of components that have minimal levels of loose, embedded, and adhered particulates. But no matter what contingencies are put in place, the production process should include a level of semi-automatic inspection to allow rouge particulates to be rejected from the final product.

Human inspectors are adaptable and can provide a response to something they have never seen before or something that “doesn’t look right”. They are also able to more easily withstand typical variations in containers, particularly those generated by moulding, which results in a reduction in the frequency of wrongly rejected good products. This compares to fully automated visual inspection, which has rigid boundaries for a pass and fails. However, people are restricted in the number of inspections that can be performed (i.e., the number of containers per minute or hour that they can inspect). Therefore, semi-automatic inspection is the solution to allow a high volume of product to be inspected at speed by an operator while still complying with the relevant regulatory levels.

Operators are also prone to weariness and require numerous pauses in order to work at a high level for extended periods of time. All of these constraints contribute to a greater degree of variation in the outcomes of manual inspections; however, this variation can be reduced by semi-automated inspection, combined with receiving enough training and adhering to standard operating procedures.

Manufacturers should conduct a 100% inspection during the stage at which there is the greatest likelihood that visible particulates will be detected in the final container (for example, before labelling to maximise container clarity). This is the stage at which the likelihood that visible particulates will be detected in the final container is highest. The equipment and the physical environment in which the visual inspection will be performed should both be designed by the manufacturers to reduce the amount of unpredictability in the inspection process while simultaneously increasing the amount of information that can be gleaned from it.

After 100% semi-automated inspection is completed, a manual inspection based on ISO 2859-1/ANSI/ASQ Z1.4 should be performed. The size of the AQL sampling depends on the batch size. Inspection Level II should be used.

Overall, Semi-automatic inspection of pharmaceutical products provides a route to regulatory compliance prior to the adoption of fully automated visual quality control.

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