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” and “Container Handling during Manual Visual Inspection of Pharmaceuticals”.

Accordingly, this article shall provide information on qualification and validation of visual inspectors and inspection processes.

 

Qualification and Training of Inspectors:

 

Who are Visual Inspectors?? The staff involved in observing and detection of potential defects in a drug product are termed as Inspectors.

 

What are the requirements of a good inspector?? Apart from various soft skills like patience, concentration, integrity etc. a good visual inspector shall be tested for visual acuity and color perception. Near-vision performance should be the equivalent of 20/20 with no impairment of color vision.

How to train visual inspectors? The identified visual inspectors shall be thoroughly trained on the internal SOP on visual inspection. The training shall be phase wise. Specific number of hours shall be at least provided for each segment or type of defect and product. The trainees shall be trained using defect photographs. The type of defects shall be displayed in the inspection room also. Test sets or defect standards shall be used to provide hands-on training.

Silent counting and following the paced sequence shall be reinforced to achieve consistent inspection timing. Importance of strict adherence to the inspection process (procedure, sequence, and timing) shall be stressed. All the inspectors shall be trained on common procedures. It shall be ensured that the inspection practices are standardized and consistently executed across all inspection groups.

How to qualify visual inspectors? Each inspector appointed to perform the important task of visual inspection shall be trained and qualified before putting him on the job. Qualification shall be performed for each product type and package that the inspector will encounter. A bracketed or matrix approach can be used to simplify qualification of products with similar physical or visual characteristics such as container type and size, formulation type, product viscosity, color and others.

In case of parenteral, the inspectors shall be trained and qualified on clear solutions in clear containers initially. Later on, they may be trained and qualified to handle difficult formulations or presentations.

For qualification of a visual inspector, a manual test set shall be inspected under normal operating conditions and inspection critical parameters, including inspection timing and sequence, physical environment, and inspection duration. Three successful inspections of the test set are recommended to demonstrate consistent performance for initial qualification of new inspectors. Acceptance criteria for each defect class should be based on the Probability of Detection (POD) or Reject Zone Efficiency (RZE) observed during test set qualification. A limit is also needed for false rejection, with a recommended target of <5% falsely rejected good units.

Inspector fatigue may be addressed in the qualification process by testing under worst case conditions (e.g., at the end of a typical inspection shift).

Does visual inspector needs to be requalified? If yes how and when? Like any other qualification, requalification of visual inspector is must. They should be requalified at least annually. Requalification shall include a test of visual acuity and testing with at least one product/test set configuration. A single successful inspection of the test set is sufficient for requalification.

Requalification may also be necessary in the event that poor performance is observed during routine inspection or if the inspector has been away from the inspection operation for an extended period of time (e.g., 3 months).

If an inspector fails the requalification test, a retraining process should be initiated to identify the root cause and allow the inspector to receive additional instruction. After this process has been completed, the inspector may attempt to meet the acceptance criteria one additional time. If the inspector fails, he or she may attempt to qualify again after a specified time period.

Standard Defect Kit: Each industry must have a standard defect kit which is very important for the training and qualification of visual inspectors. The test kits or defect kits helps to identify and characterize the defect types. Visual inspection standards may be identified from known production rejects, or may be created manually with characterized particulate material. A single particle/seeded container should be used when determining detection thresholds. Similarly, for other dosage forms like tablets, capsules a test kit containing samples with all the identified and probable defects shall be prepared.

The defects observed in the manufacturing area shall be further characterized. Characterization helps to re-create equivalent defect types in a controlled laboratory environment. Characterization information on defects should include, where appropriate, the range of sizes typically observed and the specific location on the container. If feasible, a photograph of the defect should be included. All information that could support consistent re-creation of the defect standards should be included in the characterization description.

The defect standards are then qualified and assembled into test sets. 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.

A firm shall have a written procedure for the creation and maintenance of standards. This procedure should define the qualification criteria, appropriate storage conditions, periodic examination and requalification, expiration, and sample custody during use. Test sets should be approved by the quality unit. The container in which the specific particle set is stored must be clearly labeled with the test set identification information.

Qualification of test kit/ Rejection Probability Determination: After the availability of well-defined defect standards, a detection frequency or probability of detection (POD) is assigned. It is done by conducting a well-documented, manual human inspection qualification that is accomplished by repeated manual inspection. This repeated inspection is the basis for qualifying the defect standard. The Knapp methodology recognizes that the detection of particles is probabilistic, and repeated inspections with strict controls on lighting and inspection pacing/sequencing generate the statistical confidence to assign a reject probability to each standard unit. A manual, visual inspection POD of ≥0.7 or 70%, is required to assign the container to the Reject Zone for subsequent calculation of the reject zone efficiency (RZE).

Secure probabilistic data for particulate standards can be achieved with 30–50 inspections of each container. This is best achieved with multiple inspectors.

Inspection reject probability is calculated for the defect as follows:

POD = (Number of times rejected)/(Number of times inspected)

Precautions with the test Kit: A firm shall ensure the verification of the presence of particles before and after use, as particles may become lodged between the container and the closure. When a freely moving particle cannot be verified, the unit should not be used and the data should be excluded from subsequent calculations. When this happens, it may be possible to free the particle with the use of an ultrasonic bath. If this is not possible, the unit should be replaced.

The number of defective units in each test set should be limited to approximately 10% to prevent rejection bias. The accept containers will be identified as having a pre-determined manual, visual inspection POD of <0.3 or 30%. Any particle standards found to fall within the acceptable “grey zone”, indicating a manual inspection rejection probability ≥30% and <70%, may be included as an “acceptable unit” in a test set, if desired.