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Indirect visual testing is modernizing cleaning validation (La Vague 54)

Visual testing remains a vital operation in a cleaning validation strategy, and is a precondition to initiating this cleaning validation step. This is still too often neglected, the compliance of this visual test gives us a first indication of the efficacy of our cleaning step during a process. It is a pharmaceutical operation in the same way as all the other operations performed during manufacturing or packaging.

1Historically, when cleaning validation studies were set up, the “visually clean” method was the only existing method. It is still used today but it is integrated into cleaning validation programs and is not enough, as indicated by the GMP in Annex 15: § 10.2. A visual examination of cleanliness represents an important part of the acceptance criteria formulated for cleaning validation. The use of this criterion on its own is not generally acceptable (…)”.

Glossary

Endoscopy: medical or industrial method of visual investigation of the interior of a cavity inaccessible to the eye (Greek: endon).
The instrument used, called an endoscope is composed of a optical tube fitted with an a lighting system.
Inspection camera: this is an endoscope with a probe diameter greater than 20mm
Objective: optical component intended to be turned towards the object to be observed
VT : (Direct) Visual Testing
IVT: Indirect Visual Testing

For its part the FDA in the “Guide to inspection of validation of cleaning processes” considers that the acceptance criterion based on visual inspection may be acceptable only in the case of inter-batch cleaning for the same product.

These different regulatory sources confirm that visual testing is an important part of the validation of a cleaning process.
Technological progress and the miniaturization of cameras make this test more reliable and still more effective in relation to the places to be reached.

Visual testing must be conducted on a clean, dry surface, (with no trace whatsoever of humidity), as traces appear most often on drying.
The execution of a visual test requires that no part/surface of the equipment concerned is forgotten. It therefore involves adopting a methodological sequence in order to make sure that no part of our equipment has been overlooked. This can appear in a visual test performance instruction drafted on site.

As long as “visually clean” status is not achieved, samples for cleaning validation are not taken.

Two types of visual tests may be distinguished: direct/indirect.
Direct visual tests are to be favored but depending on the observation conditions and the geometry of the equipment involved this operation will be combined with indirect visual tests.


Direct visual tests

Visual tests are direct if the optical path between the surface inspected and the tester’s eye is not interrupted. This category includes tests with the naked eye and those using: mirrors, magnifying glasses, etc.

The eye and its limits:
The special characteristics of visual testing give rise to the observation that all individuals in a population do not have the same visual acuity.

The normal visual field angle in humans is 50 to 55°. The important thing is to focus visual tests on the possibility that all testers characterize the trace observed on the surface (trace of product, trace of detergent, trace of rust, trace of lime scale…) in the same way. The objective is to be able to maximally vary the angle of gaze on the surface observed (optimal angle of 45°), this allows for example rough patches that pass unnoticed at an angle of 90° to be seen.
The lighting of the item where the inspection takes place, the shadows caused by the configuration of the equipment, as well as the operator’s gaze distance relative to the equipment have their importance. This entails training in visual testing for each person who carries out this operation.

Fourman and Mullen determined that most substances would be visible at a rate of around 100μg/ 25cm2 of cleaned surface area that is 4 μg/cm2, taking account of the observation conditions.
Jenkis et al are thought to have observed that with a good light source, the detection threshold was 1μg/cm2.
It is estimated that the visibility threshold for particles on a surface examined with the naked eye at a distance of 10cm is: 50μm under ambient light and 30μm under intense light (additional lighting, such as a flashlight…).

The other limit on direct visual testing, is that the operator conducting the test certifies the test as compliant or non-compliant on their honor.


Indirect visual testing (IVT)

Visual testing is indirect if the optical path between the surface inspected and the tester’s eye is interrupted. This category includes tests using photography, cameras, videoscopes, etc. It allows greater sensitivity than that of the naked human eye to be obtained and permits access to complex or restricted geometrical areas.

In fact it is possible to choose the angle of view of the objective depending on need. An objective with an angle of view:

• >50°, will approach panoramic vision
• <50°, will allow macroscopic vision, therefore magnification and better detection than by eye.


3 other technical criteria must be defined:

The working distance: this is the minimum distance between the object to be observed and the objective
The depth of field of the objective: : this the area where the image is still sharp (distance between the first and last planes in which the image of an object located a certain distance from the objective is in focus)
The type of viewfinder: axial or radial

IVT produces an image of the item and the indications that are potentially detected.
In most cases, this image can be recorded to provide test traceability. In the context of a manual test using optical instruments, the precise determination of the location and dimensions of the indications can be complex; in the context of a mechanized test, this characterization is simple to perform and can be very precise.

The major objective of the use of all these new tools is to be able to inspect the entirety of an item of equipment. We can look into a tank in complete safety and are no longer obliged to climb into it to inspect it. Risky, tiresome operations in confined spaces occur more rarely. The rapid, secure deployment of IVT equipment enables the frequency of tests to be increased.

The improved detectability of residues and the increased frequency of indirect visual tests brings better control of equipment and washing processes. Therefore it should be expected that anomalies not previously seen will be detected and appropriate corrective action plans should be provided for.

In conclusion, indirect visual testing brings significant benefits compared to direct visual testing provided that the choice of equipment is adapted to need. It allows larger difficult-to-access areas to be covered, with improved illumination. Now nothing can escape us.
Currently, indirect visual testing has not yet become a routine standard practice, but this should be encouraged.

2

Is it possible to envisage a future in which: the performance and reproducibility of indirect visual testing methods will be qualified for pharmaceutical and cosmetic industry applications ; the operator carrying out this type of test will have been certified by an independent approved body

This allows indirect visual testing to be substituted for surface sampling with equanimity… when the visual detectability of the product under investigation allows.

3

Staff training
Training of operators in the use of the endoscope will be as a minimum provided by the distributor of the test equipment. It is also possible to use the guide “OPÉRATEURS EN ENDOSCOPIE: BONNES PRATIQUES (ENDOSCOPE OPERATORS: BEST PRACTICE)” Editions LEXITIS, developed by a COFREND working group.
This document applies to all industry fields. It aims to describe the “best practice” of the profession of the industrial endoscope operator: their role, the context in which they practice, a vocabulary and some points to be considered when introducing endoscopy as a test method, for example information on the compromises to be made.

Bibliography
Fourman and Mullen
Jenkis and Al
COFREND Editions LEXITIS, via this link: http://www.lexitiseditions.fr
GMP in force
FDA - GUIDE TO INSPECTIONS VALIDATION OF CLEANING PROCESSES

 

By Guillaume GARREAU - Lab. Galderma & François BLACHÈRE - Cophaclean

 


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