Cleaning validations aim to prove that cleaning methods are effective, reliable, robust and capable of removing contamination up to a set level.

A visual inspection of equipment is required by the regulations after the cleaning steps as well as before the start of production. Visual inspection forms part of routine cleaning and represents the first criterion in cleaning validation. The results of this inspection must be judged acceptable before taking samples by swabbing or by other methods from the cleaned equipment for the purposes of analytical confirmation.

Since the 1990s, several publications ^{(1),(2),(3),(4),(5),(6)} have addressed the theme of the study of visual inspection, stating that the limit of detection is thought to be located in a concentration range extending from around 1 µg/cm² to more than 10 µg/cm² depending on the products investigated and inspection conditions. US regulations ⁽⁷⁾ require “an inspection of production equipment immediately before use”. The PIC/S ⁽⁸⁾ advises carrying out “an investigation of surface contamination in order to determine the concentration at which most ingredients are visible”. The latest EMA text Q&A8 ⁽⁹⁾ specifies that within the context of cleaning inspection after validation and in certain specific cases “staff carrying out visual inspections must receive specific training and regular tests of visual acuity. And that accreditation must be proven by practical trials”.

It is therefore important to take account of this technique and it is essential to be able to provide justification that these tests are carried out under the right conditions. It must be supervised by an appropriate quality system.

Visual inspection must be carried out on the surfaces of equipment in direct and indirect contact with the product and requires that these surfaces are visually accessible. In the event that surfaces are not visually accessible, it is recommended that the equipment be disassembled to access it or to use light sources, mirrors or endoscopes. The residues or defects looked for may be from different sources: previous products, cleaning agents, microbial contamination, equipment wear (e.g. scratches, rouging, etc.), foreign materials, technical liquids (such as oil or grease), rinsing solvent residues (e.g. residual water), etc.

Routinely, this visual inspection is carried out on equipment by many people during or at the end of use, after automatic cleaning (clean in place), semi-automatic or manual cleaning, on large surfaces or on small parts cleaned in a washer. These inspections are usually tracked in checklists left on the equipment until use, then attached to the batch record and to site internal quality documents in order to justify that the equipment is clean and usable for upcoming production. Teams also carry out a visual inspection of the equipment at the start of production. This information is also tracked in batch records and in equipment or production area logbooks. Most often, an initial check is carried out when cleaning is finished by one person and just before the equipment is reused by a second person different from the first. The quality and qualification/validation teams also inspect the equipment regularly as part of their activities. Very often, the training and accreditation of these individuals in visual inspection is not tracked in an appropriate manner, nor considered a critical activity during accreditations and often forms part of global training and accreditation at the workstation.

Likewise, as part of the process of putting cleaning validations in place, the samplers who take swabs, samples of rinsing water or microbiological samples are specifically trained and accredited in an official way (e.g. laboratory-based recovery tests). Accreditation in visual inspection should then be referenced and carried out in the same way as other accreditation processes performed on the site and considered as being equally important.

This article details one of the approaches possible for the implementation, management and monitoring of the accreditation of teams in visual inspection in the context of cleaning validations and routine inspection of equipment. It describes the broad lines of an approach which can be adapted, optimised and modified so as to enable its application to the internal procedures of each site. This accreditation cannot justify the fact that only visual inspection is taken into account when ruling on the compliance of cleaning. This accreditation proves that staff that have undergone training will be capable of visually detecting surface contamination below the acceptable contamination limit, of defining the clean status of equipment and in this way of confirming that the risk of cross contamination of equipment is controlled.

Qualification of the principles of visual inspection must be differentiated from staff accreditation. The accreditation of teams is the final step in the establishment of the overall visual inspection strategy. It will be necessary to determine beforehand the acceptance limits for residues on equipment surfaces, then to determine the visual detection limit before being able to put in place the process for accreditation of teams. The qualification of visual inspection principles should be validated before carrying out team accreditation trials ⁽¹⁰⁾.

Implementation of accreditation in visual inspection requires transversal organisation. It is carried out on small groups of individuals (production operators, samplers, etc.) under the responsibility of the Quality Assurance Department. The test is usually developed by the laboratory which has the resources to implement these tests successfully (products, solvents, coupons made from different materials, etc.).

Routinely, visual inspection is different when the inspection is performed on small parts which can be placed in ideal test conditions (angle, lighting, distance) unlike inspections carried out on large items of fixed equipment for which the inspection parameters will be more restrictive (fixed angle and non-optimal light conditions, low light levels inside tubing or large containers and distanced from surfaces). In order to homogenise the approach to qualification and accreditation, tests are carried out on coupons of defined size (e.g.: coupon of 100 cm²), of a material and with a surface quality as close as possible to the materials encountered in production. Tests are conventionally carried out with stainless steel, glass and teflon coupons.

The visual inspection acceptance criteria must be defined for all contaminants potentially present on equipment: residues of active substances, finished products or cleaning agents. It is not necessary to carry out “visually clean” tests for microbial contamination as the latter is closely linked to the residues of other products which might remain on the surfaces.

1. Determination of the visible residue limit (VRL)

The first step in the visual inspection strategy is the definition of the visible residue limit, that is the smallest concentration of product which can be detected by human eye on the surface of a material. The marker to be used preferentially for these tests is the product derived from the “worst case” risk analysis detailed in the cleaning validations strategy (e.g.: cleaning validation master plan), that is to say the raw material, active substance, finished product or residue that is the hardest to clean from each defined product family. If it is easier to use the finished product that contains the active substance that is most difficult to clean, then this finished product can be used for tests and vice versa. The choice of contaminant used to carry out the study must be justified.

Several concentrations must be studied. In the first instance it is necessary to determine the acceptable surface limit: (ASL which is evaluated in µg /cm²) according to the toxicological and therapeutic approaches of the products manufactured. These acceptance criteria are normally defined when cleaning validations are being established with the value being calculated in accordance with the recommendations of the cleaning validation master plan.

Secondly, the visual residue limit VRL (in µg/cm²) must be defined. It is recommended that various dilutions of the ASL concentration be deposited on coupons of different materials up to a very weak concentration (e.g.: several successive dilutions by a factor of 10, or 2). These concentrations are to be defined and adjusted by the team implementing the test on site. Enough coupons must be used to provide proper representation of the concentration range under investigation: around ten plates is appropriate as a minimum.

The deposit is produced preferably with a spray so that it is distributed homogeneously on the coupon surface and between coupons. Deposits produced using a pipette may cause heaping of the product which is difficult to repeat from one deposit to the next. The deposits must be dry and produced as close as possible in time to the viewing tests. A study of the stability of the visual appearance of residues on surfaces can be performed beforehand in order to be able to keep the coupons overloaded for a defined time after deposit.

It is recommended that the test be conducted in light conditions close to those encountered in the production area. Light levels can be noted in different production areas and a range of light levels can be taken into account in conducting qualification and accreditation tests.

The coupons can be arranged in order of decreasing concentration on a flat surface, with light levels close to those of production areas. Note down and transfer the light level associated with each coupon onto the result sheets before the test.