Guidance 012 – Visual Inspection and Quantitation Practices

Depending upon the desired outcome of the cleaning activity the visual inspection can take on different emphasis to achieve the desired goals. Visual inspection will be a part of all cleaning procedures developed, and as such, each site should define the significant operations, responsibilities, and expected results within site SOPs or individual cleaning instructions.

Any visual inspection regime should employ training and effective tool use, e.g., mirrors, flashlights, and boroscope cameras, to accomplish the desired goal of visual cleanliness.

1. Visual Inspection following/during manual cleaning:

Manual intervention during the cleaning of major equipment is often required as part of a robust cleaning process. The purpose of these manual interventions is almost exclusively to remove residues that are not effectively dissolved/emulsified by the cleaning agent. For example, they have become too entrained as a side effect of extreme processing or cleaning conditions (e.g., “bath-tub ring”), they are insoluble in the cleaning agent (e.g., carbon, spent catalyst, or drug product dyes, polymers, flavors, etc.), or they are trapped in difficult to clean areas not effectively cleaned by the CIP system (e.g., dome nozzles or dead-legs).

Consideration of the following is suggested as part of the development of a manual cleaning methodology:

– The inspection of major equipment following or during manual cleaning should take place prior to the analytical rinsing or swabbing to provide a greater probability that target residues are removed prior to sampling.

– The inspection should not substitute for the final visual inspection that would typically take place following analytical sampling. The final visual inspection determines the success or failure of the validation execution.

– For those areas that will be inspected again for final determination of visual cleanliness, this in-process inspection may be less stringent than the final visual inspection. For instance, flashlights and mirrors might not be necessary, complete absence of visible residues might not be required, and complete disassembly of equipment might not be justifiable. The justification for this approach being that this type of inspection is not the final inspection and once a residue has been acted upon in some manual manner (e.g., scrubbing, power washing) it is more likely to be effectively removed subsequently by the CIP system.

– The inspection is at the discretion of the process designer(s) and is not required. The purpose of inspection after manual cleaning is to measure the effectiveness of the manual methodology before resuming CIP cleaning. It might not be justified for example, if the manual methodology has been shown to be rugged in the past, or is simply a precautionary measure to provide a greater probability of passing acceptance criteria at the conclusion of the cleaning process.

Inspection of equipment that is cleaned manually and can be 100% visually inspected prior to release back to production (e.g., mills and minor equipment) is not the subject of this specific section. Rather, the inspection of these examples should follow the guidance of “final visual inspection” detailed below.

2 (a). Visual Inspection of Dedicated Equipment – Interval Cleaning:

Interval cleaning, or cleaning processes that take place within a campaign of the same product, are appropriate when an evaluation of the material being cleaned has been completed and there are no quality concerns (e.g. degradation of material) about carryover of some amount of one batch into the next batch.

Although the intent of this section of the procedure is focused primarily on dedicated equipment it may also be applied to interval cleaning that takes place between batches within a campaign using multi-purpose equipment. Consideration of the following is suggested as part of the development of an interval cleaning methodology:

– The acceptance criteria for this type of visual inspection should be defined exclusively by an understanding of the quality needs of the manufacturing process as a required output of the cleaning evaluation.

– Product contact surfaces need not be free of visible residues if deemed appropriate by the cleaning evaluation activity.

– The amount of carry-over permitted between batches and the visual allowance for residue at some level to be present should be clearly defined and described within the cleaning instruction or site procedure.

– The operations related to interval cleaning may be organized into their own cleaning instructions or it may be beneficial to incorporate interval cleaning activities into processing instructions (e.g., a post processing rinse).

– If a cleaning agent is used that is not shared by the manufacturing process, such as detergents or highly toxic solvents, the appropriate residual limit must be applied to the procedures acceptance criteria. (detergents must also have their removal validated).

2 (b). Visual Inspection of Dedicated Equipment – Cleaning Between Campaigns:

Dedicated equipment campaign cleaning refers to the cleaning process performed between the end of one product campaign and the start of the next campaign of the same product. This section of the procedure addresses those cases where there is known to be a potential quality concern with

carryover of amounts of material (e.g. degradation products) in excess of a specific RAL.

Consideration of the following is suggested as part of the development of an end of campaign cleaning methodology:

– For those products where the visually quantifiable amount is known, or is believed to be within a range referenced in literature sources1,2 , and is below the established RAL; standards may be developed that allow some amount of visible residue. The visual standard should be well defined, and training of inspectors on how to subjectively determine pass/fail results should be documented. Otherwise;

– The minimum requirement is visually free of residues.

– For large closed systems, if the only acceptance criterion for release of equipment back to the production of product is visual inspection; and if the cleaning evaluation activity determines that there is a potential quality concern of carryover of excessive amounts of material (e.g. due to degradation products), areas that are difficult to clean may require more emphasis during the cleaning process. These areas would be characterized as difficult to clean, with disassembly as necessary, and would provide evidence of cleanliness beyond viewing the vessel interior through a sight glass or a man-way with the use of a mirror and flashlight.

It should be noted that the validation of cleaning procedures with respect to the active ingredient for dedicated equipment does not require. The resource required to perform equipment disassembly on a routine basis, however, may justify the performance of a study to “validate” that the hard to clean areas are visibly clean for a number of consecutive cleanings as evidence that the visual inspection can be relaxed for subsequent cleaning. This approach is appropriate for the same reasons that swabbing provides additional assurance of cleanliness during validation but may be discontinued after a given number of successful cleanings.

3. Routine Visual Inspection of Multi-Purpose Equipment.

For routine visual inspection of multi-purpose equipment, or those inspections that occur as the last visual check of a system prior to release back to production of the next product, consideration of the following is suggested as part of the development of a multi-purpose cleaning methodology:

– There will be a visual inspection and an analytical sampling method (if required) employed for verification of cleanliness.

– The inspection should be performed on dry equipment surfaces under well-lit conditions with the necessary training and tools to insure compliance to a visually clean standard.

– The minimum standard should be no visible residues observed on the surfaces inspected.

– For large, difficult to access equipment a light source, such as a flashlight, and mirror should be employed to observe those interior surfaces that are not within the line of vision through a portal or man-way (e.g., the dome, dome nozzles, and the back of the agitator shaft and baffles).

– Disassembly of minor equipment product contact surfaces should be completed and the disassembled parts should be protected from contamination until reassembly and production of the next batch.

– At a minimum, disassembly of major equipment should typically be targeted at those hard to clean and inspect areas that historical evidence suggests resist the removal of residues by the CIP process. An example is the disassembly points identified during the validation or visual inspection that continue to require inspection and possibly manual intervention to free them of visible residues (e.g., dead-legs, valves, and blind flanges).

– Directions in cleaning instructions should consist of enough detail to ensure the activities listed above are performed consistently on a routine basis.

4. Visual Inspection during Validation.

During validation there may be reasons to perform more intensive equipment disassembly and visual inspection than during routine inspection. The inspections are specific to the product(s) that is (are) identified by the validation protocol as the most difficult to clean (marker) compound or is the marker by default for a single product cleaning procedure. The routine cleaning procedure with any disassembly would be used in validation. Consideration of the following is suggested as part of the development of these types of visual inspection for validation:

– Those areas identified as difficult to clean by the cleaning evaluation exercise should be visually inspected with disassembly as necessary.

– The areas described above are often times swab sampled as part of the acceptance criteria of the cleaning validation protocol and they should be verified as visually clean prior to sampling, and any non-conformance reported as a cleaning failure.

– There might be some areas that are identified as requiring persistent manual intervention and inspection (i.e., where product hold-up is found and which are not addressed through a corrective action that changes the design of the equipment or the procedure). During the execution of the validation these areas should be included as a point of inspection. These areas should also be included in the routine visual inspection after validation to insure effective cleaning subsequent to the validation activity. These same areas may be included in the inspection following manual intervention during cleaning as the situation warrants, however, each of these hard to clean areas should be re-examined as part of the final visual inspection.

5. Visual Quantitation

If the only verification of cleaning changeover processes to be conducted on equipment is visual, then the visually detectable quantity must be known and documented.

An exception can be made for generally recognized as safe (GRAS) compounds.

Laboratory Studies

The study leading to the required documentation should be conducted using a standard methodology and conditions that limit variability. The method and conditions should be defined within an approved site procedure. The determination of visual quantitation in production equipment should be discouraged for the inherent safety, equipment integrity, and subjectivity considerations associated with such an approach. Laboratory studies typically include:

– The spiking of coupons of a known surface area that represent the materials of construction present within the system.

– The coupons are spiked at the swab RAL concentration and adjusted to be directly proportional to thesizeof the coupon.

– The coupons are then dried and examined under conditions designed to represent the actual manufacturing environment by trained analysts and designated as visible, or not visible, at the RAL.

The nature and age of the manufacturing equipment and coupon surfaces are factors in laboratories studies and thus more useful when visual limits are well above 4 ug/cm2. Thus, the extent of the difference between the visual detection limit and the calculated RAL are to be considered when using laboratory studies.

While determining the likelihood of visual detection at a given RAL, the trained individuals who are responsible for actual visual inspections in the production environment should report any evidence that suggests the compound of interest is not visible at the RAL.

For instance, if rinse and/or swab checks for cleanliness fail test acceptance criteria, but the visual inspection noted no visible residues. After failure investigation to eliminate other potential root causes, these anomalies should be monitored and if deemed necessary the compound of interest should have its visual detection limit determined in the laboratory. The same can be true for the laboratory determined visual limit. If evidence from the manufacturing environment contradicts the limit reported by the laboratory the anomalies should be monitored carefully and if deemed necessary, changes made to the lab conditions intended to represent the actual manufacturing environment (e.g., light intensity, distance from the subject, and use of representative tools).

Difficult-to-Clean Inactive Raw Materials

When an inactive material is known or expected to be difficult to clean (i.e. not expected to pass visual inspection), then a risk assessment is recommended to be conducted. In these special cases, the risk assessment may include:

1) Detectability of the residue.

2) A comparison of the calculated non-therapeutic RAL (residue acceptability limit) to the visual inspection limit to confirm that the RAL is above the visual limit.

3) History or recurring issues, and

4) Toxicity concerns (GRAS or ADI (acceptable daily intake data). Examples of difficult materials are water-insoluble polymers, dyes, flavors, or odorants. Typical visual detection limits are reported in the literature in the range of 0.2-4mcg/cm2 (or about 25 mcg/in2) (Ref 7-9). If the calculated RAL is below the visually detectable quantity, then additional analytical residue testing may be required. If there are toxicity concerns the non-therapeutic RAL can be compared to the visual detection limit (VDL), whereas if there are no toxicity concerns, a low-risk approach may be taken (no RAL calculation).

In cases where the equipment cannot be 100% visually inspected, then one or more of the following may be used:

• Disassembly may be necessary to conduct a complete examination.
• Rinse checks solutions for solution clarity, color, particulates or another applicable test.
• Dedication of equipment, parts or piping.