Cleaning validation, how clean is clean?

Pharmaceutical process equipment in operation.

Cleaning validation is a process to ensure that equipment cleaning procedures are removing residues to predetermined levels of acceptability. Although "equipment cleaning" is part of current Good Manufacturing Practice requirements the term "cleaning validation" was not popular until late 1980s. The need for a systematic approach to proving the effectiveness of all the cleaning procedures was achieved in 1993 with a revised Food and Drug Administration Inspection Guide on Cleaning Validation.

Pharmaceutical products and active pharmaceutical ingredients (APIs) can be contaminated by other pharmaceutical products, by cleaning agents, micro-organisms or by other material (e.g. air-borne particles, dust, lubricants). Further sources of contamination might be raw materials, intermediates, auxiliaries, etc.

In many cases, the same equipment may be used for processing different products. To avoid contamination of the following product, adequate cleaning procedures are essential.

High risk products, such as penicillins, are a major concern in the cleaning validation field. Sensitive sampling methods require development and must be applicable to each specific piece of equipment used. Due to the possibility of inter-product contamination, highly sensitive analytical methods such as Liquid Chromatography are required for trace level analysis.

These detection methods should be specific for the target analyte, sensitive for trace and ultra-trace analysis, and be sufficiently able to separate and quantify the target analyte from potential interference. Currently there are two sampling methods in use.

The direct method, incorporating a swabbing material, is favoured over the indirect rinsate analysis approach. However caution must be taken when choosing the correct swab, as factors such as recovery, background contribution and particle generation can hinder residue determinations. Therefore each should be evaluated independently and an overall correction factor applied to the swab. Swab recoveries may be determined using spiking studies incorporating coupons of equipment surfaces.

Rinsate analysis is a useful sampling tool for equipment such as blenders and reaction vessels. The theory is that by analysing an aliquot of rinse water, the total quantity of analyte residue can be estimated. This method however assumes that the residue is uniformly removed from the equipment and also presumes that if the rinsate is clean then the equipment is clean.

Probably the most important aspect of cleaning validation programmes is establishing predetermined levels of acceptability. In order to establish Acceptable Residue Limits (ARL), various product and equipment attributes are evaluated. This leads to wide variations in ARL values between different product trains and different manufacturing facilities. The most important aspect is therefore proving that the ARL values determined in the cleaning validation programme have been established using a sound scientific rationale.