A question that often comes up: should you favour rinsing (indirect sampling) or swabbing (direct sampling)?
Both approaches share the same objective: detecting and quantifying residues on manufacturing equipment. Yet they rest on different principles, involve specific implementation requirements, and provide distinct types of information.
Both methods are accepted by regulatory authorities, but their application raises important nuances. Let us revisit the technical fundamentals, regulatory requirements, and best practices for their use.
1. Two Approaches, Two Sampling Logics
Swab Sampling: When Precision Comes First
Direct sampling, or swab sampling, involves rubbing a defined surface area (often 25 cm²) with a swab moistened with an appropriate solvent. It is a remarkably effective method for precisely quantifying residues present on a targeted surface.
It is particularly useful when residues are poorly soluble, sticky, or localised in critical areas such as gaskets, welds, or hard-to-reach corners. In other words, it is the option to favour when you want to seek out information where it is truly hiding.
However, this precision has a downside: the analysed surface area remains limited, and the quality of the sample depends heavily on the operator's technique (hence the need for training). Moreover, this method is absolutely not suited to closed systems or inaccessible areas.
Have you ever tried taking a sample from the bottom of a tank with a 3-metre pole and a swab at the end? If so, you know it is not exactly a pleasant experience... It is far from the ideal sample, and we won't even mention reproducibility and operator training.
Despite these constraints, swab sampling remains an indispensable reference for obtaining a direct and reliable measurement of residues.
Rinse Sampling: The Simple and Effective Option
Rinse sampling involves circulating a solvent (generally water) over the target equipment surface and then analysing this water to detect any carried-over residues. This approach makes it possible to cover large surface areas and reach areas inaccessible to a swab.
It is the method of choice in automated CIP (Cleaning-In-Place) systems, where reproducibility is a genuine advantage. Another benefit: there is no need to dismantle the equipment or risk recontaminating samples by handling surfaces.
However, rinsing also has its limitations. If residues are poorly soluble or if hard-to-reach areas remain, they may slip through undetected. And depending on the volume-to-surface ratio, the residue concentration may be so low that it falls below the analytical method's limit of quantification (LOQ).
2. What the Regulatory Texts Say
The official positions of the FDA and EMA (GMP Annex 15) are clear: both methods are acceptable, but their use must be justified and scientifically demonstrated.
FDA – Guide to Inspections: Validation of Cleaning Processes (1993)
« There are two general types of sampling that have been found acceptable. The most desirable is the direct method of sampling the surface. Another method is the use of rinse solutions. »
« A larger surface area may be sampled and inaccessible systems can be evaluated. »
« The residue or contaminant may not be soluble or may be physically occluded in the equipment. A direct measurement of the residue or contaminant should be made. »
FDA – Current Good Manufacturing Practice Q&A (2015)
« Rinse samples alone would not be acceptable; firms should also measure the residue or contaminant on the equipment surface using a direct method (if feasible). »
EMA / EU GMP – Annex 15 (2015)
« Cleaning validation protocols should specify or reference the locations to be sampled as well as the justification for the selection of these locations. Sampling should be carried out by swabbing and/or rinsing, or by other means depending on the production equipment. »
3. Why Rinsing Has Sometimes Had a Bad Reputation
Rinse sampling has long suffered from misinterpretation in the pharmaceutical industry.
Two main reasons explain this perception: on one hand, sometimes erroneous interpretations of regulatory texts have led some to believe the method was not compliant; on the other hand, poor field application has led to unreliable results.
Among the most common mistakes:
- The absence of recovery studies (recovery rates) specific to rinsing
- The association of rinsing with non-specific analytical methods (conductivity, TOC) to conclude cleanliness without specifically measuring the targeted residues
- Confusion between validation samples and those carried out as part of routine monitoring
Yet, when properly mastered and correctly validated, the rinse sampling method fully meets regulatory requirements and can play a key role in a robust validation strategy.
4. When and How to Use Rinsing Alone
In certain well-defined cases, rinse sampling can be used as the sole method. To do so, it must cover the entire surface area of the equipment and rely on an analytical method sufficiently sensitive to detect the targeted residues. It is therefore essential to verify beforehand that the surface-to-volume ratio allows for a measurable and quantifiable concentration.
A recovery study is equally indispensable to demonstrate the reliability of the method, and of course, acceptance limits must be clearly justified.
Pooling Rinse Samples: An Asset for the Method
Rinse sampling comes into its own when it is possible to pool the rinse volumes from different steps or zones of the equipment. This approach provides an overall picture of cleanliness while simplifying analysis. Conversely, when pooling is not possible, the question of the optimal sampling moment inevitably arises: should samples be taken at the beginning of the rinse, in the middle, or at the end?
5. Combining Both Methods: An Ideal Approach
Where possible, combining rinse sampling and swab sampling remains the most comprehensive strategy. Rinsing provides an overall view, particularly of hard-to-reach areas, while swabbing allows precise targeting of critical zones where the risk of contamination is highest.
Even though regulations do not systematically require the combined use of both methods, their complementarity strengthens the robustness of the approach. This strategy covers a wider spectrum of potential risks and proves more easily defensible during an inspection.
In Summary
The choice between rinse sampling and direct sampling should not be seen as a dilemma, but as the result of rigorous scientific analysis, taking into account equipment characteristics, the nature of residues, and the validation objectives.
Rinsing can perfectly well be used alone, provided all validation requirements are met: complete surface coverage, adequate analytical method, specific recovery study, and clear justification of acceptance limits.
That said, combining both methods remains the most robust strategy. Reference texts, notably those from the FDA and EMA (GMP Annex 15), provide a clear framework for scientifically justifying the choice and implementation of these methods.