Validating non API?

Hello - I have an odd situation regarding a cleaning validation:

Although considered a medical device – the formulation has no actives in it (API). It is for internal/oral consumption, but you can eat your weight in it and not have any dire consequences. (This information is documented)

In addition, the equipment used to batch manufacture the cream is dedicated and the cream is water soluble

I was under the impression if something had no API in it and the equipment was dedicated, then there was no need for cleaning validatation. Is this so? The equipment is, “visually clean” after a standard cleaning.

If validation were to be done – would just a TOC analysis of the final rinse be adequate? –or would swabbing be necessary for micro??

What would be the best way to go to meet cGMP standards/ FDA??

Dear pingpong,

in my opinion there are two issues to focus on: the contamination with degradation products, and the microbiological contamination.

For the microbiological contamination, the way is as usual, setting acceptance criteria according to product specification for microbiological counts, with a safety factor.

For the degradation products it is far more complicated, and i think there are two ways: The first, quantifying the degradation substances, is the more defendable one, but requires a lot of investigational work because for nonactive substances the degradation pathways are often unknown, especially under cleaning conditions (exposure to heat and water together with acid, alcaline or neutral cleaning agents). Try to start with the most unstable substance. The other way is sampling and analizing with TOC, building up a database and setting acceptance limits based on historical data. Not knowing the formulation of the cream, my advice is to carry out a sound recovery test (if the cream is an emulsion, be sure the rinse effectively draws the oily phase with it) and verify that the method is sensitive enough (toothpaste has a lot of inorganic components, and even visually dirty equipment can render low TOC values).

Best regards


I’d research the LD50 of the excipients to calculate the toxicity acceptance criteria. Also calculate the 10 ppm carryover AC. Pick the lower one and see how it compares to a visual limit. Spike a plate at this level and see if you can detect it in production. Document findings. I’d be surpised if you aren’t in the Visual Residue Limit level for that specific residue. As far as micro, if you have no data I’d start a program…clean hold time after sanitization (not sure your specific criteria…sterile or sanitized).

The customer wants micro done by swabbing and rinsewater for TOC.

This emulsion is water soluble, so it is expected to leave little residue. -Easily visably clean. At this point the residue from the cleaning agent is probably of more concern to them.

Is there a rule of thumb for swabbing area? I have 25 cm^2 and 100cm^2 on larger areas. Is there a rule of thumb or logic/formula to determining the adequate area??

I feel the cusomer is making a mountain out of a mole hill as they can provide documents declaring their emulsion non-toxic.

Dear pingpong,

there is no rule of thumb for the swabbing area, if you want you can swab the entire surface of your equipment. The adequacy of the area chosen is more an analytical issue (swab an area to get sufficient analyte to be quantified, but no so big as to saturate the swab with analyte), and 100 cm² has been proved as a good compromise. As a matter of fact, there can be a lot of sampling points smaller than 100 cm² simply because the swabbed piece is too small.

For micro a swabbed surface of 25 cm² is more usual, but only because this is the surface of a RODAC plate, and it is easier to handle the data if all the swabbed areas are the same.

Regarding the cream, I do not agree completely with you, in that it can be expected to leave “no” residue. If it is an emulsion, it has a non water soluble component, which may be uniformly spread over the surface after cleaning, and thus being not readily visible and even be oxidised or decomposed, and if this is the case, rinsewater analysis with TOC makes no sense, because if the cleaning water did not remove that component, why should the rinsewater? My advice is to perform the limit calculation with the toxicity of the most toxic component or degradation product, compare it with the 10 ppm limit, and take tho lower of both (most probably the 10 ppm limit). Then calculate the amount of cream that could remain if the entire formulation was made of the most toxic component (worst case), and spike a coupon/surface with the corresponding proportion of each component of the cream. Spike the entire surface, not only one 100 cm² spot, because a spot is far more visible than a uniform film covering the surface. If all of them are readily visible you have a good reason to convince the customer.

Best regards