I sometimes get the question as to why I recommend a “default” value for a detergent limit based on the solids content of the detergent. After all, shouldn’t the default value for a detergent be the same as the default value for an active (an API), which is 10 ppm. This Cleaning Memo will discuss the rationale for the default value being 10 ppm detergent solids.
I’ll start with two clarifications. First is that the default value we are talking about here is one for a L1 value, or the limit in the next drug product. This default value is only used if it is more stringent than the L1 value in a carryover calculation based on a HBEL or 0.001 of a dose. Secondly, in a carryover calculation the limit for the detergent is independent of the concentration of the detergent as it is diluted for use in the cleaning process. That is, if the detergent is Detergent ABC, then it doesn’t matter whether Detergent ABC is used at a diluted concentration of 1%, 2%, or 5%. For carryover calculations purposes, it is the limit of the concentrated detergent (as purchased) that is ordinarily used.
So, let’s get back to the rationale for 10 ppm solids. Clearly if the detergent is 100% solids (for example, just surfactant with no water), then the limit is the same whether it is based on the detergent product or the detergent product solids. However, most detergents as used in the pharmaceutical industry are liquids for the reason that it make dispensing, measuring and dissolution much easier. In most cases, formulated detergents contain much greater than 50% water content (that is, the solids are much less than 50%). Does it make sense to include the percentage (>50%) of water in the formulated detergent when calculating the limit? Let’s look at a simple example.
Suppose I wanted to clean my equipment with a detergent just containing sodium lauryl sulfate (SLS) and water. I have the option of purchasing a product containing 10% SLS (Detergent A), or a product with 20% SLS (Detergent B), or a third product with 30% SLS (Detergent C). As a side note, in that situation if I were to use in my cleaning process a 3% dilution of Detergent A, I would only use a 1.5% dilution of Detergent B or a 1% dilution of Detergent C (but those considerations are not be relevant to the calculation of limits). If I set my requirement that the L1 default should be 10 ppm of the formulated detergent, that would mean I would be allowing a carryover of 1 ppm of SLS in the situation of using Detergent A, 1.5 ppm of SLS in the situation of using Detergent B, or 3 ppm SLS in the situation of using Detergent C. That just doesn’t make sense (although I must confess that any of those would be a worst case compared to what should be a scientifically justified L1 default limit of 10 ppm SLS).
Where does this leave us? If the scientifically justified limit in this situation is 10 ppm SLS, then that value would correspond to 100 ppm of Detergent A, 50 ppm of Detergent B, and 33.3 ppm of Detergent C. In each situation the concentration of SLS allowed would be 10 ppm. From a practical point of view, if I am requiring no more than 10 ppm of drug active, does it make sense in a risk-based approach to require no more than 3 ppm of SLS, which most likely has less safety concerns than most drug actives (the only exception I can think of might be where calcium carbonate is the drug active).
Some might suggest that in the example I have given it would be preferable to set the default L1 as 10 ppm SLS, because my analytical method is validated to report out the concentration of SLS rather than the concentration of Detergent A (or Detergent B or Detergent C). In that case, I could agree that setting the limit at 10 ppm SLS is acceptable (in that it is essentially the same as setting the default L1 value at 10 ppm detergent solids). However, most formulated detergents are not water with a single component. Most have multiple components, and the analytical approach is usually based on a specific method for one component or based on a non-specific method for a general property such a TOC or conductivity. This makes the simple situation with only one component (SLS) much it more difficult to use this suggested alternative approach. For example, if I have a specific method to measure the surfactant in a multicomponent detergent, do I base the toxicity (for calculation purposes) on just the toxicity of the surfactant or on the toxicity of the detergent as a whole? The latter is preferred (and more relevant), but the water in the detergent product formulation should not contribute to toxicity; therefore it makes sense to exclude it as part of the “10 ppm” default value.
You might be asking “How do I determine the percent solids in my formulated detergent?” One option is to ask your detergent supplier. If they give you a range (such as 20%-30%), use the upper value as a worst case to determine “10 ppm solids” Alternatively, consider using a laboratory dry-down solids, which is fine as long as there are not any non-aqueous volatile components.
I want to repeat that it is okay from a compliance perspective to base the L1 default value on 10 ppm of the detergent product; however, it is an unnecessary “worst case”; please see the Cleaning Memo of February 2021 for a discussion of “required” worst cases and “not required” (but allowed) worst cases.