This is the first of several Cleaning Memos dealing with selection of a worst-case product in a grouping approach for cleaning validation. I have taught for many years that solubility of the active (API or drug substance) alone is not the best parameter for determining the worst-case product in drug product cleaning validation. So over the next few months I will revisit the rationale and present in a more organized (and consistent) way why this is the case, and what better options there might be. The focus will be on the manufacture of oral solid dosage (OSD) products, but modification for the manufacture of liquids, topicals and drug substances will also be addressed.
Introductory Concerns about Solubility
But before I start on all those options, there is a definite need to consider how solubility is defined for cleaning validation purposes. If solubility is to be used (whether it is the solubility of an active or the solubility of an excipient), there is a need to carefully define how solubility so that a solubility rating or ranking can be appropriately used. As used for cleaning validation purposes, most will base solubility on solubility in water in the range of 20-25° Celsius. Two issues arise:
I should make it clear that even though there are concerns about these issues, I am not saying to completely avoid the issue of solubility. I am merely saying it could be a complex issue based on a scientific analysis. Furthermore, most companies do not use the solubility of a compound based on a quantified number (which may vary with pH and temperature), but rather use solubility “bands” as given in various pharmacopeias. Since those bands generally cover wide ranges, they may be useful to distinguish between compounds in different bands, but do little to distinguish compounds within the same band.
Concerns about Pharmacopeia Solubility Categories
While the solubility bands found in USP can be helpful, they should be modified for use in a cleaning validation program where the worst-case product is being established. Here is a summary of the solubility categories from USP:
| Descriptive Term | Parts Solvent for 1 Part Solute | ppm (Micrograms of solute per gram of solvent) |
|---|---|---|
| Very soluble | < 1 | >1,000,000 |
| Freely soluble | From 1 to <10 | From 1,000,000 to 100,000 |
| Soluble | From 10 to <30 | From 100,000 to 33,333 |
| Sparingly soluble | From 30 to <100 | From 33,333 to 10,000 |
| Slightly soluble | From 100 to <1,000 | From 10,000 to 1,000 |
| Very slightly soluble | From 1,000 to <10;000 | From 1,000 to 100 |
| Practically insoluble, or Insoluble | 10,000 and over | ≤ 100 |
Note that the third column is one I have created, and that the units are not micrograms per gram of the solution, but rather (to be consistent with the pharmacopeia presentation) in units of micrograms of solute per gram of solvent. If you like a different presentation (like micrograms of solute per gram of solution or if you want it expressed as a percentage), please make that change so it is readily expressed consistent with your company’s practices.
Now we get to my concerns with utilizing these “bands” as defined in a pharmacopeia. The first concern is what could be considered “imprecision”. For example, if a compound requires “1,000 parts of Water for 1 Part of Solute”, does this fit into the descriptive term “slightly soluble” or “very slightly soluble”? That is, does the phrase “From 100 to 1,000” for descriptive term “slightly soluble” mean “From 100 up to and including 1,000”, or does it mean “From 100 up to but not including 1,000”? This situation of having solubility exactly on the lower limit of one descriptive term and at the same time on the upper limit of another descriptive term may be rare, but it is something for cleaning validation purposes that should be avoided.
Here is one modification (Table 2) of the pharmacopeia table that would not allow for this possible confusion. Note also that for the third column of this table, I have left out “ppm values” for the first four terms. As a practical matter in using solubility to determine the difficulty of cleaning, any compound which has a solubility greater than 10,000 ppm (equivalent to 1%) should be readily cleaned using water alone. While the first four USP descriptive terms may be applicable for theoretical purposes, as applied to the difficulty of cleaning, they are generally not practically relevant.
| Descriptive Term | Parts Solvent for 1 Part Solute | ppm (Micrograms of solute per gram of solution) |
|---|---|---|
| Very soluble | < 1 | — |
| Freely soluble | From 1 to <10 | — |
| Soluble | From 10 to <30 | — |
| Sparingly soluble | From 30 to <100 | — |
| Slightly soluble | From 100 to <1,000 | From 10,000 to >1,000 |
| Very slightly soluble | From 1,000 to <10;000 | From 1,000 to >100 |
| Practically insoluble, or Insoluble | 10,000 and over | ≤ 100 |
Below is a further modification (Table 3) that is possible. In that table, I have not used the pharmacopeia descriptive terms and have substituted a “Solubility Band”. The purpose of doing so is just to avoid any direct link to the pharmacopeia terms. I have also reduced the number of categories to five; this has been done by combining the top four categories (as Band I) and adding an additional category (Band V) at the lower end of solubility (to separate residues at the 10 ppm solubility concentration level). It is more likely that the added lower end band will be useful in separating out differences in solubility that are relevant to establish the difficulty of cleaning. Note further that with this “decoupling” from the pharmacopeia terms, it may be possible for individual companies to modify the band values or even to increase the number of bands. Finally, it is probably useful to avoid phrases like “parts solvent for 1 part solute” and just use terms that are more familiar in the cleaning validation programs (such as ppm or mcg/g or mcg/mL).
| Solubility Band | ppm (micrograms solute per gram of solution) |
|---|---|
| Band I | 10,000 ppm |
| Band II | From 10,000 ppm to >1,000 ppm |
| Band III | From 1,000 ppm to >100 ppm |
| Band IV | From 100 ppm to >10 ppm |
| Band V | ≤ 10 ppm |
If the intention is to use solubility “bands” (as opposed to quantified numbers), then Table 3 may be more useful to define relevant differences in “difficulty of cleaning”. That said, the band ranges in Table 3 would consider two different actives with solubilities of 150 ppm and 350 ppm to be in the same solubility band (which also occurs with the pharmacopeia categories in Table 1). Furthermore, two different actives, one with a solubility of 9 ppm and the other with a solubility of 11 ppm, would be placed in different Solubility Bands, even though the solubility difference is not practically significant. Alas! That is just one of the unfortunate features of establishing defined bands as opposed to a continuum of values. If this is problematic for your company, then avoid these types of bands and just use actual quantified values. But, as we will cover in the next months, these types of bands are useful in pharmaceutical cleaning validation for establishing the worst-case (that is, “most difficult to clean”) drug product in a grouping approach. So stay tuned for next month, where we will get more into the “nitty gritty”.
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