清洁验证最差情况产品选择标准第1部分：溶解度判据的问题与药典区间调整思路

Worst-Case Product Selection Criteria – Part 1
最差情况产品选择标准 – 第1部分

Sep 2023/2023年9月

This is the first of several Cleaning Memos dealing with selection of a worst-case product in a grouping approach for cleaning validation.
这是关于清洁验证中采用分组法选择最差情况产品的若干《清洁备忘录》中的第一篇。

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.
我多年来一直教导，仅凭活性成分（API或原料药）的溶解度并不是确定药品清洁验证中最差情况产品的最佳参数。

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.
因此，在接下来的几个月中，我将重新审视其理由，并以更有条理（且一致）的方式说明为什么如此，以及可能存在哪些更好的选择。

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.
重点将放在口服固体制剂（OSD）的生产上，但也会讨论针对液体、局部用药和原料药生产的调整。

Introductory Concerns about Solubility
关于溶解度的初步关切

But before I start on all those options, there is a definite need to consider how solubility is defined for cleaning validation purposes.
但在我开始讨论所有这些选择之前，确实需要考虑如何为清洁验证目的定义溶解度。

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.
如果要使用溶解度（无论是活性成分的溶解度还是辅料的溶解度），就需要仔细定义溶解度，以便溶解度评级或排序能够被恰当使用。

As used for cleaning validation purposes, most will base solubility on solubility in water in the range of 20-25° Celsius.
就清洁验证目的而言，大多数人会将溶解度基于20–25°C范围内的水中溶解度。

Two issues arise:
由此产生两个问题：

The first issue is whether solubility in water is the best consideration.
第一个问题是，水中溶解度是否是最好的考虑因素。

Certainly, if water alone is used for cleaning, that makes some sense.
当然，如果仅用水清洁，这有一定道理。

But if a detergent is used in the washing step, is that relevant?
但如果在洗涤步骤中使用清洁剂，这还相关吗？

Perhaps if it involves a neutral pH detergent, then a reasonable case can be made for using water solubility to evaluate the difficulty of cleaning.
也许如果涉及中性pH清洁剂，那么使用水溶解度来评估清洁难度是合理的。

There may be less support for using water solubility as the relevant criterion if the detergent is a highly alkaline one (> pH 10.0), since it is well known that solubility may change with increasing pH.
如果清洁剂是强碱性（> pH 10.0），那么用水溶解度作为相关标准可能支持较少，因为众所周知溶解度可能随pH升高而变化。

This latter concern is more pronounced when we are comparing the relative solubility of two different compounds, because the rate at which solubility increases or decreases with an increase in pH may be different.
当我们比较两种不同化合物的相对溶解度时，后一个关切更为明显，因为溶解度随pH升高而增加或降低的速率可能不同。

That is, it may be that API-A is more soluble at a pH of 7.0, but that API-B is more soluble at a pH of 10.5.
也就是说，可能API-A在pH 7.0时溶解度更高，而API-B在pH 10.5时溶解度更高。

Furthermore, for detergent use, is it the solubility of the compounds in the washing solution or in the rinsing solution that is most relevant?
此外，对于使用清洁剂的情况，最相关的是化合物在洗涤溶液中的溶解度，还是在冲洗溶液中的溶解度？

I can make a theoretical argument both ways.
我可以从理论上为两者都提出论据。

For solubility in the detergent solution, it is the detergent solution that “dissolves” the drug product being cleaned, so it would seem to be the key.
就清洁剂溶液中的溶解度而言，是清洁剂溶液“溶解”了正在被清洁的药品，因此它似乎是关键。

But, it is also possible that the drug active is more soluble at a higher pH, and as rinsing with water proceeds, it becomes less soluble at the neutral pH of the rinse water.
但是，也有可能药物活性成分在较高pH下溶解度更高，而随着用水冲洗进行，在中性pH的冲洗水中它变得溶解度更低。

A counterargument might be that even though the solubility decreases as rinsing proceeds, during the rinsing proceeds the concentration of the compound may be so low that the solubility difference is not significant.
一个反驳论点可能是，即使溶解度随着冲洗进行而降低，在冲洗过程中化合物的浓度可能已经低到溶解度差异不显著。

It should be clear that the dynamics of the situation of using one pH for washing and a different pH for rinsing complicates the analysis.
应当清楚，洗涤使用一个pH而冲洗使用不同pH这种动态情况使分析复杂化。

A second issue is the temperature of the washing and the rinsing steps.
第二个问题是洗涤和冲洗步骤的温度。

It is well-known that temperature affects the solubility of many compounds.
众所周知，温度会影响许多化合物的溶解度。

In most cases, the solubility increases with increasing temperature, but there are certainly situations where the opposite is true.
在大多数情况下，溶解度随温度升高而增加，但当然也存在相反的情况。

In addition, the slope of the curve for “solubility versus temperature” will be different for different compounds.
此外，不同化合物的“溶解度 versus 温度”曲线斜率会不同。

Without such specific information, it may be difficult to appropriately select the “least soluble” compound.
没有这些具体信息，可能难以恰当地选择“溶解度最低”的化合物。

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.
我应当说明，尽管存在对这些问题的关切，我并不是说完全回避溶解度问题。

I am merely saying it could be a complex issue based on a scientific analysis.
我只是说，基于科学分析，它可能是一个复杂问题。

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.
此外，大多数公司并不使用基于量化数值的化合物溶解度（该数值可能随pH和温度变化），而是使用各药典给出的溶解度“区间”。

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.
由于这些区间通常覆盖很宽的范围，它们可能有助于区分不同区间中的化合物，但对区分同一区间内的化合物作用甚微。

Concerns about Pharmacopeia Solubility Categories
关于药典溶解度分类的关切

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.
虽然USP中的溶解度区间可能有帮助，但在建立最差情况产品的清洁验证程序中，应对其进行修改。

Here is a summary of the solubility categories from USP:
以下是USP溶解度分类的摘要：

Table 1: USP Solubility Categories
表1：USP溶解度分类

Table 1: USP Solubility Categories
表1：USP溶解度分类

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.
注意第三列是我创建的，单位不是每克溶液中的微克数，而是（为了与药典表述一致）每克溶剂中溶质的微克数。

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.
如果你喜欢不同的表述（如每克溶液中溶质的微克数，或希望表示为百分比），请做出更改，使其易于按照你公司的惯例表达。

Now we get to my concerns with utilizing these “bands” as defined in a pharmacopeia.
现在我们来看我对使用药典所定义这些“区间”的关切。

The first concern is what could be considered “imprecision”.
第一个关切可以认为是“不精确”。

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”?
例如，如果一种化合物需要“1,000份水对1份溶质”，这属于描述性术语“微溶”还是“极微溶”？

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”?
也就是说，对于描述性术语“微溶”，“从100到1,000”这个短语是指“从100到并包括1,000”，还是指“从100到但不包括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.
溶解度恰好在一个描述性术语的下限、同时又另一个描述性术语的上限，这种情况可能很少见，但就清洁验证目的而言，这是应当避免的。

Here is one modification (Table 2) of the pharmacopeia table that would not allow for this possible confusion.
以下是对药典表的一种修改（表2），可避免这种可能的混淆。

Note also that for the third column of this table, I have left out “ppm values” for the first four terms.
另请注意，对于该表第三列，我省略了前四个术语的“ppm值”。

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.
在实际使用溶解度确定清洁难度时，任何溶解度大于10,000 ppm（相当于1%）的化合物都应能仅用水就很容易地清洁。

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.
虽然前四个USP描述性术语可能适用于理论目的，但应用于清洁难度时，它们通常没有实际相关性。

Table 2: Modified USP Categories
表2：修改后的USP分类

Table 2: Modified USP Categories
表2：修改后的USP分类

Below is a further modification (Table 3) that is possible.
以下是另一种可能的进一步修改（表3）。

In that table, I have not used the pharmacopeia descriptive terms and have substituted a “Solubility Band”.
在该表中，我没有使用药典描述性术语，而是代之以“溶解度区间”。

The purpose of doing so is just to avoid any direct link to the pharmacopeia terms.
这样做的目的只是避免与药典术语有任何直接联系。

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).
我还将类别数量减少为五个；这是通过将前四个类别合并（作为区间I），并在溶解度较低端增加一个额外类别（区间V）（以区分10 ppm溶解度浓度水平的残留物）来实现的。

It is more likely that the added lower-end band will be useful in separating out differences in solubility that are relevant to establishing the difficulty of cleaning.
新增的低端区间更有可能有助于区分与建立清洁难度相关的溶解度差异。

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.
另请注意，通过这种与药典术语的“脱钩”，各公司可能可以修改区间值，甚至增加区间数量。

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).
最后，避免使用“1份溶质所需溶剂份数”之类的措辞，而只使用清洁验证程序中更熟悉的术语（如ppm或mcg/g或mcg/mL），可能是有用的。

Table 3: Rating System Avoiding Pharmacopeia Terms
表3：避免药典术语的评级系统

Table 3: Rating System Avoiding Pharmacopeia Terms
表3：避免药典术语的评级系统

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”.
如果意图是使用溶解度“区间”（而不是量化数值），那么表3可能更有用于定义“清洁难度”的相关差异。

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).
话虽如此，表3中的区间范围会将溶解度分别为150 ppm和350 ppm的两种不同活性成分视为处于同一溶解度区间（表1中的药典类别也是如此）。

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.
此外，两种不同活性成分，一个溶解度为9 ppm，另一个为11 ppm，会被置于不同的溶解度区间，即使这种溶解度差异实际上并不显著。

Alas! That is just one of the unfortunate features of establishing defined bands as opposed to a continuum of values.
唉！这只是建立定义区间而非数值连续谱的不幸特点之一。

If this is problematic for your company, then avoid these types of bands and just use actual quantified values.
如果这对你的公司是个问题，那么就避免这类区间，直接使用实际量化值。

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.
但是，正如我们将在接下来几个月中讨论的那样，这些类型的区间在制药清洁验证中对于在分组法中建立最差情况（即“最难清洁”）药品是有用的。