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10.8 Topical Drug Products 局部用药品 Themajor issue with topical drug products relates to how limits are set. Theapproach to setting limits depends on the systemic availability of the drugactive ingredient when applied to the skin.Some topical products, such as drugpatches, are actually transdermal delivery mechanisms to allow systemicavailability of the drug active ingredients. While for other topical drugproducts, the effect of the drug active ingredient is limited to the skinitself and there is generally no, or very low, systemic availability of thedrug active ingredient. 局部用药的主要问题是如何制定限度。设定限度的方法取决于药物活性成分应用到皮肤上的全身利用度。一些局部用药,如贴剂，实际上活性成分是通过经皮给药机制发挥作用。而对于其他局部药品，活性成分的作用仅限于皮肤本身，通常没有或仅有极低的活性成分的全身利用度。
10.8.1 Topical Drug Products withSystemic Availability 具有全身利用度的局部药品 Limitsfor topical drug products where the drug active ingredient is topicallydesigned to be available systemically are established based on a typicalcarryover calculation based on a safe level in the next product. That safelevel may be established on either a fraction of the dose or on a toxicologicalevaluation (see Section 5.0). A significant difference may be theportion of the active in the topical drug product that is systemicallyavailable from the cleaned topical product versus the portion of the active ingredientthat is systemically available when that active ingredient is present as aresidue in the next topical product. In the absence of specific information, itmay be assumed as a worst case that the residue of the cleaned active is 100%systemically available when in the next product. As with other carryovercalculation based on the therapeutic dose, the minimum dose of cleaned activeingredient and the maximum dose of the next product should be adjusted based onfactors such as the number of applications per day (or per other time period)and the amount of product applied per application. 对具有全身利用度的局部用药，其限度应基于在下一产品中的安全水平计算出的典型残留量而建立。这个安全水平可以建立在剂量的一部分或毒理学评价之上(见5.0节)。一个显著的差异可能是在具有全身利用度的局部用药中的部分活性成分是来自被清洁的局部用药，而另一部分具有全身利用度的活动成分作为残留出现在下一局部用药产品中。缺乏详细的信息，可以假设其为最差条件，即存在于下一产品中的被清洁的活性成分残留具有100%的全身利用度。同其他基于治疗剂量残留计算一样，被清洁的活动成分的最小剂量和下一个产品的最大剂量应根据每天(或每个其他时间周期)的应用次数和每次用量等因素进行调整。
Anotherfactor that may be considered in setting limits in this situation is dermalirritation of the active ingredient. In most cases, this will not be a limitingfactor, but it may be considered, particularly if the active ingredient, whichis the residue, is not systemically available when present in the next topicaldrug product. 在这种情况下，设定限度时需要考虑的另一因素是活性成分对皮肤的刺激性。在大多数情况下，这不会是一个限制因素，但它可能被考虑，特别是当残留的活性成分在下一个局部药物产品中不呈现全身利用度时。
10.8.2 Topical Drug Products withNo or Limited Systemic Availability 不具有或具有有限全身利用度的局部用药
Forsome topical drug products, the therapeutic effect is limited to the skin towhich the drug product is applied. An example of such a product is sunscreen (adrug product in some countries, such as theUSA). If the therapeutic effect ofthe active ingredient is so limited then a modification of a traditional carryovercalculation may be utilized. The reason is that a “dose”for such topical drug products is generally not well defined, as the “useinstructions” may typically read “Applyto the affected area.” 对于一些局部药物产品，治疗效果仅限应用于应用了药物的皮肤。例如防晒霜(在一些国家被作为药品，比如美国)。如果有效成分的治疗效果仅限于局部，那么可以对传统的残留计算方法进行调整。原因在于这种局部用药的“剂量”一般不是很好确定，因为“使用说明”通常是“应用于受影响的区域。”
10.8.2.1 Adjusted Calculation 调整计算方法 Atraditional carryover calculation bases the limit on a minimum dose of activeingredient of the productthat is cleaned and a maximum dose of the next drugproduct. However, in this situation (where the effect of the active ingredientis limited to the skin it is applied to) it is not necessary to consider theminimum dose of the cleaned active ingredient as application to a very smallarea (such as 100 cm2) and the maximum dose of the next product asapplication to the entire body (such as 1.6 m2). Those calculationscan be used but they result in extremely low limits. However, the relevantsafety concern is what happens if 0.001 of the amount of active applied to agiven area (such as 100 cm2) appears in the next drug product whichis also applied to the same surface area (in this example, 100 cm2).Because the therapeutic effect is limited to the skin surface the drug productis applied to, limits can be based on 0.001 of the concentration of the activeingredient from the cleaned product in the subsequently manufacture drugproduct (suitably modified by application conditions which will be discussedshortly). In other words, if the drug product which is cleaned contains 0.5%drug active ingredient, then the safe level in the next drug product is 0.001of that concentration, or 0.0005% (5 ppm). 传统的残留计算方法是基于被清洁产品活性成分的最小剂量和下一产品的最大剂量。但在这种状况下（活性成分的效果仅限于应用该药品的皮肤)，则不必考虑被清洁的活性成分的最小剂量（应于于非常小的区域，如100 cm2）和下一产品的最大剂量（应用到整个身体，如1.6m2)。可以这样进行计算，但得到的限度极低。但是,如果应用到一个给定的区域(如100 cm2)的活性成分的千分之一量出现在下一个药物产品中，该下一产品也应用于相同的表面面积(在这个例子中，100 cm2)，会有什么安全顾虑呢？因为治疗效果是限于应用了药物的皮肤表面，限度可以基于被清洁产品的活性成分在随后生产药品中浓度的千分之一(适当地修改应用条件不久将要讨论的)确定。换句话说，如果被清洁药物含有0.5%的药物活性成分，那么下一产品中的安全水平是该浓度的0.001倍，或0.0005%(5 ppm)。
10.8.2.2 Modification Based onFrequency of Application 基于应用频率的修改 Carryovercalculations should be modified first based on the frequency of application.For example,if the cleaned product is applied a minimum of once per day and thesecond product is applied amaximum of three times a day, then the limit shouldbe lower by a factor of 3 (with a resulting limit of 0.00016% in the examplegiven). If the first product is applied a minimum of three times a day andthesecond product applied a maximum of once per day, then the limit may be higherby a factor of 3(resulting in a limit of 0.0015% in the example given). 残留的计算首先应该基于应用频率进行修改。例如，如果被清洁产品是每天应用至少一次，下一产品每天最多3次，那么限度应该应除以3(在上述例子中，限度为0.00016%)。如果第一个产品是一天应用至少三次,第二个产品每天应用最多一次，那么限度应乘以3倍(在上述例子中，限度为0.0015%)。
10.8.2.3 Modification Based onAmount Applied per Surface Area 基于单位表面积应用量的修改 Asecond modifying factor is based on the amount applied per surface area. Thisis sometimes difficult to assess. However, if it is clear that one product isapplied at a significantly higher amount per surface area then that factorshould also be considered. For example, if the cleaned product is typicallyapplied at a rate of 2 mg/cm2 and the second product typically applied at arate of 4 mg/cm2, the concentration limit in the basic example given would belower by a factor of 2 (resulting in a concentration limit of 0.00025%). 第二个修改因子是基于单位面积的用药量。这是有时很难评估。然而，如果一个产品单位表面积的用量明显很高，则需要考虑这个因素。例如，如果被清洁产品用量通常为2mg/m2，第二种产品用量为4mg/ cm2，上述例子中浓度限度应降低2倍(浓度限度变成0.00025%)。
Oneapproach is to establish a therapeutic dose of topical preparation in terms ofarea of application covered by one fingertip unit (FTU), which is defined asthe amount of topical preparation ointment dose delivered from a tube with a5-mm diameter nozzle, applied from the distal skin-crease to the tip of indexfinger an adult forefinger (35). One FTU measures approximately 0.5g. As theaverage human adult area covered by 1 FTU is 286 cm2, approximately 1.75 mg ofthe topical formulation is applied per each square centimeter of the skinsurface area. 一种方法是依据一个指尖单位(FTU)覆盖的应用面积建立局部用药的治疗剂量，FTU被定义为从一个带有5mm直径喷嘴的管子挤出的局部药膏制剂的量，从成人的食指远端褶皱皮肤开始应用至食指指尖(35)。一个FTU大约为0.5克。因为1个FTU覆盖的成人体表面积是286 m2，大约1.75mg的局部用药应用于每cm2的皮肤表面。
10.8.2.4 AdditionalConsiderations 其他注意事项 Ifa firm has a policy or procedure for a default limit (such as 10 ppm of thecleaning active in the nextdrug product), then the calculated limit(considering the modification discussed in Sections 10.8.2.2and 10.8.2.3)should be compared to that default limit and the lower of the two valuesutilized for subsequent calculations. 如果一个公司有默认限度政策或程序(比如下一产品中含 10 ppm的被清洁活性成分)，则应将计算得出的限度(考虑10.8.2.2和10.8.2.3节所讨论的修改)同默认值进行比较，并采用较低的数值用于后续计算。
Inaddition, if there is evidence that the active ingredient in the cleanedproduct would be systemically available if it were present in the vehicle(excipients) of the next product, then the calculation in 10.8.1may not beapplicable. In such a case, either the calculation in 10.8.1 should beconsidered or the order of manufacture may be restricted. 此外，如果有证据表明被清洁产品的活性成分在下一产品中呈现全身利用度，则10.8.1所述的计算方法可能不适用。在这种情况下，或者考虑按照10.8.1进行计算或限制生产的顺序。
10.8.3 Additional SafetyConsiderations 其他的安全注意事项 Ifactive ingredients used in topical preparations produce adverse skin irritationeffects, hypersensitivity, and/or possible photosensitivity reactions, thoseconsiderations should be evaluated to determine whether more stringent residuelimits should be established. 如果用于局部给药制剂生产的活性成分有皮肤刺激性、过敏、和/或可能的光敏性反应，应对此进行评估来确定是否应该建立更严格的残留限量。
10.8.4 Additional CleaningConsiderations 其他清洁注意事项 Topicaldrug products may present cleaning challenges because of the nature of theexcipients used and the high viscosities of the drug product. In place of awater prerinse, it may be necessary to physically remove gross amounts ofproduct left on equipment surfaces using a plastic scraper or a nonwoven wipe.Particularly if the excipients are designed to make the topical drug product “waterproof”, more stringent cleaning processconditions, such as higher temperatures or higher concentrations of cleaningagents, may be required for effective cleaning. 因为所使用辅料的性质和制剂的高粘度，局部给药制剂可能给清洗带来挑战，。除了用水进行预冲洗，还可以使用塑料刮板或无纺布抹布去除设备表面的残留物。特别是当辅料的设计旨在使局部给药制剂能够“防水”，可能需要更严格的清洗工艺条件，如高温或更高的浓度清洁剂，以进行有效的清洗。 |
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