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1、GUIDE TO INSPECTIONS OF TOPICAL DRUG PRODUCTS局部外用药物检查指南 Note: This document is reference material for investigators and other FDA personnel. The document does not bind（进退两难） FDA, and does no confer（赠予） any rights,privileges（特权）, benefits（权益）, or immunities（豁免） for or on any person(s).注：该指南是FDA 检查官和其
2、他工作人员的参考材料。该指南不是约束FDA，但也不赋予任何人特权，利益或豁免的权利。 I. PURPOSE（目的） The purpose of this guide is to provide field investigators, who are familiar with the provisions（食品） of the Current Good Manufacturing Practice (CGMP) regulations for pharmaceuticals, with guidance on inspecting selected facets（方面） of topica
3、l（局部的） drug product production. The subjects covered in the guide are generally applicable to all forms of topical drug products, including those that are intended to be sterile（无菌的）. However, this guide does not address（介绍） every problem area that the investigator may encounter（碰见）, nor every polic
4、y that pertains to（附属） topical drug products.该指南的目的是向熟悉食品CGMP规程的检察官提供药品CGMP的指导，提供局部外用药物检查方面的指南。该指南中涵盖的内容适用于所有剂型的局部外用药物，包括那些无菌产品。然而，该指南未能介绍检察官可能遇到的每个问题领域，也不适用局部外用药物的每项政策。 II. INTRODUCTION（介绍） This inspectional guide addresses several problem areas that may be encountered in the production of topical
5、drug products potency（效价）, active ingredient uniformity（均一性）, physical characteristics, microbial purity and chemical purity. The guide also addresses problems relating to the growing number of transdermal（经皮吸收） products. If a new drug pre-approval inspection is being conducted, then an examination
6、of the filed manufacturing and control data, and correspondence should be accomplished early in the inspection. As with other pre-approval inspections, the manufacturing and controls information filed in the relevant application should be compared with the data used for clinical batches and for prod
7、uction (validation) batches. Filed production control data should be specific and complete.该检查指南介绍了局部外用药物可能遇到的一些问题，如效价、活性成分的均一性、物理性质、微生物纯度和化学纯度。该指南也涉及了越来越多的有关药物经皮吸收的问题。如果正在进行一个新药的审批前检查，早期应完成现场工艺和控制试验数据，以及相关内容的检查。至于其他的检查，提交的有关申请中生产工艺和现场控制的内容应与临床批次和生产(验证)批次数据比较。现场生产控制数据应具体和完整。 III. POTENCY UNIFORMITY（
8、效价均一性） Active ingredient solubility（溶剂性） and particle size（颗粒度） are generally important ingredient characteristics that need to be controlled to assure potency uniformity in many topical drug products such as emulsions（乳剂）, creams and ointments. Crystalline（晶状的） form is also important where the acti
9、ve ingredient is dispersed as a solid phase in either the oil or water phase of an emulsion, cream, or ointment.活性成分的溶解度和颗粒度通常是重要的原料性质，这些性质需要进行控制以确保其在许多局部外用药物如乳状液、乳膏或软膏中的效价均一性。晶体形式也是重要的，其中活性成分作为固相分散在油或水相中形成乳状液、乳膏或软膏。 It is important that active ingredient solubility in the carrier vehicle be known a
10、nd quantified at the manufacturing step in which the ingredient is added to the liquid phase. The inspection should determine if the manufacturer has data on such solubility and how that data was considered by the firm in validating the process. 重要的是，活性成分在赋形剂中的溶解度是已知的，并且生产过程中是定量的。检查应确定生厂商是否有关于溶解度的数据
11、，并且生产商考虑如何使整个生产过程有效。 Substances which are very soluble, as is frequently the case with ointments, would be expected to present less of a problem than if the drug substance were to be suspended, as is the case with creams. If the drug substance is soluble, then potency uniformity would be based large
12、ly upon adequate distribution of the component throughout the mix.极易溶解的物质，制成软膏剂预计比混悬成乳膏剂的情形出现较少的问题。如果药物是可溶的，效价均一性很大程度上取决于整个混合过程中组分的适度分散。 If the active ingredient is insoluble in the vehicle, then in addition to assuring uniformity of distribution in the mix, potency uniformity depends upon control o
13、f particle size, and use of a validated mixing process. Particle size can also affect the activity of the drug substance because the smaller the particle size the greater its surface area, which may influence its activity. Particle size also affects the degree to which the product may be physically
14、irritating when applied; generally, smaller particles are less irritating. 如果活性成分在赋形剂中不溶，除保证在混合物中分散的均一性外，效价的均一性取决于粒度控制和混合过程的验证。粒度会影响药物活性，因为粒径越小，其表面积越大，这可能影响药物的活性。粒度也影响人们使用药物带来的物理刺激。一般而言，粒径越小，刺激程度也越小。 Production controls should be implemented that account for the solubility characteristics of the dru
15、g substance; inadequate controls can adversely affect product potency, efficacy and safety. For example, in one instance, residual water remaining in the manufacturing vessel, used to produce an ophthalmic ointment, resulted in partial solubilization and subsequent recrystallization of the drug subs
16、tance; the substance recrystallized in a larger particle size than expected and thereby raised questions about the product efficacy.由于溶解性差异应实行生产过程的控制：控制不当会影响产品效价、疗效和安全性。例如，用于生产眼膏的水仍残留在生产管道内，会导致只有部分组分溶解，以及药物的重结晶。所形成的重结晶颗粒会比预计大，这样问题就上升到了产品疗效问题。 In addition to ingredient solubility/particle size, the inspection should include a review of other
