FDA外用制剂检查指南中英文版

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 topical（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 policy 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 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 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 production (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（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 active 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 and 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，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 largely 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 of 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 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 drug 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 substance; 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 physical characteristics and specifications for both ingredients and finished products. 除了组分的溶解度/颗粒大小外，检查应包括组分和成品的其他物理性质和规范的审查。 IV. EQUIPMENT AND PRODUCTION CONTROL（设备和产品控制） Mixers（搅拌机） There are many different kinds of mixers used in the manufacture of topical products. It is important that the design of a given mixer is appropriate for the type of topical product being mixed. One important aspect of mixer design is how well the internal walls of the mixer are scraped during the mixing process. This can present some problems with stainless steel mixers because scraper blades should be flexible enough to remove interior material, yet not rigid enough to damage the mixer itself. Generally, good design of a stainless steel mixer includes blades which are made of some hard plastic, such as teflon, which facilitates scrapping of the mixer walls without damaging the mixer. 生产局部外用药物的搅拌机有很多不同的种类。设计一个适合局部外用产品混合的搅拌机是重要的。搅拌机设计的一个重要方面是在搅拌过程中内壁的磨损程度。不锈钢搅拌机会出现一些问题，因为搅拌叶不够弯曲以刮除内壁物质，但又不能太硬而损坏搅拌机本身。一般而言，良好设计的不锈钢搅拌机的搅拌叶由硬塑料构成，如聚四氟乙烯树脂，这种材料便于刮除搅拌机内壁物质，且不损坏搅拌机本身。 If the internal walls of the mixer are not adequately scraped during mixing, and the residual material becomes part of the batch, the result may be non-uniformity. Such non-uniformity may occur, for example, if operators use hand held spatulas to scrape the walls of the mixer. 如果搅拌过程中内壁没有刮除干净，残留物质会成为下一批量的一部分，这会导致产品不均一。这种情况可能发生，例如操作员人工刮除搅拌机内壁的物质。 Another mixer design concern is the presence of "dead spots" where quantities of the formula are stationary and not subject to mixing. Where such "dead spots" exist, there should be adequate procedures for recirculation or non-use of the cream or ointment removed from the dead spots in the tank. 搅拌机的另一个设计要点是“盲点”的存在，该处许多剂型是固定的，并且搅拌叶延伸不到。“盲点”处的物料应进行再循环操作或者将“盲点”处的乳膏或软膏刮除。 Ideally, during the inspection, mixers should be observed under operating conditions. 理想条件下，检查期间，搅拌机应在工作状态下检查。 Filling and Packaging（灌装和包装） Suspension（混悬剂） products often require constant mixing of the bulk suspension during filling to maintain uniformity. When inspecting a suspension manufacturing process determine how the firm assures that the product remains homogeneous during the filling process and audit the data that supports the adequacy of the firm's process. When the batch size is large and the bulk suspension is in large tanks, determine how the firm deals with low levels of bulk suspension near the end of the filling process. Does the bulk suspension drop below a level where it can be adequately mixed? Is residual material transferred to a smaller tank? Does the firm rely upon hand mixing of the residual material? The firm should have demonstrated the adequacy of the process for dealing with residual material. 混悬剂在灌装时经常需要对大量的混悬液进行不断搅拌以维持产品的均一性。当进行混悬剂的生产过程检查时确定公司如何保证灌装时产品均一性，以及审查数据支持是否充分。当一批次量较大或大桶中装有大量混悬液时，公司应确定如何处理灌装快结束时少量的混悬液。混悬液少于一定的量时是否能充分混合？残留物质是否要转移到一个小的桶当中？公司是否依靠人工进行残留物质的搅拌？公司应对残留物质的处理提出合理的规程。 Process Temperature Control（过程温度控制） Typically, heat is applied in the manufacture of topicals to facilitate mixing and/or filling operations. Heat may also be generated by the action of high energy mixers. It is important to control the temperature within specified parameters, not only to facilitate those operations, but also to assure that product stability is not adversely affected. Excessive temperatures may cause physical and/or chemical degradation of the drug product, vehicle, the active ingredient(s), and/or preservatives. Furthermore, excessive temperatures may cause insoluble ingredients to dissolve, reprecipitate, or change particle size or crystalline form. 通常情况下，生产局部外用药物时需要加热以利于搅拌和/或灌装。热量来自于高能搅拌机的运行。具体参数中温度控制是重要的，不仅便于搅拌和灌装操作，也保证了产品稳定性不受到不利的影响。过高的温度可能引起药物、赋形剂、活性成分和/或防腐剂的物理和/或化学讲解。而且，过高的温度可能引起不溶性成分溶解，沉淀或粒径改变或结晶。 Temperature control is also important where microbial quality of the product is a concern. The processing of topicals at higher temperatures can destroy some of the objectionable microorganisms that may be present. However, elevated temperatures may also promote incubation of microorganisms. 温度控制在产品微生物限度中也是一个重点。生产温度过高会破坏某些微生物。然而，温度升高可能会促进微生物的生长。 Temperature uniformity within a mixer should be controlled. In addressing temperature uniformity, firms should consider the complex interaction among vat size, mixer speed, blade design, viscosity of the contents and the rate of heat transfer. Where temperature control is critical, use of recording thermometers to continuously monitor/document temperature measurements is preferred to frequent manual checks. Where temperature control is not critical, it may be adequate to manually monitor/document temperatures periodically by use of hand held thermometers. 应当控制搅拌机中温度的一致性。在处理温度一致性问题上，公司应考虑桶大小、搅拌速度，搅拌叶的设计、内容物粘度和热传导速度的作用。温度控制重要的地方，使用自动温度计进行温度的连续监控/ 记录 混凝土 养护记录下载土方回填监理旁站记录免费下载集备记录下载集备记录下载集备记录下载 比人工监控更适宜。温度控制不大重要的地方，人工进行温度的定期监控/记录。 V. CLEANING VALIDATION（清洁验证） It is CGMP for a manufacturer to establish and follow written SOPs to clean production equipment in a manner that precludes contamination of current and future batches. This is especially critical where contamination may present direct safety concerns, as with a potent drug, such as a steroid (e.g., cortisone, and estrogen), antibiotic, or a sulfa drug where there are hypersensitivity concerns. CGMP是为生产厂家建立和遵循SOP，并按照一定方法清洁生产设备，清除目前和以后批次生产的污染。这项规范尤其重要，因为污染可能直接导致产品安全问题，对于强效药，例如类固醇（如可的松和雌激素）、抗生素或磺胺类药物可能引起超敏反应。 The insolubility of some excipients and active substances used in the manufacture of topicals makes some equipment, such as mixing vessels, pipes and plastic hoses, difficult to clean. Often, piping and transfer lines are inaccessible to direct physical cleaning. Some firms address this problem by dedicating lines and hoses to specific products or product classes. 生产局部外用药物时某些不溶性辅料和活性成分使得一些设备，如搅拌机、管道和塑料软管难以清洁。通常情况下，管道和转移流水线不能直接清洗。一些公司通过对特定产品或产品种类配备专门的流水线和软管来解决这个问题。 It is therefore important that the following considerations be adequately addressed in a firm's cleaning validation protocol and in the procedures that are established for production batches. 因此，重要的是，公司的清洁验证记录和批量生产的操作规程中下列因素应当充分考虑。 Detailed Cleaning Procedures（详细的清洁规范） Cleaning procedures should be detailed and provide specific understandable instructions. The procedure should identify equipment, cleaning method(s), solvents/detergents approved for use, inspection/release mechanisms, and documentation. For some of the more complex systems, such as clean-in-place (CIP) systems, it is usually necessary to provide a level of detail that includes drawings, and provision to label valves. The time that may elapse from completion of a manufacturing operation to initiation of equipment cleaning should also be stated where excessive delay may affect the adequacy of the established cleaning procedure. For example, residual product may dry and become more difficult to clean. 清洁规范应当详细，并提供具体易懂的说明。该规范应检验设备、清洁方法、批准使用的溶解/去污剂、检查/放行机制和文件。对于某些复杂的系统，如CIP系统，通常需要提供包括图纸和标签阀的详细规范。忽略的从一个生产操作完成到开始清洗设备的时间也应说明，因为过度的延迟可能影响已建立的清洁规程的适应性。例如，副产品可能变干和更加难以清洁。 Sampling Plan For Contaminants（污染物抽样 方案 气瓶 现场处置方案 .pdf气瓶 现场处置方案 .doc见习基地管理方案.doc关于群访事件的化解方案建筑工地扬尘治理专项方案下载 ） As part of the validation of the cleaning method, the cleaned surface is sampled for the presence of residues. Sampling should be by an appropriate method, selected based on factors such as equipment and solubility of idues. For example, representative swabbing of surfaces is often used, especially in hard to clean areas and/or where the residue is relatively insoluble. Analysis of rinse solutions for residues has also been shown to be of value where the residue is soluble and/or difficult to access for direct swabbing. Both methods are useful when there is a direct measurement of the residual substance. However, it is unacceptable to test rinse solutions (such as purified water) for conformance to the purity specifications for those solutions, instead of testing directly for the presence of possible residues. 作为清洁方法验证的一部分，清洁表面的残留物进行采样。取样应采用适当的方法，根据设备和残留物的溶解性等因素进行选择。例如，具代表性的经常使用的清洁表面，尤其是难以清洁的地方和/或残留物相对不溶时。当残留物可溶和/或难以直接擦洗时，对残留物冲洗液进行分析是值得的。当直接测定残留物质时两种方法均适用。然而，不能接受冲洗液（如纯化水）的检验纯度一致，代替直接检验可能残留的物质。 Equipment Residue Limits（设备残渣限度） Because of improved technology, analytical methods are becoming much more sensitive and capable of determining very low levels of residues. Thus, it is important that a firm establish appropriate limits on levels of post-equipment cleaning residues. Such limits must be safe, practical, achievable, verifiable and must ensure that residues remaining in the equipment will not cause the quality of subsequent batches to be altered beyond established product specifications. During inspections, the rationale for residue limits should be reviewed. 由于技术革新，分析方法能更灵敏和准确地检测出低水平含量的残渣。因此，公司建立后设备清洗残渣水平的适当限度是重要的。该限度必须安全、实际、可达到和证实，也必须确保留在设备内的残渣不会引起下一批次产品质量改变。检查期间，理论残渣限度应当审查。 Because surface residues will not be uniform, it should be recognized that a detected residue level may not represent the maximum amount that may be present. This is particularly true when surface sampling by swabs is performed on equipment. 由于表面残渣不均一，应当意识到检测到的残留量可能并不代表出现的最大量。当从设备表面取样检测时尤其如此。 VI. MICROBIOLOGICAL CONTROLS (NON-STERILE TOPICALS)（微生物控制（非无菌-局部外用药物） The extent of microbiological controls needed for a given topical product will depend upon the nature of the product, the use of the product, and the potential hazard to users posed by microbial contamination. This concept is reflected in the Current Good Manufacturing (CGMP) regulations at 21 Code of Federal Regulations (CFR) 211.113(a) (Control of microbiological contamination), and in the U.S. Pharmacopeia (USP). It is therefore vital that manufacturers assess the health hazard of all organisms isolated from the product. 一种局部外用药物的微生物控制程度取决于药品本身性质、药品的使用和由于微生物污染带来的对使用者的潜在危害。这个理论体现在美国联邦法规21CFR211.113(a)（微生物污染控制）CGMP规程和美国药典内（USP）。因此，药品生产厂家评估从产品中分离的所有微生物的健康危害是至关重要的。 Deionized Water Systems For Purified Water（纯化水的去离子水系统） Inspectional coverage should extend to microbiological control of deionized water systems used to produce purified water. Deionizers are usually excellent breeding areas for microorganisms. The microbial population tends to increase as the length of time between deionizer service periods increases. Other factors which influence microbial growth include flow rates, temperature, surface area of resin beds and, of course, the microbial quality of the feed water. These factors should be considered in assessing the suitability of deionizing systems where microbial integrity of the product incorporating the purified water is significant. From this assessment, a firm should be able to design a suitable routine water monitoring program and a program of other controls as necessary. 用于生产纯化水的去离子水系统的微生物控制范围应当扩大。离子交换树脂通常是微生物生长的有利温床。随着离子交换树脂工作时间的增加，微生物数也不断增大。其他影响微生物的因素包括流速、温度、交换树脂的表面积，当然，还有饮用水的微生物。评估去离子系统适应性时应当考虑这些因素，加入纯化水的产品其微生物的完整性显著。通过该项评估，公司应当能够设计出一套合适的日常水监测方案和其他必要的控制方案。 It would be inappropriate for a firm to assess and monitor the suitability of a deionizer by relying solely upon representations of the deionizer manufacturer. Specifically, product quality could be compromised if a firm had a deionizer serviced at intervals based not on validation studies, but rather on the "recharge" indicator built into the unit. Unfortunately, such indicators are not triggered by microbial population, but rather they are typically triggered by measures of electrical conductivity or resistance. If a unit is infrequently used, sufficient time could elapse between recharging/sanitizing to allow the microbial population to increase significantly. 公司仅通过离子交换树脂厂家来评估和监控离子交换树脂的系统适应性是不合适的。尤其地，如果公司有一台没有进行验证研究的离子交换树脂间断运行，显示“再充电”指示时，产品质量会大打折扣。不幸的是，这种指示不会是由于微生物引发，而通常是由于电导或电阻引起。如果这台交换树脂不常使用，可略去再充电/消毒间的时间以得到微生物增加明显的结果。 Pre-use validation of deionizing systems used to produce purified water should include consideration of such factors as microbial quality of feed water (and residual chlorine levels of feed water where applicable), surface area of ion-exchange resin beds, temperature range of water during processing, operational range of flow rates,recirculation systems to minimize intermittent use and low flow, frequency of use, quality of regenerant chemicals, and frequency and method of sanitization. 用于生产纯化水的去离子系统的使用前验证应考虑这些因素如饮用水的微生物（和饮用水残留的氯含量）、离子交换树脂床的表面积，纯化过程水温范围、流速范围、最少间隔的再循环系统和低流速、使用频率、化学试剂的质量和清洁频率和清洁方法。 A monitoring program used to control deionizing systems should include established water quality and conductivity monitoring intervals, measurement of conditions and quality at significant stages through the deionizer (influent, post cation, post anion, post mixed-bed, etc.), microbial conditions of the bed, and specific methods of microbial testing. Frequency of monitoring should be based upon the firm's experience with the systems. 用于去离子系统控制的监测方案应包括建立水质和电导监测的时间间隔、关键时期整个交换树脂的测定条件和质量（进水、后阳离子、后阴离子、后混合床等）、微生物生长条件和微生物检验的具体方法。监测频率应根据公司对系统的经验确定。 Other methods of controlling deionizing systems include establishment of water quality specifications and corresponding action levels, remedial action when microbial levels are exceeded, documentation of regeneration and a description of sanitization/ sterilization procedures for piping, filters, etc.. 去离子系统控制的其他方法包括建立水的质量标准和相应的浓度、当微生物浓度超标时的补救、重新编制有关文档、管道、过滤器等的清洁/消毒... Microbiological Specifications and Test Methods(微生物属性和检验方法) During inspections it is important to audit the microbiological specifications and microbial test methods used for each topical product to assure that they are consistent with any described in the relevant application, or U.S.P.. It is often helpful for the inspection to include an FDA microbiologist. 在检查期间，重要的是审查局部外用药物的微生物属性和检验方法，以确保它们与有关用法或USP描述的一致。这往往是对检查包括FDA专家有帮助的。 Generally, product specifications should cover the total number of organisms permitted, as well as specific organisms that must not be present. These specifications must be based on use of specified sampling and analytical procedures. Where appropriate, the specifications should describe action levels where additional sampling and/or speciation of organisms is necessary. 一般来说，药品说明书应包括允许的微生物总量，不能出现具体的某种微生物。该说明书必须是用于指定的取样和分析方法的基础上。适当情况下，单独描述取样和/或形成微生物的作用浓度是必要的。 Manufacturers must demonstrate that the test methods and specifications are appropriate for their intended purpose. Where possible, firms should utilize methods that isolate and identify organisms that may present a hazard to the user under the intended use. It should be noted that the USP does not state methods that are specific for water insoluble topical products. 生产厂家应证明检验方法和规范是适合预期目的的。可能的情况下，公司应该利用方法以分离和鉴别可能出现危害的微生物。值得注意的是，USP没有说明不溶于水的局部外用药物的具体方法。 One test deficiency to be aware of during inspections is inadequate dispersement of a cream or ointment on microbial test plates. Firms may claim to follow USP procedures, yet in actual practice may not disperse product over the test plate, resulting in inhibited growth due to concentrated preservative in the non- dispersed inoculate. The spread technique is critical and the firm should have documentation that the personnel performing the technique have been adequately trained and are capable of perform