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天道酬勤--药品注册质量管理

 
 
 

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原料药审查指南--2  

2008-08-22 15:58:18|  分类: FDA&EDQM Inspect |  标签: |举报 |字号 订阅

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PART II - SPECIFIC INTERPRETATIONS FOR BPC OPERATIONS

第II部分—原料药操作中具体的解释

General

总则

The following sections will discuss those specific points of the CGMPs which are clearly different in a BPC operation in contrast to a finished product operation. Points not separately discussed here should be viewed as appropriate to BPC manufacturing operations using finished product GMPs for guidance.

如下章节将回讨论CGMP中具体的要点,这些要点在原料药操作和制剂的操作是不同的。这里未单独讨论的要点应视为适用于原料药的制造操作,使用制剂GMP作为指南。

Buildings and Facilities

厂房和设施

(a)   Contamination/Cross Contamination

污染/交叉污染

Cross contamination is not permitted under any circumstances. However, the fact that a BPC plant is, or can be, used for manufacturing multiple drugs, even simultaneously, is not in itself objectionable with only a few exceptions. There must be separate facilities and completely separate air handling systems for the production of penicillin as the CGMP regulations require for dosage form drug products. It is also encouraged that separate facilities and air handling systems be used for the production of certain steroids, alkaloids, cephalosporins, certain hazardous or toxic drugs, pesticides, chemicals, and/or starting materials.

任何情况下都不容许交叉污染。然而,事实是,原料药工厂是,或可是是用于制造多种药品,甚至是同时生产地,极少数情况是可以接受的。对于青霉素的生产,必须有单独的设施和完整的分离空气处理系统,因为CGMP法规对制剂要求。对于某些甾体,生物碱, 头雹菌素类,某些环境污染或毒性药物,杀冲剂, 化学物质,和/或起始物料,鼓励使用单独的设备和空气处理系统。

NOTE: Containment via closed system is considered a separate facility. The intent is to require isolation of penicillin production operations from operations for non-penicillin products. Separation can be achieved in a facility, building, or plant by effectively isolating and sealing off from one another these two types of operations. Isolation of facilities does not necessarily mean separation by geographical distance or the placement of these operations in separate buildings. Effective means can almost certainly be developed to separate activities from one another to prevent cross-contamination problems within a single building. Containment in a fermentor would meet this criterion and they are applicable to both dry and liquid state penicillin production.

备注:经过密闭系统的污染被视为是单独的设施。意旨在于分离青霉素生产操作和其他的非青霉素产品的分离操作。可以在某一设施,建筑或工厂,通过有效地分离和加封其它两中类型操作实现分离。设施的分离并不必定意味着地理距离或在单独建筑里这些操作的处理的分离。有效的措施可以开发来分离各相互间的操作,以排除在同一个建筑里交叉污染的问题。发酵罐里的污染,应满足标准,并且它们适用于干的和液体状态的青霉素的生产。

Even though penicillin production may take place in the same building as non-penicillin production, air handling systems must at all times be completely separate. This includes fermentation procedures. This is the only means by which cross-contamination can be prevented through air facilities.

尽管青霉素的生产可能会在和非青霉素生产在相同的建筑中进行,空气处理系统必须一直是完整分开的。这包括发酵程序。这是唯一的手段,通过此手段防止经过空气设备的交叉污染。

The point at which the final BPC product is initially recovered (usually as a moist cake from a centrifuge or filter press) should be in a clean environment and not exposed to airborne contaminants such as dust from other drugs or industrial chemicals. Typically, the damp product will be unloaded into clean, covered containers and transported elsewhere for drying and other manipulations. These subsequent operations should be performed in separate areas because, once dry, the BPC is more likely to contaminate its environment; this in turn makes it likely that other products in the same area might become contaminated. The primary consideration is that the building and facilities should not contribute to an actual or potential contamination of the BPC.

最后的原料药最初被回收(通常由离心机或压滤器而来的滤饼)的点应处于干净的环境中,并未暴露在大气污染物中,如来自其它药品或工业化学品的灰尘。典型地,潮湿的产品需卸至干净的,有封盖的容器中,并转移到其他地方用于干燥和其它的操作。这些随后的操作应在隔离的区域中进行,因为,一旦干燥,原料药更易于污染环境;这反过来,使得相同区域中的其它产品可能受到污染。主要的考虑是建筑和设施不应该导致实际的或潜在的原料药的污染。

Air handling systems for BPC plants should be designed to prevent cross-contamination. For economic reasons, it is a common practice to recycle a portion of the exhaust air back into the same area. For dedicated areas processing the same BPC, this is not objectionable. The adequacy of such a system of operation for multi-use areas, especially if several products are processed simultaneously, should be carefully analyzed. In multi-use areas where several products are completely confined in closed vessels and piping systems, the extent of filtration of the supply air (combined fresh make-up air and recycled air) is not a problem (although other regulatory agencies or company policy may impose restrictions) except when the closed system must be opened (charging). In those areas where the BPCs are in a damp or moistened form (such as filter or centrifuge cake) and may be exposed to the room air environment, filter efficiencies on the supply air system as low as 85% may be perfectly adequate. In those areas wherein one or more of the products is being processed in a dry form, even total filtration of the entire supply air flow with HEPA filters may not be adequate. In all cases, the firm should be able to demonstrate adequacy of their air handling system with data and (in case of doubt) the investigator should consider collection of product samples for analysis for cross-contamination.

应设计空气处理系统以防止交叉污染。由于经济上的原因,回收一部分排出的气体进入到相同区域是常见的情况。对于处理相同原料药的专门区域,这是可以接受的。多重用途区域的操作体系的准确性,尤其是几个产品同时处理的情况,需仔细分析。在多重用途的区域,不同的产品完全限定在密闭的容器中和管道系统中,提供奇特的过滤的程度(联合新制空气和回收空气)并不是问题(尽管其它的法规机构或公司政策可能回强制限定),密闭的容器必须开口除外(装料)。在原料药是潮湿的区域(如过滤或离心滤饼)可能会暴露于室内空气环境中,低于85%的供气系统的过滤效率为85%就足够了。在那些区域,一个或以上的产品在干的形态上处理,甚至整个供气流速,带有HEPA过滤器也不够充分。在所有的情况下,公司应能够证明它们空气处理系统的准确性,带有数据,调查者应考虑收集产品样品用于交叉污染的分析。

Process wastes and unusable residues should be removed and disposed of in a manner that will insure that they do not interfere with subsequent steps of the process or adulterate the product.

工艺废弃物和不可以再用的残渣应移走并处理,确认其不会对随后的工艺步骤有影响或者掺杂到产品中。

Adequate sanitation of buildings and areas for BPCs requires considerable judgement. Many starting materials, particularly botanicals, may have some unavoidable contamination with rodent or other animal filth or be infested with insects. In such cases, it is not realistic to expect high standards in storage areas for starting materials and perhaps in the limited area of the plant wherein the initial steps of processing are conducted.

建筑物和原料药的区域的充分消毒需要相当的鉴定。许多起始物料,尤其是植物药,可能会有不可避免的带有侵蚀性或动物污染或昆虫污染的污染。在这些情况下,在储存区域预期高质量水平的起始物料是不现实的并且在工厂有限的区域内,工艺的起始步骤被做。

The control methods utilized by the firm to prevent an increase of such contamination or infestation in holding areas, or its spread to other areas of the plant, are of primary importance.

公司使用的防止这些污染或在储存区域,或扩散到公司的其它区域,易污染的控制方法是很重要的。

(b)   Water Systems/Water Quality

水系统/水质量

Water used in the production of BPCs in many instances (e.g., fermentation of antibiotics) may be potable water obtained from wells or surface sources. This is acceptable provided that water quality standards are established that are consistent with compendial or other regulatory requirements for source drinking water. Although it is not expected that potable water be routinely tested as a component, sufficient data from periodic testing should be available to show compliance with standards from both chemical and microbiological standpoints, including freedom from pathogenic organisms. Where adequate data are available from municipal water authorities, it need not be generated by the manufacturer.

在许多情况下(如,抗生素的发酵)原料药的生产中使用的水可能是来源于井或表面水源的饮用水。假若水的质量标准建立了,并符合药典或其它饮用水的要求。这些来源的水是可以接受的。尽管并不期望饮用水以某一成分常规检测,定期检测的数据应可得,以表明符合于化学和微生物方面的标准。包括无病原微生物。在充分的资料可以从市政水利局得到的情况,无需有制造商产生这些数据。

Purified water is widely used in the manufacture of BPCs. Because of the well recognized potential for microbial growth in deionizers and ultrafiltration (UF) or reverse osmosis (RO) systems used to produce purified water, such systems must be properly validated and controlled. Proper control methods include the establishment of water quality specifications and corresponding action levels, remedial action when microbial levels are exceeded, and adequate maintenance procedures such as regeneration and sanitation/sterilization. Appropriate specifications for chemical and microbial quality should be established and periodic testing conducted. Such specifications will vary depending on the process and the point in the process where the water is used. For example, if the water is used in later processing steps such as for a final wash of the filter cake, or if the BPC is crystallized from an aqueous system, the water quality standards should be higher than normally specified for purified water. This is particularly important where the BPC is intended for use in parenteral dosage forms. The frequency of microbial and chemical testing of purified water is dependent upon a variety of factors including the test results and the point in the process (e.g., final wash in centrifuge) at which such water is used.

纯化水广泛地用于原料药的制造中。由于公认用于生产纯化水的离子交换树脂装置和超过滤中或反渗透法中有潜在微生物增长的可能,这些系统必须恰当的验证和控制。适当的控制方法包括水质量标准的建立和相关的措施,当微生物水平超过时的补正措施。恰当的维护措施,如再生和消毒/灭菌。化学和微生物质量的合适的质量标准应建立并进行周期检测。根据水在工艺中的使用,在工艺中使用的点,这些质量标准将会改变。如,水用于工艺中的比较靠后的步骤中,如滤饼的最后清洗,或如原料药在含水体系中结晶,水质量标准应比纯化水的通常标准要严格点。当原料药旨在用于非肠胃剂型,这尤其重要。纯化水的微生物和化学检测的频率取决于多种因素,包括检测结果和水在工艺中使用的点(如,离心机的最后清洗)。

The USP includes suggested microbial action guidelines for source drinking water and purified water in the General Chapter on Water for Pharmaceutical Purposes and includes standards for specific types of water in monographs (e.g. Purified Water, USP). If the firm specifies a water of compendial quality in an application, the water should meet the standards given in the compendium.

美国药典在关于药用目的的水的总章节中,包括对来源的饮用水和纯化水有建议的微生物措施指导以及专论中具体类型水的标准(如,纯化水,USP)。如果公司在申请中将水的质量具体到药典的质量,水应该满足药典中给出的标准。

Similar principles to those discussed above for purified water apply to Water For Injection (WFI) utilized in sterile and pyrogen-free BPC processing. The WFI system must be monitored for microorganisms and the validation data and reports of monitoring should be reviewed as is required for the production of finished dosage forms.

对于上述纯化水的讨论原则也适用于无菌和无热源BPC工艺中使用的注射用水(WFI)。注射用水系统必须检测微生物,验证数据和检测报告应审核,因这要用于最后的剂型的生产。

Most purified and WFI water systems, including RO and UF systems, have the potential for the development of endotoxins. If the final BPC is purported to be pyrogen free or sterile, or will be used in preparing parenteral products, routine testing of the process water for endotoxins (preferably by the LAL method) is indicated. However, end point testing alone is not adequate and validation of the system to control endotoxin development should be conducted.

绝大多数纯化和注射水系统,包括RO和UF系统,有潜在引起内毒素的可能。如过最后的原料药旨在是无热源的或无菌的,或将用于制备非肠胃的制剂,指定进行工艺用水内毒素的常规检测(最好用LAL方法)然而,最后单独的检测点并不充分,应进行控制内毒素发生的系统的验证

(c)   Aseptic/Sterile Processing

无菌工艺

One of the more difficult processes is the manufacture of a sterile BPC. The aseptic crystallization and subsequent processing (drying, milling, and blending) present unique challenges. Since the operators are the primary source of contamination in an aseptic operation, processes are being designed to eliminate direct operator contact. However, some aseptic bulk operations still utilize considerable operator involvement which requires adequate controls. Major potential problem areas include aseptic removal of the BPC from the centrifuge, manual transfer to drying trays and mills, and the inability to sterilize the dryer.

许多复杂工艺之一是制造无菌的原料药。无菌的结晶和随后的过程(干燥,粉碎,和混合)存在罕见的挑战。因为无菌操作中,操作者是污染的主要来源,设计工艺减少操作者直接接触。然而,一些的无菌原料药操作仍需要相当的操作者牵涉在内,这需要充分的控制。主要的潜在的问题区域包括离心机原料药的无菌除去,手动移动托盘和粉碎机,和无能力将干燥器灭菌。

Unfortunately, not all equipment currently in use can be sterilized. The BPC manufacturer must have data to document the sanitizing of critical processing equipment such as centrifuges and dryers.

不辛地是,并不是所有的当前使用的设备能被无菌。原料药制造商必须有数据证明关键工艺设备的消毒,如离心和干燥。

Sterilization by use of ethylene oxide is sometimes attempted for powders. In this operation, the powders are spread in a thin layer and exposed to the gas. Typically, however, ethylene oxide does not penetrate the BPC in this powdered form. The manufacturer should validate that the ethylene oxide exposure does, in fact, produce a sterile product.

使用环氧乙烷灭菌,有时会使用粉末灭菌剂。在这一操作中,粉末扩散到薄层里并暴露于气体中。典型地,然而,环氧乙烷并不会以粉末的形式渗透到原料药中。制造商应验证环氧乙烷的暴露,实际上,生产无菌的制剂。

The Sterile Drug Process Inspections Compliance Program (CP 7356.002A) provides detailed inspectional guidance for coverage of the manufacture of sterile BPCs. Also, the Aseptic Processing Guidelines, although intended for coverage of dosage forms, includes principles that are also applicable to aseptic processing of sterile bulks. Both documents should be reviewed in association with any inspections of the manufacture of sterile BPCs.

无菌药工艺审查程序(CP 7356.002A)提供了详细的审查指南用于制造无菌原料药。同时,无菌工艺指南,尽管旨在用于制剂,包括也适用于无菌原料药的无菌操作。文件应根据无菌原料药制造审查相关内容审查。

Equipment

设备

(a)   Multipurpose Equipment

多重目的设备

As is the case with buildings, many BPCs are produced using multipurpose equipment. Fermentation tanks, reactors, centrifuges, and other pieces of equipment are readily used or adapted for a variety of products. With few exceptions, such multiple usage is satisfactory provided that the equipment is cleanable and is in fact cleaned according to written procedures. The cleaning program should take into consideration the need for different procedures depending on what product or intermediate was produced. Equipment that contains tarry or gummy residues that cannot be removed readily should be dedicated for use only with limited portions of a synthesis.

通常是这样的,许多原料药的生产使用多种用途的设备。发酵罐,反应罐,离心机,和其它的设备容易使用或适用于多种产品。极少数情况,这些多重用途是另人满意的,假若设备可以清洁,实际上根据书面程序清洁。清洁方案应考虑不同程序的需要,取决于什么样的产品或中间体被生产。含有焦油或树脂残留的设备,这些残留不容易移去,应专门用于合成中有限的部分。

Where temperature control is important, temperature recording devices should be utilized, with recording charts retained as part of the batch record. For example, reactors may require narrow temperature ranges for consistent operation, and when recorders are absent, the manufacturer should justify their absence.

当温度控制是重要的,应使用温度记录装置,带有记录表,保留为批记录中的部分。如,反映器可能要求较窄的温度范围用语持续的操作,当记录不存在了,制造商应对其不存在进行合理性说明

(b)   Equipment Cleaning and Use Log

设备清洁和使用记录

Where multipurpose equipment is in use, it is important to be able to determine previous usage as an aid in investigating cross-contamination or the possibility thereof.

在多重用途的设备在使用中,能够确定以前的使用作为调查交叉污染或可能引起污染的是很重要的。

An equipment cleaning and use log, while desirable and even preferable, is not the only method of determining prior use. Generally speaking, any documentation system that clearly identifies the previous batch and shows that the equipment was in fact cleaned is acceptable.

设备清洁和使用记录,当想要并较好的,不是测定以前用途的唯一的方法。一般来讲,清晰确定以前批次,表明设备实际上被清洁的文件系统是可以接受的。

(c)   Equipment Located Outdoors

户外安置的设备

Some fermentation tanks, reaction vessels, and other equipment are not situated within buildings; thus a considerable amount of processing occurs out-of-doors. Such processing is unobjectionable provided that it occurs in a closed system.

一些发酵罐,反应容器,和其它的设备并不是安装在建筑物内的,因此,相当的工艺在室外操作。如果在密闭系统中发生,这些操作是可以被接受的。

(d)   Protected Environment

保护环境

Isolation of intermediates or products may require the use of a protected environment to avoid microbial contamination or degradation caused by exposure to air or light. The degree of protection required may vary depending on the stage of the process. Equipment should be designed to minimize the possibility of contamination when used by the operator. Often, direct contact is involved in the unloading of centrifuge bags, transfer hoses (particularly those used to transfer powders), drying equipment and pumps.

中间体或产品的分离可能需要使用保护的环境以避免微生物污染或由于暴露在空气或光中的降解。要求保护的程度取决于工艺的阶段而不同。指定设备缩小污染的可能性,当被操作者使用时。通常直接的接触设计离心袋的卸载,软管的转移(尤其是用于转移粉末的),干燥设备和泵。

Also, the sanitary design of transfer equipment such as pumps should be evaluated. Those with moving parts should be assessed in regard to the integrity of seals and other packing materials to avoid product contamination.

通常,转移设备的清洁设计,如泵应评估。那些带有带有移动部分的装置,根据密封条和其它包装材料的完整性来评估以避免产品污染。

Processes requiring special environments to assure product quality (inert atmosphere, protection from light, etc.) should be carefully scrutinized for any lapses in the special environment. If any such lapses are found in the production process, adequate evidence and appropriate rationales must be shown that such lapses have not compromised the quality of the BPC. Such environmental concerns become more important after the purification of the BPC has been completed. The area where the BPC may be exposed, and especially those used to manufacture parenteral substances, should have environmental quality similar to that used for the manufacture of dosage forms. For example, controlled areas may need to be established along with appropriate air quality classifications. Such areas should be serviced by suitable air handling systems and there should be adequate environmental monitoring programs. Any manipulation of sterile BPCs post-sterilization must be performed as an aseptic process, including the utilization of Class 100 air and other aseptic controls.

要求专门环境的工艺以确定产品质量(惰性环境,避光保护等)应仔细核查,以避免在专门环境中的失误。如果有失误在生产过程中发现,充分的证明和合理的原理必须给出,表明这些失误不会影响原料药的质量。这些环境项,在原料药精制完成后变得更重要。原料药可能会暴露的区域,尤其那些用于制造非肠胃的原料药的区域,应有和制剂制造使用的相近似的环境。如,应建立控制区域,以及带有合适的控制质量分类。这些区域应用于合适的空气处理系统,应有充分的环境检测程序。其它的无菌原料药的操作,批准后无菌操作必须进行作为无菌工艺,包括100等级空气和其它无菌控制的使用。

(e)   Cleaning of Product Contact Surfaces

产品接触表面的清洁

Cleaning of multiple use equipment is an area where validation must be carried out. The manufacturer should have determined the degree of effectiveness of the cleaning procedure for each BPC or intermediate used in that particular piece of equipment.

多重用途的设备的清洁必须进行验证。制造商应确定在特别的设备中每一原料药或中间体清洁程序的有效性程度。

Validation data should verify that the cleaning process will remove residues to an acceptable level. However, it may not be possible to remove absolutely every trace of material, even with a reasonable number of cleaning cycles.

验证数据需证明清洁工艺将要移去残留至可接受的程度。然而,完全除去痕量的物料是不可能的,尽管带有合理的清洁次数。

Specific inspectional coverage for cleaning should include:

清洁具体的审查范围应包括:

1.      Detailed Cleaning Procedure:

详细的清洁程序:

There should be a written equipment cleaning procedure that provides details of what should be done and materials to be utilized. Some manufacturers list the specific solvent for each BPC and intermediate.

有书面设备清洁程序,其提供了什么应该被做,使用什么材料的详细情况。一些制造商列出了每一原料药和中间体的具体溶剂。

For stationary vessels, often clean-in-place (CIP) apparatus may be encountered. For evaluation of these systems, diagrams will be necessary, along with identification of specific valves.

对于固定容器,应遇到内部清洁的设备。对于这些系统的评估,图是必要的,带有具体的阀门的确定。

2.      Sampling Plan:

取样计划:

After cleaning, there should be some periodic testing to assure that the surface has been cleaned to the validated level. One common method is the analysis of the final rinse water or solvent for the presence of the substance last used in that piece of equipment. There should always be a specific analytical determination for such a residual substance.

清洁后,应有定期的检测以确定表面被清洁至验证的水平。一个常用的方法是分析最后冲洗的水或溶剂,在那块设备上存在物质的持续的时间。应有具体的分析测定用于残留溶剂。

3.      Analytical Method/Cleaning Limits:

分析方法/清洁限度:

Part of the answer to the question, "how clean is clean?", is, "how good is your analytical system?" The sensitivity of modern analytical apparatus has lowered some detection thresholds past parts per million, down to parts per billion.

问题的答案的部分内容,“清洁到何种程度”是“你的分析系统有多好?”现在的分析设备的灵敏度已经降低了一些检测限,高至百万分率,低至十亿分率。

The residue limits established for each piece of apparatus should be practical, achievable, and verifiable. When reviewing these limits, ascertain the rationale for establishment at that level. The manufacturer should be able to document, by means of data, that the residual level permitted is scientifically sound.

每一设备的残留限度应是实际的,可获得的,和被证实的,当审核这些限度,确定这些水平建立的基本原理。制造商应证明,根据数据,允许的残留的水平和科学合理的。

Another factor to consider is the possible non-uniformity of the residue. If residue is found, it may not necessarily be at the maximum detectable level due to the random sampling, such as taking a swab from a limited area on that piece of equipment.

另一个考虑的因素是残留可能是不一致的,如果残留被发现的话,可能并未最大检测程度的检测,是因为随机取样,如对一设备的有限区域的檫试清洁。

Raw Materials

原料

(a) Raw materials, especially those received in large quantities (hundreds of bags or in bulk), should not be physically moved from a quarantine area to a released area prior to quality control acceptance. However, such raw materials may remain in the quarantine area after release. The important consideration is that an unreleased material should not be used prior to quality control acceptance.

原料,尤其那些大量(数百包或大容量)接受的物料,在质量控制认可前,不应从待检区移至放行区。然而,这些物料在放行后,仍放在待检区。重要的考虑是未放行的物料在质量控制认可前不应使用。

Effective quarantine can be established with suitable identifying labels or signs, sound and valid documentation systems, etc. With increasing frequency, it is noted that such quarantine and documentation is widely being accomplished internally with a computer system in lieu of a physical stock control system. This is acceptable provided that system controls are adequate to prevent use of unreleased material.

建立有效的待检,带有合适的鉴定标签或标志,合理有效的文件系统,等。较大的频率,注意到这些待检和文件常常在机械库存控制系统场所由计算机系统内部完成。如果系统控制能够充分地防止未放行的物料的使用,这也是可以接受的。

(b) Film-wrapped palletized bags may not be individually identified by information normally applied to every container in a lot. To insist otherwise would destroy many of the advantages of film wrapped pallets. This is acceptable provided the pallet load itself is adequately identified. If issued individually, bags should be identified with the necessary information at the time of issuance.

为强调薄膜包着的托盘的有利,薄膜包着的托盘包根据适用于一批中每一容器的资料不可以单一确定。假如托盘本身可以准确地鉴定,这是可以接受的。如果单个发行,包需要确定,在发行时,附有必要的信息。

(c) Some raw materials are stored in silos or other large containers, making precise separation of lots difficult. Considering that such materials are usually nutrients or are inactive, such storage is acceptable. It should be possible, via inventory or other records, to show usage of such materials with reasonable accuracy.

一些原料储存在地窖或其他大的容器中,使得批次的精密分离变得困难。鉴于这些物料通常是营养素或非活性的,这样的储存是可接受的。表明对这些物料具有合理准确度的使用,经由详细目录或其它记录是可以的。

(d) Solvents used in BPC production are frequently stored in large tanks. Often, fresh and recovered solvents are commingled so that precise lot identity is missing. This is satisfactory provided incoming solvents are identified and tested prior to being mixed with recovered solvents and if the latter are tested for contaminates from the process in which they were used previously. The quality of the solvent mixture must also be monitored at suitable intervals.

原料药的生产中使用的溶剂通常储存在大的储罐中。通常新鲜的和回收的溶剂混合起来,以使省略精密的批鉴定。如果进厂溶剂经过确定,在和回收溶剂混合前检测并且如果后者对工艺中污染检测。溶剂混合物的质量必须在合适的时间间隔内检测。

(e) Some raw materials are stored out-of-doors; e.g., acids, other corrosive substances, explosive materials, etc. Such storage conditions are satisfactory provided the containers give suitable protection to their contents, identifying labels remain legible, and containers are adequately cleaned prior to opening and use.

一些原料储存在室外,如,酸,其它的腐蚀性物质,爆炸 物质,等。这些储存条件是令人满意的,假若容器对内含物有合适的保护,确认标签仍然清晰,在开启和使用前,容器是充分清洗了的。

(f)    Some raw materials may not be acceptance tested by the firm because of the hazards involved; e.g., phosphorus pentachloride, sodium azide, etc. This is acceptable where there is a reason based on safety or other valid considerations. In such a circumstance, assay certification from the vendor should be on file. There should always be some evidence of an attempt by the BPC manufacturer to establish identity even if it is only a visual examination of containers, examination of labels, and recording of lot numbers from the labels.

一些原料并不可以接受检测,由于涉及污染;如五氯化磷,叠氮化钠,等。这是可以接受的,基于安全性或其它的考虑。在这一情形下,来自售货商的含量证明也应递交。总是有原料药制造商的尝试证明来建立确定,尽管只是对容器的视觉检测,标签的检测,和批号的记录。

Containers, Closures, and Packaging

容器密闭系统

Components

成分

A system for BPC containers, closures, and packaging components should include the following features at a minimum:

原料药溶剂密闭系统至少应包含如下的特征:

(a) Suitable written specifications, examination or testing methods, and cleaning procedures where so indicated.

合适的书面质量标准,检测方法和清洁程序

(b) Determination that the container-closure system is not reactive, additive, or absorptive so as to alter the quality of the BPC beyond its established specifications and that it provides adequate protection against deterioration and contamination.

确定容器密闭系统是不反应的,累加的,或吸附的,以是原料药的质量超出建立的质量标准,对变质和污染提供了充分的保护。

(c) Storage and handling in a manner to protect containers and closures from contamination and deterioration and to avoid mixups (e.g., between containers that have different specifications but are similar in appearance).

以保护容器和密闭系统免收污染和变质的方式储存,以避免混淆(如,有不同质量标准但在外观上是相似的容器间)

(d)   Use of bulk shipping containers in which bulk pharmaceutical components were received should be avoided for BPC storage or shipment unless a suitable polymer lining or inner bag is used.

主要运输容器的使用,通过其,接受原料药,除非使用聚合物或内部的包,否则应避免使用。

Production and Process Controls

生产和工艺控制

(a)   Mother Liquors

母液

Mother liquors containing recoverable amounts of BPCs are frequently re-used. Such re-use may consist of employing the mother liquor to dissolve the reactants in the next run of that step in the synthesis. Re-use may also consist of a separate reaction to obtain a "second crop" of final product. Finally, since crystallizations are sometimes slow, some second crops are obtained simply by allowing the second crystallization to continue for long periods after the first crop is removed. These secondary recovery procedures are acceptable providing the isolated BPC meets its original, or other suitable, specifications. The recovery procedures should be indicated in batch production records.

包含可回收原料药的母液通常可以再次使用。这些再次使用可能会包括使用母液溶解下一合成步骤中的反应物。再次使用也包括使用母液以获得第二收率。最后,因为结晶有时很低,一些第二次收率简单的通过长时间的结晶。假如分离的原料药合格,这些二次回收方法是可以接受的。回收方法应包含在批记录中。

Similarly, mother liquors may contain unreacted starting materials or intermediates that are not recoverable. Secondary recovery procedures for these materials are acceptable provided that the materials meet suitable specifications.

类似地,母液可能回包含不反应的起始物料或不可回收的中间体。这些物料的第二次回收方法是可接受的,如果这些无聊符合适当的质量标准。

(b)   In Process Blending/Mixing

过程中混合

Deliberate in-process blending, or mixing, is that blending required in the process for a variety of reasons and is carried out with reasonable reproducibility from run to run during the process. Examples include: 1) Collection of multiple fermentation batches in a single holding tank (with a new batch number); 2) Recycling solution from one batch for further use in a succeeding batch; 3) Repeated crystallizations of the same mother liquor for better yield of crystals; and 4) Collecting several centrifuge loads in a single dryer/blender. Such in-process blending is acceptable provided it is adequately documented in batch production records.

详细的过程内混合,由于多种原因工艺中要求的混合,带有合理的重复性进行的混合。例子,包括:1)单一保留容器中多重发酵批次的收集(带有新的批号);2)回收一批溶液,用于成功的批次;3)重复结晶相同母液用于对晶体较好的收率;以及4)在单一干燥器/混合器中,收集单个离心袋。过程内控制是可接受的,若在批生产记录中可以充分地证明。

Incidental carryover is another type of in-process mixing that occurs frequently. Examples include: 1) Residue adhering to the wall of a micronizer used for milling the finished BPC; 2) Residual layer of damp crystals remaining in a centrifuge bowl after discharge of the bulk of the crystals from a prior batch; and 3) Incomplete discharge of fluids or crystals from a processing vessel upon transfer of the material to the next step in the process. These practices are usually acceptable since we do not normally require complete cleanup between successive batches of the same drug during a production campaign. However, in the case of non-dedicated production units, complete cleaning procedures designed to prevent contamination that would alter the quality of the substance must be employed when changing from one BPC to another. The effectiveness of these cleaning procedures may require the use of analytical testing for the substances involved.

意外的携带污染是常发生的过程内混合的另一类型。例子包括:1)用于粉碎最后原料药的微粉碎机墙壁上附有的残留。2)先前批次结晶原料药的卸载后离心罩上遗留的潮湿的晶体的残留层;3)液体或晶体的不完整的卸载,从工艺容器转移至工艺的下一步骤。这些操作通常是可接受的,因为我们通常不需要在一批中对相同原料药彻底的清洁。然而,在非专用地址的情况下,旨定防止污染的清洁程序应采用,当从一个原料药换成另一个原料药时。这些清洁程序的有效性要求使用分析来检测可能会有的物质。

In contrast to in-process blending and incidental carryover discussed above, the process intent should be directed toward achieving homogeneity of the batch of finished BPC to the maximum extent feasible. Three areas in the processing of finished batches of BPCs should be examined carefully and critically. These are: 1) The final blending operation that will constitute the finished batch; 2) The point in the process at which the lot number is assigned; 3) The sampling procedure used to obtain the sample is intended to be representative of the batch.

与工艺中混合和上述讨论的意外的携带的对比,工艺的意图应获得一批最后的最大可行程度的均质的原料药。最后原料药的处理中的三个区域应仔细并关键检查。它们是:1)最后的混合操作,这些可能构成完整的批次;2)工艺点,在这一点批号指定了;3)用于获得样品的取样程序,是用来反映批次的。

Note: Blending of batches or lots that individually do not conform to specifications with other lots that do conform (to salvage adulterated material) is not acceptable practice.

备注:批次的混合,这些批次不符合于其它批次的质量标准的混合是不可以接受的。

(c)   Validation of Process and Control

工艺验证和控制

Procedures

程序

An important factor in the assurance of product quality includes the adequate design and control of the manufacturing process. Routine end product testing alone is not necessarily sufficient because of limited sensitivity of such testing to reveal all variations that may occur and affect the chemical, physical, and microbial characteristics of the product. Each step of the manufacturing process must be controlled to the extent necessary to assure that the product meets established specifications. The concept of process validation is a key element in assuring that these quality assurance goals are met.

产品质量确认的重要的因素包括成分的设计和对制造工艺的控制。单独的常规终端产品检测是不够充分的,因为这些检测的有限灵敏度,以表明所有的变化可能会发生,和影响产品的化学的,物理的,和微生物的特征。制造工艺的每一步必须控制到一定的程度,以确认产品符合建立的质量标准。工艺验证的概念在确定这些质量确认目标是符合的是很重要的。

Process validation is required in general and specific terms by the CGMP regulations for finished dosage forms (21 CFR Parts 210 and 211). More specific guidance on process validation is provided in guidelines (See References). Many of these concepts are applicable to BPCs to assure that such BPCs are manufacturered in accordance with CGMPs as required by the Act under Section 501 (a)(2)(B).

工艺验证在制剂CGMP法规的一般和具体范围中都有要求(21CFR Parts 210 和211)。关于工艺验证的更多的具体的指南提供在指南中(见参考文献)。这其中的许多概念是适用于原料药的以确认这些原料药的制造是根据CGMP的要求的,如501(a)(2)(B)章中所要求的。

BPC manufacturers are expected to adequately determine and document that significant manufacturing processes perform consistently. The type of BPC, the range of specifications and other factors determine the extent of the process development and documentation required. However, most bulk manufacturing processes and control procedures can be validated with less arduous procedures than would be required for finished dosage forms.

期待原料药制造商充分地测定和证明显著的制造工艺可以持续的进行生产。原料药的类型,质量标准的范围和其它因素确定工艺开发的程度,需要文件证明。然而,主要的原料药制造工艺和控制方法可以验证,比制剂的要求松一点。

Many firms already possess the data necessary to prepare an evaluation of the process and demonstrate that it works consistently. For example, limitations of a reaction and/or purification steps are usually identified in the development phase. Impurities with acceptable levels and tests used to determine them are established at this phase. The report describing the process reactions and purifications, impurities, and key tests needed for process control provide the basis for validation. Thus, when the process is scaled up to production batch sizes, a comparison can be made with development batches. Scale-up and development reports, along with purity profiles would constitute such a validation report.

许多厂商已经拥有必要的数据以制备工艺的评估,并证明可以持续地生产。例如,反应和/或精制步骤的限制常常在开发阶段确定。带有可认可标准的杂质和检测在这个阶段建立。叙述工艺反应,和精制,杂质的报告以及工艺控制需要的关键的检测提供了验证的基础。因此,当工艺放大到生产批量时,和开发阶段的批次进行比较。放大和开发报告,以及杂质概况将构成验证报告。

While validation can be applied to any process, greater emphasis should be placed on validation of the BPC production at the stage(s) in the synthesis and purification steps used for the bulk substance and/or the removal of impurities.

然而,验证可以用于任何工艺,重点应在原料药生产验证上,在用于原料药和/或杂质的除去的合成和精制步骤。

(d)   Reprocessing

返工

Where reprocessing occurs during the synthesis of a BPC, there should be written documentation covering the reason for the failure, the procedures involved in the reprocessing, and changes made to eliminate a recurrence of the problem. Merely relying on final testing of the reprocessed BPC as a means of demonstrating compliance with specifications, and neglecting the investigation and evaluation of the manufacturing process, is unacceptable.

在返工在原料药的合成中发生时,应有文件证明,包括失败的原因,返工中涉及的程序,消除问题再现的变更。仅仅依赖于对返工原料药最后的检测,作为证明符合质量标准的手段,忽视了制造工艺的调查和评估是不可接受的。

Equivalence of the quality of reworked material to the original material must also be evaluated and documented to insure that the reprocessed batches will conform with all established standards, specifications, and characteristics. Obviously, if the product failure results from a human error, it will not reflect on the process, but may reflect on other aspects such as adequacy of training. However, there should be sufficient investigation, evaluation, and documentation to show that reprocessed product is at least equivalent to other acceptable product and that the failure did not result from an inadequate process.

重新加工的物料和原始物料的质量等同性必须要评估和证明以确定返工批次将符合所有建立的标准,质量标准,和特征。明显地,如果产品的失误由于人为的错误引起的,它不反映工艺,但可能反映其它的方面,如培训的充分性。然而,需要有足够的调查,评估和文件证明比表明返工产品至少等同于其它的可接受的产品并且失误并不是有不充分的工艺引起的。

(e)   Process Change

工艺变更

Manufacturers should have a formal process change system in place with standard operating procedures covering such changes. Management of the change system should be assigned to an independent quality unit having responsibility and authority for final approval of process changes.

制造商应有正式的适当的工艺变更体系,带有标准的操作程序,覆盖这些变更。变更体系的管理应分配到有责任和对最后变更批准授权的独立质量部。

(f)    Impurities

杂质

Characterization and control of impurities in a BPC are important because of the adverse effects that such impurities may have on dosage form stability, safety and efficacy. Consequently, it is important that manufacturers identify and set appropriate limits for impurities and adequately control manufacturing processes so that the impurities consistently meet established specifications.

由于这些杂质对剂型的稳定性,安全性和有效性有不利影响,原料药的杂志的界定和控制是很重要的。因此,制造商确定和设置适当的杂质限度,对制造工艺的充分控制是很重要的,以使杂质持续地符合建立的质量标准。

The attached Appendix A (Impurities) includes a more detailed discussion of impurities and should be reviewed prior to conducting inspections.

附录的附件A(杂质)包含了对杂质更为详细的讨论,并需要在进行审查前进行审核。

In-process Testing

过程内检测

BPCs are normally subjected to various in-process tests to show that a synthesis or fermentation is proceeding satisfactorily. Such tests are often performed by production personnel in production laboratory facilities. Approval to continue with the synthesis (process) is often issued within the production department. The important considerations are that specified tests are performed, recorded, and results are within specified limits. In addition, instruments should be calibrated at appropriate intervals.

原料药通常需要进行不同的过程内检测以表明合成或发酵是另人满意的。这些检测通常在生产试验室设备中由生产人员进行的检测。继续合成的批准通常在生产部门发放。重要的考虑是具体的检测许做,记录并且结果需要在具体的限度内。此外,仪器应在适当的时间间隔内进行校正。

It is important that a firm utilize a quality control unit independent from production that has the responsibility and authority to reject in-process materials not meeting specifications. Such responsibility and authority should also extend beyond testing to include overall quality assurance activities such as procedure approvals, investigation of product failures, process change approvals, and product record reviews.

公司使用质量控制部(独立于生产,具有据收不符合质量标准物料的责任和权利)是很重要的。这些责任和权利应延伸至包括整体质量确认活动的检测,如方法批准,产品失败调查,工艺变更控制,和产品记录审核。

Packaging and Labeling of Finished BPC

原料药的包装和标签

(a) Sound procedures must be employed to protect the quality and purity of the BPC when it is packaged and to assure that the correct label is applied to containers. A good system of packaging and labeling should have the following features at a minimum:

必须采用合理的程序保护原料药的质量和纯度,当包装时并确定正确的标签用于容器。好的包装和标签体系至少应有如下特征:

(1) A file of master labels. A responsible individual reviews incoming labels against the appropriate master labels.

主标签文件。个人审核根据适当的主标签审核进厂标签

(2) Storage of labels in separate containers, or compartments, to prevent mixups.

标签储存于单一容器或公寓中,以方法混合。

(3) Formal issuance by requisition or other document.

请求或其他文件的正式发放。

(4) Issuance of an exact number of labels sufficient for the number of containers to be labeled, retention copies, and calculated excesses, if any.

准确数量的标签的发放,足够用于容器的编号,保留分数,并计算过多的,如果有。

(5) The employment of a lot number from which the complete batch history can be determined.

批号的使用,倨其完整的批历史可以确定。

(6) Avoidance of labeling more than one batch at a time without adequate separation and controls.

标签的避免,超过一个批次的标签在一次位充分的分离和控制。

(7) Reconciliation of the number of labels issued with the number of units packaged, together with the destruction of excess labels bearing lot numbers.

调节发放的标签数,过多的标签的销毁

(b) If returnable BPC containers are re-used, all previous labeling should be removed or defaced. If the containers are repetitively used solely for the same BPC, all previous lot numbers, or the entire label, should be removed or completely obliterated.

如果可归还的原料药容器被重新使用,所有先前的标签应移去或磨灭。如果容器重复的使用用于相同原料药,所有先前的批号,或者完整的标签,应移去或完全檫去。

(c) Labeling for containers of BPCs is subject to all applicable provisions of 21 CFR, Parts 200 and 201. In case questionable labeling is encountered, collect samples of the labeling for submission to the appropriate Center(s) for review.

原料药容器标签应适用于所有适用的条款21CFR,200和201部分。碰到有问题的标签,收集标签的样本用于递交给适当的中心审核。

Expiration Dating or Re-evaluation Dating

过期日期或重新评估日期

(a) With few exceptions, expiration dates are not presently considered to be a general requirement for all BPCs. Thus the absence of an expiration date may not be objectionable. The chief exception is antibiotic BPCs where expiration dates are required by the antibiotics regulations.

极少数情况下,有效日期并不是所有原料药都要考虑的。因此,无有效期可能是可接受的。主要的例子是抗生素原料药,有效日期由抗生素法规规定。

(b) Where expiration or re-evaluation dates are used on BPCs either because of a regulatory requirement or voluntarily, they must be derived from appropriate stability testing.

在有效期或重新评估日期被用于原料药,或者由于法规要求,或自愿的,必须由稳定性检测获得。

(c) Where stability testing reveals a limited shelf life, e.g., less than two years, the label should declare a supportable expiration date or indicate the need for re-evaluation testing at an appropriate interval to assure quality at time of use.

在稳定性检测表明有限的有效期时,如,不到两年,标签应声明可支持的有效日期或指明在适当的时间间隔内重新评估检测的需要以确定使用时的质量。

Laboratory Controls

实验室控制

(a) Raw materials are usually subjected to an identity test and additional testing to determine if they meet appropriate specifications. Such specifications will vary in depth, sophistication, and the amount of testing required to show conformance. This in turn will depend on various factors such as the critical nature of the raw material, its function in the process, the stage of the synthesis, etc. Raw material specifications should be written documents, even if only minimal requirements are required/requested. The specifications should be organized to separate those tests that are routine from those that are performed infrequently or for new suppliers.

原料通常需要做鉴定试验和其它的检测以确定它们是否满足适当的质量标准。这些质量标准在深度,残杂,和表明一致性所要求的检测的量上有差别。这反过来取决于不同的因素,如原料的关键特征,工艺中的作用,合成阶段等。原料药的质量标准应是书面的,尽管只有一小部分的要求。构建的质量标准以将那些不常检测或为新供货商检测和常规检测分离开。

(b) Laboratory controls should include a comprehensive set of meaningful analytical procedures designed to substantiate that each batch of finished BPC meets established specifications for quality, purity, identity, and assay. Data derived from manufacturing processes and from in-process controls also provide some assurance that a batch may be acceptable.

实验室控制应包括对有意义的分析方法的广泛设定,旨在确定每一批原料药满足建立的质量,纯度,鉴定和含量的质量标准。制造工艺和过程内控制获得的数据也提供了一些确认,表明批次是可以接受的。

(c) Many BPCs are extracted from, or purified by, the use of organic solvents in the later (final) stages of recovery. The solvents are normally removed by drying the moist BPC. In view of the varying (and sometimes unknown) toxicity of solvents, it is important that BPC specifications include tests and limits for residues of solvents and other reactants. Refer to the attached Appendix A for further information about impurities, including volatile organic impurities.

许多原料药是在回收的最后阶段从有机溶剂中提取,或用有机溶剂精制的。考虑到溶剂的不同的毒性(一些不知道毒性),原料药的质量标准中包括对溶剂的残留的检测和限度及其它的反应物是很重要的。更多信息参考附录的附件A,关于杂质,包括挥发有机杂质。

(e)   Appropriate analytical methods should be validated.

适当的分析方法应验证。

Stability Testing

稳定性检测

Most BPC manufacturers conduct stability testing programs for their products; however, such programs may be less comprehensive than the programs now required for finished pharmaceuticals.

绝大多数原料药制造商对它们的产品进行稳定性检测,然而,这些程序可能没有最后的原料药要求的程序广泛。

Undetected changes in raw materials specifications, or subtle changes in manufacturing procedures, may affect the stability of BPCs. This, together with the generally widespread existence of stability testing programs, make it reasonable to require such programs for BPCs.

原料质量标准中未发现的变化,或制造工艺中微小的差别,可能会影响原料的稳定性。这,连同广泛存在的稳定性检测程序,使得要求原料药的此程序变得合理。

(a) A stability testing program for BPCs should contain the following features:

原料药稳定性检测程序,应包括如下特征:

(1) The program should be formalized in writing.

程序在书面上应正式

(2) Stability samples should be stored in containers that approximate the market container. For example, where the product is marketed in polylined drums, it is acceptable to keep stability samples in the same container material/closure system within mini-fiber drums. Such samples may be stored in glass or other suitable containers only if there are data developed by the firm or others to show that results are comparable.

稳定性样品应储存在容器中,接近于销售容器。如,产品包装在多线箱中,保持稳定性样品在相同的容器材料/密闭系统中是可接受的。这些样品应储存在搪瓷或其它适合的容器中,只有公司或其它的人员得到了开发的数据以表明结果是可比拟的。

(3) The program should include samples from the first three commercial size batches.

程序应包含前三批商业批次的样品

(4) Thereafter, a minimum of one batch a year, if there is one, should be entered in the program.

其后,一批至少一年,如果有一批进入此程序中。

NOTE: Lower levels of sampling may be acceptable if previous stability studies have shown the BPC to be stable for extended periods and the normal period between production and ultimate use of the BPC is relatively short.

备注:较低水平的取样是可以接受的,如果先前的稳定性研究表明原料药在延长的时间内稳定,在生产和原料药的最终使用中常规时间相对较短。

(5) The samples should be stored under conditions specified on the label for the marketed product.

样品应储存在销售产品的标签上注明的条件下。

(6) It is recommended that additional samples be stored under stressful conditions (e.g., elevated temperature, light, humidity or freezing) if such conditions can be reasonably anticipated.

建议其它的样品储存在强降解条件下(如,提高的温度,光,湿度或冰冻)如果这些条件可以合理地提前提出

(7) Stability indicating methods should be used.

使用稳定性指示方法

(b) Conducting a stability testing program does not usually lead to a requirement to employ expiration dates. If testing does not indicate a reasonable shelf life, e.g., two years or more, under anticipated storage conditions, then the BPC can be labeled with an expiration date or should be re-evaluated at appropriate intervals. If the need for special storage conditions exists, e.g., protection from light, such restrictions should be placed on the labeling.

进行稳定性检测计划,通常并不引起采用有效日期的要求。如果检测不能表明合理的货架寿命,如,两年或更多,在预期的储存条件下,原料药可以标有有效日期或在适当的时间间隔内重新评估。如果专门的储存条件需要的情况,如,避光保护,这些限定应置于标签上。

Reserve Samples

留样

Reserve samples of the released BPCs should be retained for one year after distribution is complete or for one year after expiration or re-evaluation date.

放行原料药的留样应保留至完全销售后一年或有效期或重新评估日期后一年。

Batch Production Records

批生产记录

Documentation of the BPC manufacturing process should include a written description of the process and production records similar to those required for dosage form production. However, it is likely that computer systems will be associated with BPC production. Computer systems are increasingly used to initiate, monitor, adjust, and otherwise control both fermentations and syntheses. These operations may be accompanied by recording charts that show key parameters (e.g., temperature) at suitable intervals, or even continuously throughout the process. In other cases, key measurements (e.g., pH) may be displayed on a television screen for that moment in time but are not available in hard copy.

原料药的制造工艺的文件应包含对工艺和批生产记录的书面叙述,这和制剂生产要求相似。然而,计算机系统将和原料药的生产相关。计算机系统越来越多地用于启动,检测,调整,和控制发酵和合成。这些操作可以和记录图表同时进行,在适当的时间间隔内,表明关键工艺参数(如,温度),或工艺中持续进行。在其它的情况下,关键的测量(如,PH)可能会会显示在电视屏幕上一会,硬件上不可得。

In both cases, conventional hard-copy batch production records may be missing. In other words, records showing addition of ingredients, actual performance of operations by identifiable individuals, and other information usually seen in conventional records may be missing. As a practical matter, when computers and other sophisticated equipment are employed, the emphasis must change from conventional, hand-written records to:

两者的情况,常规的硬副本批生产记录可能会遗失。换句话说,表明组分增加的记录,实际操作,常规记录中看到的其它信息可能会缺失。实际存在的,当计算机和其它成熟的设备被使用,重点应由常规的, 手写记录变为:

(a) Systems and procedures that show the equipment is in fact performing as intended;

系统和程序,表明设备实际上按预期的方案进行

(b) Checking and calibration of the equipment at appropriate intervals;

在适当的时间间隔内,核对和校正设备

(c) Retention of suitable backup systems such as copies of the program, duplicate tapes, or microfilm;

保留适当的备份系统,如程序的复制,复制磁带或缩影胶片;

(d) Assurance that changes in the program are made only by authorized personnel and that they are clearly documented.

程序中变更的确认仅由授权的人员制定,并清楚地文件证明。

APPENDIX A

附录 A

Impurities

杂质

The United States Pharmacopeia (USP) defines an impurity as any component of a drug substance (excluding water) that is not the chemical entity defined as the drug substance.

美国药典定义杂质为原料药中非原料药的的任何组分(不包括水)

It has been demonstrated that impurities in a finished drug product can cause degradation and lead to stability problems. Further, some adverse reactions in patients have been traced to impurities in the active ingredient. Therefore, the presence or absence of impurities at the time of clinical trial and stability testing is a very important element of drug testing and development, and the appearance of an impurity in scaled up product that was not present during test stages presents serious questions about the stability of the product and its impact on safety and efficacy.

证明杂质在最后的制剂中可能会引起降解,并导致稳定性有问题。进一步,原料药中的痕量的杂质可能会对病人产生有害反应。因此,杂质的存在或不存在在临床研究和稳定性检测中是药物检测和开发的重要组分部分。在放大规模的产品中杂质的出现,在检测阶段并不存在,存在严重的产品稳定性的问题,并且对安全性和有效性有影响。

We expect the manufacturer to establish an appropriate impurity profile for each BPC based on adequate consideration of the process and test results. Because different manufacturers synthesize drug substances by different processes and, therefore, will probably have different impurities, the USP has developed the Ordinary Impurities Test in an effort to establish some specification. Also, in order to protect proprietary information, tests for specific impurities and even solvents are typically not listed in the compendia.

我们期望制造商对每一原料药建立适当的杂质概况,基于工艺和检测结果。因为不同的制造商使用不同的工艺合成原料药。因此,可能会有不同的杂质,美国药典已经开发了常规的杂质检测,尝试建立相同的质量标准。同时,为了保护专利信息,具体杂质的检测和药典中未列溶剂。

The USP also notes that the impurity profile of a drug substance is a description of the impurities present in a typical lot of drug substance produced by a given manufacturing process. Such impurities should not only be detected and quanitated, but should also be identified and characterized when this is possible with reasonable effort. Individual limits should be established for all major impurities.

美国药典也注明原料药的杂质概况是对由给出工艺生产的原料药典型批次中存在的杂质的叙述。这些杂质不应仅仅检测出并且需定量,但也应确定和结构确认,当这在合理努力下可以结构确认的话。多所有主要杂质建立单个限度。

During the inspection, compare the impurity profile for the pilot batch material to that of the commercial size BPC batches to determine if the profile has significant changes. In some cases, drug manufacturers have submitted purity profiles in filings. Yet, when covered in some detail in an inspection, it became apparent that additional impurity data obtained by other methods (gradient HPLC) had become available but not yet filed. Thus, manufacturers should be asked specifically for current complete purity profiles, and these profiles should include the levels of solvents normally found in the purified drug substance along with acceptable specifications. Determine if the current impurity profile is reported to dose form manufacturers, especially if it has changed. Also, determine if the DMF (or AADA for bulk antibiotics) is current.

在审查中,比较中试物料和商业批次原料药的杂质概况,以确定杂质概况是否有显著的变化。在一些情况下,制造商在申请中递交了杂质概况。然而,在审查的细节中,这变得很明显,由其它方法(梯度HPLC)获得的杂质资料可得,但在递交时不可得。因此,制造商应告直当前的完整的杂质概况,这些杂质概况应包含在精制的原料药中发现的溶剂的水平,带有适当的质量标准。确定当前的杂质概况是否汇报给制剂商,尤其在改变的情况下,同时,确定DMF(或抗生素原料药AADA)是现行的。

The USP provides extensive coverage of impurities in the following three sections:

美国药典提供了广泛的杂质覆盖程度,在如下章节中:

(a)   USP Section 1086 - Impurities In Official Articles

美国药典1086-法定条款中的杂质

This section defines five different types of impurities, both known and unknown including foreign substances, toxic impurities, con- comitant components (such as isomers or racemates), signal impurities (which are process related), and ordinary impurities. The USP notes that when a specific test and limit is specified for a known impurity, generally a reference standard for that impurity is required.

这些章节定义了五种不同的杂质,已知和未知的,包括异物,毒性杂质,共生组分(如异构体或消旋体),信号杂质(工艺相关),和常规的杂质。美国药典注明对某一有机杂质具体检测和限度,一般的杂质的标准品是需要的。

Two of the impurities are singled out for in-depth coverage, ordinary impurities and organic or volatile impurities.

杂质中的两个被挑选出,常见杂质和有机或挥发的杂质

(b)   USP Section 466 - Ordinary Impurities

美国药典章节466-常见杂质

These are generally specified for each BPC in the individual monograph. The method of detection involves comparison with a USP reference standard, on a thin layer chromatographic (TLC) plate, with a review for spots other than the principal spot. The ordinary impurity total should not exceed 2% as a general limit.

这些通常在个论中为每一个原料药具体。检测方法包括和美国药典标准品的比较。关于TLC板,对点的审核而不是基本的点。常规的的总的杂志不应超过2%作为总的限度。

Be sure to review the extensive USP coverage of 8 factors that should be considered in setting limits for impurity levels.

确定审核全面的美国药典对杂质水平和限度设定,包括8个主要因素

Related substances are defined as those structurally related to a drug substance such as a degradation product or impurities arising from a manufacturing process or during storage of the BPC.

有关物质被定义为结构和原料药相关的物质,如降解物或由制造工艺产生或原料药储存中产生的杂质。

Process contaminants are substances including reagents, inorganics (e.g., heavy metals, chloride, or sulfate), raw materials, and solvents. The USP notes that these substances may be introduced during manufacturing or handling procedures.

工艺污染物是包括试剂,无机杂质(如,重金属,氯化物或硫酸盐),原料,和溶剂。美国药典注明这些物质可能会在制造或处理工序中引入。

The third and most recent USP section regarding impurities is one that appears in the USP-NF XXII third supplement:

第三个和关于杂质的美国药典的章节是在USP-NF中出现的部分:

(c)   USP Section 467 - Organic Volative Impurities

 USP 章467- 有机挥发杂质

Several gas chromatography (GC) methods are given for the detection of specific toxic solvents and the determination involves use of a standard solution of solvents. There are limits for specified organic volatile impurities present in the BPC unless otherwise noted in the individual monograph.

几种气相色谱方法被用于检测具体的毒性溶剂,以及包括使用标准溶剂溶液涉及的测定。具体的有机挥发杂质有限度,除非在个论中有注明。

As the USP notes, the setting of limits on impurities in a BPC for use in an approved new drug may be much lower than those levels encountered when the substance was initially synthesized.

如USP注明,对已批准的新药的原料药的杂质的限度设定可能比那些刚合成的物质的限度低。

Further, additional purity data may be obtained by other methods such as gradient high performance liquid chromatography (HPLC). Be sure to ask for complete impurity profiles.

再者,其它的纯度数据可以通过其它的方法获得,如剃度HPLC。确定完整的杂质概况。

In preparation for a BPC inspection, these sections of the USP should be given a detailed review.

原料药审查的准备中,这些美国药典的章节应给予详细的审核。

APPENDIX B

附录 B

References

参考

1. CP 7356.002A - Sterile Drug Process Inspections.

2. CP 7356.002F - Bulk Pharmaceutical Chemicals (BPCs).

3. Guideline on General Principles of Process Validation, May, 1987.

4. Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacturer of Drug Substances, Feb. 1987.

5. Guideline on Sterile Drug Products Produced by Aseptic Processing, June 1987.

6. Code of Federal Regulations, Title 21 Part 210 and 211, Drugs: Current Good Manufacturing Practice

314.420 - Drug Master Files

201.122 - Drugs for Processing, Repacking, or Manufacturing (bulk labeling requirements)

7. United States Pharmacopeia, Current Revision, and Supplements.

 

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