原创 USP1115 非无菌产品的微生物负载 翻译

最新USP1115 翻译上半部分，有生以来第一次把翻译写下了，虽然翻译的想**，但是还是希望加个分投个票，等有空再把下半部分翻译了。
BRIEFING
1115 Bioburden Control of Nonsterile Drug Substances and Products.
In terms of microbiological contamination risk control, there are two broad categories of drug products: a) sterile products and b) nonsterile products.
从微生物风险控制的角度来讲有两大类药品：1.无菌样品2.非无菌药品
Microbial content in nonsterile products is controlled to a level consistent with patient safety. Use of excessive controls that would add complexity or cost without a commensurate safety benefit is not advantageous in terms of added value to either the patient or the manufacturer. Therefore, a pragmatic scientific approach to management of the microbial bioburden in nonsterile products requires consideration of patient risk and contamination control objectives to achieve a practical and appropriate level of risk management.
非无菌药品的微生物含量要符合病人安全的水平，从患者和制造商附加值的角度来讲，采用过分的控制将增加复杂性或成本但不会得到相应的安全收益，因此，一个科学实用的无菌药品中微生物负载的管理方法要求考虑病人的风险和污染控制的目的已达到一个实际并且合适的风险管理水平。
This chapter outlines a risk-based approach to the control of potential contamination in nonsterile product manufacturing. It provides information about microbial control considerations in product development, microbial control considerations in routine manufacturing, microbial control of drug substance manufacturing, equipment design and use considerations, personnel, the manufacturing environment, microbial assessment of nonsterile product manufacturing environments, active measures for microbial control, and overall management of a microbiological control program.
本章概括了基于风险的非无菌药品生产过程中的潜在污染控制方法。本章提供了关于产品开发、日常生产、设备设计和使用、人员、环境、非无菌药品生产环境中微生物评估、微生物控制的主动措施和整体的微生物控制计划管理的信息。
(GCM: R. Tirumalai.)
Correspondence Number—C129896
Comment deadline: September 30, 2013
Add the following:
1115 BIOBURDEN CONTROL OF NONSTERILE DRUG SUBSTANCES AND
PRODUCTS
INTRODUCTION
In terms of microbiological contamination risk control, there are two broad categories of drug products: a) sterile products, in which the bioburden is essentially eliminated using validated methodologies, and b) nonsterile products for which the final product bioburden is controlled to appropriate levels based on product attributes, route of administration, and target patient population.
从微生物风险控制的角度来讲有两大类药品：1.无菌样品：使用已验证的方法将微生物负载基本上消除2.非无菌药品：基于产品属性、给药途径及目标人群，最终产品被控制在合适的水平，
Microbial content in nonsterile products is controlled to a level consistent with patient safety. Use of excessive controls that would add complexity or cost without a commensurate safety benefit is not advantageous in terms of added value to either the patient or the manufacturer. Therefore, a pragmatic scientific approach to management of the microbial bioburden in nonsterile products requires consideration of patient risk and contamination control objectives to achieve a practical and appropriate level of risk management.
非无菌药品的微生物含量要符合病人安全的水平，从患者和制造商附加值的角度来讲，采用过分的控制将增加复杂性或成本但不会得到相应的安全收益，因此，一个科学实用的无菌药品中微生物负载的管理方法要求考虑病人的风险和污染控制的目的已达到一个实际并且合适的风险管理水平。
A critical consideration in ensuring product quality is to prevent conditions within the manufacturing facility or manufacturing process that favor the proliferation of microorganisms. Microbial growth in excipients, components, and drug substances is a concern because it creates the possibility that viable microbial content could reach unacceptable levels. Bioburden levels lower than those recommended in Microbiological Examination of Nonsterile Products: Acceptance Criteria for Pharmaceutical Preparations and Substances for Pharmaceutical Use 1111 are unlikely to pose a risk of microbial toxins. Manufacturers should have a clear understanding of situations that favor microbial presence and growth within their facilities and materials and should implement practical countermeasures.
防止（避免、）生产设备或生产工艺中有利于微生物繁殖的条件是保证产品质量的关键因素。微生物在赋形剂、组分和药物成分中生产是应该关系的事，因为这可能导致活微生物能达到不可接受的水平。微生物负载水平低于药典1111《非无菌药品微生物检测：制剂和药物物质的接受标准》中的那些建议不太可能造成微生物毒性的风险。制造商对微生物在设备、物料中微生物的出现、生长情况应该有一个明确的理解并且应该执行实际的对策。
This chapter outlines a risk-based approach to the control of contamination in nonsterile product manufacturing. The manufacture of nonsterile products and the management of their microbiological content are distinctly different from those required for sterile products. Sterile products are administered parenterally by means of injection or are applied topically to sensitive tissues where the risk of infection is comparatively high. The products themselves are sterile or harbor a low population of microorganisms.
本章概括了基于风险的非无菌药品生产过程中的潜在污染控制方法。非无菌药品的生产和微生物含量管理与无菌产品的要求明显不同。无菌药品通过注射或应用于感染风险相当高的局部敏感组织。产品本身是无菌的或有很低微生物数。
In contrast, nonsterile products are administered to regions of the human body that are rich in microbial flora and have physical or immunological barriers to infection. Examples include the oral cavity, skin, nasopharynx, vagina, and rectum, which harbor a high and diverse viable microbial population. Recent findings from the human microbiome project (1) underscore the enormous size and diversity of bacterial populations associated with humans. A healthy adult has a bacterial population that averages approximately 1014 bacteria, a number that exceeds the individual’s own cells by a factor of 10. All humans carry on or in their bodies microorganisms that under certain conditions may produce infections in other humans. Because of the ubiquity of opportunistic pathogens within healthy individuals, it is inevitable that pathogens will be found in manufacturing areas where people work.
相比之下，非无菌药品用于有大量的微生物并且对感染有物理或免疫学屏障的部位，例如口腔、皮肤、鼻咽、阴道、直肠，这些部位能庇护大量的多种多样的微生物，最近从人类微生物工程中的发现强调超大规模和多种多样的细菌数量与人类有关，一个健康的成年人平均有将近1014个细菌，超过自身细胞的10倍。人类携带在身体内外的微生物在特定条件下可能感染其他人。因为微生物在健康个体中普遍存在，微生物会在人们工作的生产区域被发现是必然的。
The following list provides a hierarchy of broad categories of nonsterile pharmaceutical products with respect to potential risk of microbiological contamination (from high to low) :
下面的清单提供了非无菌样品的微生物污染潜在风险层次的分类：
? metered-dose and dry powder inhalants 计量剂型和干粉的吸入剂
? nasal sprays 鼻用喷雾
? otics 耳部的
? vaginal suppositories 阴道栓剂
? topicals 局部用药
? rectal suppositories 直肠栓剂
? oral liquids (aqueous) 口服液体
? liquid-filled capsules 液体胶囊
? oral tablets and powder-filled capsules 口服片剂和粉末胶囊
When formulators evaluate the susceptibility of nonsterile pharmaceutical products to microbial hazards, considerations include whether the active ingredient has inherent antimicrobial activity, the microbiological content of excipients, inclusion of antimicrobial preservatives in the formulation, and water activity. In addition, manufacturers should consider whether processing steps and hold periods could result in changes in the bioburden and whether the product is a multiple- or single-dose product.
当设计师评估非无菌药品对微生物危害的敏感性，考虑因素包括活性物质本身是否有抗菌性、赋形剂的微生物含量、配方中包含的防腐剂和水分活度。另外，生产者应该考虑生产工艺和保持时间是否能导致微生物负载变化、产品是否多次剂量或单次剂量产品。
Nonsterile products are expected to have some bioburden, which should be controlled within a suitable range (see 1111 ). The risk of infection resulting from a nonsterile drug product generally is low, regardless of the route of administration, provided appropriate precautions and procedures are followed. General chapters Microbiological Examination of Nonsterile Products: Microbial Enumeration Tests 61 and Microbiological Examination of Nonsterile Products: Tests for Specified Microorganisms 62 provide methods, and 1111 provides information for the evaluation of microorganisms isolated during nonsterile drug product manufacturing. It is not possible to provide a comprehensive product-by-product list of objectionable microorganisms. The degree to which any organism may be objectionable depends on the product attributes, route of administration, and patient population. Manufacturers are responsible for determining whether microorganisms recovered from drug products are objectionable. In general, objectionable microorganisms are those that are known to be frankly pathogenic and, given the product’s route of administration, are present in sufficient numbers that could result in an unacceptable level of patient risk. Microbiological risk should be assessed on a case-by-case basis during the development of a new product and should be evaluated during the validation of the manufacturing process.
非无菌药品允许控制在合适范围的微生物负载（见1111），来自非无菌药品的感染风险一般比较低，不管给药途径，适当的预防措施和程序如下：非无菌药品的微生物检测：微生物总计数《61》和非无菌药品的微生物检测：控制菌检查《62》提供了方法，1111提供了提供了非无菌药品生产过程中分离的微生物的相关信息。提供一个综合产品的有害微生物清单不太可能。哪种微生物是有害的决定于产品的属性、给药途径和患者。制造商有责任确定从药品中复苏的微生物是否有害。通常，有害微生物是那些有害的，按给药途径使用，存在一定数量是，能导不可接受的病人风险水平。微生物风险应该以新产品开发过程中的个例为基础评估，并且工艺验证过程中应该被评估。
The proliferation of microbial contamination in a production facility, in products, or in product ingredients is an objectionable condition. Microbial proliferation within a facility creates conditions that favor the spread of contaminants, potentially in dangerous numbers, into ingredients, primary packaging materials, and even into product itself.
Proliferation of microorganisms in ingredients or production intermediates must be prevented because not only is this a microbial toxin risk, but also in some cases it could result in damage to the chemical and pharmacological properties of the drug.
微生物污染物在生产设施、产品或组分中繁殖是一个不利条件。微生物在设备中增殖创造如下条件：使污染物快速扩散，达到潜在危险数量，进入组分包材甚至产品本身。
US REGULATORY GUIDANCE DOCUMENTS美国监管的指导文件
The US Code of Federal Regulations includes the Food and Drug Administration’s Good Manufacturing Practice (GMP) requirements, which are found in Part 211 (3). These regulations contain general requirements for the manufacture of pharmaceutical products.
Pertinent sections require that buildings used for pharmaceutical manufacturing and associated activities should be of suitable size, construction, and location (211.42 Design and construction) and that adequate equipment to control microorganisms, dust, humidity, temperature, and differential air pressures should be provided when appropriate for drug product manufacturing (211.46 Ventilation, air filtration, air heating and cooling). GMP regulations also require written procedures for use of suitable rodenticides, insecticides, fungicides, fumigating agents, and cleaning and sanitizing agents, and written procedures should be designed to prevent the contamination of equipment, components, drug product containers, closures, packaging, and labeling materials (211.56 Sanitation), and appropriate written procedures to prevent objectionable microorganisms in drug products not required to be sterile should be established and followed (211.113 Control of microbiological contamination).
MICROBIAL CONTROL CONSIDERATIONS DURING PRODUCT DEVELOPMENT
产品开发过程总的微生物控制注意事项
A formal risk assessment program that identifies risk modalities and assigns critical control points for manufacture of nonsterile product is useful. Hazard Analysis and Critical Control Point programs (4) are widely used to assess and mitigate microbial risk in food manufacturing and may also be useful for manufacturers of nonsterile drug products.
一个正式的风险识别形式的风险评估项目和布置（确定）非无菌产品生产的关键控制点很有用，危害分析和关键控制点项目被广泛应用于评估和缓和食品生产过程过程中的微生物风险，并且很多对非无菌药品的生产很有用。
Points to be considered by pharmaceutical microbiologists when they assess the potential risk associated with nonsterile drug product manufacture are listed below:
当药学微生物学家评估非无菌药品相关的潜在风险时考虑的点如下：
? synthesis, isolation, and final purification of the drug substance
药品的合成、分离和最终纯化。
? microbiological attributes of the drug substance
药品的微生物属性。
? microbiological attributes of excipients
赋形剂的微生物属性
? formulation and chemical and physical attributes of the drug product
产品的配方、理化性质
? water content and water activity of the drug product
药品中水分的含量和活度
? manufacturing process
生产工艺
? delivery system
运输系统
? packaging
包装
? storage conditions for intermediates and the finished dosage form
中间体的储存条件和最终剂型
? route of administration
给药途径
? expected treatment procedure and dosage regimen
预定的治疗程序和给药方案
? age and probable general health of intended recipients of the drug product
用药人群的年龄和可能的综合健康状况
Thorough consideration of these factors is valuable in defining appropriate manufacturing facility requirements and critical manufacturing process control points that reduce or eliminate conditions that favor microbial contamination.
这些关键因素的周全考虑在定义合适的生产设备要求和降低和消除有利于微生物污染的关键生产工艺控制点方面很有用。
MICROBIAL CONTROL CONSIDERATIONS DURING MANUFACTURING
生产过程总的微生物控制注意事项
Although many factors (Figure 1) can result in the introduction of microorganisms, recent data about product failures and recalls indicate that some of these are more likely to result in product recalls because of higher than acceptable microbial levels. These manufacturing risk factors are, in descending order (5): (1) ingredient water, (2) pharmaceutical ingredients, (3) process equipment, (4) manufacturing personnel, and (5) manufacturing environment.
尽管很多因素（图一）能导致微生物引入，最近的产品失败和召回数据显示，有些因素可能产品召回事与因为高于可接受的微生物水平，这些生产风险因素是（降序排列）：1.原料水2.药用组分3.工业设备4.生产人员5.生产环境

Figure 1. Factors that contribute to nonsterile product bioburden.
非无菌产品微生物负载贡献因素
Water Systems and Use 水系统
Process water is the single most important risk element contributing to the contamination of nonsterile products. The quality or type of water used for nonsterile product formulation and final rinse of clean equipment should be chosen based on product risk. Purified waters used in pharmaceutical manufacturing are deionized and thus do not contain chlorine to control microbial growth. Substantial populations of Gram negative rod-shaped bacteria and many molds are able to grow in such purified dechlorinated water. Therefore, purified water should not be allowed to stand in pools or puddles for extended periods of time. Standing purified water should be drained or physically removed quickly and efficiently from both production vessels and equipment, as well as work surfaces and floors. Chlorinated potable water (city water) may be appropriate for early-stage cleaning and in housekeeping and sanitization activities, but such uses should be determined on a case-by-case basis and with a full understanding of risk. Additional guidance for water system design and operation can be found in Water for Pharmaceutical Purposes 1231 .
工艺用水是非无菌药品污染的重要因素。应基于产品风险来选择非无菌药品配方中使用的和最后清洁设备的水的质量或类型。药品生产中使用的纯化水是去离子的，因此控制微生物生长不要使用氯离子。大量的革兰氏阴性杆菌和霉菌能够在这些去氯离子的纯化水中生长。因此，纯化水不能在水池、水坑中长时间储存。死水应该排掉或从产品容器、设备、工作面、地面高效快速的去除。氯化饮用水（城市用水）也许适用于早期的清洁和（家务）卫生中，但是这些用途应基于个例确定，并且对风险有一个全面理解。更多水系统的设计和操作指导见《1231》 制药用水。
Process waters used for manufacturing of excipients, and, in some cases, active ingredients for nonsterile products present a substantial risk for microbial colonization and proliferation, particularly for ingredients of natural origin that have received minimal processing to reduce bioburden or to control microbial proliferation. Formulating and manufacturing equipment can be a source of contamination, and risks are higher when water and ingredients that are susceptible to microbial survival or growth are used. Therefore, cleaning, drying, and, where appropriate, sanitization of manufacturing equipment can be beneficial, but disinfectant residues should be limited in the operating environment and should be removed from product-contact surfaces. The isolation of waterborne organisms, particularly Gram negative rods, is a likely indicator of failure to remove standing water on equipment and environmental surfaces.
用于赋形剂的工艺用水，有时候包括生产非无菌产品的活性成分的水显现出微生物增殖的较大风险，尤其是经过最低限度的处理来降低微生物负载或控制微生物繁殖的天然(原料）组分。Formulating和生产设备可能是污染源，当易受微生物存活或生殖影响的水和组分使用时风险会更高。因此，一些合适的地方，清洁干燥、生产设备的卫生处理有好处，但是在设备中的消毒剂残留应被现在，并且应从产品接触的表面去除。水生微生物的隔离，尤其是革兰氏阴性杆菌，可能是设备和环境表面死水却出失败的指示。
Active Pharmaceutical Ingredients, In-Process Materials, and Excipients Ingredients and excipients used in nonsterile product manufacturing processes are important sources of microbiological contamination. Vendor audits, specifications, testing, package selection, shipping, storage conditions, and expiry dates are all critically important in the reduction of microbial risk associated with these materials. When manufacturers cannot conduct extensive vendor audits, they should select vendors who have submitted a Drug Master File to a competent regulatory authority and have satisfactorily passed GMP inspections conducted by regulators. Of particular concern are unprocessed materials of natural origin and those that have a high level of water activity.
非无菌药品生产中使用的药用活性物质，中间体、辅料是微生物污染的重要污染源。供应商升级，质量标准，测试，包装选择，运输，储存条件和有效期对降低这些物料的微生物风险很重要。当制造商不能进行广泛的供应商升级，那么应该选择那些向能胜任的监管部门已经提交过DMF的供应商，并且通过了gmp审计。特别关注那些未经加工的天然材料和那些高水活动的物料。
Manufacturers should sample incoming materials and should ensure proper contamination-control conditions for weighing and compounding. All sampling and weighing equipment should be properly cleaned, sanitized, stored, and labeled with respect to microbiological status. The activities and the associated controls implemented to prevent microbial colonization and proliferation should be based on a documented, prospective risk-assessment and contamination-control strategy.
供应商应该对到货的物料取样并且应确保适当的称量、混合污染控制。所有的取样和称量仪器应该经适当的清洁、消毒、储存，并且应有微生物状态的标签。预防微生物增殖的活动和相关控制应基于文件、预期风险评估和污染控制策略。
Pharmaceutical ingredients of consistently suitable microbiological quality are an important element of the microbiological control program for nonsterile products. Procurement of ingredients of appropriate microbial quality requires the identification of vendors with the demonstrated capacity to produce drug substances or excipients of suitable quality. Supplier audits should be conducted to establish that the supplier has a well-designed and validated microbiological control program for its manufacturing and packaging facilities. Depending on the microbial characteristics of an ingredient, manufacturers should consider periodic monitoring of the supplier’s facility to assess microbiological contamination. Materials that have low water activity, possess high or low pH, are not of natural origin, are inherently antimicrobial, or contain an antimicrobial preservative have a low risk for microbial colonization or proliferation. Risk assessments should consider ingredient characteristics regarding microbial survival, support of microbial growth, or frank antagonism to microbial survival.
一贯符合微生物质量的药用物料对于非无菌药品的微生物控制计划是一个非常重要的元素。采购合适微生物质量的组分要求确认供应商有生产药用物质和辅料的能力。应建立供应商审计（程序）以确定他们对产品的生产和包装设施有一个精心审计并验证的微生物控制程序。
根据产品组分的微生物特征，供应商应该考虑周期性的检查供应商的设施来评估微生物污染。低水活度，高或低PH的物料不是天然材料，本身有抗菌性或含有防腐剂的物料微生物增殖的风险较低，风险评估应该考虑与微生物存活、支持微生物生长和frank antagonism to microbial survival有关的组分特性。

太谢谢了，正好需要

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