FDA灭菌工艺验证申报资料指南(中英文)

Guidance for Industry for the Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug Products
人药和兽药无菌工艺验证申报资料的工业指南
Center for Drug Evaluation and Research (CDER)
Center for Veterinary Medicine (CVM)
November 1994
CMC 2
FDA药品评价与研究中心（CDER）
FDA兽药中心（CVM）
1994年11月
TABLE OF CONTENTS
I. INTRODUCTION (1)
A. Purpose (1)
B. Documenting Sterilization Process Validation (2)
C. Remarks (2)
II. INFORMATION FOR TERMINAL MOIST HEAT STERILIZATION
PROCESSES (3)
A. Description of the Process and Product ........................ .. (3)
1. The Drug Product and Container-Closure System (3)
2. The Sterilization Process (3)
3. The Autoclave Process and Performance Specifications (4)
4. Autoclave Loading Patterns (4)
5. Methods and Controls to Monitor Production Cycles (4)
6. Requalification of Production Autoclaves (4)
7. Reprocessing (4)
B. Thermal Qualification of the Cycle (4)
1. Heat Distribution and Penetration Studies (4)
2. Thermal Monitors (5)
3. The Effects of Loading on Thermal Input (5)
4. Information Included in the Batch Record ........................................... . 5
C. Microbiological Efficacy of the Cycle (5)
1. Identification and Characterization of Bioburden Organisms (6)
2. Specifications for Bioburden (6)
3. Identification, Resistance, and Stability of Biological
Indicators (6)
4. The Resistance of the Biological Indicator Relative to That of
Bioburden (6)
5. Microbiological Challenge Studies (7)
D. Microbiological Monitoring of the Environment (7)
E. Container-Closure and Package Integrity (7)
1. Simulation of the Stresses From Processing (7)
2. Demonstrate Integrity Following the Maximum Exposure (8)
3. Multiple Barriers (8)
4. The Sensitivity of the Test (8)
5. Integrity Over the Product Shelf Life (8)
F. Bacterial Endotoxins Test and Method (8)
G. Sterility Testing Methods and Release Criteria (8)
H. Evidence of Formal, Written Procedures (9)
III. OTHER TERMINAL STERILIZATION PROCESSES (9)
A. Ethylene Oxide (9)
1. Description of the Sterilizer (9)
2. Cycle Parameters (10)
3. Microbiological Methods (10)
4. Stability (10)
B. Radiation (10)
1. The Facility and the Process (10)
2. The Packaging of the Product (10)
3. Multiple-Dose Mapping Studies (10)
4. Microbiological Methods and Controls (11)
5. Monitoring Stability (11)
IV. INFORMATION FOR ASEPTIC FILL MANUFACTURING PROCESSES WHICH SHOULD BE INCLUDED IN DRUG APPLICATIONS (11)
A. Buildings and Facilities (11)
1. Floor Plan (11)
2. Location of equipment (11)
B. Overall Manufacturing Operation (11)
1. Drug Product Solution Filtration (12)
2. Specifications Concerning Holding Periods (12)
3. Critical Operations (12)
C. Sterilization and Depyrogenation of Containers, Closures, Equipment, and
Components (12)
1. Bulk Drug Solution Components That are Sterilized
Separately (13)
2. Sterilization Information in the Batch Records (13)
D. Procedures and Specifications for Media Fills (13)
E. Actions Concerning Product When Media Fills Fail (14)
F. Microbiological monitoring of the environment (15)
1. Microbiological Methods (15)
2. Yeasts, Molds, and Anaerobic Microorganisms (15)
3. Exceeded Limits (15)
G. Container-Closure and Package Integrity (15)
H. Sterility Testing Methods and Release Criteria (16)
I. Bacterial Endotoxins Test and Method (16)
J. Evidence of Formal Written Procedures (16)
V. MAINTENANCE OF MICROBIOLOGICAL CONTROL AND QUALITY: STABILITY CONSIDERATIONS (16)
A. Container-Closure Integrity (16)
B. Preservative Effectiveness (17)
C. Pyrogen or Endotoxin Testing (17)
VI. ADDITIONAL INFORMATION (17)
GUIDANCE FOR INDUSTRY1
FOR THE SUBMISSION OF DOCUMENTATION FOR STERILIZATION PROCESS VALIDATION IN APPLICATIONS FOR HUMAN AND VETERINARY DRUG
PRODUCTS
人药和兽药无菌工艺验证申报资料的工业指南
I. INTRODUCTION
1、概述
A. Purpose
This document is intended to provide guidance for the submission of information and data in support of the efficacy of sterilization processes in drug applications for both human and veterinary drugs. The recommendations in the guidance apply to applications for sterile drug products (new drug applications, new animal drug applications, abbreviated new drug applications, abbreviated antibiotic applications, and abbreviated new animal drug applications). These recommendations also apply to previously approved applications when supplements associated with the sterile processing of approved drugs are submitted. Information and data in support of sterility assurance may also be necessary in investigational new drug and investigational new animal drug applications.
A. 目的
本文件旨在为证明人药和兽药无菌工艺有效性申请上报的信息和资料提供指南。

指南中的建议适用于无菌药物的申请（新药申请、新兽药申请、仿制新药申请、仿制抗菌药申请和仿制新兽药申请）。

这些建议同样适用于与批准的药物无菌工艺有联系的已批准申请的补充申请。

支持灭菌保证的信息和资料可能在临床新药和临床新兽药的申请中也需要。

In the FEDERAL REGISTER of October 11, 1991 (56 FR 51354), the agency published a proposed rule entitled "Use of Aseptic Processing and Terminal Sterilization in the Preparation of Sterile Pharmaceuticals for Human and Veterinary Use." This guidance is not
a substitution for or a supplement to that proposed rule. Regardless of whether the applicant uses terminal sterilization or aseptic processing to manufacture a drug product that is purported to be sterile, certain information about the validation of that process should be submitted for both of those types of sterilization.
在1991年10月11日的《美国联邦注册》（56 FR 51354）中，FDA发布了一篇题名《过程中使用无菌工艺和最终灭菌制备人用和兽用无菌药品》的规程草案。

本指南不是该规程替代或增补。

不论申报单位使用最终灭菌还是无菌工艺来生产药物产品，目的都是达到无菌，这两种灭菌都应该上报与该工艺验证有关的一些信息。

1
This guidance has been prepared by the Sterility Technical Committee of the Chemistry Manufacturing Controls Coordinating Committee of the Center for Drug Evaluation and Research (CDER), and the Center for Veterinary Medicine (CVM), at the Food and Drug Administration. Although this guidance does not create or confer any rights for or on any person and does not operate to bind FDA or the industry, it does represent the agency’s current thinking on sterilization process validation documentation. For additional copies of this guidance, contact the Division of Communications Management, HFD-210, CDER, FDA, 5600 Fishers Lane, Rockville, MD 20857 (Phone: 301-594-1012) Send one
self-addressed adhesive label to assist the office in processing your request. An electronic version of this guidance is also available via Internet via World Wide Web (WWW) (connect to the FDA Home Page at /CDER and go to the “Regulatory Guidance” section).
B. Documenting Sterilization Process Validation
B. 无菌工艺验证文件的编写
The efficacy of a given sterilization process for a specific drug product is evaluated on the basis of a series of protocols and scientific experiments designed to demonstrate that the sterilization process and associated control procedures can reproducibly deliver a sterile product. Data derived from experiments and control procedures allow conclusions to be drawn about the probability of nonsterile product units (sterility assurance level). Based on the scientific validity of the protocols and methods, as well as on the scientific validity of the results and conclusions, the agency concludes that the efficacy of the sterilization process is validated.
一个特定药物产品的无菌工艺的有效性是通过一系列实验方案和科学实验评价的，这些验证和试验是为说明无菌工艺和相关的控制程序能够稳定而可靠地生产无菌产品而设计的，试验数据和控制程序的结论允许被用到非无菌产品单元（无菌保证水平）。

基于方案和方法以及结果和结论的科学认可，FDA总结出无菌工艺效果是经过验证的。

Whether a drug product is sterilized by a terminal sterilization process or by an aseptic filling process, the efficacy of the sterilization process may be validated without the manufacture of three production batches. Sterilization process validation data, however, should be generated using procedures and conditions that are fully representative and descriptive of the procedures and conditions proposed for manufacture of the product in the application.
不管一个药品是通过终端灭菌工艺还是无菌工艺灭菌的，无菌工艺的有效性都不是通过三个生产批的数据来验证的，而是应当在确实代表生产中拟采用的条件和规程的条件下去获得灭菌程序验证的数据。

The Center for Drug Evaluation and Research's (CDER's) and the Center for Veterinary Medicine's (CVM's) review of the validation of the sterilization process consists of a scientific evaluation of the studies submitted in the applications. This review is conducted by FDA's review staff, and is part of a cooperative effort between the review staff, compliance staff, and field investigators to ensure the overall state of control of the sterile processing of human and veterinary drug products. Information and data in support of sterility assurance may be provided directly to the application or by specific reference to a drug master file (DMF), a veterinary master file (VMF), or another application. Letters of authorization to refer to the referenced files should be included.
药品评价与研究中心和兽药中心审核无菌工艺的验证，包括申请上报研究资料的科学评价。

这一审查由FDA审核官员牵头，是审核官员、监督官员以及调查员为确保对人用和售用药品无菌工艺实施全方位控制而共同努力的一项成果。

支持灭菌保证的信息和资料可直接列入申请材料或者通过引用DMF、VMF或其他申请列入申请材料，涉及引用文献的授权信函也应该包括在里面。

C. Remarks
This guidance is intended to provide recommendations for the types of information applicants
should include in human and animal drug applications. Regulatory requirements for the submission of information and data in various applications are specified in the sections listed below:
C. 备注
本指南旨在为申请人应该提供包括在人药和兽药申请里的信息类型提供建议。

各种信息和资料申报的法规要求列于下面：
1. Human Drugs:
Investigational new drug applications 21 CFR 312.23(a)(7)
New drug applications 21 CFR 314.50
Abbreviated new drug and abbreviated antibiotic drug applications 21 CFR 314.94 and 314.50 Supplements to NDA's and ANDA's 21 CFR 314.70
2. Animal Drugs:
Investigational new animal drug applications 21 CFR Part 511
New animal drug applications 21 CFR 514.1
Supplements to NADA's 21 CFR 514.8
1、人药：
新药临床研究申请21 CFR 312.23(a)(7)
新药申请21 CFR 314.50
仿制新药和仿制抗菌药申请 21 CFR 314.94 and 314.50
新药申请和仿制新药补充申请21 CFR 314.70
2、动物药
新兽药临床研究申请21 CFR Part 511
新兽药申请21 CFR 514.1
新兽药补充申请21 CFR 514.8
II. INFORMATION FOR TERMINAL MOIST HEAT STERILIZATION
PROCESSES
The following types of information should be submitted in support of sterility assurance for products produced using terminal moist heat sterilization. Although the following outline directly addresses moist heat processes, the same types of information would generally pertain to other terminal sterilization processes (e.g., ethylene oxide or radiation). (See section III of this guidance.) The following information should be submitted for each facility to be used in the manufacture of the proposed drug product:
II. 终端湿热灭菌工艺信息
应该上报以下资料以证明产品生产中使用终端湿热灭菌的无菌保证水平，即使下面的要点只讨论湿热工艺，同样类型的信息通常也适用于其他终端灭菌工艺（例如环氧乙烷或放射灭菌，参见本指南的第III部分）。

在所申报药品的生产中拟采用的每一设备，都应上报以下资料：A. Description of the Process and Product
A. 工艺和产品的描述
1. The Drug Product and Container-Closure System
Descriptions of the drug product and the container-closure system(s) to be sterilized (e.g.,
size(s), fill volume, or secondary packaging).
1、药品和密封容器系统
描述需要灭菌的药品和密封容器系统（如：尺寸、体积或第二层包装）
2. The Sterilization Process
A description of the sterilization process used to sterilize the drug product in its final
container-closure system, as well as a description of any other sterilization process(es) used to sterilize delivery sets, components, packaging, bulk drug substance or bulk product, and related items. Information and data in support of the efficacy of these processes should also be submitted. (See also sections II.B. and II.C. of this guidance.)
2、无菌工艺
描述无菌工艺产品在最后的密封容器系统中的灭菌，以及灭菌中的传送装置、组件、包装、原料及药液及有关物质的无菌工艺。

证明工艺效果的信息和资料也应该上报。

（见本指南 II.B. 和 II.C.部分）
3. The Autoclave Process and Performance Specifications
A description of the autoclave process, including pertinent information such as cycle type (e.g., saturated steam, water immersion, and water spray), cycle parameters and performance specifications including temperature, pressure, time, and minimum and maximum F0. Identify the autoclave(s) to be used for production sterilization, including manufacturer and model.
3、高压釜程序及其性能指标
高压釜灭菌过程的描述，包括的有关信息如循环类型（例如：饱和蒸汽法，热水浸泡法，热水喷淋法），循环参数和功能指标（包括温度，压力，时间，最小和最大F0值（致死因子）），鉴别用于产品灭菌的高压釜（包括生产商和模型）。

4. Autoclave Loading Patterns
A description of representative autoclave loading patterns should be provided.
4、高压釜装填方式
应该提供有代表性的高压釜装填方式。

5. Methods and Controls to Monitor Production Cycles
Methods and controls used to monitor routine production cycles (e.g., thermocouples, pilot bottles, and biological indicators) should be described, including the number and location of each as well as acceptance and rejection specifications.
5、监测生产周期的方法和控制
应该描述用于监控日常生产周期的方法和控制（例如热电偶，温度指示瓶和生物指示剂），包括各监控的数量和位置以及接收和拒收标准。

6. Requalification of Production Autoclaves
A description of the program for routine and unscheduled requalification of production autoclaves, including frequency, should be provided.
6、生产用高压釜的再确认
应该提供高压釜常规和不定期再确认方案的描述，包括频率。

7. Reprocessing
A description and validation summary of any program that provides for reprocessing (e.g., additional thermal processing) of product should be provided. Please note that the stability program is also affected by additional thermal processing. For further information concerning the stability program, reference is made to the Center for Drug Evaluation and Research "Guideline for Submitting Documentation for the Stability of Human Drugs and Biologics" and
to the Center for Veterinary Medicine "Drug Stability Guideline."
7、返工
应该提供产品返工的任何程序的描述和验证的描述（例如额外的热工艺），请注意，稳定性研究计划也受额外热工艺的影响。

关于稳定性程序的详细信息，参见药品评价与研究中心《人药和生物制剂申报资料指南》和兽药中心《兽药稳定性指南》。

B. Thermal Qualification of the Cycle
B. 循环的热量确认
1. Heat Distribution and Penetration Studies
Heat distribution and penetration study protocols and data summaries that demonstrate the uniformity, reproducibility, and conformance to specifications of the production sterilization cycle should be provided. Results from a minimum of three consecutive, successful cycles should be provided to ensure that the results are consistent and meaningful.
1、热分布和热穿透研究
应该提供说明产品灭菌周期的一致性、重现性和符合标准的热分布和热穿透研究方案以及数据总结，应提供至少连续三次运行成功的结果，以确保结果一致且有意义。

2. Thermal Monitors
The number of thermal monitors used and their location in the chamber should be described. A
diagram is helpful.
2、温度监测
应该描述所用温度监测点的数量和位置，最好有一张分布图。

3. The Effects of Loading on Thermal Input
Data should be generated with minimum and maximum load to demonstrate the effects of loading on thermal input to product. Additional studies may be necessary if different fill volumes are used in the same container line. Data summaries are acceptable for these purposes. A summary should consist of, for example, high and low temperatures (range), average temperature during the dwell period, minimum and maximum F0 values, dwell time,
run date and time, and identification of the autoclave(s) used. These data should have been generated from studies carried out in production autoclave(s) that will be used for sterilization
of the product that is the subject of the application.
3、负载热量输入的效果
应该生成最大和最小负载数据以证明负载热量输入的效果，如果同一类容器，填充体积不同，则有必要进行额外的研究，上述情况可接受采用汇总数据的形式。

例如，一份总结应包括：高低温度范围、灭菌阶段的平均温度、最大和最小F0值、灭菌时间、运行日期和时间、使用的高压釜编号），上报的资料及数据应使用所申报产品今后使用的高压釜运行获得。

4. Information Included in the Batch Record
The batch record supplied with the chemistry, manufacturing, and controls section of the application should identify the validated processes to be used for sterilization and for depyrogenation of any container-closure components. This information can be included in the batch record by reference to the validation protocol or standard operating procedure (SOP). Validation information should be provided as described above.
4、批记录信息
申请中包含化学、生产、控制方面内容的批记录应说明拟用于封闭容器系统任何组件的灭菌或去热原处理的程序，这些程序应是通过验证的程序（可采用在批记录中注明有关验证方案或标准操作规程的方式）。

验证信息应该提供以上描述的部分。

C. Microbiological Efficacy of the Cycle
Validation studies that demonstrate the efficacy (lethality) of the production cycle should be provided. A sterility assurance of 10-6 or better should be demonstrated for any terminal sterilization process. This level of sterility assurance should be demonstrated for all parts of the drug product (including the container and closure, if applicable), which are claimed to be sterile. The specific type of study and the methods used to carry out the study (or studies) are product and process specific and may vary from manufacturer to manufacturer. In general, the following types of information and data should be provided.
C.灭菌循环的微生物灭菌效果
应该提供证明灭菌循环效果（致死率）的验证研究。

终端灭菌工艺应该证明灭菌保证10-6或
更高，无菌药品的所有部分都应该证明达到这个灭菌保证水平（必要时，包括封闭容器）。

特定的研究类型和实施研究的方法因产品和工艺而异，可能各个厂家之间也不同。

通常应该提供以下类型的信息和资料。

1. Identification and Characterization of Bioburden Organisms
Describe the methods and results from studies used to identify and characterize bioburden organisms. The amount and type of information supplied may be dependent on the validation strategy chosen. For example, more information may be needed for bioburden-based autoclave processes than for overkill processes. Information concerning the number, type, and resistance of bioburden organisms may be necessary, including those organisms associated with the product solution and the container and closure. It may be necessary to identify the most heat-resistant bioburden organisms.
1、微生物鉴定
描述鉴定微生物的方法和结果。

提供的信息数量和类型可能由验证选择的策略决定，例如，以带菌量为基础的残存概率灭菌法比过多杀灭法需要更多的信息，也可能需要涉及到数量、类型、微生物耐受性的信息，包括与反应溶液、容器和密封件有联系的微生物，可能需要鉴别出最耐热的微生物。

2. Specifications for Bioburden
Specifications (alert and action levels) for bioburden should be provided. A description should be included of the program for routinely monitoring bioburden to ensure that validated and established limits are not exceeded (e.g., frequency of analysis and methods used in bioburden screening). The methods provided should be specific.
2、生物负荷检测指标
应该提供生物负荷的检测指标（警戒水平和行动水平），包括确保验证和建立的限度没有超出范围的微生物日常监测程序（例如微生物筛选的方法和分析频率），提供的方法应该是特定的。

3. Identification, Resistance, and Stability of Biological Indicators
Information and data concerning the identification, resistance (D and Z values), and stability of biological indicators used in the biological validation of the cycle should be provided. If biological indicators are purchased from a commercial source, it may be necessary to corroborate the microbial count and resistance, and provide performance specifications.
3、生物学指示剂的鉴定，耐受性和稳定性
应该提供涉及灭菌程序验证所用的生物指示剂的鉴定、耐受性和稳定性的信息和资料，如果使用市售的生物指示剂，则有必要标定孢子数和耐受性，以及提供相应的数据。

4. The Resistance of the Biological Indicator Relative to That of Bioburden
Studies characterizing the resistance of the biological indicator relative to that of bioburden may be necessary. Resistance in or on the product (i.e., in the product solution, or on the surface of container or closure parts or interfaces) should be determined as necessary. If spore carriers are used (e.g., spore strips), the resistance of spores on the carrier relative to that of directly inoculated product should be determined, if necessary.
4、微生物耐受性与生物指示剂耐受性的比较
有必要将微生物耐受性与生物指示剂耐受性的进行比较研究，产品内部和表面的耐受性（即产品溶液里，容器表面，密封部分或交界处）需要确定，使用孢子载体（如菌膜）时，应测定孢子在载体上及直接接种于产品后的耐热性，并将二者进行比较。

5. Microbiological Challenge Studies
Microbiological validation studies should be submitted that demonstrate the efficacy of the minimum cycle to provide a sterility assurance of 10-6 or better to the product under the most difficult to sterilize conditions (e.g., the most difficult to sterilize load with biological indicators at microbiological master sites or in master product or both). Use of a microbiological master product or site should be supported by scientific data. Microbiological master sites or solutions are those sites or solutions in which it is most difficult to kill the biological indicator under sterilization cycles that simulate production conditions.
5、微生物挑战试验
微生物验证研究应该上报产品在最困难灭菌条件下最小周期的效果证明，以提供灭菌保证10-6或更高水平（例如：最困难的条件下，在微生物主区域或（和）主产品上灭菌装载生物指示剂），微生物主产品或主区域的使用应该有科学的数据支持，微生物主区域或溶液是那些模拟生产条件下在灭菌周期里最难以杀灭生物指示剂的区域或溶液。

D. Microbiological Monitoring of the Environment
Section 211.160 of the Code of Federal Regulations requires, in part, the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to ensure that components, drug product containers, closures, in-process materials, and drug products conform to appropriate quality standards. Therefore, a microbiological monitoring program for production areas along with a bioburden monitoring program for product components and process water should be established. Process water includes autoclave cooling water. Applicants should provide information concerning this program. Frequency, methods used, action levels, and data summaries should be included. A description of the actions taken when specifications are exceeded should be provided.
D.微生物环境监测
联邦法规211.160节在一定程度上要求，适当的规格、标准、取样计划以及检测规程的建立完善是为了保证组成、药品容器、密封件、中间物料和药品符合适当的质量标准而设计的。

因此，应该与微生物监控计划一起，为产品组成和工艺用水建立生产区的环境监控计划，工艺用水包括高压釜的冷却水，申报单位应该提供这一监控计划有关的资料，包括频率、使用方法、行动水平和数据汇总资料。

超标时采取的措施也要提供。

E. Container-Closure and Package Integrity
An applicant should provide scientific validation studies (and data) in support of the microbial integrity of the drug packaging components. The following types of information should be included:
E.封闭容器和包装的完整性
申报单位应提供科学的验证报告（和数据），以便证明药品包装部分的微生物完整性，应该包括以下内容：
1. Simulation of the Stresses from Processing
Experimental designs should simulate the stresses of the sterilization process, handling, and storage of the drug and their effects on the container-closure system. Physical, chemical, and microbiological challenge studies may be necessary.
1、加工生产过程的模拟试验
试验的设计应模拟灭菌工艺、产品的处理、药品的贮存及其对封闭容器系统的影响，有必要进行物理、化学及微生物学挑战性试验。

2. Demonstrate Integrity Following the Maximum Exposure
Container-closure integrity should be demonstrated on product units that have been exposed
to the maximum sterilization cycle(s). If a product is exposed to more than one process, then exposure to the maximum cycle of all processes should be incorporated into the study design.
2、根据最大暴露证明完整性
封闭容器的完整性应该由暴露于最大灭菌周期中的产品单元证明，如果一个产品拟多次灭菌，实验方案的设计中应采用灭菌工序所有最长的周期。

3. Multiple Barriers
Each barrier that separates areas of the drug product claimed to be sterile should be separately evaluated and validated.
3、多腔室包装
无菌产品区分隔的每一个腔室均应分别进行验证及评价。

4. The Sensitivity of the Test
The sensitivity of the experimental method used for container-closure integrity testing should
be specified and provided.
4、试验的灵敏度
应说明并提供用于封闭容器完整性试验方法的灵敏度。

5. Integrity Over the Product Shelf Life
Microbial integrity of the container-closure system should be demonstrated over the shelf life
of the product. (See section V.A. of this guidance.)
5、在产品有效期的完整性
在产品有效期内封闭容器系统微生物的完整性应予以验证（参见本指南V.A.部分）。

F. Bacterial Endotoxins Test and Method
The bacterial endotoxins test used for the product should be described. The description should include qualification of the laboratory, inhibition and enhancement testing and results, determination of noninhibitory concentration and maximum valid dilution. For further
information see the agency guidance entitled "Guideline on Validation of the Limulus Amebocyte Lysate Test As An End-Product Endotoxin Test for Human And Animal Parenteral Drugs, Biological Products, and Medical Devices."
F.细菌内毒素测试及其方法
应该描述产品的细菌内毒素测试，包括实验室确认、抑制和促进试验及结果、非抑制检出浓度和最大有效稀释的测定，祥见我局“鲎试剂测试法作为药品内毒素检测的验证指南（用于人用和兽用注射药、生物制品以及医疗器械）。

G. Sterility Testing Methods and Release Criteria
Sterility test methods should be described and should include the protocol for the selection of representative units during production. When test methods differ significantly from compendial test methods, a demonstration of the equivalency to the compendial method should be provided. Testing performed within barrier systems should be described, and information concerning validation of the barrier system may be necessary.
G.无菌检查方法和判定合格的标准
应该描述无菌检查的方法，包括生产过程中有代表性样品的取样计划。

当测试方法与药典测试方法有显著的区别时，应该提供该方法与药典方法等效的证明。

应对在隔离系统内进行的试验作出说明，必要时应提供隔离系统验证的有关资料。

H. Evidence of Formal, Written Procedures
Section 211.113(b) of the Code of Federal Regulations requires that written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, be established and followed. Such procedures should include validation of any sterilization process. Therefore, evidence should be provided that there are formal, written procedures describing the elements listed above and that these procedures are followed. Such evidence may consist of SOP's, listing of SOP's, and protocols submitted as part of these elements.
H.正式的证据，书面规程
联邦法规211.113(b)部分要求，应该设计、制定并遵循防止无菌药品的微生物污染的书面规程，该规程应该包含任何形式的无菌工艺验证。

因此，应提供并附上列于以上要求的正式书面规程的证据。

III. OTHER TERMINAL STERILIZATION PROCESSES
Although the information above (sections I.A. through I.G. of this guidance) directly addresses moist heat processes, the same type of information would pertain to other terminal sterilization processes used singly or in combination to sterilize a drug product. The types of information outlined are, in general, also applicable to ethylene oxide and radiation (gamma and electron beam). These other processes should be addressed as each applies to the drug product, sterile packaging and in-process sterilization of components. Examples of such information might include: descriptions of loading configurations; qualification and validation of master load configurations;determination and validation of the efficacy of the minimum cycle to provide sterility assurance at the product master sites; requalification of the cycle; provisions for resterilization; specifications and monitoring program for product bioburden; and
container-closure integrity. Specific examples are provided below to demonstrate the
application of these concepts to other sterilization processes.
Additional information relating to the effects of the sterilization process on the chemical and physical attributes of the drug substance or drug product may be applicable, and should be supplied to the chemistry, manufacturing, and controls section of the application.
III.其他终端灭菌工艺
尽管上述资料（本指南I.A. ~ I.G.部分）直接讨论的议题是湿热灭菌工艺，但同类型的资料也适用于其他灭菌手段（单独使用或和其他方法配合使用）的情况。

一般来说，所简要讨论到的各类资料也适用于环氧乙烷和放射法（γ射线和电子束）。

这些应用于药品生产、无菌包装组分（件）在生产过程中的灭菌时，应分别进行讨论。

例如，这些资料可包括：装载方式的描述，主装载配置的确认和验证，支持生产主区域灭菌保证的最小周期效果的确认和验证，周期的再确认，再灭菌的规程，产品的生物负荷监控计划及限度，封闭容器的完整性。

下面将说明这些概念在其他灭菌手段上的应用。

与灭菌工艺对药物原料或产品的化学及物理性质的影响相关的其他资料也是必要的，应该分别列入申请的化学、生产和控制部分。

A. Ethylene Oxide
A.环氧乙烷
1. Description of the Sterilizer
The sterilizer(s) and controlled site(s) for prehumidification and aeration of the product load should be described.
1、灭菌剂的描述
应该描述灭菌器、产品预湿及充气的控制点。

2. Cycle Parameters
The parameters and limits for all phases of the cycle, e.g., prehumidification, gas concentration, vacuum and gas pressure cycles, exposure time and temperature, humidity, degassing, aeration, and determination of residuals should be specified. Specific procedures used to monitor and control routine production cycles to assure that performance is within validated limits should be provided.
2、周期参数
灭菌程序各阶段的参数和限度（比如预湿、气体浓度、抽真空和压力充气周期、暴露时间、温度、湿度、排气、充气、残留物的测定）应该规定。

尾确保性能达到验证过的标准，用以监控日常生产的具体规定应予以上报。

3. Microbiological Methods
The microbiological methods (growth medium, incubation temperature, and time interval) for cultivating spores from inoculated samples during validation experiments should be described as well as the microbiological methods used as part of routine production cycles.
3、微生物方法
在验证试验中将被接种样品中的孢子进行培养的微生物方法（培养基、培养温度及时间），以及在日常生产的灭菌周期中采用的那些微生物学方法，均应有说明。

4. Stability
The program for monitoring the stability of packaging and the integrity of the container-closure system barrier over the claimed shelf life should be described.
4、稳定性
监测有效期内包装的稳定性和容器包装系统的完整性程序应该描述。

B. Radiation
B.放射灭菌法。