翻译-TR27-包装完整性-PackageIntegrity-1998

1、Pharmaceutical Package Integrity药物包装完整性Technical Report No. 27技术报告第27号PDAApril 19981998年4月Preface 前言This report reviews issues of pharmaceutical product package integrity and provides guidance for evaluating the barrier qualities of a pharmaceutical package. It supersedes the previously issued PDA T

2、echnical Information Bulletin No. 4, Aspects of Container/Closure Integrity. In this updated guideline, the term product package is used, rather than the term container/closure system, as it encompasses any nonporous barrier system that protects a pharmaceutical product from the environment.Similarl

3、y, the term package seal is used generically to mean all types of seals or closure systems. Although it is written to reflect the complexity of all pharmaceutical products and packages, the emphasis throughout the document is clearly on packaging intended for sterile products.该报告审核了药物产品包装完整性的主题，为评价药

4、物包装的屏障质量的评价提供了指南。它代替了先前发布的“ PDA技术信息通告第4号：包装容器/密封完整性方面”。在 该升级的指南中，使用术语“产品包装”，而不是术语“包装容器/密封系统”，因为它包 含了任何用于保护药物产品隔绝于环境的无孔屏障系统。同样，一般也使用术语“包装 密封”，意味着所有类型的密封或密闭系统。虽然，书面上是反映所有药物产品和包装的 复杂性，整个文件强调的重点明显是意图用于无菌产品的包装。This report was written by the following members of the PDA Task Force on Container/Closure Int

5、egrity:该报告由PDA关于容器/密封完整性的特别工作组的下列成员撰写：Michael C. Carroll, The Liposome Company, Inc.Vivian F. Denny, Peak to Peak Pharmaceutical AssociatesDana M. Guazzo, Ph.D., The R. W. Johnson Pharmaceutical Research InstituteMark W. Kaiser, Lancaster LaboratoriesLee E. Kirsch, Ph.D., The University of IowaJohn

6、D. Ludwig, Ph.D., G. D. Searle and CompanyGerald K. Masover, Genentech, Inc.Jeri L. May, DuPont Merck Pharmaceutical Co.Jeanne E. Moldenhauer, Ph.D., Fujisawa USA, Inc.Jean I. Olsen, SmithKline Beecham PharmaceuticalsTerri M. Poison, Glaxo Wellcome Inc.Glenn E. Wright, Eli Lilly & Co.In addition, th

7、e Task Force acknowledges the immense help and support of Michael S. Korczynski, Ph.D. and Russell E. Madsen of PDA. Their editorial assistance and their insight into many of the key issues of package integrity were invaluable contributions to this effort.另外，特别工作组感谢PDA 成员 Michael S. Korczynski, Ph.D

8、. 和 Russell E. Madsen的很大帮助。他们的编辑辅助和他们对包装完整性很多关键关键观点的洞察，对该成就 作了非常大的贡献。This document should be considered as a guide; it is not intended to establish any mandatory or implied standard.该文件仅作为指南，不意图设立任何强制或潜在的标准Introduction 介绍Product quality can be defined in terms of the ability of a product to perform

9、its desired functions despite the stresses to which it has been exposed before and during its intended use. Pharmaceutical container systems may have a variety of functions including facilitation of product use, prevention of improper use, light protection, containment of the product, maintenance of

10、 a microbial barrier, and maintenance of a rarefied product environment. Assurance of package integrity is primarily concerned with product containment and the maintenance of an effective barrier against ingress of microorganisms or potentially reactive gases such as oxygen or water vapor, and somet

11、imes, the maintenance of a vacuum. The information provided in this guideline is intended to assist users in developing integrity assessment strategies for use during the phases of product life.产品质量可定义为产品保持期望功能的能力，无论在使用前或使用期间暴露于怎样的外 界苛刻条件。药物包装系统可以有各种各样的功能，包括使产品容易使用，防止不正确 的使用，光照防护，产品的密闭，生物屏障的维持和维持纯净的

12、产品环境。保证包装完 整性主要是有关产品密闭和维持有效屏障以防止微生物或潜在反应气体例如氧气或水汽 的侵入，有时也用于保持真空。该指南提供的信息是意图帮助用户在产品生命期间的使 用时开发出完整性评价策略。Integrity Assurance Through Product Development And Product Life 贯穿产品开发和生命周期的完整性保证Product package integrity assessment begins during a products development phase and continues throughout its life cy

13、cle, encompassing routine manufacturing and shelf-life stability assessments.产品包装完整性的评价开始于产品的开发阶段，并持续贯穿整个生命周期，包含日常的 生产和保存期间的稳定性评价。The phases of a products life cycle include:产品的生命周期阶段包括：Package design, process development, and durability assessment 包装设计，工艺开发和耐久力评价。In-process control 在线控制Product test

14、ing 产品检测Further reconfirmation of product package integrity should occur when there are major changes in the package system that may affect its integrity, including package design, package materials, and/or when changes occur in the manufacturing processing conditions, including sterilization.当包装系统包

15、括包装设计、包装材料和/或生产工艺条件包括灭菌出现变更，可能影响包装的完整性时，应进行产品包装完整性的进一步确认。The following subsections contain information on the critical factors for assessing a products package integrity over its life cycle.下列分章节包含了整个生命周期内评价产品包装完整性的关键因素信息。During the package design/process development phase, a thorough knowledge and

16、understanding of the package seal is critical for designing an appropriate package system. Subsection 3.1 describes the nature of these requirements, including a knowledge of the seal location, the sealing mechanism, and the critical factors of design, assembly, and processing that may impact seal q

17、uality. The importance of testing the package and processing parameters at extremes is stressed to ensure that the package will be able to withstand the rigors of processing, distribution, and usage. 在包装设计/工艺开发阶段，对包装密封的完整知识和了解对于设计一个合适的包装系统 很关键。章节3.1部分描述了这些要求的性质，包括密封位置、密封机制、设计关键因 素、组装和可能影响密封质量的加工等知识。

18、强调在极限条件下测试包装和加工参数的 重要性，以保证包装能够耐受加工、销售和使用中的苛刻条件。Once a product reaches commercial manufacturing, in-process control of critical production and processing steps are necessary. Subsection 3.2 describes these vital checks in greater detail.一旦产品进入了商业生产，必须对关键生产和加工步骤进行在线控制。章节 3.2部分更 详细地描述了重要的检查。Product lea

19、k testing is discussed in subsection 3.3. The types of methods available for product testing are included, along with their limitations.产品泄漏测试在章节 3.3部分讨论。包括了产品测试可利用的方法类型以及它们的限度。Package Design, Process Development, and Durability Assessment 包装设计、工艺开发和耐久力评价Package integrity quality assurance involves

20、the selection of appropriate packaging materials, the design of the seal or closure system, and the verification that the incoming components meet specifications. Establishing leakage rate specifications may be desirable early during product development based on the particular product and package pe

21、rformance characteristics to ensure that the product will reflect these limits. Integrity tests used during package design may include gross leak tests that simply check for leak presence or location, but should also consist of those that test at or near the established leakage/permeation rate speci

22、fication.包装完整性质量的保证包括了合适的包装材料的选择、密封或包装密闭系统的设计，检查收到的组分符合标准。最好在包装开发的早期阶段以特定的产品和包装性能特性为基 础来设立泄漏速率标准，以保证产品反映了这些限度。在包装设计期间使用的完整性测 试可能包括大泄漏量的测试来简单检查泄漏出现或位置，但应包括那些位于或接近设立 的泄漏/渗透速率标准的测试。Packages may be closed via either seals or closures. By definition, a seal is the result of the bonding of two similar or

23、dissimilar surfaces. Examples of seals include: 1) contiguous containers formed from a single material (for example, glass or plastic ampoules); 2) the direct fusion of two material surfaces, usually by heat (for example, heat sealed plastic bags or unit dose blister packaging for solid oral dosage

24、forms); and 3) the bonding of two material surfaces with an intermediate adhesive agent. A closure, on the other hand, is the physical mating of two surfaces. In the strictest sense, all closures are tortuous path barriers. The degree to which a closure can limit leakage is a function of the closure

25、 design, the viscoelastic nature of the package components, and the extent of package component fit. For instance, an elastomeric rubber stoppered sterile vial is capable of achieving a very low gaseous leakage rate due to the viscoelastic nature of the rubber and its ability to conform to the vial

26、surface upon compression. Other closure systems, such as metal on metal or plastic on metal, rely on the frictional mating of relatively incompressible materials. Still other closures do not depend on component fit as much as the existence of a tortuous path. In this guideline, the term package seal

27、 will be used generically to mean all seal and closure system types.包装可通过密封或密闭来保持密闭。通过定义，密封是两个相似或不相似表面的接合的 结果。密封的例子包括：1)单一材料形成的接触容器(例如玻璃或塑料安甑)；2)两种材料表面的直接熔合，一般通过加热(例如热密封的塑料袋或固体口服制剂的单个水泡 眼包装)；3)两种材料表面带有中间粘合剂的连接。另外一方面，密闭是两个表面的物 理交接。严格意义上，所有的密闭是弯曲通道屏障。密闭能够限制泄漏的程度，是密闭 设计、包装组分的粘性和包装组分适合程度共同起作用的结果。当前，弹性橡胶

28、塞塞住 的无菌小瓶，由于橡胶的粘性以及在受压后能够适合瓶子表面的能力，能够达到很低的 气体泄漏率。其他密闭系统，例如金属对金属或塑料对金属，依赖于相对压缩材质的摩 擦交接。还有其他密闭不依赖于组分的适配性，而是存在曲折通路。该指南中，一般使 用术语“包装密封”来指所有类型的密封和密闭系统。There are critical factors that impact the quality of each package seal. Such factors typically include package component variables of composition, dimensi

29、on, and critical defects; and sealing operation variables of time, temperature, pressure, and torque. The impact of processing on package integrity must also be characterized. Package component washing, drying, siliconization and sterilization, and product processing such as terminal sterilization m

30、ay all impact the ability of the package seal to maintain its effectiveness.存在关键因素影响每个包装密封的质量。这些因素主要包括包装部件的成分变量、尺寸 和关键缺陷、和密封操作的时间、温度、压力和扭矩变量。工艺加工对包装完整性的影 响也应特定刻画。包装部件的清洗、干燥、硅化和灭菌，以及产品加工例如最终灭菌， 都可能影响包装密封维持有效性的能力。During the package design and process development phases, the acceptable ranges for each

31、critical variable should be established based on package performance criteria that incorporate integrity testing. Wherever feasible, the variables of design and processing should be exaggerated and their impact on package integrity evaluated to help define the margin of safety for that variable. Suc

32、h factors may include, for example, time, temperature, and pressure variables for heat seal operations and for steam sterilization cycles. Stability studies extending through shelf-life must also include integrity tests of the packaged product produced under typical manufacturing conditions. In some

33、 cases it may also be prudent, although not mandatory, to place product on stability that has been manufactured at critical processing or package design extremes. When greater time and effort are spent on package integrity verification during the design and process development phases, fewer problems

34、 will likely be encountered after commercialization.在包装设计和工艺开发阶段，应与完整性测试结合，基于包装性能标准设立每个关键变 量的可接受标准。可行条件下，设计和工艺加工变量应扩大，评价它们对包装完整性的 影响，以帮助定义变量的安全余量。这些因素包括，例如热密封操作和蒸汽灭菌循环的 时间、温度、压力变量。贯穿整个产品生命周期的稳定性考察也必须包括在典型的生产 条件下生产的包装产品的完整性测试。某些情况下，也可以谨慎的，虽然不是强制的， 将在关键工艺和包装设计极限条件下生产的产品进行稳定性考察。在设计和工艺开发阶 段在包装完整性检查上花费的时

35、间和精力越多，商业化后出现的问题更少。The assurance of product quality depends on the ability of the product to maintain integrity throughout the stresses anticipated during storage, distribution, and use. During product development, the effects of various environmental and handling stresses may need to be considered

36、in addressing package integrity. Relevant types of stress may include temperature, pressure, and relative humidity extremes, shock and vibrational stress, and exposure to microorganisms. The evaluation of package integrity may include exposure of the product to simulated conditions of storage, distr

37、ibution, and use coupled with appropriate leakage detection methodology. The integrity tests chosen are generally those that detect sporadic damage to the product, which may result in gross leakage or product loss, and in the case of sterile products, microbial ingress.产品质量的保证依赖于产品在整个储存、销售和使用期间的极限不利

38、条件下维持完整性 的能力。产品开发期间，在选择包装完整性时，需要考虑各种环境和操作重要条件的影 响。相关的极端条件类型包括温度、压力和相对湿度极端条件、撞击和振动不利条件， 以及暴露于微生物。包装完整性的评价可包括将产品暴露于储存、销售和使用的模拟条 件，结合适当的泄漏检测方法。选择的完整性测试一般是检测零星的产品损坏而导致的 明显的泄漏或产品损失，或是无菌产品时的微生物侵入。In-Process Control在线控制The processes that have been determinedduring product development to mostcritically impa

39、ct package integrity should be those that are targeted for in-process control. Performance criteria for in-processcontrols are typically based on theperformance of a specific unit operation rather than the performance of the final product. For example, in-process controls and tests may be used to st

40、atistically verify that the time, temperature, and pressure variables of a sealing operation are in control as opposed to final product testing used to demonstrate that microbial barrier or rarefied internal atmosphere criteria have been met. During validation studies it must be demonstrated that a

41、process in control yields only products that meet the established leakage rate specifications.在产品开发阶段决定的对包装完整性有最大关键影响的工艺，是在线控制的目标对象。 在线控制的性能标准主要基于各个单元单元操作的性能而不是最终产品的性能。例如， 在线控制和测试可用于统计检查密封操作的时间、温度和压力变量是受控的，相对于证 明微生物屏障或符合纯净的内部气体标准的最终产品测试而言。在验证测试时，必须证 明工艺“受控”在产品能符合已设立的泄漏级别标准内。For a limited number of p

42、roducts, instrumentation exists that permits high-speed 100% on-line verification of package integrity at the established leakage rate specifications. But for many sterile products in-process leak test instruments have limitations that preclude high speed, on-line integrity verification at the requi

43、red product leakage rate specifications. In-process leak test instruments are designed to check for intermittent defective packages leaking at a gross rate that circumvented the various in-process controls. Certainly no instrumentation currently available for in-process use is intended to measure pe

44、rmeation rates of gases through the package itself. In-process testing is strictly limited to leakage through package imperfections.对于有限数量的产品，允许用仪表在设立的泄漏速率标准进行高速的100%在线包装完整性检查。但对于许多无菌产品，在线泄漏测试仪表受到限制，在设立的泄漏速率标准 进行高速在线包装完整性检查行不通。设计的在线泄漏测试仪表用于围绕各种在线控制， 检查间歇性的泄漏量较大的缺陷包装。当然，当前还没有仪表可以意图用于在线测量透 过包装本身的漏气速率。

45、在线测试严格限制于不完整包装的泄漏。There are a variety of logical, validatable in-process integrity tests that can help verify product/package integrity. However, no amount of in-process or final product testing can replace the need for the control and monitoring of various critical package and sealing parameters. F

46、or example, vision systems can be used to cull out defective components, gas flow rate meters can be installed on ample sealing lines, time/temperature/pressure controls can be used on thermal sealing equipment, and torque monitors can be placed on screw-capping equipment. These online in-process co

47、ntrols, in combination with well-designed product/process validation studies, are an essential part of the total package integrity quality assurance.存在各种合理的、可验证的在线完整性测试，能帮助检查产品/包装完整性。但是，没有哪个在线或最终产品测试可以代替对各种关键包装和密封参数进行控制和监测。例如， 视觉系统可以用于剔除有缺陷的部件，在安甑密封线上可以安装气流速度表，在热封设 备上可以使用时间/温度/压力控制，在螺旋压盖设备上可以放置扭矩监测仪

48、。这些在线在线控制，结合良好设计的产品/工艺验证试验，是整个包装完整性质量保证的关键部分。Product Testing 产品测试A product that has been properly and carefully designed with critical production processes well characterized and controlled should have little need for final product release testing for package integrity. Certainly the quality of a ph

49、armaceutical product cannot merely be based on the results of a product integrity test, especially when such tests are usually performed on a fraction of the production lot. Sterility tests have historically been considered an indicator of package integrity; however, due to the insensitive nature of

50、 sterility tests, the small number of samples tested, and the possibility of false positives, these results are no longer considered reliable as a final indicator of package integrity.正确和仔细设计的产品，有良好描绘和控制的关键产品工艺，最终产品放行需要进行的 包装完整性测试就很有限。当然，药物产品的质量不能仅基于产品完整性测试的结果， 特别是这些测试通常仅对部分产品批进行。历来都认为无菌测试是包装完整性的指示指

51、 标；但是由于无菌测试的不敏感的特性，仅测试少量样品，且可能出现阳性失败，不再 认为这些结果可以作为包装完整性的最终指示指标。Generally, integrity test methods selected for final product testing are designed to verify the absence of gross leaks well above permeation rate levels. For those package systems that can be tested 100% on-line with instruments shown to

52、 measure near or below the leakage rate specification there is no need for additional product integrity testing. For other products a statistically established percentage of the batch may be integrity tested for in-house process control purposes.通常，为最终产品测试所选择的完整性测试方法是设计用来检查是否有超过泄漏等级的 大量泄漏。对于那些带有仪表可以

53、进行100%在线测试，显示能测量接近或低于泄漏等级标准的的包装系统，不再需要额外的产品完整性测试。对于其他产品，统计设立的百分比的批次可以用于进行内部控制目的的完整性测试。Indirect tests of package integrity may also be employed on production lot samples.For example, indirect measures of integrity may include visual inspection, residual seal force of a serum vial with elastomeric clo

54、sure, or seal strength of an adhesive or thermal seal. The acceptance criteria for such tests should be based on the critical variable acceptance ranges established during the development phases of package design and process development.在产品批样品上同样可以进行包装完整性的间接测试。例如，完整性间接措施可包括目 视检查、带弹性胶塞的浆液瓶的剩余密封力，粘接或热

55、密封的密封强度。这些测试的可 接受标准应基于包装设计的开发阶段和工艺开发期间设立的关键变量可接受范围。Package Integrity and Leak Rate Specifications包装完整性和泄漏速率标准This section provides a definition of leaks and leakage, and presents examples of leakage rate units of measure. The concept that all packages leak to some extent is introduced, although such

56、 leakage may not have a negative impact on product quality.Therefore, when designing a product/package system, a leak rate specification must be established. Examples of leak rate specifications are provided.该部分提供了渗漏和泄漏的定义，给出了测量泄漏率单位的例子。引入了所有包装泄漏 到何种程度的概念，虽然这些泄漏可能对产品质量没有负面影响。因此，当设计一个产 品/包装系统时，应设立泄漏率

57、标准。提供了泄漏率标准的定义。A leak is an unintended crack, hole, or porosity in a package capable of passing aliquid or gas through the package. Leakage is the movement of the liquid or gas through the leak. Leakage is defined in units of mass or volume flow of a gas or liquid over time under defined conditions

58、of temperature and pressure. Leakage is often described in units of standard cubic centimeters of gas (air) that can move through an orifice per second (std cc/sec or sees1) under defined conditions of temperature and differential pressure. Similarly, leakage units of atm cc/s are also used to defin

59、e leakage measured at local atmospheric pressure and temperature.While thetwo arenot identical, units of sees and atm ccs are often used interchangeably. Another common unit of measure is the SI unit of Pa m3/s, or Pascal cubic meters per second. One Pa m3/s is equal to 9.87 sees or roughly 10 sees.

60、 Various general references on the subjects of leakage, leak test methods, and units of measure are referenced at the end of this document.泄漏处即包装上可通过液体或气体的裂口、漏洞或小孔。泄漏就是液体或气体通过泄露孔的过程，由一定温度压力条件下流经的液体或气体的质量或体 积进行描述，通常以一定温度和压差下每秒流经一个漏孔的标准气体(空气)的立方数 为单位(std cc/sec或sees1 )。同样，在大气压和现场温度下，atm cc/s也可作为衡量泄漏量的