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[技术干货] USP<1207.1>中文翻译连载 | 包装密封性测试方法的选择 (2之3)

第三章 方法选择的标准

TEST METHOD SELECTION CRITERIA


No single package leak test or package seal quality test method is applicable to all product–package systems. Test method ion is made on a product–package on a case-by-case basis. Often more than one test method is employed during a given products life cycle. Package test method ion as a function of product life-cycle phase, along with important integrity considerations, are discussed in Package Integrity Testing in the Product Life Cycle. A broad discussion of additional ion criteria for leak test methods follows. Specific leak test method examples are provided for informational purposes but are not intended as recommendations. The attributes and general capabilities of tests can be found in Package Integrity Leak Test Tech- nologies <1207.2> and are helpful in the method ion process.

没有哪个单一的泄露测试方法或包装封口质量测试适用于所有包装产品,方法选择需要基于个例决定。对于给定的产品生命周期,经常使用不止一种方法。作为产品生命周期管理的一部分,包装测试方法的选择和重要的密封性关注点一起,在“产品生命周期的包装密封性测试”中有讨论到,随之也广泛讨论了泄露测试方法的其他选择标准。特定的泄露测试方法例子仅作为信息提供,而非推荐性意见。各测试方法的用途和能力可以在<1207.2>包装完整性测试技术中读到,这些信息将帮助选择合适的方法。


3.1 Package Contents

包装内容物


When ing a leak test method, the first determining factor is the nature of the package contents. Whether the package contains a liquid or solid formulation, and whether it contains a headspace of inert gas, air, vacuum, or even no headspace at all, will influence leak test method choice. For example, if testing liquid-filled packages by vacuum decay or mass extraction, test vacuum conditions may trigger some formulations to solidify inside leak paths, thereby blocking gas leakage flow and making the test ineffective. Alternatively, electrical conductivity and capacitance tests can be used, but only if the liquid product is more electrically conductive than the package materials.

选择泄露测试方法,首要因素就是明确包装内容物的特性。是否含有液体或固体组分,是否有顶空气体、空气、真空,或根本就没有顶空,都会影响到泄露检测方法的选择。比如,用真空衰减或质量提取法测试内充液体的包装产品,真空测试条件可能会导致某些组分在漏洞内固化,堵塞漏洞气流而导致方法失效。用高压放电法替代就没问题了,只要液体成分导电性强于包装材料。


3.2 Package Design, Materials of Construction, and Mechanics

包装设计,材料组成和设计机理


Packages vary widely in their design, their materials of construction, and the mechanisms whereby package closure is affected. Each of these variables influences the leak test method choice, as the following examples illustrate.

包装设计、材料组成和机理诸方面都有广泛差别,并影响到包装的封闭。这些差别也都会影响到包装泄露检测方法的选择,以下举例说明:


3.2.1 RIGID OR FLEXIBLE PACKAGES

硬质包装或软包装


Rigid (nonporous) packages can tolerate the pressure or vacuum-challenge conditions required in several leak tests, including tracer liquid ingress, vacuum decay, mass extraction, and some tracer gas tests. In contrast, some flexible packages can tolerate differential-pressure test conditions only if special tooling is used to restrict package expansion and prevent subsequent seal damage. Package restriction is necessary to ensure consistent differential pressure conditions across the package barrier.

硬质(无孔隙)包装可以耐受多种泄露测试中的压力或真空挑战性条件,包括示踪液的侵入、真空衰减、质量提取和一些示踪性气体。相较之下,一些软包装只有在运用特定工具来限制包装膨胀并阻止相应的封口破损时,才可以耐受有压差的测试条件。所以,包装的限制性选用或使用很有必要,可以确保包装屏障两侧保持持续的压差。


3.2.2 MOVEABLE OR FIXED COMPONENTS

非固定的或固定的部件


Moveable package components, such as syringe stoppers (plungers or pistons), may require restraint to prevent their dislocation during the differential pressure test conditions required for a majority of leak test procedures (e.g., tracer liquid test, pressure or vacuum decay test, mass extraction test, bubble emission test, and microbial challenge by immersion test).

非固定的包装部件,比如注射器胶塞(插头或推杆)可能需要固定以防止位移,因为在大部分的泄露测试过程中都存在压差(比如示踪液试验、压力或真空衰减测试、质量提取测试、起泡试验和微生物侵入试验)。


3.2.3 POLYMERIC MATERIALS

聚合物材料


When exposed to test vacuum conditions, package materials such as plastics and some elastomers may outgas volatiles that raise vacuum-decay leak test results as well as mass extraction results, falsely implicating package leakage. Plastic packages that are highly permeable to tracer gases may not be compatible with helium tracer gas leak detection, as helium permeating through the package could be mistaken for package leakage or may mask small leaks. Special fixtures to limit tracer gas permeation effects and isolate tracer gas exposure to the seal area under test have been used to mitigate such difficulties.

当暴露在真空测试条件下,类似塑料和橡胶类的包装材料可能发散出挥发物,导致真空衰减测试结果和质量提取法结果升高,错误指征包装泄露水平。还有,极易透气的塑料包装可能不适用于氦气示踪的泄露测试,因为氦气渗透过包装会导致包装泄露的错误结果,或掩饰小的泄露。为了减轻这种问题,可以采用特殊的装置,在测试中限制示踪气效应和避免示踪气在测试过程中暴露在封口区域。


3.2.4 METALLIC MATERIALS

金属材料


Packages made of foil laminate materials may prove incompatible with electrical conductivity and capacitance leak detection, which works best with relatively nonconductive package materials. However, aluminum caps used to secure vials closed with elastomeric closures pose no hindrance to electrical conductivity and capacitance tests, even for finding leaks located between the closure and the vial finish.

铝箔材料包装可能被证实不适用于高压放电泄露检测法,这种检测方法最适用于相对不导电的包装材料。然而,用于保护有橡胶塞的西林瓶铝盖不会妨碍高压放电法进行泄露测试,即使是探测胶塞和瓶口之间的漏洞也不会有影响。


3.2.5 TRANSPARENT OR OPAQUE MATERIALS

透明或不透明材料


Packages made of transparent or translucent materials allow for visual inspection and electromagnetic wave passage. Therefore, transparent or translucent materials can be tested by laser-based gas headspace analysis techniques, as well as tracer-liquid ingress or microbial ingress. Opaque packages are incompatible with testing approaches that require visual inspection of the package contents.

透明或半透明包装可以目视和透过电磁波。因此,透明或半透明材料可以通过激光顶空分析技术、示踪液侵入或微生物侵入等不同的方式进行检测。非透明的包装则不适用于需要目视包装内容物的检测方法。


3.3 Closure Type and Mechanics

封闭方式和机理


Refer to Package Integrity Evaluation—Sterile Products <1207>, Closure Type and Mechanics for a discussion of the closure type categories represented by the various product–package systems. The design of the closure system and its leakage restriction function (i.e., the maximum allowable leakage), plus the types of defects anticipated, influence  the  integrity  test  method choice.

参阅包装完整性评估--无菌产品 <1207>,本部分“封闭方式和机理”讨论不同产品--包装体系对应的封闭方式类别。封闭系统设计和泄露限制功能(即最大允许泄露),结合对应封闭系统类别可能的缺陷,影响到密封性测试方法的最终选择。


3.4 Maximum Allowable Leakage Limit 

最大允许泄露限度


The maximum allowable leakage limit as a function of the product–package quality requirement is discussed in Package Integrity Evaluation—Sterile Products <1207>, Product–Package Quality Requirements and the Maximum Allowable Leakage Limit. The following integrity test method ion considerations are offered in light of that discussion.

最大允许泄露限度作为包装产品质量属性的一部分,在包装完整性评估--无菌产品<1207> “包装产品质量要求和最大允许包装限度”中讨论到。以下特引述该讨论中涉及到的包装可靠性测试方法考虑要点。


3.4.1 STERILITY AND PRODUCT FORMULATION CONTENT MUST BE PRESERVED; GAS HEADSPACE PRESERVATION IS NOT REQUIRED

要求维持无菌属性和产品组分含量;无顶空气维持要求类型


Integrity tests for this product quality category include those able to verify that the maximum allowable leakage limit that prevents liquid and microbial ingress is not exceeded. Tracer gas tests performed using the vacuum mode and laser-based gas headspace analysis test methods are two examples. Both have been shown to be sensitive enough to quantitatively analyze leakage through the smallest leak paths found to pose the smallest chance of liquid leakage or microbial ingress in rigid packaging. Such tests have also proven useful for defining relationships among package design, component fit, package assembly parameters, and leakage rate, even in the absence of package defects.

这类产品密封性测试涵盖的方法,应能被证实可以测试泄露是否超出最大允许泄露限度,从而防止液体和微生物侵入。采用真空模式和激光顶空分析模式的示踪气测试方法就是两个典型例子。这两种方法都显示出足够的灵敏度来定量分析最小的泄露,而这些最小泄露存在最小几率让液体或微生物侵入硬质包装。这些测试还证明对于阐述以下数者的关联性上有所助益,具体指包装设计、组件安装、包装组装测试、泄漏速率、甚至是避免包装瑕疵之间的关联性。


Leak testing of product-filled packages during later product-life-cycle phases often requires other tests. Leak test methods available for this phase of the product life cycle are able to be validated to reliably detect defects a few micrometers and larger. Examples of such physicochemical leak tests include vacuum or pressure-decay tests, mass extraction methods, electrical con- ductivity and capacitance tests, and liquid tracer tests.

已填充的包装产品之后生命周期阶段的泄露测试经常要求其他检测。适用于此阶段的泄露测试方法应能被验证可用于测试几微米和更大的泄露。这种理化泄露测试方法例子包括真空或压力衰减测试,质量提取测试,高压放电测试,还有液体示踪测试。


3.4.2 STERILITY, PRODUCT FORMULATION CONTENT, AND GAS HEADSPACE CONTENT MUST BE PRESERVED

无菌性、产品组份含量和顶空气都必须保持的类型


For this product quality category, leak test options include those that directly check for package headspace pressure and/or content, such as laser-based gas headspace analysis techniques. The detection limit for such methods is a function of the methods ability to accurately measure package headspace content or absolute pressure at the product acceptance limit, given the package headspace volume and the time lapse after package assembly. Such methods have broad application throughout the product life cycle.

对于此类产品的泄露测试优选方法,包括那些直接测试包装顶空压力和/或含量的方法,比如激光顶空分析技术。即便是包装顶空体积伴随着时间流逝而衰减,这些方法的检测限也意味着方法在接受限度水平,仍然可以准确测量顶空气体含量或顶空绝对压力。这些方法在产品生命周期内有广泛应用。


3.4.3 STERILITY MUST BE PRESERVED; PRODUCT ACCESS IS REQUIRED

要求维持无菌且接触产品的类型


The product quality subcategory relates to the additional integrity requirement for those products that are contained in multiple-dose packages once the product is accessed by the end user. As discussed in Package Integrity Evaluation—Sterile Products <1207>, Product–Package Quality Requirements and the Maximum Allowable Leakage Limit, Sterility Must Be Preserved; Product Access is Required, physicochemical as well as microbiological test methods designed to characterize and verify the unique barrier properties specific for the given container–closure system and its end-use application may be required (2) Elastomeric closures of multiple-dose parenteral products are meant to reseal, limiting microbial ingress and product leakage during and between product access via needle puncture. The test in Elastomeric Closures for Injection <381>, Functionality Tests, Self-Sealing Capacity is a blue dye liquid tracer test intended to screen closures for their ability to prevent gross liquid leakage post puncture. Caution is advised when solely relying on this test to prove a given closures ability to reseal. Other test method(s) may need to be designed and implemented that more fully characterize the closures leak prevention capabilities for the given product–package system and product end-use application.

这类产品使用多次给药包装,如此分类是因为一旦进入患者体内后,存在额外的密封性要求。如“无菌产品包装密封性评估”<1207>中 “需保持无菌且进入产品”部分所讨论,这类包装可能会被要求提供理化和微生物检测方法,来表征和确认其特殊的屏障特性,这些屏障特性用于保护最终包装密封系统,也用于保护终端患者。用于多次给药包装的橡胶塞的作用在于复闭包装,以限制针头刺入和药物进入过程中微生物的侵入和药液的泄露。“注射剂用橡胶塞的检测”<381>,自封闭能力采用蓝色示踪液检测模式,此功能性测试用于检查封闭系统在针刺后阻止泄露的能力。当仅依靠此方法证明给定的封闭系统的复闭能力的时候要特别谨慎,也许还需要设计和执行其他方法,更充分的表征封闭系统防止给定包装产品泄露的能力,和表征该产品在使用中途防止泄露的能力。


3.5 Deterministic or Probabilistic Methods

确定的方法和概率性方法


A “deterministic leak test method” is one in which the leakage event is based on phenomena that follow a predictable chain of events, and leakage is measured using physicochemical technologies that are readily controlled and monitored, yielding objective quantitative data. Most deterministic leak test methods rely on the predictable movement of gas that inevitably occurs through an open leak path, given specific differential pressure and/or partial pressure test conditions (e.g., tracer gas, laser- based gas headspace analysis, pressure decay, vacuum decay, and mass extraction). The electrical conductivity and capacitance test is a deterministic leak test approach that relies on the more predictable presence of liquid near a leak path, rather than the less predictable movement of liquid through a leak. Deterministic methods are characterized as being capable of reproducibly detecting leaks at clearly defined and predictable detection limits. Because the majority of deterministic leak test methods described in this chapter require no special test sample preparation, sample preparation error is eliminated.

一个确定的泄露测试方法基于一个可预见的事件链条产生了泄露现象,这个泄露可以采用可控和可监测的理化技术进行检查,从而获取定量数据。大多确定性方法依赖于给定压差和/或部分压力测试条件下(比如示踪气、激光顶空分析、压力衰减、真空衰减和质量提取),气体在泄露通道内不可避免会发生的可预见性运动。高压放电法测试就是一种确定性测试,依赖于液体在漏洞附近的可预见性运动,而不是可预见性偏弱的通过漏洞的运动。确定性方法的特点在于:可以在明确规定和可推算的检测限水平来检测泄露,并且具有可重现性。由于本章节大部分确定性测试方法不需要特别的样品制备过程,样品制备导致的错误也可以被消除。


A “probabilistic leak test method” is stochastic in nature in that it relies on a series of sequential and/or simultaneous events each associated with uncertainties, yielding random outcomes described by probability distributions. Thus, the findings are associated with uncertainties that necessitate larger sample sizes and rigorous test condition controls to obtain meaningful results. Typically, sample size and test condition rigor are inversely related to leak size. Therefore probabilistic leak test methods are more challenging to design, develop, validate, and implement, especially when used to find leaks near the upper and lower limits of the test methods detection range. Probabilistic methods include microbial challenge tests, as well as some physico-chemical tests. These methods include bubble emission tests, tracer liquid tests (employing either qualitative or quantitative measurement methods), and tracer gas tests by the sniffer probe approach.

概率性泄露测试具有随机属性,因为是基于一系列含有一定不确定性的关联事件来实现,从而获取基于概率分布的随机结果。如此,所获取的结果具有不确定性,从而要求更大的样品量和严格的测试条件以获得有意义的结果。通常的,样品量和测试条件的严苛程度和漏洞的尺寸成反比。故而概率性测试方法更不易于设计、开发、验证和实施,尤其是当检测测试范围上下限附近的泄露时。概率性测试方法包括微生物侵入测试,和其他一些理化测试方法。这些理化方法包括发泡试验、示踪液测试(定性或定量)和嗅气探针模式的示踪气测试。


A deterministic leak test method having the ability to detect leaks at the products maximum allowable leakage limit is preferred when establishing the inherent integrity of a container–closure system. Deterministic methods may also be chosen if test sample quantities are limited, when checking for rarely occurring leaks of concern and/or when the potential risk for failing to find leaks of a given size or type is too great. Probabilistic methods are best chosen when the method outcome requirements demand a specific probabilistic testing approach. Probabilistic tests are further discussed in Method Outcome and Quantitative or Qualitative Methods of Analysis below.

当开发包装封闭系统内在密封完整性时,应优选可以在产品最大允许泄露限度水平探测漏洞的确定性测试方法;样品量有限也优选确定性测试方法;当检测的泄露类型极少发生,或发现特定尺寸特定类型泄露的失败几率很大时,同样优选确定性测试方法。当测试结果需要进行概率学检查时,则优选概率性测试方法。概率性测试在下文“测试输出及定性与定量方法分析”部分会进一步讨论。


3.6 Physicochemical or Microbiological Methods

理化或微生物方法


“Physico-chemical leak test methods” are those that use physical and/or chemical analysis techniques to test for package integrity. Physicochemical methods include both deterministic and probabilistic leak test methods. “Microbiological leak test methods” are probabilistic methods of analysis that use viable microorganisms to evaluate test sample integrity. This chapter includes the microbial challenge test by immersion exposure.

理化泄露测试方法采用物理和/或化学分析技术测试包装密封性。理化方法包括确定性和概率性泄露测试。微生物泄露测试方法属于概率性分析技术,该法采用活性微生物评价测试样品的密封性。本章描述了微生物浸入式挑战试验。


The following section includes additional information on the test method outcome criterion that is related to the microbiological challenge test method.

以下章节包括和微生物挑战性试验测试结果相关的额外信息。


3.7 Method Outcome

测试结果输出


The outcome(s) sought from leak test results will often drive the test method choice. These desired outcomes may include:

  • Leak path presence of detection

  • Leak path location determination

  • Leakage rate measurement

  • Liquid egress/ingress potential

  • Microbial ingress potential

从泄露测试结果中获取的结论经常会决定方法的选择。测试结果输出包括以下内容:

  • 漏洞是否存在

  • 漏洞位置的确认

  • 泄露速率的测量

  • 液体出入量

  • 微生物侵入量


All leak test methods are meant to identify the leak path presence. Often, leak tests are able to provide additional outcome information. Methods that also provide evidence of leak path location include electrical conductivity and capacitance tests, bubble emission tests, tracer gas sniffer probe tests, and some tracer liquid tests. Methods that provide a measure of whole- package leakage rate include laser-based gas headspace analysis, mass extraction, pressure and vacuum decay methods, and tracer gas tests by the vacuum mode.

所有泄露测试是为了识别所存在的漏洞,泄露经常还可以提供额外的信息。可以提供泄露点证据的测试,包括高压放电法、发泡法、示踪气嗅针测试和一些示踪液测试方法;可以测试包装总泄漏速率的方法则包括激光顶空分析、质量提取、压力衰减和顶空衰减方法,还有真空模式的示踪气测试。


Microbial challenge tests provide information on the degree of protection afforded by the product–package against microbial ingress that occurs via active growth or motility through leak pathways and/or by liquid carrier passive transport through leak pathways. Microbiological challenge tests help to clarify the risks to product sterility posed by specific package materials, package designs, or potential package barrier breaches. Sterility risks linked to particular environmental exposure or product use conditions may also demand a microbiological challenge methodology. In summary, all leak test methods at minimum detect leaks; some methods may provide more information, but no single method alone can yield all four outcomes listed above.

微生物挑战性试验提供了包装产品防止微生物侵入能力的信息,方式是测试包装产品阻止微生物以生长繁殖或主动通过漏洞的能力,和/或带菌液被动通过漏洞的能力。当产品暴露在在特定包装材料、包装设计,或潜在的包装屏障缺口下,微生物挑战性试验有利于澄清产品仍然可以维持无菌属性的潜在风险。特定的暴露环境或产品使用条件带来的风险,客观上可能也要求采用微生物挑战性试验。总而言之,对于所有的测试方法在其自身检测限水平而言,其中一些方法可能可以提供更多的信息,但是没有哪个单一方法可以提供以上所有五个方面的信息。


3.8 Quantitative or Qualitative Methods of Analysis

定量或定性测试


The measure of analysis can play a part in leak test method ion. In other words, does the method yield quantitative data that allow for objective analysis, or are the data strictly qualitative and require more subjective interpretation? Leak test methods that use a “quantitative measure of analysis” include electrical conductivity and capacitance tests, laser-based gas headspace analysis, mass extraction, pressure and vacuum decay, tracer gas tests (especially when testing via the vacuum mode), and tracer liquid tests that use quantitative analysis (e.g., spectrophotometric analysis).

检测手段可以影响到分析方法的选择。换句话,方法是否产生可以用于客观分析的定量数据?数据是否严格定量,又是否需要更多主观演绎?采用定量测量的泄露检测方法包括高压放电法测试,激光顶空测试、质量提取、压力和真空衰减、示踪气测试(特别是真空模式)和示踪液定量测试(比如用到光谱分析)。


Conversely, a “qualitative measure of analysis” is based on subjective observation of a specific quality, attribute, or characteristic of the test sample, e.g., a visual check for turbidity when evaluating microbial challenge test samples. Bubble emission tests that report visible evidence of continuous bubbling, and tracer liquid tests that rely on visible evidence of dye migration are other examples of subjective and qualitative analysis. Because qualitative measurement results are subject to interpretation, they may be prone to human error. When method considerations permit, leak test methods that yield quantitative measurements are preferred.

反之,定性测试方法基于对测试样品特定质量属性、分布或表征进行的主观观察。比如,微生物挑战性试验过程中目测浊度。发泡测试报告目测持续起泡的结果,和示踪液测试中报告染色液的迁移也是一些主观的定性检测的例子。由于定性测试依赖于主观演绎,就可能导致人员误差。当方法许可时,还是优先考虑可以产生定量数据的泄露测试方法。


3.9 Leak Test Detection Limit

泄露测试的检测限


The detection limit of a leak test is the smallest leakage rate or leak size that the method can reliably detect, given the product–package of interest. A large variety of measurement units are used to describe leakage rates and leak sizes when specifying the detection limits (and detection ranges of leak test methods. This often leads to confusion when comparing the performance claims of various instrument manufacturers or examining test results generated by multiple methods.

泄露测试的检测限是方法对于给定包装产品,可确信测试到的最小泄漏速率或漏洞尺寸。当定义检测限(和泄露方法的检测范围)时,可以有一大系列的计量单位用于描述泄漏速率和泄露尺寸。这点也经常导致混乱,特别是当比较不同仪器厂家的测试能力,或不同方法的测试结果时。


To address this, Table 1 presents the relationship between orifice size (assuming a perfect hole of negligible length) and the rate at which dry air would pass through such a hole when exposed to 1 atmosphere (atm) differential pressure at a specified temperature.

解决此问题,表1展示了洞口尺寸(假定是一个规则漏洞,忽略长度)和干燥气体透过速率的关系(1个大气压,指定温度)。


These leakage rates and leak sizes are theoretical approximations and are not definitive.

这些泄漏率和漏洞尺寸理论上是大致相当,而非绝对。


Table 1 services two purposes. First, it is meant to help the reader better grasp the relationship between theoretical hole diameter and the gas leakage rate. Second, it provides a common measurement scale that can be referred to later in this chapter to more simply state leak detection limits for the various technologies described. For example, test technology X found in published studies to detect leaks as small as about 8 um would be referred to in <1207.2> as having an approximate leak detection limit of row 4 in Table 1.

表1基于两个目的。其一,帮助读者更好把握理论洞口直径和气体泄漏速率之间的关系。其二,提供了一个普遍的测量度量,在本章节中可以更简便的定义不同测试技术的泄露检测限。比如,在发表的研究中声明可以用于测试小到8um的漏洞的X方法,可以在USP<1207.2>表1第四行对应一个近似的检测限值。


Leak detection limit should not be the only or perhaps even the primary basis for choosing a test method. Often, the best method for a given application is dictated by other factors. For example, a tracer gas leak test method having an extremely small leakage rate detection limit may be the proper choice for establishing the inherent package integrity of a stoppered glass vial as a function of capping machine parameters during package development. Yet this method would be an inappropriate choice for rapid on-line testing in routine manufacturing. Instead, an electrical conductivity and capacitance test with a larger leak detection limit, able to test product-filled packages at on-line speeds, may be the best option. Refer to Detection Limit for a discussion on how to determine the limit of detection.

漏洞检测限不应是选择测试方法唯一的,或首要的考虑点。针对特定应用的最佳检测方法通常由其他因素决定。比如,一种示踪气泄露测试方法有极小的泄漏率探测限度,在包装开发过程中确认压盖机参数时,这种方法可能适合于建立加塞玻璃西林瓶内在密封性的测试方法。但是,这种方法在快速的流水生产线上进行在线监控,可能是不合适的选择。对于这种情况,检测限偏大的高压放电法测试则可能是最佳的替代性选择,此方法可以流水线速度测试已灌装的包装产品。参阅“检测限”中关于如何测试检测限。 


a) This table is not intended for ranking test methods but is offered as an aid forexpressing test method leak detection capabilities in this chapter.

a) 本表不用于对不同的测试方法进行排序,而用于帮助表达本章节中不同方法泄露检测的能力

b) Dry air leakage rate measured at 1 atm differentialpressure across an orifice leak (i.e., leak inlet pressure of 1 atm versusoutlet pressure of approximately 1 Torr) at 25°. The theoretical correlationsof orifice sizes to air leakage rates were provided by Lenox Laser, Glen Arm,MD. Leakage rates are approximation ranges.

b) 一个大气压(比如,漏洞入口1大气压,出口压力1托,约1/1000的一大气压),25度条件下,干燥空气通过漏洞的泄露速率。此相关性由Lenox Laser, Glen Arm, MD.在“泄露速率为近似范围”一文中报道。

c) Nominal diameter orifice sizesassume a leak path of negligible length. Orifice sizes are approximationranges.

c) 漏洞标称直径假定长度忽略不计。洞口尺寸是近似的范围


3.10 Leak Test Method Range

泄露测试范围


Leak test method range is the interval between the smallest and largest leak size (or leakage rate) that can be detected by a given leak test method with a suitable level of accuracy and precision. All leak test methods have an optimum detection range. Therefore, it is possible that additional tests may be needed to catch those leaks of concern that fall outside the chosen leak       test methods detection range. For example, a test method able to find the smallest leaks may miss gross leakage such as a missing package component. Vision systems that check for major package defects such as a missing package component or apackage crack may be required. Finally, before using a test method to check for large leaks, the impact of gross defects on leak   test instrumentation should be considered; some instruments may malfunction or become damaged upon exposure to a leaking product or damaged packages. Refer to Range for additional detection range information.

泄露测试范围涵盖最小和最大的漏洞检测尺寸(或泄露速率),并且可以保证适当的准确度和精密度水平。所有泄露测试方法有其最适宜的测试范围。但是,可能需要考虑采取其他的方法来检测不在该范围的泄露。比如,可以发现最小泄露的某个方法可能遗漏总的泄露速率,如确实单一部件导致的泄露。这时,检测大的包装缺陷或包装碎片的视觉系统可能被用到。最后,在采用检测大的泄露的方法之前,应考虑总的泄露对检测仪器的影响;有些仪器暴露在泄露产品或破损包装面前时,可能故障或损坏。参阅“范围”部分了解其他的检测范围信息。


3.11 Nondestructive or Destructive Methods

非破坏性或破坏性方法


The need to preserve the test product–packages may influence the decision to a nondestructive leak test method, rather than a destructive one. Destructive test methods damage the test sample and/or expose it to potential contaminants; hence, the product is not recoverable. Only nondestructive test methods are appropriate for leak testing product–package  units earmarked for commercial or clinical study distribution.

保护包装产品的考虑可能影响到最终决定,从而倾向采用非破坏性,而不是破坏性的检测方法。破坏性的检测方法会损坏测试样品,和/或将其暴露在潜在的污染环境下。进而,产品无法复原。只有非破坏性的测试方法,针对指定用于商业或临床研究的包装产品进行泄露测试是合适的。


Examples of destructive leak test methods include tracer liquid ingress tests, bubble emission tests, and microbiological challenge tests. Tracer gas and pressure decay leak tests are considered destructive if they require that the package barrier be compromised in order to introduce tracer or pressurizing gas into the assembled package. Examples of nondestructive leak test methods include mass extraction and vacuum decay leak tests, as well as noninvasive gas headspace analysis tests. Electrical conductivity and capacitance leak tests are deemed nondestructive if it can be shown that electrical current exposure causes no harm to the product; in rare instances, exposure has triggered headspace ozone formation, causing product oxidation (3).

破坏性测试的例子包括示踪液侵入试验、发泡试验和微生物挑战性试验。如果需要包装屏障潜在受损以引入示踪物或压力气体进入组装包装,那么示踪气和压力衰减测试也被认为是破坏性的。非破坏性的泄露测试方法包括质量提取法和真空衰减泄露测试,以及非侵入性的顶空气体测试。如果能显示高压电流对产品未带来损伤,那么高压放电法泄露测试也被认为是非破坏性的。有极少的例子,暴露释放了顶空臭氧成分,会导致产品氧化。


3.12 Off-Line or On-Line Methods

在线或离线测试


Off-line leak testing is generally performed on a stratified random sampling of the product lot, away from the manufacturing line. Off-line package evaluation allows for the use of any validated nondestructive or destructive leak test and seal quality test option compatible with the product–package. Off-line testing can accommodate slower test cycle times; for methods in which test time is a performance factor, a slower off-line test is often more sensitive than its on-line counterpart. Off-line tests typically are less costly to perform as they utilize bench-top or smaller scale equipment without the sophisticated product-handling machinery required to support higher speed on-line processes.

离线泄露测试通常远离生产线,通过在批产品中分段随机取样来实现。离线包装评估允许使用最适用于包装产品的,任何经验证的非破坏性或破坏性泄露测试方法,以及密封效果测试方法。离线测试一般使用台式仪器或更小的设备,而不需要像在线测试那样依赖精密复杂的产品抓取机器来支持流水作业,因而花费少。


On-line leak testing is commonly integrated into a continuous fill and seal product–package manufacturing process. A pre- requisite for an on-line leak test method for entire lot testing is that it be nondestructive to the package and its contents. On-line testing can potentially provide greater assurance that all packages have integrity and can yield instant feedback in the event of package misassembly or breakage, enabling real-time line corrections.  For  some  test  systems,  incorporating large- scale leak detection equipment into a complex high-speed product–package filling and assembly line can be prohibitive. Higher line speeds leading to shorter leak detection test cycle times can limit test method detection capability. In addition, the impact of instrument downtime on the production run as a result of leaking packages or possible equipment malfunction is an important consideration. A separate leak testing line may be set up outside the sterile manufacturing suite to allow for full lot testing without the complications of leak test integration with package filling/sealing operations. A few examples of on-line leak test technologies include electrical conductivity and capacitance, vacuum decay leak, and noninvasive laser-based gas headspace analysis tests.

在线泄露测试一般接入产品的持续灌装和封口包装生产线。在线测试方法的一个前提条件就是对包装和内容物不具有破坏性。在线测试可以更好保证所有包装都具有密封性,并且存在错装或破损时,可以提供即时的结果反馈,从而实现即时纠正。对于一些测试系统,将体量较大的泄露测试设备融入复杂的告诉灌装包装线并不现实。更高的线速度导致更短的泄露测试循环时间,从而限制了测试方法的检测效能。另外,包装泄露可能导致生产线设备停运或可能的设备损坏,这种影响也需要重点考虑。不过,分隔的泄露测试流水线也可以考虑在无菌生产区外建立,从而实现整批测试而无需和复杂的灌装包装操作在一起进行。在线泄露测试技术的例子包括高压放电法测试、真空衰减测试,还有非侵入性激光顶空测试。


待续:

分析仪器确认,方法开发和方法验证 (3之3)


来源:洛施德GMP咨询

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