FDA发布容器密封系统（CCS）指南草案，文章摘译其中无菌制剂相关内容

FDA于今年8月份颁布了关于CCS（容器密封系统）的指南文件”Container Closure Systems for Human Drugs and Biological Products (draft, 2026)”，虽然只是草稿版（现行版为1999版），但是可以借此观察FDA目前对于CCS的最新认识。本文分享该指南中和无菌制剂相关的部分内容。

Container closure system: The sum of packaging components and materials that together contain and protect the article. This includes primary packaging components, and it includes secondary packaging componentswhen they are required to provide additional protection. CCS包括初级包装材料和次级包装材料。

Extractables: Organic and inorganic chemical entities that can be released from a pharmaceutical packaging or delivery system, packaging component, or packaging material of construction and into an extraction solvent under laboratory conditions.可提取物指的是包材通过萃取溶剂释放出来的有机物和无机物。

Leachables: Foreign organic and inorganic chemical entities that are present in a packaged drug product because they have leached into the packaged drug product from a packaging or delivery system, packaging component, or packaging material of construction under normal conditions of storage and use or during accelerated drug product stability studies.浸出物指的是包材和药液直接接触（药品常规储存条件下，加速稳定性研究条件下）后所释放出来的有机物和无机物。

A CCS is the sum of packaging components that together contain and protect a drug. It includes the primary packaging components, and it also includes the secondary packaging components if their purpose is to further protect the drug.如果次级包装组件也用于保护产品，则也属于本指南的范围内。A CCS must provide adequate protection in storage and use without altering the safety, identity, strength, quality, or purity of the drug beyond the official or established requirements. For example, packaging components should be constructed of materials that will not leach harmful or undesirable amounts of substances to which patients could be exposed directly or indirectly.

Examples of CCSs that may also be a device constituent part of a combination product include piston syringes, pumps, metered dose inhalers (MDIs), and intravenous bags. Combination products raise additional premarket review considerations relating, for example, to performance of the device, engineering, and user interface, all of which may be affected by interactions (e.g., adsorption) between the device and drug or biological product it holds. 活塞注射器、泵、计量吸入器、输液袋等，都属于组合产品的一部分，属于CCS的范畴。

A suitable framework for evaluating the quality of a CCS should use a risk management process. The process should begin with an assessment of the CCS used for a specific drug, including the CCS’s selected MOC材质, the drug’s manufacturing processes, and the drug’s clinical use. The potential risks associated with the CCS should be adequately identified and characterized based on these assessments. For example, interactions between drugs and packaging materials could produce leachables that cause unintended chemical toxicity. Or, these leachables could cause undesirable changes in the drug’s quality (e.g., reduced stability, variations in the impurity profile, increased particulate matter, altered antigenicity) that result in an unacceptable alteration of the drug’s intended therapeutic effects.药液和包材之间接触可能产生浸出物，可能会影响药品的储存稳定性、杂质谱、颗粒增多、改变抗原结合性等。The qualification and quality control of packaging components should include mitigation strategies that address knowledge gaps and risks identified through testing and other evaluations.

The primary CCS is the most likely source of leachables because the packaging components are in direct contact with the drug, but leachables can also come from secondary CCSs (e.g., protective packaging, inks, labels, adhesives) and from manufacturing equipment used in drug production. 内包材产生浸出物的风险最大，次级包装也有可能产生浸出物的风险。Assessments of safety- and compatibility-related risks should be relevant to the drug’s intended use (e.g., route of administration, delivery mechanism) and the dosage form (e.g., solid- or liquid-based).安全或兼容性相关的风险应基于药品的预期用途（例如给药途径、递送机制）、剂型（固体制剂、液体制剂）。

A CCS must protect against ingress from external contaminants and should prevent leakage. A CCS must also protect against external factors that can cause deterioration or contamination of the drug product, such as exposure to light, loss of solvent, physical stress during transportation and storage, exposure to reactive gases(e.g., oxygen), absorption of water vapor, and ingress of microbial contaminants. 容器密封系统应能保护产品免受外界因素的影响，比如避光、漏液、运输过程中被挤压、被氧化、吸潮、微生物污染等。

A CCS can have functional features in addition to containing and protecting drugs. For example, for a multiple-dose product, the elastomeric closures of the CCS are pierced穿刺multiple times; it is important to evaluate the performance of the closure during the piercing process. Specifically, the functional parameters that include penetrability, fragmentation, and self-sealing efficiency should be evaluated.对于多剂量的注射剂产品，因多次抽取药液导致胶塞会被多次刺入，所以应评估多次穿刺对于胶塞性能的影响，包括穿刺力、穿刺落屑、自密封性。A CCS that performs drug delivery should deliver the drug to the intended delivery site in the amount and rate described in the drug labeling. As appropriate, data should be provided to demonstrate that the CCS operates as designed. Integrity failures in primary packaging components could cause dimensional incompatibility among the packaging components (e.g., closures with imperfect seals, plunger-syringe incompatibility, variation in dimensional parameters between stopper and container neck). These incompatibilities can further affect CCS performance.胶塞和瓶子的尺寸搭配问题直接影响密封完整性。

The risk assessment should include an evaluation of any potential effects of direct or indirect treatment (e.g., washing, coating, lyophilization, sterilization) of the CCS during the drug manufacturing process. 在药品生产过程中，应关注内包材的处理方式（如清洗、涂层、冻干、灭菌）对CCS的影响。The compatibility of a CCS with a given treatment (a pre- or post-processing method) should be evaluated to ensure that these processes will not adversely affect the CCS’s suitability, compatibility, or functionality. Terminal sterilization and depyrogenation processes that employ high heat, irradiation, or exposure to reactive gases (e.g., ethylene oxide, vaporized hydrogen peroxide) could negatively affect the CCS’s quality.高温、辐照、反应性气体（环氧乙烷、过氧化氢）等都可能对CCS产生负面影响。For example, these processes could cause glass to delaminate, which could result in particulate matter in the drug product, and insufficient aeration during sterilization by vapor hydrogen peroxide or ethylene oxide, which could cause leaching of harmful chemicals from the packaging components to the drug.这些条件可能会导致玻璃表面分层，从而产生可见异物；内包材的VHP灭菌或环氧乙烷灭菌可能产生浸出物风险。

The risk assessment should account for the product’s intended storage and handling conditions to ensure that the CCS can maintain integrity and functional performance. For example, if the final product is stored at very low temperatures (e.g., frozen temperature of -20°C or cryotemperature of less than -160°C), the integrity and functionality of a CCS should be assessed after storage under worst-case conditions. One way to conduct this type of assessment is to use freeze-thaw cycles or thermal cycling to simulate the storage and handling of the product.对于产品在很低的温度下储存时，应评估低温条件对于CCS的完整性、功能性的影响。

Examples of Packaging Concerns for Common Dosage Forms of Drug Products:

评估围绕给药途径和药液和材质的相容性，吸入剂的风险相对最高，口服制剂风险最低，注射剂相较于口服、贴剂等更高，水针注射剂比冻干注射剂的相容性风险更高。

There are many routes for administration of injectable drug products (e.g., subcutaneous皮下注射, intramuscular肌肉注射, intravenous静脉注射). Injectable drug products may be liquids in the form of solutions, emulsions, or suspensions, or they may be dry solids that are to be combined with an appropriate vehicle to yield a solution or suspension. These products typically have a medium risk of interactions between packaging components and the drug product. However, the risk can be elevated for certain injectable products if the excipients used in the drug product promote the leaching of chemicals from the CCS. 注射剂的药液和包材材质的相容性风险通常是中风险，但假如某些辅料和包材材质接触后容易提高浸出物水平，则风险较高。Injectable products that contain organic solvents (e.g., ethanol or dimethyl sulfoxide in a depot injection drug product长效注射剂) in their formulations have high potential to interact with their packaging materials. 对于一些注射剂的配方中有有机溶剂的，则相容性的风险较高。Drug products administered by the intravenous route are 100% bioavailable; therefore, any leachables in the product would be administered with the intended dosage form and have wide access to organs and tissues. Similar concerns exist for leachables in drug products administered by the subcutaneous and intramuscular routes, given the potential for significant exposure to organs and tissues. For injectable products that are delivered into specific tissues (e.g., ocular眼用, perineural神经, intra-articular关节腔), local tissue toxicity should be considered in the safety evaluation. 一些用于特定组织的注射剂，需要关注对于局部组织毒性的影响。Drug products intended for administration into uniquely vulnerable tissues, such as the central nervous system中枢神经系统 or the intrathecal/epidural space鞘内/硬膜外腔, generally represent the highest level of toxicological concerns for leachables because these tissues have limited or no ability to recover from toxicity.一些比较脆弱的组织部位的注射用药物，其对于浸出物风险的控制最为严格。

The risk of interactions between packaging components and the drug product is generally lower for powder for injection than it is for liquid-based products (e.g., solutions) because interaction between the powder and the primary CCS is minimal. However, some risk factors may enhance the potential for interactions between the product and the primary CCS and lead to elevated levels of leachables. For example, an elastomeric stopper may interact with the organic solventvapor during the lyophilization process, or it may interact with the organic solvent present in the reconstituted solution. 通常冻干制剂和包材材质的相容性风险较低，但是对于辅料中含有有机溶剂时，弹性体胶塞与冻干过程中蒸发的有机溶剂接触，或与复溶后的药液接触，会增加浸出物的风险。

The overall quality evaluation of a CCS, including a variety of tests and assessments, should employ appropriate risk-based approaches. CCS的选择和质量控制等应基于风险评估。Procedures regarding the receipt, identification, storage, handling, sampling, testing (e.g., methods and analytical reference standards, acceptance criteria or specifications, and validation information for studies and evaluations), and approval or rejection of components and drug product containers and closures must be written and followed for a drug product’s CCS.应书面规定CCS的来料接收、鉴别、储存、处理、取样、检测、放行/拒绝等。 For containers of drug substances, FDA recommends the analytical test methods and criteria for accepting and releasing each packaging component also be written and followed. 对于原料（API/DS）储存的容器，FDA推荐有书面的文件规定其检测与放行。

Tests and evaluation methods for CCS quality assessments and controls should be selected based on the identified risks and potential methods of mitigating these risks. Table 2 provides an overview of the typical quality assessments for qualification and quality control of CCSs for different classes of drug products, including packaging components. The following sections describe these assessments in greater detail.

The MOC (e.g., plastics, paper, metal, glass, elastomers, coatings, adhesives) identified by a specific product designation and source (name of the manufacturer). Alternate MOC should also be identified.Postconsumer recycled plastic should not be used in the manufacture of a primary packaging component. If it is used for a secondary packaging component, then the safety and compatibility of the material for its intended use should be addressed appropriately.消费后再生的塑料不可以用于初级包装的生产，如果用于次级包装的生产，应基于其用途评估安全性和相容性。

CCIT is used to evaluate CCS integrity to ensure the product is protected from ingress of environmental factors. For sterile products, CCIT is used:

• To demonstrate that the CCS selected is suitable to provide an adequate sterile barrier;

• To validate related manufacturing parameters (e.g., capping parameters) for the selected CCS and as an in-process test for appropriate CCS closure; 用于验证生产工艺参数（比如轧盖工艺参数）、中控检测。

• To demonstrate that the CCS maintains its integrity at the labeled storage conditions over expiry ensuring protection of the product quality and sterility, if applicable. 用于证明药品在货架期内能够保证CCS密封完整性。

The selected method for CCIT should include method validation for the specific CCSs, sensitivity information, and negative and positive controls. Factors to consider when selecting a method for evaluating the container’s integrity include the suitability of the method for the type of CCS, the intended use of the CCS, the sensitivity of the test method, and the storage conditions of the drug product. Worst-case conditions should be considered and represented when selecting an appropriate CCIT method. In some instances, the CCS’s seal integrity can be transiently compromised at extreme storage conditions or during shipping and handling, which could affect product quality and safety. For example, rubber stoppers can lose their elastic properties at extreme low temperatures, and this transient loss in seal integrity can lead to overpressure in the container caused by accumulation of ingressed gas during storage.产品在完成密封后，如果在很低的温度下储存时，其弹性会短暂降低，从而可能影响CCI，外界气体可能会进入容器内。The ingressed gas can then become trapped when the elastomers reseal after being removed from the extreme temperature. 当胶塞离开超低温环境时，又会恢复弹性，困住进入的气体。This transient loss of integrity would not be captured when the CCIT is conducted after the container is removed from the extreme conditions. 如果不是在超低温存储时检测CCI，就不能识别该风险了。Therefore, a test method that can be performed at extreme temperature conditions (e.g., freezing) should be considered.

对于无菌制剂常用的西林瓶（vial）和预充针（PFS），CCIT的方法：

氦气泄露测试（Henlium leak testing）、压力/真空衰减测试(Pressure and/or vacuum decay)、色水法（Dye ingress，属于破坏性方法）、质量抽取测试（Mass extraction test，测量从包装容器中经泄露通道被“抽出”的气体质量或流量）。

All sterile products must be tested to verify the maintenance of sterility over the drug product’s shelf life. Because of the limitations of sterility testing, the Agency encourages performing CCIT in lieu of sterility testing as a component of a stability program to ensure that containers are able to maintain sterility throughout the drug product’s shelf life. 对于药品的稳定性研究，应在货架期末检测CCI，以证明CCS在药品的生命周期内具有保持产品无菌的能力。

In general, leachables studies are performed throughout the shelf life of a drug product. These studies are conducted under specified storage conditions as part of formal stability studies in which multiple batches (e.g., three batches) of the drug product are tested at multiple time points under both accelerated and long-term stability conditions, as well as intermediate conditions when appropriate. 浸出物研究在药品特定的储存条件下进行，一般选择三批产品，加速＆长期条件。A justification should be provided for selections of batches other than the formal stability batches or if fewer than three batches are selected. 如果选择的批次数低于三批，应有合理解释。The CCS (including secondary components such as labels, adhesives, over-pouches, wraps, and cartons) used in leachables studies should be representative of the future commercial product. 浸出物研究的批次，其二级包装材料（如标签、粘合剂、外袋、包裹材料、纸盒）应能够代表未来的商业化包装。The analytical methods used for leachables studies are typically the same as, or similar to, those used for the extractables studies and should be properly validated. 通常浸出物研究的分析方法与可提取物研究的分析方法一致或类似。A correlationbetween extractables and leachables could be established when sufficient extractables and leachables data from the same CCS are generated. 有充分的可提取物和浸出物数据时，应建立二者之间的相关性。

A toxicological risk assessment of the leachables from a CCS should be provided to support the CCS’s safety for drugs. A toxicological risk assessment addressing general toxicological concerns should be provided for all leachables exceeding the recommended qualification threshold (QT). 对所有超出合格阈值的浸出物都应开展毒理学的风险评估。A toxicological risk assessment should also be provided for any leachables with identified concerns for DNA reactivity or carcinogenicityif they exceed the appropriate threshold of toxicologic concern-based acceptable intake (TTC-based AI). 对于已知的超出合适阈值就会造成DNA损伤性或致癌性的浸出物，应开展毒理学的风险评估。When local tissue toxicity is a primary concern, a concentration-based QT may also be appropriate. The safety concern threshold (SCT) should be based on the TTC-based AI or the QT, whichever is lowest. The analytical evaluation threshold (AET) should be based on the SCT established for a given CCS for a drug. FDA generally recommends the following:

• An SCT of 1.5 mcg/day should be applied for most chronic-use drugs.

• A QT should be applied for general toxicity for all products.

• A QT based on concentration also applies for drugs in which local tissue toxicity is of concern (e.g., ophthalmic, intrathecal, perineural).

• A lower SCT may be recommended if the CCS may contain compounds of specific toxicological concern (e.g., polynuclear aromatic hydrocarbons多环芳烃, nitrosamines亚硝胺).

The toxicological risk assessment should be based on the highest level of confirmed leachables present in the product over the proposed shelf life. Leachables exceeding the AET should be identifiedin a leachables study that is based on the results of extraction studies performed with appropriate extraction solvents. The leachables should be identified and quantified using validated analytical methods. 浸出物研究中识别的超出分析评价阈值的浸出物应进行鉴定和定量，方法应经验验证。

The shipping study of the drug may include evaluating the mechanical protective function of the CCS, which should not have been compromised or otherwise affected during shipping. An integrity evaluation of a CCS should also be considered after shipping sterile drugs. 无菌制剂的运输验证应评估CCI。

Stress testing used in a shipping study ensures that a CCS adequately protects the drug from both environmental stress (e.g., light, reactive gas permeation, moisture permeation) and physical stress(e.g., compression, shock, vibration, change in air pressure, expansion) during transportation and handling. The design may include packaging components that supplement the CCS’s mechanical strength to enhance its protective function. 运输验证涉及的压力测试包括环境压力（光、气体渗透、水汽渗透）和物理压力（压、撞击、震动、气压变化、膨胀）对CCS功能性的影响。Stress testing may include laboratory simulation studies using appropriate test protocols to evaluate the CCS’s protective function. 压力测试包括在实验室模拟进行的研究。The CCS should be able to withstand simulated mechanical stress in order to demonstrate it provides adequate protection for the drug and the accompanying labels during shipping and handling. 运输验证应证明标签在药品运输过程中不会受到影响（比如脱落）。For drugs shipped under cold-chain conditions (e.g., frozen or refrigerated), the shipping containers should be appropriately qualified using temperature recording systems to ensure the intended product temperature is maintained when the CCS is exposed to the worst-case temperature and shipping time expected. 对于冷链运输验证，应考虑环境温度、运输时间这二个最差条件。The qualification of the CCS under specified temperature conditions (e.g., insulated dry ice box or temperature-controlled shipping container) is typically performed using temperature recording instruments as part of shipping validation. When applicable, drug development should include freeze-thaw and thermal cycling studies to demonstrate that drug quality and CCS integrity and functionality can be maintained under temperatures that represent both normal and worst-case transportation, storage, and handling conditions. These studies typically include exposing the drug, while in the intended commercial CCS, to multiple freeze-thaw cycles or thermal cycles. The assessment of CCS integrity and functionality may include the visual inspection of defects(e.g., cracks, breakage, particulates) and CCIT. 药品研发涉及冻融工艺时，在考察药液质量时，也可以同步考察反复冻融过程对CCS完整性和功能性的影响。

次级包装的考量：

Secondary packaging can have an additional protective function, as when it prevents external factors (e.g., moisture, light, microbial contaminants) from reaching the primary CCS, or when it provides added protection for a primary CCS that is flexible or subject to rough handling. 对于初级包装比较柔软或可能被粗暴使用时，次级包装起到保护初级包装的作用。For example, the CCS for inhalation aerosols and inhalation powders may include overwraps or foil pouches as secondary packaging in addition to the inhaler. Secondary packaging components are also used to maintain surface sterility of a primary CCS intended for use in a sterile surgical field. The amount of information needed to demonstrate a secondary packaging’s suitability depends

on the packaging’s purpose. Typically, a brief description of a secondary packaging component is sufficient. If the secondary packaging component is intended to provide additional protection or function beyond container closure (e.g., drug delivery, controlled access to the drug, electronic monitoringof the drug), appropriate assessments should demonstrate that the component provides the additional protection or functions as intended, without adversely interacting with the drug. In such cases, relevant in-process controls should be established with additional testing, including seal integrity testing, stability studies of the drug within the secondary packaging, and in-use stability testing of the drug once the protective secondary packaging is opened, as applicable. 对于一些次级包装的用途是药物递送、限制药物的获取、药物的电子监控的，应评估确认这些次级包装能够实现其功能。这种情况下，应建立相关的过程控制，包括密封性测试、包含次级包装的稳定性研究、次级包装打开后的药品使用过程中的稳定性研究。If the primary CCS is relatively permeable, the drug could be contaminated by the migration of an ink, an adhesive component, or a volatile substance present in the secondary packaging component. 假如初级包装材料具有渗透性，则次级包装中存在的墨水、粘合剂、挥发性物质等可能会对药品造成污染。If the secondary packaging component is a potential source of contamination, the safety of its MOC should be demonstrated.

For a CCS that is also a device constituent part of a combination product, appropriate testing should be performed to demonstrate the device’s function and delivery performance. Evaluations should verify and validate the drug delivery performanceafter shipping, during storage, and in use. For example, pre-filled syringes serve as a delivery device by action of the plunger system; the elastomeric component (i.e., the plunger) must move to empty the container upon demand. Tests of this function (e.g., glide force滑动力, break force启动力) as well as the device’s container closure function (e.g., seal integrity tests), should be provided to help evaluate these systems. 对于预充针这一组合器械的药品，运输验证、储存条件下的稳定性研究、使用期间的稳定性研究均应考察其功能性（例如滑动力、启动力）。

A bulk container may be used to transport bulk drug products for filling, packaging, or repackaging. The bulk container should meet the same requirements for protection, compatibility, and safety as the final or primary CCS during the specified storage time and conditions of the bulk drug products.

eCTD资料中涉及CCS的章节：