| Q1 |
不同產品特性，是否有相對應之完整性測試選擇規定 |
| A1 |
布川 麻里絵回覆:
Most geographies do not have specific guidelines on exactly what needs to be done. But Annex 1 does specify that containers closed by fusion (like glass and plastic ampoules) should be subject to 100% integrity testing. Also, NMPA from China specifies that if the pCCIT method you are using does not have a detection limit comparable to the minimum acceptable leakage limit, then you should also use a mCCIT method and establish the correlation in detection sensitivity between the pCCIT and mCCIT method |
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| Q2 |
是否一定要使用微生物法? |
| A2 |
布川 麻里絵回覆:
In China, according to NMPA, if the physical CCIT method you are using does not have a detection limit comparable to the minimum acceptable leakage limit, then you should also use a mCCIT method and establish the correlation in detection sensitivity between the pCCIT and mCCIT method. Most European and American agencies, like Annex 1 and FDA, do not specify that microbial challenge must be implemented, but it is good practice (and is recommended in documents such as USP1207) and widely done by many pharmaceutical companies. At the end of the day, the root reason for conducting CCIT in the first place is because drug firms are worried about microbials entering the container and resulting in patient safety. That said, microbial CCIT is almost always done during method development phase, not as a high volume production-level inspection method. |
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| Q4 |
如何確保鋁箔包裝之錠劑的密封完整度，以避免藥錠於鋁箔包裝內變質潮解? |
| A4 |
布川 麻里絵回覆:
Vacuum decay is frequently used. |
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| Q5 |
無菌產品在檢驗完整性試驗的有效抽樣檢驗樣品量才具合理性? |
| A5 |
布川 麻里絵回覆:
An exact number is not specified, but documents like Annex 1 do specify that a scientifically valid sampling plan should be realized. In practice, many companies utilize standards such as MIL-STD-105E for its sampling reference during production, or ISO 3951-2:2013, or ASTM E1402-13(2018) Standard Guide for Sampling Design, or WHO Technical Report Series, No. 929, 2005. |
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| Q6 |
CCIT實驗設計和試驗時間需與效期長度一致嗎? |
| A6 |
布川 麻里絵回覆:
Although it is good practice to implement CCIT during the entire lifecycle of the production, in practice, for it is mostly done during method development phase and during (or right after) production of the products (whether that is in-line or off-line). But this does depend on country and regulation. For example, FDA’s Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products Guideline (2008) recommends CCIT be performed in lieu of sterility testing for stability samples every 12 months (annually) until expiry. |
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| Q7 |
向廠商購買之陽性樣品，藥廠是否需要再做入廠驗收測試？ |
| A7 |
Chris Randon回覆:
This depends on the position of the pharmaceutical company and the type of positive control that is purchased. For example, is the positive control 100% non-destructively tested? How is it tested? Is the testing equipment verified to certain standards? If so (and if the positive control provider is reputable in the industry), most firms choose not to retest upon good incoming (due to difficulty in implementing the retest). If incoming inspection is chosen, there are usually two approaches. One is to use in-house vacuum decay or helium leak detect equipment to undergo a rough inspection to confirm flow specifications are in-line with previously received samples. Second is to send out to 3rd parties that would conduct the verification on behalf of the pharmaceutical company. |
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| Q8 |
如何能稱得上合理的陽性樣品，不被質疑漏孔過大。若有經過測漏實驗測試，測漏設備對於此包裝容器，測得的最高靈敏度可以直接作為陽性樣品選擇的孔徑嗎？ |
| A8 |
Chris Randon回覆:
This depends on the geography in which you are filing your application. If it is the FDA, usually it is recommended that the positive control hole size should be less than 20microns. In order to demonstrate detection limit and detection range, a firm seeking to establish a robust dataset, one would opt to use positive controls sized 3μm, 5μm, 10μm, 15μm, 20μm. If you are filing in China, most firms would use positive controls 3μm, 5μm, 10μm (for pCCIT methods that cannot detect under 3μm), and correlate that to mCCIT experiments. If methods that can detect lower than this, some firms would use positive controls with 0.1μm in defect size. |
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| Q9 |
常規分析中，是否每次需要分析陽性樣品? |
| A9 |
Chris Randon回覆:
Depends on the method in use. If probabilistic methods like dye ingress or the bubble emission test is used, generally it is good practice to always utilize positive controls in each batch. However, if the method is deterministic in nature (for example HVLD or vacuum decay), then usually positive controls are utilized during method development and validation. During regular production, positive controls are generally not used on a day to day basis. Positive controls are only re-employed at specified intervals (for example once a month, or once a year, or if there are major changes to the leak test equipment), to re-validate to robustness and accuracy of the equipment. |
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| Q10 |
對於陽性標準品的保存方式和校正期限，是否有建議的規範 |
| A10 |
Chris Randon回覆:
Depends on what type of positive control, but in general, would recommend placing in clean environments without significant temperature and humidity changes over time. The main reason for positive controls being blocked include dust entrance and humidity entrance. The main reasons for positive controls increasing in defect size including continued exposure to temperature changes. |
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| Q11 |
運輸的確效內容要求(需要哪些必要項目）? |
| A11 |
Chris Randon回覆:
In general, regulators expect generating CCI data in transport validation studies. The draft revised EU Annex 1 makes this very explicit: “8.23 The container closure integrity validation should take into consideration any transportation or shipping requirements that may negatively impact the integrity of the container (e.g. by decompression or temperature extremes). |
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| Q12 |
What is the action to be taken for the medical products if their loss of closure on dry ice after shipping was occurred? |
| A12 |
Derek Duncan回覆:
In general, this should be addressed by a risk assessment. What is the risk to the formulation and patient? Was there risk of microbial contamination? Is there risk to the formulation to have the container filled with CO2? In general, it is highly probable that a risk assessment will conclude that there is significant risk to the patient and/or drug product quality if there is a loss of closure on dry ice. |
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| Q13 |
In general, what is the detection limit of headspace analysis (in terms of laser drilled defect size? |
| A13 |
Derek Duncan回覆:
principle, headspace analysis is sensitive to all leak sizes in any positive control configuration (it can even detect permeation). During method development, it should be assessed if a headspace method can be developed that also fits the process (for example, detecting permeation takes time and this should fit the process. |
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| Q14 |
If the defect is below the product fill line, can headspace analysis pick it up? Or does the defect have to be in the headspace area for it to be picked up? (because if defect in liquid area, defect small enough for liquid to not go out, so liquid block defect, maybe no gas leak) |
| A14 |
Derek Duncan回覆:
Yes, it has been demonstrated that by exposing the samples are exposed to an overpressure of a tracer gas, it is possible to use headspace to detect leaks below the fill level. The gas overpressure pushes the gas through the liquid-filled leak defect and the gas goes to the headspace. This should be verified with a method development study.
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