近日，ECA發(fā)布最新版的ECA《無菌產(chǎn)品燈檢指南-2025》，以為制藥行業(yè)中對無菌產(chǎn)品進(jìn)行100%目視檢查的過程提供最佳實(shí)踐建議，核心是規(guī)范人工、半自動及全自動檢查的流程、要求與標(biāo)準(zhǔn)。

文件規(guī)定目視檢查位置的照度應(yīng)至少為2000勒克斯。對于吹灌封產(chǎn)品，建議照度為10000勒克斯。使用CRI指數(shù)，色彩還原度應(yīng)最好具有大于90%的RA值。檢查照度的適當(dāng)間隔至少為每6個月一次。測試點(diǎn)應(yīng)非?？拷僮魅藛T的檢查位置。環(huán)境照度不得干擾工作場所的照度，并且在可能的情況下，應(yīng)在檢查期間調(diào)低。應(yīng)避免反光表面。

文件指出，環(huán)境條件對該操作的質(zhì)量有很大影響。環(huán)境溫度通常應(yīng)為室溫，夏季不應(yīng)超過23°C，除非另有正當(dāng)理由。相對濕度和空氣流速應(yīng)加以控制，以確保舒適的工作條件。噪音水平應(yīng)低于55分貝。

目視檢查人員的確認(rèn)應(yīng)針對每種劑型（例如注射器、小瓶、安瓿）分別進(jìn)行。確認(rèn)過程中待檢查的單元數(shù)量應(yīng)與日常工藝中一次休息到下一次休息期間所檢查的物品數(shù)量一致。在初始確認(rèn)中，應(yīng)識別出所有關(guān)鍵缺陷以及預(yù)先確定的主要缺陷等級。此外，還應(yīng)預(yù)先確定誤判拒收（無缺陷樣品被拒收）的限度（例如，5-10%）。日常再確認(rèn)應(yīng)至少每12個月進(jìn)行一次。

對于人工燈檢，要求每個物品應(yīng)在白色背景下檢查約5秒，在黑色背景下再額外檢查5秒。應(yīng)規(guī)定兩次休息之間連續(xù)檢查活動的最長時(shí)間，以及一個班次/工作日的總最長檢查時(shí)間。行業(yè)慣例是檢查20-60分鐘。當(dāng)前的良好實(shí)踐目標(biāo)是檢查30分鐘后至少休息5分鐘，總持續(xù)時(shí)間目標(biāo)不超過4小時(shí)。所有最長不間斷檢查活動都應(yīng)經(jīng)過確認(rèn)。

對于半自動檢查，檢查間應(yīng)隔絕外部光源，應(yīng)確保單元在檢查區(qū)域內(nèi)至少完整旋轉(zhuǎn)360°，并對單元的頂部和底部進(jìn)行檢查，檢查區(qū)域的照度度通常高于人工檢查（例如8000勒克斯），操作員的坐姿應(yīng)符合人體工學(xué)，使操作員的視覺焦點(diǎn)對準(zhǔn)檢查位置。還應(yīng)定期確認(rèn)設(shè)備的潛在漂移（例如照度），例如至少每六個月一次。

對于全自動檢查，PQ應(yīng)針對具體產(chǎn)品開展，確認(rèn)套件應(yīng)至少檢查十次，以確保統(tǒng)計(jì)穩(wěn)健性。應(yīng)考慮所謂的克納普測試（Knapp Test）原理。確認(rèn)套件通常包含約10%的缺陷單元以防止偏差。全自動檢查系統(tǒng)的再確認(rèn)理想情況下應(yīng)每年進(jìn)行一次，最遲每兩年進(jìn)行一次。

關(guān)于燈檢缺陷分析的行動限要求必須根據(jù)生產(chǎn)歷史按具體產(chǎn)品確定。若沒有以往經(jīng)驗(yàn)，單個缺陷的典型行動限值例如：

關(guān)鍵缺陷：0.5%至1% *

主要缺陷：3%至5%

微小缺陷：5%至10%

對于關(guān)鍵缺陷，嚴(yán)重性限值（如影響無菌性的缺陷（例如渾濁、裂縫或混淆）等GMP問題，表明GMP符合性為0，需啟動調(diào)查。

一旦確定根本原因，且檢查方法適用于挑出導(dǎo)致問題的缺陷，可對批次進(jìn)行復(fù)檢。未事先調(diào)查不得進(jìn)行復(fù)檢。復(fù)檢方法的決定應(yīng)由批準(zhǔn)且受權(quán)的人員做出。不得對拒收的容器進(jìn)行復(fù)檢。

對于批放行，典型的最低AQL要求為：

關(guān)鍵缺陷：AQL樣品中無缺陷

主要缺陷：≤0.65 AQL

微小缺陷：≤4.0 AQL

2025版ECA無菌產(chǎn)品燈檢指南發(fā)布

 

 

 

 

 

文件翻譯如下：

 

 

 

Table of Contents

目錄

 

1 SCOPE

1 范圍

2 MANUAL INSPECTION

2 人工檢查

2.1 Workplace

2.1 工作場所

2.2 Personnel

2.2 人員

2.3 Regulatory expectations

2.3 法規(guī)要求

2.4 Operation

2.4 操作

3 SEMI-AUTOMATED INSPECTION

3 半全自動檢查

4 AUTOMATED INSPECTION – QUALIFICATION, VALIDATION AND ROUTINE OPERATION

4 全自動檢查——確認(rèn)、驗(yàn)證和日常操作

4.1 General

4.1 總則

4.2 IQ & OQ – Installation and Operational Qualification

4.2 安裝確認(rèn)與運(yùn)行確認(rèn)

4.3 PQ – Performance Qualification

4.3 性能確認(rèn)

4.4 Validation

4.4 驗(yàn)證

4.5 Requalification and Revalidation

4.5 再確認(rèn)和再驗(yàn)證

4.6 Routine operation

4.6 日常操作

5 INSPECTION OF DIFFICULT-TO-INSPECT PRODUCTS AND CONTAINERS

5 難檢查產(chǎn)品和容器的檢查

5.1 Inspection of lyophilized product

5.1 凍干產(chǎn)品的檢查

5.2 Brown glass, coloured/turbid solutions

5.2 棕色玻璃、有色/渾濁溶液

6 DEFECT CLASSES

6 缺陷類別

7 EVALUATION OF DEFECT CLASSES AND TRENDING

7 缺陷類別評估與趨勢分析

7.1 Manual, semi-automated and fully automated inspection

7.1 人工、半自動化和全全自動檢查

8 BATCH CERTIFICATION/RELEASE

8 批次認(rèn)證/放行

9 CONCERNS REGARDING DISTRIBUTED PRODUCT

9 已分銷產(chǎn)品的相關(guān)問題

10 DEFINITIONS

10 定義

11 REFERENCES

11 參考文獻(xiàn)

 

1 Scope

1 范圍

 

This paper aims to highlight best practices for carrying out 100 % visual inspection of medicinal products for parenteral use in the Pharmaceutical Industry. It should be seen in addition and complementary to the monographs of the different Pharmacopoeias.

本文旨在強(qiáng)調(diào)制藥行業(yè)對無菌藥品進(jìn)行100%目視檢查的最佳實(shí)踐。它應(yīng)被視為對不同藥典專著的補(bǔ)充。

 

Visual inspection of medicinal products for parenteral use should detect any readily identifiable visible container defect and ensure constant quality of the product in terms of absence of particulate matter and/or turbidity, and correct or uniform appearance of a lyo cake.

對無菌藥品的目視檢查應(yīng)能發(fā)現(xiàn)任何易于識別的可見容器缺陷，并從無顆粒物質(zhì)和/或渾濁、凍干產(chǎn)品外觀正確或均一等方面確保產(chǎn)品質(zhì)量的穩(wěn)定性。

 

Modifications of the procedures and figures proposed in this paper are possible at any time. However, following the proposed procedures and figures may lead to safer inspection processes and may avoid discussions in GMP audits and inspections, as the described approach reflects current practice and has shown its suitability during many years of industrial operation and GMP inspections.

本文中提出的程序和圖表可隨時(shí)修改。然而，遵循所提出的程序和圖表可能會使檢查過程更安全，并可能避免在GMP審計(jì)和檢查中出現(xiàn)爭議，因?yàn)樗枋龅姆椒ǚ从沉水?dāng)前的實(shí)踐，并且在多年的行業(yè)操作和GMP檢查中已證明其適當(dāng)性。

 

The CCI (Container Closure Integrity) topic is out of scope of this paper (see ECA position paper “Container Closure Integrity testing of medicinal products for parenteral use”).

容器密封完整性（CCI）主題不在本文范圍內(nèi)（參見ECA立場文件《無菌藥品的容器密封完整性測試》）。

 

2 Manual Inspection

2 人工檢查

 

2.1 Workplace

2.1 工作場所

 

The area where manual visual inspection is performed should be suitable for this operation. Besides common GMP requirements for manufacturing or quality control areas, the following inspection conditions are of substantial importance:

進(jìn)行人工目視檢查的區(qū)域應(yīng)適合該操作。除了生產(chǎn)或質(zhì)量控制區(qū)域的常見GMP要求外，以下檢查條件至關(guān)重要：

 

Illumination:

照度：

 

The intensity of the illumination at the inspection point should have at least 2000 lux. For Blow-Fill-Seal products, an illumination of 10.000 lux is recommended (see also chapter 5). Accuracy of the lux-meter measuring light intensity should be considered. The colour reproduction, using the CRI index, should preferably have an RA value > 90%.

檢查位置的照度強(qiáng)度應(yīng)至少為2000勒克斯。對于吹灌封產(chǎn)品，建議照度為10000勒克斯（另見第5章）。應(yīng)考慮照度計(jì)測量光強(qiáng)度的準(zhǔn)確性。使用CRI指數(shù)，色彩還原度應(yīng)最好具有大于90%的RA值。

 

Illumination should be regularly qualified and part of the preventive maintenance programme. An appropriate interval for checking the illumination is at least every 6 months. It is recommended that the technical measurement used to determine the light intensity is performed at a prefixed point, which should be very close to the inspection point of the operator.

照度應(yīng)定期確認(rèn)，并應(yīng)是預(yù)防性維護(hù)計(jì)劃的一部分。檢查照度的適當(dāng)間隔至少為每6個月一次。建議用于確定光強(qiáng)度的技術(shù)測量在一個預(yù)先設(shè)定的點(diǎn)進(jìn)行，該點(diǎn)應(yīng)非?？拷僮魅藛T的檢查位置。

 

The ambient illumination must not interfere with the illumination of the workplace and should be turned down during inspection, if possible. Reflecting surfaces should be avoided.

環(huán)境照度不得干擾工作場所的照度，并且在可能的情況下，應(yīng)在檢查期間調(diào)低。應(yīng)避免反光表面。

 

Ambient conditions:

環(huán)境條件：

 

Ambient conditions have a high impact on the quality of this operation. Ambient temperature should normally be at room temperature and should not exceed 23 °C in summer, unless otherwise justified. Relative humidity and air velocity should be controlled and ensure comfortable working conditions. The noise level should therefore be below 55dB (source: German Workplace Ordinance ArbStättV).

環(huán)境條件對該操作的質(zhì)量有很大影響。環(huán)境溫度通常應(yīng)為室溫，夏季不應(yīng)超過23°C，除非另有正當(dāng)理由。相對濕度和空氣流速應(yīng)加以控制，以確保舒適的工作條件。噪音水平應(yīng)低于55分貝（來源：德國工作場所條例ArbStättV）。

 

2.2 Personnel

2.2 人員

 

Personnel involved in the visual inspection should regularly undergo eye tests. The optometrist should focus on the ability to discriminate small differences in uniform structures, e.g. open/closed circles. Also, colour vision of the inspector should be tested.

參與目視檢查的人員應(yīng)定期進(jìn)行眼科檢查。驗(yàn)光師應(yīng)關(guān)注辨別均勻結(jié)構(gòu)中細(xì)微差異的能力，例如開/閉的圓圈。此外，還應(yīng)測試檢查人員的色覺。

 

Personnel performing visual inspection should be qualified, comprising initial qualification and periodic requalification. Qualification should be specific for each dosage form (e.g. syringe, vial, ampoule).

進(jìn)行目視檢查的人員應(yīng)進(jìn)行確認(rèn)，包括初始確認(rèn)和定期再確認(rèn)。確認(rèn)應(yīng)針對每種劑型（例如注射器、小瓶、安瓿）分別進(jìn)行。

 

Initial qualification should follow a predefined schedule, starting with the introduction of the new employee to training kits. These training kits should contain all kinds of defects and should be updated constantly with new evolving defects out of production. These training kits should be specific for the dosage form. In case of unstable defects or defects which are not available photos of defects or artificial defects may be used.

初始確認(rèn)應(yīng)遵循預(yù)先設(shè)定的程序，從向新員工介紹培訓(xùn)套件開始。這些培訓(xùn)套件應(yīng)包含各類缺陷，且應(yīng)隨著生產(chǎn)中出現(xiàn)的新缺陷不斷更新。培訓(xùn)套件應(yīng)針對具體劑型。若存在不穩(wěn)定的缺陷或無法獲取缺陷照片的情況，可使用人工缺陷。

 

A bracketing approach for different products is acceptable when process equivalence is scientifically justified. Following the training via training kits there should be a side-by-side training with an experienced operator. The trainee should have the chance to ask questions with the experienced operator performing a parallel 100 % inspection of the inspected units of the trainee.

當(dāng)工藝等效性有科學(xué)依據(jù)時(shí)，對不同產(chǎn)品采用分組法是可接受的。通過培訓(xùn)套件完成培訓(xùn)后，應(yīng)與有經(jīng)驗(yàn)的操作員進(jìn)行結(jié)對培訓(xùn)。受訓(xùn)人員應(yīng)有機(jī)會向有經(jīng)驗(yàn)的操作員提問，操作人員同時(shí)對受訓(xùn)人員檢查的單元進(jìn)行100%平行檢查。

 

Following successful completion of the side by side training, the initial qualification should be performed using a qualification kit. This kit should focus on critical and major defects and also contain a limited number of minor defects. The number of units to be inspected should represent the number of objects which are inspected in the routine process from one eye break to the next eye break.

在成功完成結(jié)對培訓(xùn)后，應(yīng)使用確認(rèn)套件進(jìn)行初始確認(rèn)。該套件應(yīng)關(guān)注關(guān)鍵和主要缺陷，同時(shí)包含一定數(shù)量的微小缺陷。待檢查的單元數(shù)量應(yīng)與日常工藝中一次休息到下一次休息期間所檢查的物品數(shù)量一致。

 

2.3 Regulatory expectations

2.3 法規(guī)期望

 

The European GMP requirements with regard to the visual inspection are - among others - included in EU GMP Guide, Annex <1> “Manufacture of Sterile Products” in the section “Finishing of sterile products”. This guidance document addresses expectations relevant to visual inspection.

EU GMP中關(guān)于目視檢查的要求，除其他外，包含在歐盟GMP指南附錄1《無菌產(chǎn)品的生產(chǎn)》中“無菌產(chǎn)品的最終處理”部分。該指導(dǎo)文件闡述了與目視檢查相關(guān)的期望。

 

Despite the fact that current regulations cover many topics concerning visual inspection, situations may occur where expectations of a regulatory inspector differ from to the scientific understanding of the pharmaceutical company.

盡管當(dāng)前法規(guī)涵蓋了許多與目視檢查相關(guān)的主題，但仍可能出現(xiàn)監(jiān)管檢查人員的期望與制藥公司的科學(xué)理解存在差異的情況。

 

Expectation 1:

期望1：

 

There is sometimes the expectation for operators to wear corrective lenses when undergoing visual inspection qualification, if they are worn during daily life.

往往會期望操作員在進(jìn)行目視檢查確認(rèn)時(shí)，若日常生活中佩戴矯正鏡片，則需佩戴該鏡片。

 

Corrective lenses are used to shift an observed object into the focus point of the human eye. It is a known fact that individuals may shift an observed object into their (individual) eye focus point simply by varying the distance to the object, without the use of corrective lenses. Operators need correct corrective lenses in everyday life might be able to perform visual inspection without.

矯正鏡片用于將觀察到的物體移至人眼的焦點(diǎn)。眾所周知，不使用矯正鏡片時(shí)，個體僅通過改變與物體的距離，就可將觀察到的物體移至其眼睛焦點(diǎn)。日常生活中需要佩戴矯正鏡片的操作員可能在不佩戴的情況下進(jìn)行目視檢查。

 

The requested medical check should examine e.g. three-dimensional sight, color identification, stigmatic corrections and most importantly reflecting the normal “daily life” visual capability. This ensures that the operator can see defects.

要求的醫(yī)療檢查應(yīng)檢查例如立體視覺、顏色識別、散光矯正，最重要的是反映正常“日常生活”中的視覺能力。這確保操作員能夠發(fā)現(xiàn)缺陷。

 

The medical check is not related to the competence of performing visual inspection activity. This is checked during qualification of the operator and whether he has to wear visibility aids is determined during this process.

醫(yī)療檢查與執(zhí)行目視檢查活動的能力無關(guān)。這在操作員確認(rèn)期間進(jìn)行檢查，且其是否需要佩戴視覺輔助設(shè)備也在該過程中確定。

 

Expectation 2:

期望2：

 

There is sometimes the expectation for operators to be qualified considering different stress factors, including fatigue at the end of shift. It can be doubted that a fatigue effect can be simulated in an examination situation which has an impact on the operator whether he/she can keep his/her job. With this there is always nervousness, and some people have even examination anxiety which leads to release of Adrenaline in the human body which counters a fatigue effect. Additionally, when performing initial qualification, the fatigue at the end of shift can’t be simulated anyway, as the operators are not yet allowed to perform a “normal” visual inspection workday.

有時(shí)會期望在對操作員進(jìn)行確認(rèn)時(shí)考慮不同的壓力因素，包括換班結(jié)束時(shí)的疲勞。在會影響操作員是否能保住工作的考試情境中，能否模擬疲勞效應(yīng)是值得懷疑的。這種情況下總會存在緊張情緒，有些人甚至有考試焦慮，這會導(dǎo)致人體釋放腎上腺素，從而抵消疲勞效應(yīng)。此外，在進(jìn)行初始確認(rèn)時(shí)，換班結(jié)束時(shí)的疲勞無論如何都無法模擬，因?yàn)椴僮鲉T尚未被允許進(jìn)行“正常”的目視檢查工作日。

 

As Annex 1 requests that “operators performing visual inspection should be following a work and rest regime specifically designed to minimize distractions, there should be no fatigue effects at end of shift, which would impact the validity of the visual inspection.

正如附錄1要求“進(jìn)行目視檢查的操作員應(yīng)遵循專門設(shè)計(jì)的工作和休息制度，以盡量減少干擾，換班結(jié)束時(shí)不應(yīng)出現(xiàn)疲勞效應(yīng)，否則會影響目視檢查的有效性。

 

Keeping this in mind, it should be considered to address these two topics/aspects/expectations by a Quality Risk Management approach.

考慮到這一點(diǎn)，應(yīng)考慮通過質(zhì)量風(fēng)險(xiǎn)管理方法來處理這兩個主題/方面/期望。

 

Acceptance criteria for the qualification should be predefined. In the initial qualification all critical defects and a predefined level for major defects should be found. Also, a limit for the False Rejects (rejection of samples without defects) should be predefined (e.g., 5-10%).

應(yīng)預(yù)先確定確認(rèn)的接受標(biāo)準(zhǔn)。在初始確認(rèn)中，應(yīng)識別出所有關(guān)鍵缺陷以及預(yù)先確定的主要缺陷等級。此外，還應(yīng)預(yù)先確定誤判拒收（無缺陷樣品被拒收）的限度（例如，5-10%）。

 

Routine requalification should be performed at least every 12 months. After a second significant inspection failure the operator should undergo a repeated eye test and a subsequent new qualification with the training kit as well as a subsequent new qualification via a qualification kit.

日常再確認(rèn)應(yīng)至少每12個月進(jìn)行一次。在第二次重大檢查失敗后，操作員應(yīng)重新進(jìn)行視力測試，隨后使用培訓(xùn)工具包進(jìn)行新的確認(rèn)，并通過確認(rèn)工具包進(jìn)行后續(xù)的新確認(rèn)。

 

2.4 Operation

2.4 操作

 

Routinely, during the 100 % inspection each object should be inspected for at about 5 seconds against a white background and an additional 5 seconds against a black background. Times may be shorter when using a semi-automatic system. The objects should be slightly twisted or slowly rotated to swirl up particles whilst avoiding the formation of air bubbles.

通常，在100%檢查過程中，每個物品應(yīng)在白色背景下檢查約5秒，在黑色背景下再額外檢查5秒。使用半自動系統(tǒng)時(shí)，檢查時(shí)間可能更短。物品應(yīng)輕微扭轉(zhuǎn)或緩慢旋轉(zhuǎn)，使顆粒旋起，同時(shí)避免氣泡形成。

 

The post inspection recovery time for visual Inspection staff is of essential importance. The maximum time for continuous inspection activity between breaks and the total maximum inspection time for a shift/workday should be defined.

目視檢查人員的檢查后恢復(fù)時(shí)間至關(guān)重要。應(yīng)規(guī)定兩次休息之間連續(xù)檢查活動的最長時(shí)間，以及一個班次/工作日的總最長檢查時(shí)間。

 

Industry practice is 20-60 minutes of inspection. A current good practice goal is 30 minutes of inspection followed by a break of at least 5 minutes continued for a total maximum duration goal of no longer than 4 hours. All maximum uninterrupted inspection activity should be qualified.

行業(yè)慣例是檢查20-60分鐘。當(dāng)前的良好實(shí)踐目標(biāo)是檢查30分鐘后至少休息5分鐘，總持續(xù)時(shí)間目標(biāo)不超過4小時(shí)。所有最長不間斷檢查活動都應(yīng)經(jīng)過確認(rèn)。

 

3 Semi-Automated Inspection

3 半自動檢查

 

Semi-automated visual inspection is the combination of manual visual inspection and an automated transporting system of the units. The inspection system presents the object to a human inspector allowing inspection of the units using a defined set-up (inspection booth) and a qualified human operator.

半自動目視檢查是人工目視檢查與單元自動傳輸系統(tǒng)的結(jié)合。檢查系統(tǒng)將物品呈現(xiàn)給人工檢查人員，允許檢查人員使用規(guī)定的裝置（檢查間）和經(jīng)確認(rèn)的人工操作員對單元進(jìn)行檢查。

 

The complete inspection of each unit is ensured by the following aspects:

每個單元的完整檢查通過以下方面確保：

 

To avoid disturbances of the inspector, an inspection booth should exclude external light sources.

為避免干擾檢查人員，檢查間應(yīng)隔絕外部光源。

At least a full 360° rotation of the unit in the inspection field facilitates inspection.

單元在檢查區(qū)域內(nèi)至少完整旋轉(zhuǎn)360°，便于檢查。

Inspection of the top and the bottom of the unit ensures complete inspection of the unit.

對單元的頂部和底部進(jìn)行檢查，確保單元的完整檢查。

For liquid products, particle inspection can be supported by pre-rotating the objects before inspection to get the particles moving within the solution.

對于液體產(chǎn)品，可在檢查前預(yù)先旋轉(zhuǎn)物品，使顆粒在溶液中移動，以輔助顆粒檢查。

Due to the nature of semi-automated inspection the inspection field is typically illuminated higher than in manual inspection (for example 8,000 lux) and may be adjusted to suit for difficult to inspect objects. Inspection of difficult to inspect objects are described in chapter 5.

由于半自動檢查的特性，檢查區(qū)域的照度度通常高于人工檢查（例如8000勒克斯），并且可根據(jù)難以檢查的物品進(jìn)行調(diào)整。難以檢查物品的檢查在第5章中描述。

For an undisturbed visual inspection, the surrounding of the booth should be designed in such a way to prevent extraneous light and/or reflections.

為了實(shí)現(xiàn)無干擾的目視檢查，檢查間的周邊應(yīng)設(shè)計(jì)成可防止外來光線和/或反射的形式。

Magnification or other suitable aids should be used in order to bring the visual focus point of the operator’s eyes to the point of inspection using an ergonomic sitting situation of the operator.

應(yīng)使用放大設(shè)備或其他合適的輔助工具，結(jié)合操作員符合人體工學(xué)的坐姿，使操作員的視覺焦點(diǎn)對準(zhǔn)檢查位置。

 

Risk Management Principles as part assessments should be established and then implemented in a controlled manner noted above. Pre-start up tests should be used during qualification of all the variable parameters to be used periodically. Functional control kits should be used to ensure variable parameters are within the validated state before commencement of the inspection process, whereas potential drifts of the equipment (e.g., Illumination) is more suited to be verified periodically, e.g., at least every six months.

風(fēng)險(xiǎn)管理原則作為部分評估應(yīng)予以建立，然后以上述受控方式實(shí)施。在對所有定期使用的可變參數(shù)進(jìn)行確認(rèn)時(shí)，應(yīng)使用啟動前測試。功能控制工具包應(yīng)用于確保在檢查過程開始前可變參數(shù)處于驗(yàn)證狀態(tài)，而設(shè)備的潛在漂移（例如照度）更適合定期確認(rèn)，例如至少每六個月一次。

 

The most important parameters are:

最重要的參數(shù)有：

 

Conveyor Speed

傳送帶速度

Illumination

照度

pre-spinning / if applicable

預(yù)旋轉(zhuǎn)/若適用

Rotation within the inspection field to ensure 360-degree inspection of the unit

檢查區(qū)域內(nèi)的旋轉(zhuǎn)，以確保對單元進(jìn)行360度檢查

 

Validation of the semi-automated inspection process should show at least equivalence to manual inspection results.

半自動檢查過程的驗(yàn)證應(yīng)至少顯示出與人工檢查結(jié)果相當(dāng)?shù)乃健?/p>

 

For lyophilized products, inspectors are qualified at maximum inspection speed and may inspect during routine operation at maximum or any lower inspection speed.

對于凍干產(chǎn)品，檢查人員需在最高檢查速度下確認(rèn)，且可在日常操作中以最高速度或任何更低速度進(jìn)行檢查。

 

For liquid products, inspection at the qualified speed should be routinely used at all times due to the influence of speed on the inspection validity.

對于液體產(chǎn)品，由于速度會影響檢查有效性，應(yīng)始終常規(guī)使用經(jīng)確認(rèn)的速度進(jìn)行檢查。

 

After an inspection process of an uninterrupted and predefined duration, operators require an eye break. Semi-automated visual inspection requires greater concentration by the operator. For that, times of uninterrupted inspection are typically shorter than manual visual inspection and times of breaks may differ from the numbers given in chapter 2.3 (Operation of the Manual Visual Inspection).

在一段不間斷且預(yù)定義時(shí)長的檢查過程后，操作人員需要讓眼睛休息。半自動目視檢查要求操作人員更加集中注意力。因此，不間斷檢查的時(shí)長通常比人工目視檢查更短，休息時(shí)長也可能與第2.3章（人工目視檢查的操作）中給出的數(shù)值不同。

 

4 Automated Inspection – Qualification, Validation and Routine Operation

4 全自動檢查——確認(rèn)、驗(yàn)證和日常操作

 

4.1 General

4.1 總則

 

The central aspect of qualification and validation of a fully automated inspection machine is the verification that the machine is at least as good as the comparative group of human inspectors (without magnification) with regards to defect detection rates. Qualification and validation can be done consecutively or combined.

全自動燈檢機(jī)確認(rèn)和驗(yàn)證的核心方面是，在缺陷檢出率方面，驗(yàn)證該設(shè)備至少與人工檢查人員組（不使用放大設(shè)備）水平相當(dāng)。確認(rèn)和驗(yàn)證可連續(xù)進(jìn)行或結(jié)合進(jìn)行。

 

Basically, qualification is the documented evidence that the inspection machine is fit for purpose, while validation is the documented evidence that the machine achieves reproducible results of desired quality in the manufacturing process. In simple terms, the qualification is done to ensure that the machine works as specified (URS), whereas the validation ensures that it consistently delivers the desired (inspection-) results in the manufacturing process.

從根本上說，確認(rèn)是證明燈檢機(jī)適用用途的書面證據(jù)，而驗(yàn)證是證明該設(shè)備在生產(chǎn)過程中能穩(wěn)定產(chǎn)出符合預(yù)期質(zhì)量的可重復(fù)結(jié)果的書面證據(jù)。簡而言之，確認(rèn)是為了確保設(shè)備按規(guī)定（URS）運(yùn)行，而驗(yàn)證是為了確保其在生產(chǎn)過程中持續(xù)交付預(yù)期的（檢查）結(jié)果。

 

4.2 IQ & OQ – Installation and Operational Qualification

4.2 安裝確認(rèn)（IQ）與運(yùn)行確認(rèn)（OQ）

 

Qualification begins with the development of the user requirements and ends with the verification of proper implementation. As part of the qualification phases, it should be confirmed that the machine complies with the user requirements specifications (URS).

確認(rèn)始于用戶需求的制定，終于對正確實(shí)施的驗(yàn)證。作為確認(rèn)階段的一部分，應(yīng)確認(rèn)設(shè)備符合用戶需求說明（URS）。

 

Installation Qualification (IQ) usually includes verification of the correct installation of components and equipment against technical drawings and specifications and the provision of the agreed operating and work instructions and maintenance requirements by the supplier.

安裝確認(rèn)（IQ）通常包括根據(jù)技術(shù)圖紙和規(guī)范驗(yàn)證部件和設(shè)備的正確安裝，以及供應(yīng)商提供約定的操作和工作指令及維護(hù)要求。

 

Operational Qualification (OQ) covers cross-product and format-specific functionality tests such as

運(yùn)行確認(rèn)（OQ）涵蓋跨產(chǎn)品和特定規(guī)格的功能測試，例如

 

the management of users, recipes, alarms, and warnings

用戶、配方、警報(bào)和報(bào)警的管理

proper transport, handling, and ejection of units for all formats

所有規(guī)格下單元的正確輸送、處理和排出

counting of units, batch report and audit trail functionality

單元計(jì)數(shù)、批次報(bào)告和審計(jì)追蹤功能

presentation of the units in front of the cameras, such as correct positioning, rotation, illumination, etc.

單元在攝像頭前的呈現(xiàn)，例如正確的定位、旋轉(zhuǎn)、照度等

 

4.3 PQ – Performance Qualification

4.3 性能確認(rèn)（PQ）

 

As part of the PQ, documented evidence should be provided demonstrating that the automated inspection machine (AIM) fulfills the defined performance requirements under intended (real) production conditions.

作為PQ的一部分，應(yīng)提供書面證據(jù)，證明自動化燈檢機(jī)（AIM）在預(yù)期（實(shí)際）生產(chǎn)條件下滿足既定的性能要求。

 

The central aspect of performance qualification is the verification that the AIM performs at least as well as the comparative group of qualified human inspectors (without magnification) regarding defect detection capability. PQ should be performed product specific.

性能確認(rèn)的核心方面是，在缺陷檢查能力方面，驗(yàn)證AIM至少與經(jīng)確認(rèn)的人工檢查人員組（不使用放大設(shè)備）表現(xiàn)相當(dāng)。PQ應(yīng)針對具體產(chǎn)品開展。

 

Throughout performance qualification, product-specific qualification kits should be used to evaluate detection rates after an appropriate number of inspections. These kits should consist of production materials, qualified substitutes, or simulated products that have been demonstrated to exhibit equivalent physical and optical characteristics relevant to automated visual inspection (e.g., size, shape, and color of defects, particle mobility), irrespective of their pharmaceutical relevance. The qualification kit should be inspected at least ten times to ensure statistical robustness.

在整個性能確認(rèn)過程中，應(yīng)使用針對具體產(chǎn)品的確認(rèn)套件，在完成適當(dāng)次數(shù)的檢查后評估檢出率。這些套件應(yīng)包含生產(chǎn)物料、經(jīng)確認(rèn)的替代品或模擬產(chǎn)品，這些產(chǎn)品已被證明具有與自動化目視檢查相關(guān)的等效物理和光學(xué)特性（例如，缺陷的大小、形狀和顏色，顆粒流動性），無論其藥學(xué)相關(guān)性如何。確認(rèn)套件應(yīng)至少檢查十次，以確保統(tǒng)計(jì)穩(wěn)健性。

 

Detection rates should be compared with the results of a representative group of qualified human inspectors and should be at least equivalent to manual inspection, assessed at the level of defined defect categories (comparison of individual container results is not required).

檢出率應(yīng)與一組有代表性的經(jīng)確認(rèn)人工檢查人員的結(jié)果進(jìn)行比較，且至少應(yīng)與人工檢查相當(dāng)，在既定缺陷類別的層面進(jìn)行評估（無需對單個容器的結(jié)果進(jìn)行比較）。

 

When evaluating particle detection performance, the principles of the so-called Knapp Test should be considered. Jülius Knapp demonstrated that a ratio of not more than 25% defective units within a set of confirmed good units provides optimal statistical accuracy for determining detection performance while avoiding rejection bias. Such enrichment qualification kits typically contain around 10% defective units to prevent bias. In practice, however, qualification kits are required whenever the Knapp Test is applied in the context of a man-machine comparison to demonstrate the performance of the automated inspection system, which is typically the case for the confirmation of particle detection capability. If, however, the machine's performance is evaluated against predefined acceptance criteria, i.e., detection rates, the inclusion of good units may be omitted, as automated systems are not subject to operator bias and fatigue.

在評估顆粒檢查性能時(shí)，應(yīng)考慮所謂的克納普測試（Knapp Test）原理。尤利烏斯·克納普（Jülius Knapp）證明，在一組已確認(rèn)的合格單元中，缺陷單元比例不超過25%時(shí)，在確定檢查性能并避免拒收偏差的情況下，可提供最佳統(tǒng)計(jì)準(zhǔn)確性。此類富集確認(rèn)套件通常包含約10%的缺陷單元以防止偏差。然而，在人機(jī)對比的背景下應(yīng)用克納普測試以證明全自動檢查系統(tǒng)的性能時(shí)，通常需要確認(rèn)套件，這在顆粒檢查能力的確認(rèn)中尤為常見。但如果是根據(jù)預(yù)定義的接受標(biāo)準(zhǔn)（即檢出率）評估設(shè)備性能，則可省略合格單元的納入，因?yàn)樽詣踊到y(tǒng)不受操作人員偏差和疲勞的影響。

 

Success is demonstrated when the machine's detection performance, based on a predefined number of at least ten repeated inspections, is statistically equivalent to that obtained from the same number of repeated manual inspections. If a higher number of repeated inspections are required, the corresponding number shall be adjusted accordingly for both the automated and manual inspections to ensure statistical comparability. This constitutes the so-called Knapp Test.

當(dāng)設(shè)備基于預(yù)定義的至少十次重復(fù)檢查次數(shù)，其檢查性能在統(tǒng)計(jì)上與相同次數(shù)的人工重復(fù)檢查結(jié)果相當(dāng)，則證明成功。如果需要更多次數(shù)的重復(fù)檢查，應(yīng)為自動化和人工檢查相應(yīng)調(diào)整次數(shù)，以確保統(tǒng)計(jì)可比性。這就構(gòu)成了所謂的克納普測試。

 

Bracketing approaches may be applicable, provided that they are justified by quality approved rationales.

括號法可能可以使用，但應(yīng)經(jīng)質(zhì)量部門批準(zhǔn)。

 

4.4 Validation

4.4 驗(yàn)證

 

Validation provides documented evidence that the automated inspection machine consistently produces results of the required quality during routine manufacturing. Tests should cover the operating range, simulating the intended process supported by quality-approved protocols.

驗(yàn)證提供書面證據(jù)，證明自動化燈檢機(jī)在日常生產(chǎn)中持續(xù)產(chǎn)出符合要求質(zhì)量的結(jié)果。測試應(yīng)涵蓋操作范圍，模擬經(jīng)質(zhì)量批準(zhǔn)方案支持的預(yù)期工藝。

 

This includes confirmation of process capabilities in terms of product stability, defined AQL limits, and trend limits. Furthermore, validation is intended to provide guidance on the information and data to be provided in the regulatory submission.

這包括在產(chǎn)品穩(wěn)定性、既定可接受質(zhì)量水平（AQL）限值和趨勢限值方面對工藝能力的確認(rèn)。此外，驗(yàn)證可以為監(jiān)管申報(bào)中應(yīng)提供的信息和數(shù)據(jù)提供指導(dǎo)。

 

Validation may be performed by comparing the results of manual human inspection with those obtained from the automated inspection machine. For example, this can involve manual re-inspection of a previously inspected batch or sub-batch (e.g., 5000 units) to confirm that the machine's performance is at least as good as the comparable group of human inspectors. Alternatively, validation can be confirmed by assessing the achievement of the expected AQL limits based on a defined number of batches (e.g., three consecutive production batches).

驗(yàn)證可通過將人工檢查結(jié)果與自動化燈檢機(jī)的結(jié)果進(jìn)行比較來實(shí)施。例如，這可以包括對先前檢查過的批次或子批次（例如，5000個單元）進(jìn)行人工復(fù)檢，以確認(rèn)設(shè)備的性能至少與可比較的人工檢查人員組相當(dāng)。或者，可通過基于規(guī)定數(shù)量的批次（例如，連續(xù)三個生產(chǎn)批次）評估預(yù)期AQL限值的達(dá)成情況來確認(rèn)驗(yàn)證。

 

4.5 Requalification and Revalidation

4.5 再確認(rèn)與再驗(yàn)證

 

Requalification of an automated inspection system should ideally be carried out annually, or every two years at the latest. Requalification should include a review of all changes and deviations that occurred during the period of operation. This review should include statistical trend analysis of performance data obtained during routine batch production. System suitability testing based on representative defect kits before and after every inspection and if necessary, additional inspections of test kits assessed may be carried out during production to ensure the inspection equipment remains in a state of control.

全自動檢查系統(tǒng)的再確認(rèn)理想情況下應(yīng)每年進(jìn)行一次，最遲每兩年進(jìn)行一次。再確認(rèn)應(yīng)包括對運(yùn)行期間發(fā)生的所有變更和偏差的審查。該審查應(yīng)包括對日常批次生產(chǎn)期間獲得的性能數(shù)據(jù)的統(tǒng)計(jì)趨勢分析。在每次檢查前后基于代表性缺陷套件進(jìn)行系統(tǒng)適用性測試，必要時(shí)，在生產(chǎn)期間對評估的測試套件進(jìn)行額外檢查，以確保檢查設(shè)備保持在受控狀態(tài)。

 

Revalidation can be performed by repeating the verification of the human inspection versus the inspection results of the machine, for example by manual re-inspection of an automatically inspected batch or part of the batch (e.g., 5000 units). The acceptance criteria are the same as during the initial validation.

再驗(yàn)證可通過重復(fù)驗(yàn)證人工檢查與設(shè)備檢查結(jié)果的比對來實(shí)施，例如對自動檢查的批次或部分批次（例如，5000個單元）進(jìn)行人工復(fù)檢。接受標(biāo)準(zhǔn)與初始驗(yàn)證時(shí)相同。

 

In addition to such periodic revalidation activities, continuous revalidation of the automated inspection machine performance may be established through the ongoing statistical evaluation of AQL results. Since the AQL represents a manual inspection of a representative sample from every batch, this data provides continuous evidence of the machine’s inspection performance. Statistical trending of AQL results in accordance with Quality Risk Management (QRM) principles enables early detection of performance shifts. Consistent performance within predefined limits demonstrates maintained process control and can be considered a continuous confirmation of the AIM’s validated state – thus fulfilling the intent of revalidation on a batch-by-batch basis.

除了此類周期性再驗(yàn)證活動外，還可通過對可接受質(zhì)量水平（AQL）結(jié)果的持續(xù)統(tǒng)計(jì)評估來建立對自動化燈檢機(jī)性能的持續(xù)再驗(yàn)證。由于AQL代表對每批中代表性樣品的人工檢查，該數(shù)據(jù)可持續(xù)證明設(shè)備的檢查性能。根據(jù)質(zhì)量風(fēng)險(xiǎn)管理（QRM）原則對AQL結(jié)果進(jìn)行統(tǒng)計(jì)趨勢分析，可早期發(fā)現(xiàn)性能偏移。在預(yù)定義限值內(nèi)的穩(wěn)定性能表明過程控制得以維持，可被視為對自動化燈檢機(jī)（AIM）驗(yàn)證狀態(tài)的持續(xù)確認(rèn)——從而實(shí)現(xiàn)逐批次再驗(yàn)證的目的。

 

Results and evaluations should be documented in a revalidation report.

結(jié)果和評估應(yīng)記錄在再驗(yàn)證報(bào)告中。

 

4.6 Routine operation

4.6 日常操作

 

During routine operation the overall functional performance of the automated system should be demonstrated to be within the acceptable range of the normal operating conditions and validated state. This is achieved by using the functional test kit containing representatives of the range of defects that has been used in the qualification, which should be applied before and after the inspection of a batch. An abridged or reduced functional test kit may also be used. In the event of a risk, such as a malfunction or machine drifts (misalignments of visual components, camera defects, etc.) of the inspection system or in the case of a prolonged inspection time (e.g., campaign production, large volume batches), the described functional test can also be useful within a batch.

在日常操作期間，應(yīng)證明自動化系統(tǒng)的整體功能性能處于正常操作條件和驗(yàn)證狀態(tài)的可接受范圍內(nèi)。這可通過使用包含確認(rèn)過程中所用缺陷范圍代表的功能測試套件來實(shí)現(xiàn)，該套件應(yīng)在批次檢查前后使用。也可使用簡化或縮減的功能測試套件。在出現(xiàn)風(fēng)險(xiǎn)的情況下，例如檢查系統(tǒng)發(fā)生故障或設(shè)備偏移（視覺組件錯位、攝像頭缺陷等），或在檢查時(shí)間延長的情況下（例如，連續(xù)生產(chǎn)、大批量批次），上述功能測試在批次內(nèi)也可能有用。

 

5 Inspection of difficult-to-inspect Products and Containers

5 難檢查產(chǎn)品和容器的檢查

 

All drug products must be 100% visually inspected, even if they are difficult to inspect due to their product characteristics and/or container. A difficult to inspect product may be defined as either cloudy (suspension products) or turbidly oily products (emulsions) or a mixture of these characteristics. Difficult-to-inspect containers can be defined as amber, coloured, opaque, or plastics, essentially any material that is not 100% transparent. Additionally, a small product volume sometimes may be considered as difficult to inspect.

所有藥品都必須進(jìn)行100%的目視檢查，即使由于其產(chǎn)品特性和/或容器原因而難以檢查。難檢查產(chǎn)品可定義為渾濁的（混懸劑產(chǎn)品）、渾濁油性的產(chǎn)品（乳劑）或這些特性的混合物。難檢查容器可定義為琥珀色、有色、不透明或塑料材質(zhì)的，本質(zhì)上是任何不是100%透明的材料。此外，小容量產(chǎn)品有時(shí)也可能被視為難以檢查。

 

If any characteristics of the product cannot be visually inspected by the 100% inspection, suitable inspection methods should be used additionally, e.g., destructive random sampling. Samples are taken according to a sampling plan, please refer to DIN ISO 2859-1 or ANSI/ASQ Z1.4. In case additional testing is carried out to test for particles, the destructive testing should be performed in a grade A (ISO 100) environment at laminar conditions to avoid sample contamination with particles from the environment. During testing process, product solution is withdrawn from the container and filtered through a filter membrane (e.g., 0.8 μm pore size similar to USP <788>), prewetted with particle free water. After residues of the product are washed away with particle free water, the dried membranes are visually inspected with a stereomicroscope for particles > 100 μm (see USP <790>, AQL 0.65).

如果產(chǎn)品的任何特性無法通過100%目視檢查進(jìn)行檢查，應(yīng)額外使用合適的檢查方法，例如破壞性隨機(jī)抽樣。樣品根據(jù)抽樣計(jì)劃抽取，詳情請參考DIN ISO 2859-1或ANSI/ASQ Z1.4。如果進(jìn)行額外的顆粒測試，破壞性測試應(yīng)在A級（ISO 100）層流環(huán)境中進(jìn)行，以避免樣品被環(huán)境中的顆粒污染。在測試過程中，從容器中取出產(chǎn)品溶液并通過過濾膜（例如，孔徑0.8 μm，類似于USP <788>）過濾，該過濾膜需用無顆粒水預(yù)潤濕。用無顆粒水沖洗掉產(chǎn)品殘留物后，將干燥的濾膜用立體顯微鏡目視檢查>100 μm的顆粒（參見USP <790>，AQL 0.65）。

 

5.1 Inspection of lyophilized product

5.1 凍干產(chǎn)品的檢查

 

In case of lyophilized products, particles can only be detected on the cake, not within the cake during 100% visual inspection. For within-cake-inspection, a number of samples are reconstituted and visually inspected for particulates. The result must be within the predefined particle limits.

對于凍干產(chǎn)品，在100%目視檢查期間，顆粒僅能在餅狀物表面被檢查到，無法在餅狀物內(nèi)部被檢查到。如需檢查餅狀物內(nèi)部，需將一定數(shù)量的樣品復(fù)溶后，對顆粒進(jìn)行目視檢查。結(jié)果必須在預(yù)定義的顆粒限值范圍內(nèi)。

 

5.2 Brown glass, coloured/turbid solutions

5.2 棕色玻璃、有色/渾濁溶液

 

Visual inspection of products in brown glass containers or with coloured solutions are difficult to inspect in terms of particle detection for example. Detectability of other defects like fill level, closure defects or glass defects is usually not affected with such products.

例如，對棕色玻璃容器中的產(chǎn)品或含有色溶液的產(chǎn)品進(jìn)行目視檢查時(shí)，顆粒檢查較為困難。而其他缺陷（如裝量、密封缺陷或玻璃缺陷）的可檢查性通常不受此類產(chǎn)品的影響。

 

As with brown glass containers or coloured solutions, the contrast between particles and the product is decreased. Therefore, the probability of detecting particles, in particular, small particles (> detection of particles <100 μm) or small particles is more difficult or compliance to USP 790 (detection of particles >100 μm) may be hard to achieve.

與棕色玻璃容器或有色溶液的情況類似，顆粒與產(chǎn)品之間的對比度降低。因此，檢查顆粒（尤其是小顆粒（<100 μm的顆粒檢查）或小顆粒）的難度增加，或難以符合USP 790（>100 μm顆粒的檢查）的要求。

 

Decreased visibility of particles in brown glass containers or slightly coloured or slightly turbid solutions may be improved by increasing illumination, as described in ch. Eur. 2.2.20 or JP 6.06, or by extending inspection time. Also, other measures like using a pyrolyt light or different illumination wavelength may be helpful as well. Visibility due to strong colouration of liquid, milky products or in lyophilized products may be improved by video.

對于棕色玻璃容器中或輕微有色、輕微渾濁溶液中的顆?？梢娦越档偷那闆r，可通過增加照度（如歐洲藥典第2.2.20章或日本藥典第6.06章所述）或延長檢查時(shí)間來改善。此外，使用熱解光或不同的照度波長等其他措施也可能有幫助。對于因液體、乳狀產(chǎn)品或凍干產(chǎn)品的強(qiáng)著色導(dǎo)致的可見性問題，可通過視頻方式改善。

 

If particles are not visible to ensure correlation of product light, different products in lyophilized products, destructive testing must be used as mentioned in case of lyophilized products.

如果顆粒不可見，為確保產(chǎn)品光的相關(guān)性，對于凍干產(chǎn)品中的不同產(chǎn)品，必須使用如凍干產(chǎn)品檢查中所述的破壞性測試。

 

If the product is also non-transparent (opaque) or very cloudy, microscopic examination, e.g. as described in JP 6.06. Method 2, has to be applied.

如果產(chǎn)品也是不透明的或非常渾濁的，必須采用顯微檢查，例如日本藥典第6.06章方法2中所述的方法。

 

6 Defect Classes

6 缺陷類別

 

There should be at least two product-specific defect classes defined. Additional defect classes may be defined, for example:

應(yīng)至少定義兩個針對具體產(chǎn)品的缺陷類別。還可定義其他缺陷類別，例如：

 

Critical defects: may cause a lack of sterility, container integrity or cause harm to patients.

關(guān)鍵缺陷：可能導(dǎo)致無菌性缺失、容器完整性破壞或?qū)颊咴斐蓚Α?/p>

 

Major defects: may alter the content or the function of the product.

主要缺陷：可能改變產(chǎn)品的成分或功能。

 

Minor defects: Defects that do not affect patient health or a product’s functionality.

微小缺陷：不影響患者健康或產(chǎn)品功能的缺陷。

 

Other: If a company performs additional visual inspection for a specific cosmetic appearance for products intended to be placed to culturally sensitive markets, it is recommended not to include them into the GMP – and within-product quality related - defect classification.

其他：如果某公司針對擬投放文化敏感市場的產(chǎn)品，因特定外觀要求而進(jìn)行額外的目視檢查，建議不要將這些缺陷納入與GMP及產(chǎn)品內(nèi)在質(zhì)量相關(guān)的缺陷分類中。

 

7 Evaluation of Defect Classes and Trending

7 缺陷類別評估與趨勢分析

 

7.1 Manual, semi-automated and fully automated inspection

7.1 人工、半自動和全自動檢查

 

Based on the trend analysis of the production process, a limit for each defect class should be defined. There should be limits for individual defects and for the sum of all defects within a defect class. Yields should also be monitored.

基于生產(chǎn)過程的趨勢分析，應(yīng)為每個缺陷類別定義限值。應(yīng)對單個缺陷以及同一缺陷類別內(nèi)所有缺陷的總和設(shè)定限值。同時(shí)還應(yīng)監(jiān)控收率。

 

Limits should be defined on process history (overall maximum reject rate, rate per defect / particle category) and should reflect and reference the process capability index (Cpk) for the process step.

限值應(yīng)根據(jù)工藝歷史（整體最高拒收率、每個缺陷/顆粒類別的發(fā)生率）來定義，并應(yīng)反映和參考該工藝步驟的過程能力指數(shù)（Cpk）。

 

Action limits must be determined product specific, based on production history. In case there is no previous experience, typical action limits for individual defects are for example:

行動限值必須根據(jù)生產(chǎn)歷史按具體產(chǎn)品確定。若沒有以往經(jīng)驗(yàn)，單個缺陷的典型行動限值例如：

 

Critical defects: 0.5 % to 1 % *

關(guān)鍵缺陷：0.5%至1% *

 

Previous defects: 1 % to 3 %

既往缺陷：1%至3%

 

Major defects: 3 % to 5 %

主要缺陷：3%至5%

 

Minor defects: 5 % to 10 %

微小缺陷：5%至10%

 

*For critical defects, the severity limit (GMP issues such as sterility-impairing defects (e.g., turbidity, cracks or mix-ups) indicating GMP is 0, triggering an investigation.

對于關(guān)鍵缺陷，嚴(yán)重性限值（如影響無菌性的缺陷（例如渾濁、裂縫或混淆）等GMP問題，表明GMP符合性為0，需啟動調(diào)查。

 

Typical action limits can also be based on specific defects (e.g. particles) instead of using the categories critical, major and minor.

典型行動限值也可基于特定缺陷（例如顆粒），而非使用關(guān)鍵、主要和次要這些類別。

 

Setting alert limits may be a reasonable e.g. to identify a production specific problem as early as possible.

設(shè)定警戒限值可能是合理的，例如盡早識別特定生產(chǎn)問題。

 

According to ASTM E2658-12 (Standard Practice for Use of Control Charts in Statistical Process Control), control limits for trending should be calculated from process data and not be based on fixed specification limits. However, the evaluation should optimally be based on at least 30 representative data points of the process. This would require preliminary control limits to be defined based on experience prior to the first calculation deriving from measured data points.

根據(jù)ASTM E2658-12《統(tǒng)計(jì)過程控制中控制圖的使用標(biāo)準(zhǔn)實(shí)踐》，趨勢控制限值應(yīng)根據(jù)工藝數(shù)據(jù)計(jì)算，而非基于固定規(guī)格限值。不過，評估應(yīng)最優(yōu)地基于工藝的至少30個代表性數(shù)據(jù)點(diǎn)。這就要求在根據(jù)測量數(shù)據(jù)點(diǎn)進(jìn)行首次計(jì)算之前，根據(jù)經(jīng)驗(yàn)預(yù)先定義初步控制限值。

 

If a batch exceeds a critical limit, the reason for this should be investigated. Batches exceeding the acceptance limits for trending limits should also trigger the company’s failure investigation process.

若某批次超出關(guān)鍵限值，應(yīng)調(diào)查其原因。超出趨勢限值接受標(biāo)準(zhǔn)的批次也應(yīng)觸發(fā)公司的失敗調(diào)查流程。

 

Once the root cause has been identified and the inspection method is suitable for sorting out the defects causing the problem, the batch can be re-inspected. Re-inspection should never be performed without prior investigation. It has to be assessed whether the inspection method used in the initial inspection may not be suitable for re-inspection. E.g., if an automated test method used in identifying certain defects in the first run, it is likely to fail also in a second run. The decision on the re-inspection method should be made by an authorised and qualified person.

一旦確定根本原因，且檢查方法適用于挑出導(dǎo)致問題的缺陷，可對批次進(jìn)行復(fù)檢。未事先調(diào)查不得進(jìn)行復(fù)檢。必須評估初始檢查中使用的檢查方法是否不適用于復(fù)檢。例如，若某自動化測試方法在首次運(yùn)行中用于識別某些缺陷，很可能在第二次運(yùn)行中也會失敗。復(fù)檢方法的決定應(yīng)由批準(zhǔn)且受權(quán)的人員做出。

 

When frequent re-inspection must be performed, a failure investigation should be initiated with the aim to improve the sensitivity of the primary inspection process or the manufacturing controls to prevent defects in the upstream process as determined by root cause analysis.

當(dāng)必須頻繁進(jìn)行復(fù)檢時(shí)，應(yīng)啟動失敗調(diào)查，目的是提高初始檢查過程的敏感性或制造控制措施，以防止上游過程中出現(xiàn)缺陷（由根本原因分析確定）。

 

Re-inspection of rejected containers should not be performed.

不得對拒收的容器進(jìn)行復(fù)檢。

 

NOTE:

注：

 

“Grey Channel” for fully automated inspection systems: Defining a “grey eject channel” in automated inspection may be useful to separate containers for which the inspection result is not clear. From a technical point of view, a “grey channel” is also meaningful in case of e.g., machine stops, when it is uncertain whether a unit has been fully inspected according to procedure or not.

全自動檢查系統(tǒng)的“灰色通道”：在全自動檢查中定義“灰色剔除通道”可能有助于分離檢查結(jié)果不明確的容器。從技術(shù)角度來看，在例如設(shè)備停機(jī)的情況下，當(dāng)不確定某單元是否已按程序完成全部檢查時(shí)，“灰色通道”也具有意義。

 

Examples for the Grey-Channels:

灰色通道示例：

 

Air bubbles: Air bubbles might be a reason for an unclear inspection result. Camera systems cannot distinguish between particular matter and air bubbles. Therefore re-inspection of containers from example, time reduces the number of air-bubbles, which reduces the false reject rate whilst maintaining a more stringent machine set-up.

1. 氣泡：氣泡可能是導(dǎo)致檢查結(jié)果不明確的原因。攝像系統(tǒng)無法區(qū)分顆粒物和氣泡。因此，對容器進(jìn)行復(fù)檢（例如，時(shí)間會減少氣泡數(shù)量，從而在保持更嚴(yán)格的設(shè)備設(shè)置的同時(shí)降低誤拒率）。

 

Other defects in the grey channel: from a technical point of view some small defects (e.g. small scratches) should be re-inspected manually if the inspection system is not able to differentiate predefined characteristics, for example due to ambiguities caused by the intrinsic characteristic of the product (air bubbles) at the time of inspection. The feasibility is shown during the validation.

2. 灰色通道中的其他缺陷：從技術(shù)角度來看，若檢查系統(tǒng)無法區(qū)分預(yù)定義特征（例如，由于檢查時(shí)產(chǎn)品的固有特征（氣泡）導(dǎo)致的歧義），某些小缺陷（例如小劃痕）應(yīng)進(jìn)行人工復(fù)檢。其可行性在驗(yàn)證期間得到證明。

 

Objects in the grey channel usually do not require more than one re-inspection. Trending is done over the whole batch after the objects have been classified as good or bad.

灰色通道中的物品通常不需要多次復(fù)檢。在物品被分類為合格或不合格后，對整批進(jìn)行趨勢分析。

 

8 Batch Certification/Release

8 批次認(rèn)證/放行

 

For the release decision two criteria need to be evaluated:

對于放行決策，需評估兩個標(biāo)準(zhǔn)：

 

Trending analysis of the 100% batch inspection (see chapter 7) and

1. 100%批次檢查的趨勢分析（見第7章），以及

 

The result of the AQL manual inspection.

2. 可接受質(zhì)量水平（AQL）人工檢查的結(jié)果。

 

The results of 100% visual inspection trending, done as part of manufacturing process, are an integral part of batch documentation, specifying the types of defects found (fibre, turbidity, crack, etc.) as well as a classification of the defect classes such as critical, major or minor. Acceptance criteria should be pre-defined for at least the defect classes defined from all defects found during the 100% inspection process (see above). For automated inspection, these classifications needs to be done on a technical level (side-wall defect, crimping defect,...) and cannot be done using the classification such as critical, major or minor (see above).

作為生產(chǎn)過程一部分開展的100%目視檢查趨勢分析結(jié)果，是批次文件的組成部分，需明確發(fā)現(xiàn)的缺陷類型（纖維、渾濁、裂縫等），并對關(guān)鍵、主要或次要等缺陷類別進(jìn)行分類。至少應(yīng)針對100%檢查過程中發(fā)現(xiàn)的所有缺陷所定義的缺陷類別預(yù)先確定接受標(biāo)準(zhǔn)（見上文）。對于全自動檢查，這些分類需在技術(shù)層面（側(cè)壁缺陷、壓塞缺陷……）進(jìn)行，不能使用關(guān)鍵、主要或次要等分類（見上文）。

 

For the AQL manual inspection, a randomized sampling out of the accepted containers coming from 100% inspected batch should be performed according to a pre-determined AQL procedure. AQL manual inspection may be carried out by production staff under a quality oversight or the quality unit.

對于AQL人工檢查，應(yīng)根據(jù)預(yù)先確定的AQL程序，從100%檢查過的批次中已放行的容器中隨機(jī)抽樣。AQL人工檢查可在質(zhì)量監(jiān)督下由生產(chǎn)人員執(zhí)行，或由質(zhì)量部門執(zhí)行。

 

For release of the batch, the minimum AQL is typically:

對于批放行，典型的最低AQL要求為：

 

Critical: 0 defects within the AQL samples

關(guān)鍵缺陷：AQL樣品中無缺陷

 

Major: ≤ 0.65 AQL

主要缺陷：≤0.65 AQL

 

Minor: ≤ 4.0 AQL

微小缺陷：≤4.0 AQL

 

If an AQL limit is exceeded, the whole considered-to-be-acceptable batch should be re-inspected 100% followed by a second AQL manual inspection with tightened AQL limits. This process is usually not repeated several times. Tightening of AQL limits can be considered and is possible by two ways: Stay on the AQL sample size and use the next (tighter) AQL limit- OR: Stay on the AQL limit and use the next (higher) AQL sample size.

若超出AQL限值，應(yīng)對整批被視為可接受的批次進(jìn)行100%復(fù)檢，隨后采用加嚴(yán)的AQL限值進(jìn)行第二次AQL人工檢查。該過程通常不會重復(fù)多次?？煽紤]加嚴(yán)AQL限值，有兩種方式可行：保持AQL樣本量不變，使用下一個（更嚴(yán)格的）AQL限值——或：保持AQL限值不變，使用下一個（更大的）AQL樣本量。

 

Particles found in AQL testing must be characterized and evaluated according to their nature. If characterization shows that the particle is not process-related the origin must be investigated and assessed prior to further actions. Particular attention during investigation should be paid to possible adulteration, sterility, or other cGMP-related issues of the affected batch.

在AQL測試中發(fā)現(xiàn)的顆粒必須根據(jù)其性質(zhì)進(jìn)行表征和評估。若表征顯示顆粒與工藝無關(guān)，必須在采取進(jìn)一步行動前調(diào)查并評估其來源。調(diào)查期間應(yīng)特別關(guān)注受影響批次可能存在的摻假、無菌性或其他與現(xiàn)行良好生產(chǎn)規(guī)范（cGMP）相關(guān)的問題。

 

If the characterization shows that the particle violation is process-related, the number of units found in AQL must be within the given AQL limits. AQL limit violation of those particles triggers an investigation followed by a 100% reinspection of the batch. A second AQL test of the reinspected batch must then demonstrate successful particle clearance. Using tightened AQL limits should be considered. When particles are rated as major defects (according to USP <790>), and characterization shows that the particle is process-related while AQL limits are met, the batch can be approved for further processing. If AQL limits are exceeded again, a decision on further reinspection must be taken after the investigation has been closed (see figure).

若表征顯示顆粒不符合要求與工藝相關(guān)，則AQL中發(fā)現(xiàn)的單元數(shù)量必須在給定的AQL限值內(nèi)。這些顆粒的AQL限值超標(biāo)會觸發(fā)調(diào)查，隨后對批次進(jìn)行100%復(fù)檢。復(fù)檢批次的第二次AQL測試必須證明顆粒已成功清除。應(yīng)考慮使用加嚴(yán)的AQL限值。當(dāng)顆粒被評定為主要缺陷（根據(jù)USP <790>），且表征顯示顆粒與工藝相關(guān)且AQL限值符合要求時(shí)，批次可獲準(zhǔn)進(jìn)一步加工。若AQL限值再次超標(biāo)，必須在調(diào)查結(jié)束后決定是否進(jìn)一步復(fù)檢（見圖）。

2025版ECA無菌產(chǎn)品燈檢指南發(fā)布

 

 

The number of AQL manual inspection steps should be evident in the batch documentation.

AQL人工檢查的步驟數(shù)量應(yīng)在批次文件中明確體現(xiàn)。

 

AQL manual inspection may be carried out in a separate area without time constraints for the inspectors.

AQL人工檢查可在獨(dú)立區(qū)域進(jìn)行，對檢查人員無時(shí)間限制。

 

The results of the 100% visual inspection trending, and the results of the AQL testing are part of the finished product release assessment that should embrace all relevant factors of the batch. After assessment by quality control or quality assurance, these data should be made available in an easily readable format to the Qualified Person, responsible for batch certification and release decision

100%目視檢查趨勢分析的結(jié)果以及AQL測試的結(jié)果是成品放行評估的一部分，該評估應(yīng)涵蓋批次的所有相關(guān)因素。經(jīng)質(zhì)量控制或質(zhì)量保證部門評估后，這些數(shù)據(jù)應(yīng)以易于閱讀的格式提供給負(fù)責(zé)批次認(rèn)證和放行決策的合格人員。

 

9 Concerns regarding distributed Product

9 關(guān)于已分銷產(chǎn)品的關(guān)注事項(xiàng)

 

When concerns arise regarding particulate matter of product already distributed to the market, it is recommended to inspect several samples following a practical DIN ISO 2859 compliant sampling plan.

當(dāng)對已分銷至市場的產(chǎn)品中的顆粒物產(chǎn)生擔(dān)憂時(shí)，建議按照符合DIN ISO 2859的實(shí)用抽樣計(jì)劃對若干樣品進(jìn)行檢查。

 

As visual inspection for particulates is a probabilistic and not a deterministic process, sampling plans for non-critical defects with a limit of zero are not practical as an assessment tool and should be avoided.

由于顆粒物的目視檢查是一個概率性而非確定性的過程，針對非關(guān)鍵缺陷且限值為零的抽樣計(jì)劃作為評估工具并不實(shí)用，應(yīng)予以避免。

 

The inspection needs to be performed under the same conditions as the routine inspection was performed. The relative batch and sample size will determine the acceptance criteria, if these criteria are met by inspection of these samples, the batch can be considered essentially free of particles.

檢查需在與常規(guī)檢查相同的條件下進(jìn)行。相關(guān)批次和樣品量將決定接受標(biāo)準(zhǔn)，若對這些樣品的檢查符合這些標(biāo)準(zhǔn)，則可認(rèn)為該批次基本無顆粒。

 

It is good practice to isolate particle(s) of any complaint sample and to determine the size and to characterize the nature of the particle(s) during investigation.

在調(diào)查期間，分離投訴樣品中的顆粒，確定其大小并表征其性質(zhì)，是良好的操作規(guī)范。

 

10 Definitions

10 定義

 

AQL

AQL

 

Acceptable Quality Limit, using ANSI/ASQ Z1.4 or ISO 2859-1, general inspection level II

可接受質(zhì)量水平，采用ANSI/ASQ Z1.4或ISO 2859-1，一般檢查水平II

 

CRI-Index:

CRI指數(shù)：

 

The Colour Rendering Index (CRI) is a unit of measure that defines how well colours are rendered by different illumination conditions in comparison to an ideal or natural light source. The Ra value uses only the first eight from the 14 test colours of the DIN 6169. Light sources have different Ra values, e.g. a white LED 80-95; fluorescent lamps 50-90.

顯色指數(shù)（CRI）是一種度量單位，用于界定與理想或自然光源相比，不同照度條件下顏色的呈現(xiàn)效果優(yōu)劣。Ra值僅采用DIN 6169的14種測試顏色中的前8種。光源具有不同的Ra值，例如白色LED為80-95；熒光燈為50-90。

 

Function testkit:

功能測試套件：

 

A functional test kit (system suitability test kit) used before and after the inspection of each batch to demonstrate the functionality of the fully automated inspection system. It may contain an abridged kit of more apparent defects such as big particles, cracked or empty containers.

每批檢查前后使用的功能測試套件（系統(tǒng)適用性測試套件），用于證明全自動檢查系統(tǒng)的功能。它可能包含簡化的套件，其中有較明顯的缺陷，如大顆粒、破裂或空的容器。

 

Particle:

顆粒：

 

A particle in the context of this paper means a readily visible particle with a diameter or span 150 μm or bigger that allows reliable detection (70% probability or higher) in a clear solution. Smaller, for example coloured or shiny particles may be visible down to a size of 50 μm or smaller and thus have also to be counted to the group of visible particles.

在本文中，顆粒指直徑或跨度為150μm或更大、在澄清溶液中可可靠檢查（概率70%或更高）的易見顆粒。更小的顆粒，例如有顏色或有光澤的顆粒，可能小至50μm或更小仍可見，因此也應(yīng)計(jì)入可見顆粒組。

 

PQ

PQ

 

Performance qualification (PQ) is intended to confirm the capabilities of the machine to which extent a specific set of defects (qualification kit) is detectable. This test is conducted by inspecting the samples with the machine several times by finally calculating the detection rate which is the quotient of the number of detected samples by the total amount of samples in a specific category. Thus, the PQ serves to confirm the sensitivity of the machine.

性能確認(rèn)（PQ）旨在確認(rèn)設(shè)備對特定缺陷組（確認(rèn)套件）的可檢查程度。該測試通過用設(shè)備多次檢查樣品，最終計(jì)算檢出率（檢出樣品數(shù)與特定類別中樣品總數(shù)的商）來進(jìn)行。因此，PQ用于確認(rèn)設(shè)備的靈敏度。

 

PV

PV

 

Validation of the inspection system examines the entire inspection process (incl. two-stage AVI + SAVI/MVI, impact of light, etc.). This is part of the process validation (PV). PV shows the suitability of the process under routine conditions.

檢查系統(tǒng)的驗(yàn)證檢查整個檢查過程（包括兩階段AVI + SAVI/MVI、光的影響等）。這是工藝驗(yàn)證（PV）的一部分。PV顯示工藝在常規(guī)條件下的適用性。

 

Qualification kit:

確認(rèn)套件：

 

A set of product specific containers with real product, A test kit of product specific containers with real product, containing randomly distributed defects. All known defects should be contained in the test kit. Any new defects should be added to the test kit after they have been identified. Units of tests kits for the manual inspection containing a defect should be marked or encoded invisibly. Obvious and clear readable numbers or letters should not be used. The kits should be cleaned after usage and routinely checked for defects at least every 6 months. There should be a logbook for each test kit.

一套裝有實(shí)際產(chǎn)品的特定產(chǎn)品容器，是裝有實(shí)際產(chǎn)品的特定產(chǎn)品容器的測試套件，包含隨機(jī)分布的缺陷。所有已知缺陷都應(yīng)包含在測試套件中。任何新缺陷在被識別后應(yīng)添加到測試套件中。人工檢查用的含缺陷測試套件單元應(yīng)進(jìn)行隱形標(biāo)記或編碼。不應(yīng)使用明顯且易讀的數(shù)字或字母。套件使用后應(yīng)清潔，并至少每6個月常規(guī)檢查缺陷。每個測試套件應(yīng)有一本日志。

 

Training kit:

培訓(xùn)套件：

 

A test kit used for the training of the operators of the manual inspection, to teach the possible defects. Similar to the qualification test kit but contains only containers with defects.

用于人工檢查操作員培訓(xùn)的測試套件，用于講解可能的缺陷。與確認(rèn)測試套件類似，但僅包含有缺陷的容器。

 

Visual Inspection:

目視檢查：

 

The process of sorting unacceptable units from acceptable units by human visual inspectors and/or through qualified equipment.

由人類目視檢查人員和/或通過合格設(shè)備將不合格單元從合格單元中分揀出來的過程。

 

Fully automated visual inspection:

全自動目視檢查：

 

The process of sorting unacceptable units from acceptable units by equipment (camera system). Detection and handling of units to be inspected is performed by equipment.

通過設(shè)備（攝像系統(tǒng)）將不合格單元從合格單元中分揀出來的過程。待檢查單元的檢查和處理由設(shè)備執(zhí)行。

 

Fully automated (non-inline) visual inspection:

全自動（非在線）目視檢查：

 

The process of sorting unacceptable units from acceptable units by equipment (camera system) after the batch production has been finished.

批次生產(chǎn)完成后，通過設(shè)備（攝像系統(tǒng)）將不合格單元從合格單元中分揀出來的過程。

 

In-line fully automated visual inspection:

在線全自動目視檢查：

 

The process of sorting unacceptable units from acceptable units by equipment (camera system) parallel or at the same time of the batch production.

在批次生產(chǎn)的同時(shí)，通過設(shè)備（攝像系統(tǒng)）將不合格單元從合格單元中分揀出來的過程。

 

 

本文由廣州佳譽(yù)醫(yī)療器械有限公司/佛山浩揚(yáng)醫(yī)療器械有限公司聯(lián)合編輯