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ICH Q1B 光穩(wěn)定性試驗(yàn)（中英文）
INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE
ICH HARMONISED TRIPARTITE GUIDELINE
STABILITY TESTING: 穩(wěn)定性試驗(yàn)
PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS
新原料藥和新制劑藥物的光穩(wěn)定性測(cè)試
Q1B
Current Step 4 version
現(xiàn)行版本第4步驟
dated 6 November 1996
1996年11月6日
This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA.
Q1B Document History 文件歷史
|
First Codification |
History |
Date |
New Codification November 2005 |
|
Q1B |
Approval by the Steering Committee under Step 2 and release for public consultation |
28 November 1995 |
Q1B |
Current Step 4 version
|
Q1B |
Approval by the Steering Committee under Step 4 and recommendation for adoption to the three ICH regulatory bodies |
6 November 1996 |
Q1B |
STABILITY TESTING: PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS
新原料藥和新制劑藥物的光穩(wěn)定性測(cè)試
ICH Harmonised Tripartite Guideline
Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 6 November 1996, this guideline is recommended for adoption to the three regulatory parties to ICH
TABLE OF CONTENTS 目錄
1. General 概述......................................................................................................................1
A. Preamble 前言.............................................................................................................1
B. Light Sources 光源......................................................................................................2
C. Procedure 程序............................................................................................................2
2. Drug Substance 原料藥.......................................................................................................4
A. Presentation of Samples 樣品放置.....................................................................................4
B. Analysis of Samples 樣品分析............................................................................................5
C. Judgement of Results 結(jié)果判斷.........................................................................................5
3. Drug Product 制劑...........................................................................................................5
A. Presentation of Samples 樣品放置.....................................................................................6
B. Analysis of Samples 樣品分析............................................................................................6
C. Judgement of Results 結(jié)果判斷.........................................................................................6
4. Annex 附件.........................................................................................................................7
A. Quinine Chemical Actinometry 奎寧化學(xué)計(jì)量測(cè)試......................................................7
5. Glossary 術(shù)語(yǔ).....................................................................................................................8
6. References 參考文獻(xiàn)................................................................................................................8
STABILITY TESTING: PHOTOSTABILITY TESTING OF NEW DRUG SUBSTANCES AND PRODUCTS
Q1B 新原料藥和新制劑藥物的光穩(wěn)定性測(cè)試
1. GENERAL概述
The ICH Harmonized Tripartite Guideline covering the Stability Testing of New Drug Substances and Products (hereafter referred to as the Parent Guideline) notes that light testing should be an integral part of stress testing. This document is an annex to the Parent Guideline and addresses the recommendations for photostability testing.
新原料藥和新藥制劑的ICH穩(wěn)定性試驗(yàn)指導(dǎo)原則（以下稱總指導(dǎo)原則）指出光照試驗(yàn)是強(qiáng)力破壞試驗(yàn)中的重要組成部分。本文是總指導(dǎo)原則的附加說(shuō)明，提出了光穩(wěn)定性試驗(yàn)的一些建議。
A. Preamble前言
The intrinsic photostability characteristics of new drug substances and products should be evaluated to demonstrate that, as appropriate, light exposure does not result in unacceptable change. Normally, photostability testing is carried out on a single batch of material selected as described under Selection of Batches in the Parent Guideline. Under some circumstances these studies should be repeated if certain variations and changes are made to the product (e.g., formulation, packaging). Whether these studies should be repeated depends on the photostability characteristics determined at the time of initial filing and the type of variation and/or change made.
新原料藥和新藥制劑應(yīng)經(jīng)過(guò)適當(dāng)?shù)墓夥€(wěn)定特征考察，證明其本身的光穩(wěn)定性，即光照不能引起不可接受的變化。按照總指導(dǎo)原則中“批號(hào)選擇”，光穩(wěn)定性試驗(yàn)只須選做一批樣品。在某些情況下如當(dāng)這個(gè)產(chǎn)品發(fā)生變更或變化時(shí)（如處方、包裝），這些研究應(yīng)再重復(fù)進(jìn)行。這些研究是否必須重復(fù)進(jìn)行取決于初次申報(bào)文件中所測(cè)定的該物質(zhì)的光穩(wěn)定特征及變更或變化的類型。
The guideline primarily addresses the generation of photostability information for submission in Registration Applications for new molecular entities and associated drug products. The guideline does not cover the photostability of drugs after administration (i.e. under conditions of use) and those applications not covered by the Parent Guideline. Alternative approaches may be used if they are scientifically sound and justification is provided.
本指導(dǎo)原則主要闡述注冊(cè)申報(bào)新化合物及其制劑時(shí)所需報(bào)送的光穩(wěn)定性試驗(yàn)資料，不包括給藥后（即使用中的）的光穩(wěn)定性試驗(yàn)和總指導(dǎo)原則中未包括其用法的藥物的申報(bào)內(nèi)容。如果有科學(xué)合理的其他替代方法也可采用。
A systematic approach to photostability testing is recommended covering, as appropriate, studies such as:
建議光穩(wěn)定性試驗(yàn)研究包括：
i) Tests on the drug substance;
I. 原料藥光穩(wěn)定性測(cè)試
ii) Tests on the exposed drug product outside of the immediate pack; and if necessary ;
II. 對(duì)除去內(nèi)包裝的制劑試驗(yàn)（如需要）；
iii) Tests on the drug product in the immediate pack; and if necessary ;
III. 對(duì)除去外包裝的制劑試驗(yàn)（如需要）；
iv) Tests on the drug product in the marketing pack.
IV. 上市包裝的制劑試驗(yàn)。
The extent of drug product testing should be established by assessing whether or not acceptable change has occurred at the end of the light exposure testing as described in the Decision Flow Chart for Photostability Testing of Drug Products. Acceptable change is change within limits justified by the applicant. The formal labeling requirements for photolabile drug substances and drug products are established by national/regional requirements.
按判斷圖指示進(jìn)行藥物光穩(wěn)定性試驗(yàn)，可根據(jù)到哪一步發(fā)生了可以接受的變化來(lái)決定試驗(yàn)到哪一步即可停止，“可接受的變化”是指經(jīng)申報(bào)者論證合理的限度內(nèi)的變化。光敏性藥物和制劑是否要在標(biāo)簽上標(biāo)記要求，由國(guó)家和地區(qū)確定。
B. Light Sources 光源
The light sources desc ribed below may be used for photostability testing. The applicant should either maintain an appropriate control of temperature to minimize the effect of localized temperature changes or include a dark control in the same environment unless otherwise justified. For both options 1 and 2, a pharmaceutical manufacturer/applicant may rely on the spectral distribution specification of the light source manufacturer.
以下描述的光源可以用于光穩(wěn)定性測(cè)試。申報(bào)者應(yīng)該對(duì)溫度進(jìn)行適當(dāng)?shù)目刂?，以降低溫度?duì)該檢測(cè)的影響或者是在相同的環(huán)境下進(jìn)行暗度控制（避光對(duì)照），如有另有說(shuō)明者除外。不管選擇1還是2，藥劑生產(chǎn)者或者申報(bào)者均可以采用光源生產(chǎn)商所給定的光譜分布規(guī)格數(shù)據(jù)。
Option 1
Any light source that is designed to produce an output similar to the D65/ID65 emission standard such as an artificial daylight fluorescent lamp combining visible and ultraviolet (UV) outputs, xenon, or metal halide lamp. D65 is the internationally recognized standard for outdoor daylight as defined in ISO 10977 (1993). ID65 is the equivalent indoor indirect daylight standard. For a light source emitting significant radiation below 320 nm, an appropriate filter(s) may be fitted to eliminate such radiation.
選擇1：
采用任何輸出相似于D65／ID65 發(fā)射標(biāo)淮的光源，如具有可見光和紫外光輸出的人造日光熒光燈、 氙燈或金屬鹵化物燈。D65 是國(guó)際上認(rèn)可的室外日光標(biāo)準(zhǔn)，在1993年的ISO10977中對(duì)此進(jìn)行了規(guī)定，ID65是相當(dāng)于室內(nèi)間接日光光照的標(biāo)準(zhǔn)。光源發(fā)射光低于320nm時(shí)，應(yīng)當(dāng)配備適當(dāng)?shù)难b置去濾除此光。
Option 2 選擇2
For option 2 the same sample should be exposed to both the cool white fluorescent and near ultraviolet lamp.
對(duì)于本選擇，應(yīng)使用相同的樣品同時(shí)采用于冷白熒光燈和近紫外熒光燈照射。
1. A cool white fluorescent lamp designed to produce an output similar to that specified in ISO 10977(1993) ; and
冷白熒光燈應(yīng)具有與ISO10977（1993）中規(guī)定的輸出功率
2. A near UV fluorescent lamp having a spectral distribution from 320 nm to 400 nm with a maximum energy emission between 350 nm and 370 nm; a significant proportion of UV should be in both bands of 320 to 360 nm and 360 to 400 nm.
近紫外熒光燈可以發(fā)射的光線在320~400nm，在350~370nm有一個(gè)最大的能量發(fā)射；紫外線的重要組成部分應(yīng)當(dāng)是在320~360nm，和360~400nm的范圍內(nèi)
C. Procedure規(guī)程
For confirmatory studies, samples should be exposed to light providing an overall illumination of not less than 1.2 million lux hours and an integrated near ultraviolet energy of not less than 200 watt hours/square meter to allow direct comparisons to be made between the drug substance and drug product.
在確認(rèn)研究中，樣品應(yīng)暴露在總照度不低于1.2×106Lux.hr，近紫外能量不低于200w.hr/m2，直接在藥物和制劑之間進(jìn)行比較。
Samples may be exposed side-by-side with a validated chemical actinometric system to ensure the specified light exposure is obtained, or for the appropriate duration of time when conditions have been monitored using calibrated radiometers/lux meters. An example of an actinometric procedure is provided in the Annex.
樣品可與經(jīng)論證過(guò)的光化強(qiáng)度系統(tǒng)并排暴露于有效的光化強(qiáng)度下，以確保獲得指定的光暴露，或在用經(jīng)校正的測(cè)光儀或照度儀監(jiān)測(cè)的條件下，持續(xù)相當(dāng)?shù)臅r(shí)間。附錄中提供了光化強(qiáng)度測(cè)定方法的例子。
If protected samples (e.g., wrapped in aluminum foil) are used as dark controls to evaluate the contribution of thermally induced change to the total observed change, these should be placed alongside the authentic sample.
若用遮光對(duì)照樣品（如用鋁箔包裝）作為暗度控制來(lái)考察由熱引起的變化對(duì)總變化的影響，應(yīng)使其與真實(shí)樣品并排放置。
注解：Lux：勒克斯，亮度單位，在英國(guó)叫做尺光度，在歐洲叫做lux，具體來(lái)說(shuō)1勒克斯相當(dāng)于一只蠟燭從1米外投射在一平方米的表面上的光的數(shù)量。
DECISION FLOW CHART FOR PHOTOSTABILITY TESTING OF DRUG PRODUCTS
藥物光穩(wěn)定性測(cè)試流程示意圖
2. DRUG SUBSTANCE 原料藥
For drug substances, photostability testing should consist of two parts: forced degradation testing and confirmatory testing.
對(duì)于原料藥，光穩(wěn)定性測(cè)試包括兩個(gè)方面的內(nèi)容：強(qiáng)制的降解試驗(yàn)和確認(rèn)性試驗(yàn)
The purpose of forced degradation testing studies is to evaluate the overall photosensitivity of the material for method development purposes and/or degradation pathway elucidation. This testing may involve the drug substance alone and/or in simple solutions/suspensions to validate the analytical procedures. In these studies, the samples should be in chemically inert and transparent containers. In these forced degradation studies, a variety of exposure conditions may be used, depending on the photosensitivity of the drug substance involved and the intensity of the light sources used. For development and validation purposes it is appropriate to limit exposure and end the studies if extensive decomposition occurs. For photostable materials, studies may be terminated after an appropriate exposure level has been used. The design of these experiments is left to the applicant’s discretion although the exposure levels used should be justified.
強(qiáng)制降解試驗(yàn)研究的目的是對(duì)藥物的總的光敏性進(jìn)行研究評(píng)價(jià)，以建立測(cè)試方法和說(shuō)明降解路徑。強(qiáng)制降解試驗(yàn)對(duì)象包括藥物本身和（或）它的簡(jiǎn)單的溶液或混懸液，以確證分析方法。在這些研究中，樣品應(yīng)盛裝在化學(xué)惰性的透明容器中。強(qiáng)制降解研究中可能使用各種暴露條件，這取決于藥物本身的光敏性和所使用的光源強(qiáng)度。在建立和論證（方法）時(shí)，如發(fā)生大量分解，即可限制暴露和中止研究。對(duì)于光穩(wěn)定性物質(zhì)，在適當(dāng)?shù)墓獗┞逗蠹纯梢灾兄寡芯俊ｋm然采用的暴露水平是應(yīng)經(jīng)論證的，但試驗(yàn)設(shè)計(jì)可由申報(bào)者自己定。
Under forcing conditions, decomposition products may be observed that are unlikely to be formed under the conditions used for confirmatory studies. This information may be useful in developing and validating suitable analytical methods. If in practice it has been demonstrated they are not formed in the confirmatory studies, these degradation products need not be further examined.
在強(qiáng)制條件下，可能會(huì)觀察到在確認(rèn)研究條件下不易生成的分解產(chǎn)物，這一信息對(duì)建立和論證分析方法是有用的。如果實(shí)際證明這些降解產(chǎn)物在確認(rèn)研究中并不會(huì)產(chǎn)生，就不必對(duì)它們進(jìn)一步實(shí)驗(yàn)。
Confirmatory studies should then be undertaken to provide the information necessary for handling, packaging, and labeling (see section I.C., Procedure, and II.A., Presentation, for information on the design of these studies).
接著進(jìn)行確認(rèn)研究以提供處理、包裝、標(biāo)簽等所需要的信息（設(shè)計(jì)這些研究所需的信息，見1.C方法和IIA樣品放置）
Normally, only one batch of drug substance is tested during the development phase, and then the photostability characteristics should be confirmed on a single batch selected as described in the Parent Guideline if the drug is clearly photostable or photolabile. If the results of the confirmatory study are equivocal, testing of up to two additional batches should be conducted. Samples should be selected as described in the Parent Guideline.
一般說(shuō)來(lái)，在研制階段只需測(cè)試一批樣品，如果原料藥明顯光穩(wěn)定或光不穩(wěn)定，可以根據(jù)指導(dǎo)原則選擇一批樣品來(lái)確定光穩(wěn)定性特征。如果確認(rèn)結(jié)果不明確，應(yīng)加試兩個(gè)批號(hào)的樣品，樣品選擇應(yīng)符合總指導(dǎo)原則。
A. Presentation of Samples 樣品的放置
Care should be taken to ensure that the physical characteristics of the samples under test are taken into account and efforts should be made, such as cooling and/or placing the samples in sealed containers, to ensure that the effects of the changes in physical states such as sublimation, evaporation or melting are minimized. All such precautions should be chosen to provide minimal interference with the exposure of samples under test. Possible interactions between the samples and any material used for containers or for general protection of the sample, should also be considered and eliminated wherever not relevant to the test being carried out.
應(yīng)充分考慮受試樣品的物理性質(zhì)，采取措施如冷藏和&或置密閉容器中，以確保物理狀態(tài)變化如升華、蒸發(fā)、熔化所造成的影響為最小。應(yīng)采取各種預(yù)防措施使供試品光照時(shí)少受其他因素的影響。無(wú)論與進(jìn)行的試驗(yàn)有無(wú)關(guān)系，都應(yīng)考慮并排除樣品與包裝材料之間可能存在的相互反應(yīng)。
As a direct challenge for samples of solid drug substances, an appropriate amount of sample should be taken and placed in a suitable glass or plastic dish and protected with a suitable transparent cover if considered necessary. Solid drug substances should be spread across the container to give a thickness of typically not more than 3 millimeters. Drug substances that are liquids should be exposed in chemically inert and transparent containers.
固體原料藥的樣品，應(yīng)取適量放在適宜的玻璃或塑料碟中，必要時(shí)以適宜的透明蓋子保護(hù)。固體藥物應(yīng)分散在容器中，厚度不超過(guò)3毫米。液體藥物應(yīng)存放在化學(xué)惰性的透明容器中。
B. Analysis of Samples 樣品分析
At the end of the exposure period, the samples should be examined for any changes in physical properties (e.g., appearance, clarity, or color of solution) and for assay and degradants by a method suitably validated for products likely to arise from photochemical degradation processes.
光照時(shí)間一到，就要檢查樣品是否有物理性質(zhì)（如外觀、溶液的顏色或澄清度）、含量和降解物的變化。用一種經(jīng)論證可以檢測(cè)出光降解物質(zhì)的合理方法，測(cè)定光化反應(yīng)降解產(chǎn)生的降解物質(zhì)。
Where solid drug substance samples are involved, sampling should ensure that a representative portion is used in individual tests. Similar sampling considerations, such as homogenization of the entire sample, apply to other materials that may not be homogeneous after exposure. The analysis of the exposed sample should be performed concomitantly with that of any protected samples used as dark controls if these are used in the test.
對(duì)于固體原料藥，取樣應(yīng)確保在每一項(xiàng)試驗(yàn)中所用的樣品具代表性。對(duì)于光照后可能會(huì)不均勻的物質(zhì)，取樣時(shí)需考慮整個(gè)樣品的均勻化。如果試驗(yàn)中有用于暗度控制研究的樣品（可用各種方法將樣品保護(hù)起來(lái)不受光照），則應(yīng)與光照過(guò)的樣品同時(shí)測(cè)定。
C. Judgement of Results 結(jié)果判定
The forced degradation studies should be designed to provide suitable information to develop and validate test methods for the confirmatory studies. These test methods should be capable of resolving and detecting photolytic degradants that appear during the confirmatory studies. When evaluating the results of these studies, it is important to recognize that they form part of the stress testing and are not therefore designed to establish qualitative or quantitative limits for change.
“強(qiáng)制降解”研究應(yīng)設(shè)計(jì)成能為建立和論證“確認(rèn)研究”的試驗(yàn)方法提供適當(dāng)?shù)男畔?。這些試驗(yàn)方法應(yīng)能分辨和檢測(cè)確認(rèn)研究中出現(xiàn)的光降解物質(zhì)。在評(píng)價(jià)這些研究結(jié)果時(shí)，重要的是應(yīng)考慮到他們是組成強(qiáng)力破壞試驗(yàn)的一部分，而并不是設(shè)計(jì)成去建立這些變化的定量和定性限度。
The confirmatory studies should identify precautionary measures needed in manufacturing or in formulation of the drug product, and if light resistant packaging is needed. When evaluating the results of confirmatory studies to determine whether change due to exposure to light is acceptable, it is important to consider the results from other formal stability studies in order to assure that the drug will be within justified limits at time of use (see the relevant ICH Stability and Impurity Guidelines).
確認(rèn)研究應(yīng)提供生產(chǎn)和制劑處方中所必要的預(yù)防措施，是否需要避光包裝。當(dāng)評(píng)估確認(rèn)研究的結(jié)果以決定光照所引起的變化是否可接受時(shí)，必須同時(shí)考慮其他正式的穩(wěn)定性研究結(jié)果，以確保藥物在使用期內(nèi)符合合理范圍。（見ICH 穩(wěn)定性及雜質(zhì)指導(dǎo)原則）
3. DRUG PRODUCT制劑藥物
Normally, the studies on drug products should be carried out in a sequential manner starting with testing the fully exposed product then progressing as necessary to the product in the immediate pack and then in the marketing pack. Testing should progress until the results demonstrate that the drug product is adequately protected from exposure to light. The drug product should be exposed to the light conditions described under the procedure in section I.C.
通常對(duì)制劑的研究應(yīng)進(jìn)行一系列試驗(yàn)，首先制劑應(yīng)完全暴露進(jìn)行試驗(yàn)，如有必要，再以內(nèi)包裝進(jìn)行試驗(yàn)，最后以上市包裝進(jìn)行試驗(yàn)。試驗(yàn)一直做到結(jié)果證明在光照下藥物也受到了足夠的保護(hù)。制劑應(yīng)按1.C 章節(jié)中所描述的方法進(jìn)行光照試驗(yàn)。
Normally, only one batch of drug product is tested during the development phase, and then the photostability characteristics should be confirmed on a single batch selected as described in the Parent Guideline if the product is clearly photostable or photolabile. If the results of the confirmatory study are equivocal, testing of up to two additional batches should be conducted.
一般來(lái)說(shuō)，在開發(fā)研究階段，只測(cè)試一批樣品，如果產(chǎn)品對(duì)光穩(wěn)定或不穩(wěn)定表現(xiàn)明顯，則光穩(wěn)定試驗(yàn)應(yīng)按照總指導(dǎo)原則所描述的方法選擇一個(gè)批號(hào)進(jìn)行；如果確認(rèn)研究結(jié)果比較含糊，應(yīng)再試驗(yàn)兩批以上的樣品。
For some products where it has been demonstrated that the immediate pack is completely impenetrable to light, such as aluminium tubes or cans, testing should normally only be conducted on directly exposed drug product.
對(duì)有些制劑已證明其內(nèi)包裝完全避光，如鋁管或鋁罐，一般只需做制劑的直接暴露試驗(yàn)。
It may be appropriate to test certain products such as infusion liquids, dermal creams, etc., to support their photostability in-use. The extent of this testing should depend on and relate to the directions for use, and is left to the applicant’s discretion.
有些制劑如輸液、皮膚用霜?jiǎng)┑?，?yīng)做一些試驗(yàn)證明其使用時(shí)的光穩(wěn)定性。試驗(yàn)的程度取決于使用方式，由申報(bào)者自行考慮。
The analytical procedures used should be suitably validated.
所有分析方法應(yīng)經(jīng)合適的論證。
A. Presentation of Samples樣品的放置
Care should be taken to ensure that the physical characteristics of the samples under test are taken into account and efforts, such as cooling and/or placing the samples in sealed containers, should be made to ensure that the effects of the changes in physical states are minimized, such as sublimation, evaporation, or melting. All such precautions should be chosen to provide a minimal interference with the irradiation of samples under test. Possible interactions between the samples and any material used for containers or for general protection of the sample should also be considered and eliminated wherever not relevant to the test being carried out.
應(yīng)認(rèn)真考慮受試樣品的物理性質(zhì)，例如采取措施如冷藏和(或置密閉容器中，以確保物理狀態(tài)變化如升華、蒸發(fā)、熔化所造成的影響為最小。預(yù)先應(yīng)采取必要措施，使受試樣品少受這些因素的影響。無(wú)論與進(jìn)行的試驗(yàn)有無(wú)關(guān)系，都應(yīng)考慮并排除樣品與包裝材料之間可能存在的相互反應(yīng)。
Where practicable when testing samples of the drug product outside of the primary pack, these should be presented in a way similar to the conditions mentioned for the drug substance. The samples should be positioned to provide maximum area of exposure to the light source. For example, tablets, capsules, etc., should be spread in a single layer.
除去包裝的受試樣品放置條件應(yīng)與原料藥條件相似，保證受到最大面積的光照，如片劑、膠囊劑應(yīng)分散為單層。
If direct exposure is not practical (e.g., due to oxidation of a product), the sample should be placed in a suitable protective inert transparent container (e.g., quartz).
如果直接暴露不可行（如由于藥品易氧化），樣品應(yīng)放在合適的惰性透明容器中（如石英容器）。
If testing of the drug product in the immediate container or as marketed is needed, the samples should be placed horizontally or transversely with respect to the light source, whichever provides for the most uniform exposure of the samples. Some adjustment of testing conditions may have to be made when testing large volume containers (e.g., dispensing packs).
若樣品需在內(nèi)包裝或在上市包裝的條件下進(jìn)行試驗(yàn)，樣品應(yīng)水平放置或橫面對(duì)光源，以保證樣品得到最大均勻的光照，當(dāng)試驗(yàn)大體積容器包裝的樣品時(shí)，有些試驗(yàn)條件應(yīng)調(diào)整（如分散包裝）。
B. Analysis of Samples樣品的分析
At the end of the exposure period, the samples should be examined for any changes in physical properties (e.g., appearance, clarity or color of solution, dissolution/disintegration for dosage forms such as capsules, etc.) and for assay and degradants by a method suitably validated for products likely to arise from photochemical degradation processes.
光照結(jié)束后，應(yīng)檢查樣品的所有物理性質(zhì)（如：外觀、溶液的澄清度或顏色、固體制劑如膠囊劑等的溶解度或崩解度）的變化并進(jìn)行含量、降解產(chǎn)物測(cè)定。所采用的分析方法應(yīng)經(jīng)過(guò)論證，可證實(shí)它適合檢出光化學(xué)降解過(guò)程中所生成的物質(zhì)。
When powder samples are involved, sampling should ensure that a representative portion is used in individual tests. For solid oral dosage form products, testing should be conducted on an appropriately sized composite of, for example, 20 tablets or capsules. Similar sampling considerations, such as homogenization or solubilization of the entire sample, apply to other materials that may not be homogeneous after exposure (e.g., creams, ointments, suspensions, etc.). The analysis of the exposed sample should be performed concomitantly with that of any protected samples used as dark controls if these are used in the test.
對(duì)于粉末狀樣品，取樣時(shí)應(yīng)確保每一份測(cè)定的供試品具有代表性。對(duì)固體口服制劑，應(yīng)取合適的量，如片劑或膠囊20 片或粒。對(duì)光照后可能不均一的樣品（如霜?jiǎng)④浉?、混懸劑）也同樣?yīng)考慮其采樣的代表性問(wèn)題，如對(duì)整個(gè)樣品進(jìn)行均勻化或溶解增溶。如果有暗度控制的樣品，則光照的樣品應(yīng)與這些保護(hù)性樣品同時(shí)進(jìn)行分析。
C. Judgement of Results結(jié)果判定
Depending on the extent of change special labeling or packaging may be needed to mitigate exposure to light. When evaluating the results of photostability studies to determine whether change due to exposure to light is acceptable, it is important to consider the results obtained from other formal stability studies in order to assure that the product will be within proposed specifications during the shelf life (see the relevant ICH Stability and Impurity Guidelines).
根據(jù)變化的程度，可采用特殊標(biāo)簽或包裝來(lái)限制儲(chǔ)藏中的樣品的光照。當(dāng)評(píng)估光穩(wěn)定性試驗(yàn)結(jié)果以確定由光照引起何種程度的變化是可接受時(shí)，必須綜合考慮其他正式穩(wěn)定性研究的結(jié)果，以確保藥品在貨架壽命產(chǎn)品會(huì)一直在規(guī)定的規(guī)格范圍之內(nèi)。（見ICH穩(wěn)定性和雜質(zhì)指導(dǎo)原則）
4. ANNEX附件
A. Quinine Chemical Actinometry
The following provides details of an actinometric procedure for monitoring exposure to a near UV fluorescent lamp (based on FDA/National Institute of Standards and Technology study). For other light sources/actinometric systems, the same approach may be used, but each actinometric system should be calibrated for the light source used.
Prepare a sufficient quantity of a 2 per cent weight/volume aqueous solution of quinine monohydrochloride dihydrate (if necessary, dissolve by heating).
A. 奎寧的光化強(qiáng)度
以下詳細(xì)介紹監(jiān)控暴露在近UV, 熒光燈（根據(jù)FDA/國(guó)家標(biāo)準(zhǔn)和技術(shù)研究所）下的光化強(qiáng)度方法。對(duì)其他光源/ 光化體系，也可使用相同的方法，但各光化系統(tǒng)均應(yīng)根據(jù)所采用的光源作校正。
準(zhǔn)備足量的2%（W/V）鹽酸奎寧二水合物的水溶液（必要時(shí)加熱溶解）。
Option 1
Put 10 milliliters (ml) of the solution into a 20 ml colorless ampoule seal it hermetically, and use this as the sample. Separately, put 10 ml of the solution into a 20 ml colourless ampoule (see note 1), seal it hermetically, wrap in aluminum foil to protect completely from light, and use this as the control. Expose the sample and control to the light source for an appropriate number of hours. After exposure determine the absorbances of the sample (AT) and the control (Ao) at 400 nm using a 1 centimeter (cm) path length. Calculate the change in absorbance, Δ A = AT - Ao. The length of exposure should be sufficient to ensure a change in absorbance of at least 0.9.
方法1
將10ml溶液置20ml無(wú)色安瓿中，密封，以此作為樣品；另將10ml 溶液置20ml無(wú)色安瓿（見注1）密封，包鋁箔避光，作為對(duì)照；將上述兩安瓿于光源中光照數(shù)小時(shí)后，在400nm波長(zhǎng)處，用1cm石英池測(cè)定樣品吸收度（At）和對(duì)照品吸收度（Ao），計(jì)算△A=At-Ao。光照時(shí)間應(yīng)足夠，確?！?/span>A 不小于0.9。
Option 2
Fill a 1 cm quartz cell and use this as the sample. Separately fill a 1 cm quartz cell, wrap in aluminum foil to protect completely from light, and use this as the control. Expose the sample and control to the light source for an appropriate number of hours. After exposure determine the absorbances of the sample (AT) and the control (Ao) at 400 nm. Calculate the change in absorbance, Δ A = AT - Ao. The length of exposure should be sufficient to ensure a change in absorbance of at least 0.5.
Alternative packaging configurations may be used if appropriately validated. Alternative validated chemical actinometers may be used.
方法2：
將溶液加到一個(gè)1cm的石英池中，將其作為樣品。另外，將溶液加入到一個(gè)1cm的石英池中，將其包在鋁薄中以保證完全避免光照，將其作為對(duì)照樣品。在一定的時(shí)間段內(nèi)，將檢測(cè)樣品和對(duì)照樣品暴露在光照下，光照會(huì)影響到樣品和對(duì)照樣品的吸收度，計(jì)算二者吸收度的變化，△A=AT-Ao。光照時(shí)間應(yīng)足夠，確保△A不小于0.5。
如果經(jīng)過(guò)了驗(yàn)證，其他包裝結(jié)構(gòu)也可以使用?？墒褂闷渌?jīng)論證的光化線測(cè)量?jī)x。
Note 1: Shape and Dimensions (See Japanese Industry Standard (JIS) R3512 (1974) for ampoule specifications)
注釋一：安瓿的形狀和直徑（參考日本工業(yè)標(biāo)準(zhǔn)（JLS）R3512（1974）中的特定安瓿）
5. GLOSSARY名詞解釋
Immediate (primary) pack is that constituent of the packaging that is in direct contact with the drug substance or drug product, and includes any appropriate label.
內(nèi)包裝指包裝中直接接觸原料藥或制劑的包裝，包括任何適當(dāng)?shù)臉?biāo)簽。
Marketing pack is the combination of immediate pack and other secondary packaging such as a carton.
上市包裝指內(nèi)包裝和其他層次包裝（如紙盒）的總和。
Forced degradation testing studies are those undertaken to degrade the sample deliberately. These studies, which may be undertaken in the development phase normally on the drug substances, are used to evaluate the overall photosensitivity of the material for method development purposes and/or degradation pathway elucidation.
強(qiáng)制降解試驗(yàn)研究指有意地使樣品降解的實(shí)驗(yàn)，這些研究一般在原料藥處于開發(fā)階段時(shí)進(jìn)行，用于評(píng)價(jià)藥物的總光敏性，以建立測(cè)試方法和（或）說(shuō)明降解途徑。
Confirmatory studies are those undertaken to establish photostability characteristics under standardized conditions. These studies are used to identify precautionary measures needed in manufacturing or formulation and whether light resistant packaging and/or special labeling is needed to mitigate exposure to light. For the confirmatory studies, the batch(es) should be selected according to batch selection for long-term and accelerated testings which is described in the Parent Guideline.
確認(rèn)研究指在標(biāo)準(zhǔn)化條件下確立一個(gè)光穩(wěn)定性特征的實(shí)驗(yàn)研究，這些研究用于指導(dǎo)生產(chǎn)工藝是否采取保護(hù)性措施，以及決定是否采用避光包裝或特使標(biāo)簽來(lái)保護(hù)藥品減少光照。確認(rèn)研究的樣品批號(hào)選擇應(yīng)根據(jù)總指導(dǎo)原則所規(guī)定的長(zhǎng)期和加速試驗(yàn)的批號(hào)選擇。
6. REFERENCES參考書
Quinine Actinometry as a method for calibrating ultraviolet radiation intensity in light-stability testing of pharmaceuticals. 藥劑光穩(wěn)定性測(cè)試中用奎寧感光法來(lái)校正紫外輻射強(qiáng)度。
Yoshioka S. et al., Drug Development and Industrial Pharmacy, 20 (13), 2049 - 2062 (1994).
Yoshioka S.et al., 藥劑研發(fā)和工業(yè)生產(chǎn)，20（13），2049～2062（1994）
蘭貝石藥品強(qiáng)光照射試驗(yàn)箱符合以上法規(guī)要求，并加入了照度的存儲(chǔ)打印功能
