2017-ich指導(dǎo)原則穩(wěn)定性---百度文庫

1、,ICH指導(dǎo)原則 ——穩(wěn)定性,主要內(nèi)容ICH簡介ICH指導(dǎo)原則 Q1A(R2) ICH指導(dǎo)原則 Q1B,ICH簡介,,,說明,ICH的論題主要分為四類，因此ICH根據(jù)論題的類別不同而進(jìn)行相應(yīng)的編碼分類：“Q”類論題：Q代表QUALITY，指那些與化工和醫(yī)藥，質(zhì)量保證方面的相關(guān)的論題。“S”類論題：S代表SAFETY，指那些與實驗室和動物實驗，臨床前研究方面的相關(guān)的論題。3. “E”類論題：

2、E代表EFFICACY，指那些與人類臨床研究相關(guān)的課題。4. “M”類論題：M代表MULTIDISCIPLINARY, 指那些不可單獨劃入以上三個分類的交叉涉及的論題。同時M又細(xì)分為5個小類    M1: 常用醫(yī)學(xué)名詞 （MedDRA）    M2: 藥政信息傳遞之電子標(biāo)準(zhǔn)    M3: 與臨床試驗相關(guān)的臨床前研究時間的安排 &

3、#160;  M4: 常規(guī)技術(shù)文件(CTD)    M5: 藥物詞典的數(shù)據(jù)要素和標(biāo)準(zhǔn),Q1A - Q1F Stability穩(wěn)定性,Q1A(R2) Stability Testing of New Drug Substances and Products 新原料藥和制劑的穩(wěn)定性試驗Q1B Stability Testing : Photostability T

4、esting of New Drug Substances and Products 新原料藥和制劑的光穩(wěn)定性試驗Q1C Stability Testing for New Dosage Forms新劑型的穩(wěn)定性試驗Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products

5、 原料藥和制劑穩(wěn)定性試驗的交叉和矩陣設(shè)計Q1E Evaluation of Stability Data穩(wěn)定性數(shù)據(jù)的評估Q1F Stability Data Package for Registration Applications in Climatic Zones III and IV 在氣候帶III和IV，藥物注冊申請所提供的穩(wěn)定性數(shù)據(jù),Q1A(R2) Stability Testing of

6、 New Drug Substances and Products,1、Drug Substance2、Drug Products,Stress Testing強(qiáng)力破壞試驗是通過建立降解途徑，鑒定可能的降解產(chǎn)物，以確定分子的內(nèi)在穩(wěn)定性，并論證所使用的分析方法是否能反映產(chǎn)品的穩(wěn)定性。,Drug Substance,Stress Testing可以是單批原料藥，包括溫度（一般比加速試驗溫度高10℃）、濕度（75%或者更高）

7、、氧化、光照。,Drug Substance,Selection of Batches 批的選擇三批以上樣品的數(shù)據(jù)試產(chǎn)規(guī)模生產(chǎn)的批次，應(yīng)與在最終規(guī)模生產(chǎn)時的合成路線和生產(chǎn)工藝相同。用于穩(wěn)定性研究的各批次原料藥的總體質(zhì)量應(yīng)既能代表臨床前研究的質(zhì)量，又能代表臨床研究以及規(guī)模生產(chǎn)時的質(zhì)量。,Drug Substance,Container Closure System 包裝與儲存和運輸?shù)陌b相同或相似,Dru

8、g Substance,Specification穩(wěn)定性研究應(yīng)檢驗在儲存期間容易變化的原料藥的屬性，并且可能影響原料藥的質(zhì)量，安全性和/或功效。 檢驗應(yīng)適當(dāng)?shù)睾w物理，化學(xué)，生物和微生物方面。 應(yīng)采用經(jīng)驗證的分析方法。,Drug Substance,Testing Frequency For long term studies, frequency of testing should be sufficient to es

9、tablish the stability profile of the drug substance. For drug substances with a proposed re-test period of at least 12 months, the frequency of testing at the long term storage condition should normally be every 3 months

10、 over the first year, every 6 months over the second year, and annually thereafter through the proposed re-test period. At the accelerated storage condition, a minimum of three time points, including the initial and fin

11、al time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended. Where an expectation (based on development experience) exists that results from accelerated studies are likely to approach significant chang

12、e criteria, increased testing should be conducted either by adding samples at the final time point or by including a fourth time point in the study design.,Drug Substance,Testing Frequency When testing at the intermedi

13、ate storage condition is called for as a result of significant change at the accelerated storage condition, a minimum of four time points, including the initial and final time points (e.g., 0, 6, 9, 12 months), from a 12

14、-month study is recommended.,Drug Substance,Storage Conditions 1、General case *有顯著變化時，增加中間條件,Drug Substance,Storage Conditions 2、Drug substances intended for storage in a refrigerator If signifi

15、cant change occurs within the first 3 months’ testing at the accelerated storage condition, a discussion should be provided to address the effect of short term excursions outside the label storage condition, e.g., during

16、 shipping or handling. 可以進(jìn)一步考察單批原料藥在少于3個月內(nèi)的穩(wěn)定性，提高檢樣頻率。,Drug Substance,Storage Conditions 3、Drug substances intended for storage in a freezer In the absence of an accelerated storage condition for drug substances

17、 intended to be stored in a freezer, testing on a single batch at an elevated temperature (e.g., 5°C ± 3°C or 25°C ± 2°C) for an appropriate time period should be conducted to address the ef

18、fect of short term excursions outside the proposed label storage condition, e.g., during shipping or handling.,Drug Substance,Storage Conditions 4、Drug substances intended for storage below -20°C Drug substances

19、 intended for storage below -20°C should be treated on a case-by-case basis.,Drug Substance,General The design of the formal stability studies for the drug product should be based on knowledge of the behavior and p

20、roperties of the drug substance and from stability studies on the drug substance and on experience gained from clinical formulation studies. The likely changes on storage and the rationale for the selection of attributes

21、 to be tested in the formal stability studies should be stated. 成品穩(wěn)定性試驗設(shè)計應(yīng)以原料藥的性質(zhì)以及從臨床處方研究和原料藥穩(wěn)定性研究中得到的經(jīng)驗為基礎(chǔ)，應(yīng)闡述貯存中可能發(fā)生的變化以及將產(chǎn)品可變因素選入試驗方案的理由。,Drug Product,Selection of Batches Data from stability studies should be prov

22、ided on at least three primary batches of the drug product. The primary batches should be of the same formulation and packaged in the same container closure system as proposed for marketing. The manufacturing process use

23、d for primary batches should simulate that to be applied to production batches and should provide product of the same quality and meeting the same specification as that intended for marketing. Two of the three batches sh

24、ould be at least pilot scale batches and the third one can be smaller, if justified. Where possible, batches of the drug product should be manufactured by using different batches of the drug substance.,Drug Product,Selec

25、tion of Batches 加速和長期試驗的穩(wěn)定性資料至少應(yīng)包括與上市產(chǎn)品具有相同處方、劑型和容器及閉塞物的三批樣品的數(shù)據(jù)，三批中至少有兩批樣品應(yīng)是試生產(chǎn)規(guī)模生產(chǎn)的，第三批可以少一些(如：固體口服劑型可以25000~50000 片劑或膠囊)。長期試驗至申報時至少應(yīng)進(jìn)行12 個月。所用生產(chǎn)工藝應(yīng)盡可能模擬用于上市藥品大規(guī)模生產(chǎn)的工藝，該生產(chǎn)工藝應(yīng)能提供與上市質(zhì)量相同的藥品，同時也要符合與出廠產(chǎn)品相同的質(zhì)量要求。若可能，應(yīng)該用不同

26、批號的原料藥生產(chǎn)幾批成品。,Drug Product,Container Closure System Stability testing should be conducted on the dosage form packaged in the container closure system proposed for marketing (including, as appropriate, any secondary pack

27、aging and container label).,Drug Product,Specification Stability studies should include testing of those attributes of the drug product that are susceptible to change during storage and are likely to influence quality,

28、safety, and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological, and microbiological attributes, preservative content (e.g., antioxidant, antimicrobial preservative), and functional

29、ity tests (e.g., for a dose delivery system). Analytical procedures should be fully validated and stability indicating. Whether and to what extent replication should be performed will depend on the results of validation

30、studies. 試驗項目應(yīng)該包括在貯存期內(nèi)易于改變和可能影響質(zhì)量、安全性和(或)藥效的那些因素。試驗范圍應(yīng)包括物理、化學(xué)、生物以及微生物穩(wěn)定性，還應(yīng)包括防腐劑含量（抗氧劑，抗菌防腐劑）。分析方法應(yīng)經(jīng)過充分論證。,Drug Product,Testing Frequency （同Drug Substance原料藥）For long term studies, frequency of testing should be suffi

31、cient to establish the stability profile of the drug substance. For drug substances with a proposed re-test period of at least 12 months, the frequency of testing at the long term storage condition should normally be eve

32、ry 3 months over the first year, every 6 months over the second year, and annually thereafter through the proposed re-test period. At the accelerated storage condition, a minimum of three time points, including the init

33、ial and final time points (e.g., 0, 3, and 6 months), from a 6-month study is recommended. Where an expectation (based on development experience) exists that results from accelerated studies are likely to approach signif

34、icant change criteria, increased testing should be conducted either by adding samples at the final time point or by including a fourth time point in the study design.,Drug Product,Testing Frequency （同Drug Substance原料藥）

35、When testing at the intermediate storage condition is called for as a result of significant change at the accelerated storage condition, a minimum of four time points, including the initial and final time points (e.g., 0

36、, 6, 9, 12 months), from a 12-month study is recommended.,Drug Product,Storage Conditions 1、General case *有顯著變化時，增加中間條件,Drug Product,In general, “significant change” for a drug product is defined as: 1.

37、A 5% change in assay from its initial value; or failure to meet the acceptance criteria for potency when using biological or immunological procedures; 2. Any degradation product’s exceeding its acceptance criterion; 3.

38、 Failure to meet the acceptance criteria for appearance, physical attributes, and functionality test (e.g., color, phase separation, resuspendibility, caking, hardness, dose delivery per actuation); however, some changes

39、 in physical attributes (e.g., softening of suppositories, melting of creams) may be expected under accelerated conditions; and, as appropriate for the dosage form: 4. Failure to meet the acceptance criterion for pH; o

40、r 5. Failure to meet the acceptance criteria for dissolution for 12 dosage units. （12 粒膠囊或片劑的溶出度超出了規(guī)定限度；）,Drug Product,Storage Conditions 2、Drug products packaged in impermeable containers （藥品包裝在不滲透容器中）Sensitivity

41、to moisture or potential for solvent loss is not a concern for drug products packaged in impermeable containers that provide a permanent barrier to passage of moisture or solvent. Thus, stability studies for products sto

42、red in impermeable containers can be conducted under any controlled or ambient humidity condition.,Drug Product,Storage Conditions 3、Drug products intended for storage in a refrigerator,Drug Product,Storage Conditions

43、4、 Drug products intended for storage in a freezer,Drug Product,Storage Conditions 4、Drug products intended for storage below -20°C Drug substances intended for storage below -20°C should be treated on a