FDA對藥物雜質(zhì)的控制要求.ppt

1、,FDA對藥物雜質(zhì)的控制要求,Dr.George Ma 馬小波博士 Toronto, CANADA 多倫多市，加拿大,國家食品藥品監(jiān)督管理局培訓(xùn)中心高級培訓(xùn)班 “美國仿制藥申報(bào)最新要求和案例分析”,FDA對藥物雜質(zhì)的控制要求：Contents 目錄,原料藥與成品藥中的有機(jī)雜質(zhì) 有機(jī)雜質(zhì)來源和控制 有機(jī)雜質(zhì)控制限度的論證 案例分析：雜質(zhì)控制限度的設(shè)置和論證 練習(xí)-雜質(zhì)控制限度的設(shè)置和論證 原料藥與成品藥中的殘留溶劑 殘留溶劑的指導(dǎo)原則和控制限額的建立 案例分析：如何建立殘留溶劑控制限額 具有基因毒性雜質(zhì)的控制 練習(xí)-殘留溶劑控制限額的建立和論證,Drug Production and Quali

2、ty Control Synthesis of API,FDA對藥物雜質(zhì)的控制要求 原料藥與成品藥中的有機(jī)雜質(zhì),1999年11月，F(xiàn)DA-“仿制藥申請的原料藥雜質(zhì)研究指導(dǎo)原則”，“仿制藥申請的制劑雜質(zhì)研究指導(dǎo)原則”。 2003年，ICH修訂的Q3A(R)“新原料藥雜質(zhì)研究指導(dǎo)原則”，“新制劑的雜質(zhì)研究指導(dǎo)原則”（簡稱Q3B(R)。 雜質(zhì)分類 有機(jī)雜質(zhì) 合成雜質(zhì)(Synthetic Impurity)或工藝雜質(zhì)(Process Impurity)：一般來自生產(chǎn)過程中殘留的原料、中間體、試劑、配體和催化劑以及反應(yīng)副產(chǎn)物。只與原料藥的生產(chǎn)過程有關(guān)，在原料藥和制劑的儲存中一般不可能增長。通過對合成路線

3、的分析可以確定某一雜質(zhì)是否為合成雜質(zhì)。 降解產(chǎn)物(Degradation Product):來源于原料藥通過各種不同的化學(xué)反應(yīng)途徑的降解，一般需要結(jié)合對合成路線的分析和試驗(yàn)研究的結(jié)果，以確定某一雜質(zhì)是否為降解產(chǎn)物。 有的有機(jī)雜質(zhì)既是合成雜質(zhì)，又是降解產(chǎn)物。 無機(jī)雜質(zhì)：來自生產(chǎn)過程所用的試劑（如氯化物）、配體和催化劑（如鈀，鉑等），包括重金屬或其它金屬殘留，以及無機(jī)鹽（例如，助濾劑、活性炭等）。它們通常是已知和確定的。 殘留溶劑：生產(chǎn)過程中使用后未完全除去的溶劑（如甲醇、甲苯、四氫呋喃等），殘留的可揮發(fā)性試劑（如三乙胺等）和反應(yīng)中生成的可揮發(fā)產(chǎn)物。,有機(jī)雜質(zhì)來源,常見的降解反應(yīng),常見的降解反應(yīng),

4、確定降解產(chǎn)物-強(qiáng)制降解研究（Forced Degradation Study),強(qiáng)制降解試驗(yàn)：將原料藥或制劑置于比通常儲存條件劇烈得多的試驗(yàn)條件下進(jìn)行穩(wěn)定性考察的一系列試驗(yàn)。 目的： 了解該藥品的穩(wěn)定性及其降解途徑與降解產(chǎn)物。 在一定程度上對有關(guān)物質(zhì)分析方法的專屬性進(jìn)行驗(yàn)證。 實(shí)際操作：試劑的濃度、反應(yīng)的溫度和時(shí)間等都應(yīng)根據(jù)具體情況作調(diào)整。 強(qiáng)制降解程度：根據(jù)經(jīng)驗(yàn)一般認(rèn)為，控制適當(dāng)?shù)膹?qiáng)制降解條件，從而達(dá)到大約10%的原料藥降解是比較合適的。 常見的強(qiáng)制降解具體試驗(yàn)項(xiàng)目與試驗(yàn)條件,確定降解產(chǎn)物-原料藥和制劑的穩(wěn)定性試驗(yàn),長期（25 2 、相對濕度60% 5%、至少12個月）穩(wěn)定性試驗(yàn) 加速（ 4

5、0 2 、相對濕度75% 5%、至少6個月）穩(wěn)定性試驗(yàn) 分析研究收集到的穩(wěn)定性測試數(shù)據(jù)（Stability Data）也是確定降解產(chǎn)物的重要依據(jù)之一。一般測定不同時(shí)間樣品的HPLC圖譜并進(jìn)行比較分析，并與長期保留制劑樣品的測定結(jié)果進(jìn)行比較。 在強(qiáng)制降解試驗(yàn)研究過程中注意觀察樣品外觀性狀、原料藥含量等變化，并與雜質(zhì)檢查結(jié)果相互印證。 原料藥和雜質(zhì)的分離和檢測：將可能的中間體和副產(chǎn)物作為雜質(zhì)進(jìn)行柱效、流動相及流動相比例、波長和分離度等方法學(xué)的研究。 待方法建立成熟后，根據(jù)中間體和副產(chǎn)物的安全性和獲得雜質(zhì)標(biāo)樣的難易程度，決定是否定為已知雜質(zhì)。 如果雜質(zhì)標(biāo)樣難以得到，且比較安全，可考慮采用雜質(zhì)校正因子

6、加上相對保留時(shí)間的方法，或采用雜質(zhì)相對保留時(shí)間加上自身對照的方法，對該雜質(zhì)進(jìn)行定量分析。 如果得不到該雜質(zhì)樣品作為標(biāo)樣，對于有紫外吸收的樣品可以用二極管陣列檢測器，考察未精制的粗品，并對比已精制過的樣品，確定粗品種各成分的分離度和樣品中可能雜質(zhì)的檢測波長。方法確立后，可采用自身對照方法或面積歸一化法控制雜質(zhì)。,原料藥與成品藥中的有機(jī)雜質(zhì),藥品中有機(jī)雜質(zhì)的分類 有機(jī)雜質(zhì) 特定雜質(zhì)（Specified Impurities)：特定雜質(zhì)是指在質(zhì)量標(biāo)準(zhǔn)中分別規(guī)定了明確的限度，并單獨(dú)進(jìn)行控制的雜質(zhì)。特定雜質(zhì)包括化學(xué)結(jié)構(gòu)已知的雜質(zhì)（Specified Identified Impurity) 和化學(xué)結(jié)構(gòu)未

7、知（Specified Unidentified Impurity）的雜質(zhì)。美國藥典通常采用代號來指認(rèn)特定雜質(zhì)，如相關(guān)化合物A（Related Compound A）等。 非特定雜質(zhì)（ Unspecified Impurities ）：在標(biāo)準(zhǔn)中未單獨(dú)列出，而僅采用一個通用的限度進(jìn)行控制的一系列雜質(zhì)。其結(jié)構(gòu)未知，在藥品中出現(xiàn)的種類與幾率并不固定。一般采用合適的定性分析指標(biāo)加以指認(rèn)，如相對保留時(shí)間為3.5的雜質(zhì)。 有機(jī)雜質(zhì)檢測 確定原料藥和制劑中潛在的合成雜質(zhì)和降解產(chǎn)物，需要應(yīng)用專業(yè)的有機(jī)化學(xué)知識對有關(guān)合成化學(xué)反應(yīng)和條件、原料藥化學(xué)結(jié)構(gòu)、理化性質(zhì)、穩(wěn)定性等進(jìn)行全面的科學(xué)分析和論證，并且比較實(shí)驗(yàn)室對

8、樣品的常規(guī)分析和強(qiáng)制降解（Forced Degradation Study），以及穩(wěn)定性研究的結(jié)果。,Impurities: Origination recommended use of less toxic solvents Testing is to be performed only for solvents “l(fā)ikely to be present” Used or produced in the final manufacturing step Used in previous steps and not removed by a validated procedure The l

9、imits for acceptable concentrations listed in the Chapter are for drug products, not for its components,Residual Solvents :Main Points,The concentration in the drug product may be Calculated from the concentrations of components Determined experimentally; mandatory if Solvents are used in its manufa

10、cture Cumulative calculation exceeds limits Manufactures of drug products may rely on data provided by the suppliers of components Provides unambiguous identification and qualification method Includes options to allow use of materials that exceed the limits established,Residual Solvents :Main Points

11、, Continued,“The procedures described in this general chapter are to be applied wherever possible. Otherwise, manufactures may select the most appropriate validated analytical procedure for a particular application.” (ICH and EP take similar approach, see Validation of Compendial Procedures Submissi

12、on of alternative methods is not required.,Scope,ICH “The guide does not apply to existing marketed products.” USP (and EP) “This general chapter applies to existing drug substances, excipients and medical products whether or not they are the subject of a monograph of the Pharmacopeia”.,Risk-based c

13、lassification of solvents,Class 1 -Unacceptable toxicities; should be avoided, unless their use can be strongly justified in a risk-based assessment. Class 2 -Less severe toxicities; should be limited. Class 3 -Less toxic; should be used where practical. Note: Other solvents may be used but only aft

14、er approval from a regulatory agency.,Supplier,USP Limits in excipients for each excipient Limits are not specifications for each excipient Some excipients used as drug products Manufacturer of drug product has to calculate, based upon PDE and limit. USP withdrew requirement in excipient monographs

15、A requirement is listed in General Notices; no need for unnecessary testing.,Supplier,Generally, Class 1 Solvents such as benzene are no longer being used in producing excipients. Many produced with Class 2 or 3. Eliminating or lowering solvent levels may change quality and performance for certain f

16、unctions. Take advantage of calculation option.,Supplier,Manufacturers of pharmaceutical products need certain information about the contents of residual solvents in drug substances or excipients in order to meet the criteria of this general chapter. Only Class 3 solvents are likely to be present. L

17、oss on drying is less than 0.5%. Only Class 2 solvents X, Y,are likely to be present. All are below the Option 1 limit. (Here the supplier would name the Class 2 solvents represented by X, Y, ) Only Class 2 solvents X, Y,and Class 3 solvents are likely to be present. Residual Class 2 solvents are be

18、llow the Option 1 limit and residual Class 3 solvents are below 0.5%.,Supplier,Need information exchange between user and supplier. However there are confidentiality concerns. Trust needed between two parties. A supplier audit may be needed, GMP concern for regulatory department and FDA. Not just re

19、ly on C of A.,Establishing Exposure Limits(Appendix 3 in the General Chapter),Permitted Daily Exposure (PDE) derived from the No-observed-effect level (NOEL) in animal studies. For Class 1 solvents, exposure limits are determined using a large safety factor (10,000 to 100,000) For Class 2 solvents,

20、PDE was calculated from NOEL, weight adjustments and correction factors (e.g. extrapolating between species and accounting for variability between individuals),Limits of Residual Solvents,Class 1: concentration limits, in ppm, are provided in a Table. They should not be exceeded unless otherwise sta

21、ted in the individual monograph. Class 2: concentration limits are to be calculated from PDE with the formula: concentration (ppm)=1000 PDE/dose, where PDE is in mg/day and dose is in g/day A table is provided, to be used when the daily dose is 10g or less, or when the daily dose is not known or fix

22、ed. Class 3: PDE is 50mg/day (“unless otherwise stated in the individual monograph”), corresponding to a concentration of 0.5% for daily doses of 10g or less,Limits of Residual Solvents: Class 1,Class 1 Residual solvents (Table 1): Should not be used in the manufacturing of drug substances, excipien

23、ts or drug products because of unacceptable toxicities or deleterious environmental effects of the residual solvents. However, if there use is unavoidable, their levels should be restricted as shown in Table 1.,Table 1. Class 1 Residual Solvents,Limits of Residual Solvents: Class 2,Class 2: 26 solve

24、nts Class 2 Residual Solvents: should be limited in drug substances, excipients or drug products because of their inherent toxicities. Their levels should be restricted as shown in Table 2. Concentration limits vary between 50 (Methylbutylketone) and 3880 (cyclohexane). When Class 2 residual solvent

25、s are used (or produced) in the manufacturing or purification process, they should be identified and quantified.,Table 2. Class 2 Residual Solvents,Table 2. Class 2 Residual Solvents Continued,Table 2. Class 2 Residual Solvents Continued,Limits of Residual Solvents: Class 3,Class 3: 28 solvents Less

26、 toxic and of lower risk to human health Unless otherwise stated in the individual monograph, PDE is NMT 50mg/day, corresponding to a concentration limit of 5000ppm for daily doses not greater than 10g of the product If the monograph allows for a concentration resulting in more than 50mg/day, Class

27、3 solvents must be identified and quantified.,Table 3. Class 3 Residual Solvents,殘留溶劑控制限度的建立,FDA要求所有在制造原料、輔料和產(chǎn)品時(shí)使用或產(chǎn)生的有機(jī)溶劑，其殘留量都必須予以檢測和控制。 仿制藥生產(chǎn)商可選擇直接在產(chǎn)品中檢測，若產(chǎn)品制造過程中均未使用有機(jī)溶劑，亦可先檢測原料、輔料的有機(jī)溶劑殘留量，檢測結(jié)果若較規(guī)定值低，則產(chǎn)品無須進(jìn)行檢測，若較高，則必須檢測產(chǎn)品，以證實(shí)制造過程中有機(jī)溶劑的殘留是否已經(jīng)降到合格標(biāo)準(zhǔn)。 若只有第3類的殘留溶劑，則可用USP干燥減重的方式控制。,Options for Determ

28、ining Levels of Class 2 Residual Solvents,Option 1: Components of the drug product (drug substances and excipients) meet the concentration limits listed in Table 2, and the daily dose does not exceed 10g. 在設(shè)定殘留溶劑時(shí)，首先采用第一選擇方法，即根據(jù)美國藥典（或ICH Q3C）中標(biāo)1-3所列的限度來建立標(biāo)準(zhǔn)中的溶劑限度。 第一選擇方法以每日用藥量10克為假設(shè)來計(jì)算“每日允許接觸量”（PDE）

29、，從而確定溶劑的限度。 MeOH第一選擇方法最高允許值 =1000微克/毫克PDE（毫克/日）/最高日劑量（克/日） =（1000 30）微克/（10 1000000）微克=3000ppm,Option 2 for Determining Levels of Class 2 Residual Solvents in Drug Products,Option 2: At least one of the components of the drug product exceeds the concentration limits, or the daily dose exceeds 10g: t

30、he daily exposure to a solvent (calculated as the sum of the components contributions) should be less than PDE. 當(dāng)殘留溶劑含量超過美國藥典第一選擇限度時(shí)可以采用第二選擇方法來建立殘留溶劑的限度。常見的是第3類的殘留溶劑，如乙醇或異丙醇，由于其對人體相對較低的毒性，在原料藥生產(chǎn)中常常把它用作最后純化工序的溶劑，加上有些原料藥具有很大的極性，生產(chǎn)中很難完全去除。,乙醇含量和第二選擇方法限度的計(jì)算,Option 2 for Determining Levels of Class 2 Res

31、idual Solvents in Drug Products,第二選擇方法以“每日允許接觸量”（PDE）和實(shí)際每日最大用藥量來計(jì)算溶劑的最高允許值。殘留溶劑的限度將根據(jù)這個允許值以及實(shí)驗(yàn)測定數(shù)據(jù)而確定。例如，乙醇的每日允許接觸量是50毫克。因此，方法1給出的限度是5000ppm。如果某藥物每日最高的配藥量是90毫克，其制劑中包含三種輔料，藥品的組分和計(jì)算得出的最高殘留乙醇量列于下表中。 第二選擇方法最高允許值 =1000 PDE（毫克/日）/最高日劑量（克/日） =1000 50/0.090=5.56 105ppm 因此，原料藥中的殘留溶劑乙醇的控制限度可以設(shè)定為高于第一選擇方法的限度（50

32、00ppm）。如果原料藥樣品的實(shí)際分析結(jié)果為6900-7000ppm，則控制限度可以設(shè)置為不超過8000ppm.,Example 1: Option 1 and Option 2, with Acetonitrile,PDE acetonitrile=4.1mg/day, thus Option 1 limits is 410ppm (from Table 2). 5.0g drug product/day. Composed of two excipients,Excipient 1 meets Option 1 limit of 410ppm/day. Drug Substance, ex

33、cipient 2, and drug product do not meet Option 1 limit of 410ppm/day. Drug product however meets Option 2 limits of 4.1 mg/day.,Example 2: Option 1 and Option 2, with Acetonitrile,PDE acetonitrile=4.1mg/day, thus Option 1 limits is 410ppm (from Table 2). 5.0g drug product/day. Composed of two excipi

34、ents,Drug product does not meet Option 1 or Option 2 limit. Manufacturer could test to see if manufacturing did reduce the level of acetonitrile in drug product below 410ppm; if so it passes.,原料藥中殘留溶劑與有機(jī)揮發(fā)性雜質(zhì)的控制及其依據(jù),根據(jù)原料藥生產(chǎn)商提供的藥物管理檔案中原料藥的合成路線，某原料藥的生產(chǎn)中使用過以下五種溶劑：丙酮、正己烷、甲苯、乙酸乙酯和四氫呋喃。 研發(fā)氣相色譜測定方法對該原料藥的樣品

35、進(jìn)行分析，檢測苯（甲苯中的一種潛在雜質(zhì)）和以上所列的五種可能的殘留溶劑。結(jié)果顯示，乙酸乙酯、四氫呋喃、正己烷、甲苯和苯（源于甲苯）均未檢出。然而，卻在樣品中檢測到了一種未知的有機(jī)揮發(fā)性雜質(zhì)。 應(yīng)用氣相色譜-質(zhì)譜（GC-MS）分析技術(shù)分析后確定該未知有機(jī)揮發(fā)性雜質(zhì)為亞異丙基丙酮（mesityloxide）。進(jìn)一步使用亞異丙基丙酮參考標(biāo)準(zhǔn)品對樣品中的該雜質(zhì)進(jìn)行了定量分析并確定了其含量。 下表總結(jié)了該原料藥樣品的殘留溶劑分析結(jié)果和所建立的限度。由于未檢出乙酸乙酯、四氫呋喃、正己烷、甲苯和苯，加上這些是早期合成階段所用的溶劑（苯除外，合成中未使用苯），因此認(rèn)為沒有必要在標(biāo)準(zhǔn)中對這些殘留溶劑建立控制限度

36、進(jìn)行常規(guī)控制。如果這些殘留溶劑出現(xiàn)在原料藥中，所采用的氣相色譜法將可以檢測到它們，并能對其進(jìn)行定量分析。另外，用不超過1000ppm的限度來分別控制原料藥中第三類溶劑丙酮和乙酸乙酯的殘留量，此限度低于ICH指南中的允許限度，與供應(yīng)商的限度也一致，因而是合理的。,原料藥中殘留溶劑與有機(jī)揮發(fā)性雜質(zhì)的控制及其依據(jù),練習(xí)-原料藥中殘留溶劑控制限度的設(shè)置和論證,原料藥中殘留溶劑與有機(jī)揮發(fā)性雜質(zhì)的控制及其依據(jù),亞異丙基丙酮(mesityl oxide):是從丙酮經(jīng)過羥醛縮合反應(yīng)而產(chǎn)生的一種有機(jī)揮發(fā)性雜質(zhì)。 由于USP和ICH都沒有對此雜質(zhì)設(shè)定控制限度，其毒理學(xué)數(shù)據(jù)也不完全，建議應(yīng)用美國FDA在2008年1

37、2月出版的產(chǎn)業(yè)指導(dǎo)中為基因毒素或可能致癌雜質(zhì)的限度（1.5微克/日）來設(shè)置控制限度。該藥的每日最高劑量為10毫克，可認(rèn)為設(shè)置不超過100ppm（0.01%）的限度恰當(dāng)?shù)乜刂屏嗽撛纤幹械倪@種有機(jī)揮發(fā)性雜質(zhì)（參見下面的計(jì)算公式） 1.5微克/日 亞異丙基丙酮控制限度= 106=150ppm 10毫克/日 103毫克/毫克 所用的氣相色譜分析方法已經(jīng)過驗(yàn)證，其準(zhǔn)確度、精密度、線性、靈敏度、可靠性、耐用性和選擇性均適用于這些殘留溶劑和有機(jī)揮發(fā)性雜質(zhì)的常規(guī)檢測控制的要求。,原料藥與成品藥中具有基因毒性和致癌性的雜質(zhì),具有基因毒性和致癌性基因毒性的雜質(zhì)：可以直接與DNA結(jié)合或通過影響參與DNA復(fù)制的酶，間接地導(dǎo)致DNA損傷。由于快速分裂的細(xì)胞在積極合成新的DNA，所以它