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1 美國與歐盟對藥品包材可浸出物 (extractables) 與可滲出物 (leacables) 之審查考量 1 張凱琳 / 張琳巧前言綜觀世界各國對藥品包裝材料之管理規範, 從上游 GMP 管理 DMF 資料上市前審查至上市後標示規定, 以美國和歐盟要求最為完備深入探討其技術性審查文件規範, 可發現前述法規單位對高風險藥品之容器封蓋系統 ( 如注射劑之塑膠容器乾粉吸入器等 ) 的要求更是嚴謹如美國之 Guidance for industry: container closure systems for packaging uman drugs and biologics (1) 以及歐盟之 Guideline on plastic immediate packaging materials (2), 除了要求包裝組件 (packaging component) 與構造材料 (materials of construction) 的描述之外, 更注重與包裝材料安全性息息相關之可浸出物 (extractables) 與可滲出物 (leacables) 的評估所謂可浸出物, 通常是在較苛酷的條件下由包裝系統中浸出 (extraction) 者, 常用以評估整體容器封蓋系統於藥品架儲期可能產生之可滲出物原則上, 浸出詴驗條件之選擇以避免破壞材質為主, 一旦詴驗中產生變形或材質降解, 應立即選擇其他較溫和之條件執行浸出詴驗 (1,2,3) 可滲出物則通常是在一般的儲存及使用條件下由包裝系統中遷移出 (migration) 者, 因此遷移詴驗之條件應儘可能模仿藥品架儲期狀況 (2,3) 由於包裝組件與構造材料在來源或製造過程可能包含或添加對人體有害的物質, 若這類物質在架儲期經由直接接觸而釋放至藥品中成為可滲出物, 就有可能造成藥品使用上的風險可浸出物與可滲出物之風險, 須考量包裝材料之材質以及藥品之使用途徑等因素做相關評估, 其多樣化之來源, 增加了可浸出物與可滲出物評估之複雜性前述兩指引雖指出評估藥品包材可浸出物與可滲出物之重要性, 卻僅描述原則, 並未說明執行細節為了釐清先進國家對藥品包材可浸出物與可滲出物之審查考量, 本文將以檢驗方法以及限量規定為中心, 整理美國與歐盟相關規定, 以期作為評估藥品包材安全性之參考 1 財團法人醫藥品查驗中心藥劑科技組 RegMed 2015 Vol. 52 1

2 審查考量 1. 美國 1.1 檢驗方法美國藥典一般通則 (general capters) 所收載之章節 <381: Elastomeric closures for s> (4) <661: Containers plastics> (5) <87: Biological reactivity tests, in vitro> (6) 以及 <88: Biological reactivity tests, in vivo> (7), 記載了浸出詴驗 (extraction) 之執行條件從表一整理之浸出詴驗條件可知, 美國藥典 <88> 對浸出詴驗條件描述得最為完整, 但所有章節僅侷限在單一詴驗項目或單一材質而在可滲出物的研究方面, 直至美國藥典第 37 版為止, 僅有一般通則 <1151: Parmaceutical dosage forms> (8) 提到可滲出物評估的必要性 (Wen evidence exists tat leacables from te container-closure systems (e.g., rubber stopper, cap liner, or plastic bottle) ave an impact on safety or efficacy of te drug product, a test is included to evaluate te presence of leacables.), 尚未收載詳細的可滲出物評估方式 (4,5,6,7) 表一美國藥典收載之浸出詴驗條件 General capters Temperature and time <381> 121 ± 2 C for 30 min Extraction medium Purified water or water for Surface area / weigt to volume ratio 1. Wole, uncut closures corresponding to a surface area of 100 ± 10 cm 2 / cm 2 / 2 <661> 70 C for 24 Purified water 120 cm 2 / 20.0 Size: 3 mm 5 cm Mecanism Autoclaving N/A <87> 37 C for 24 Sodium cloride (0.9% NaCl) or serum-free mammalian cell culture media <88> C for 60 min C for C for Sodium cloride 2. 1 in 20 solution of alcool in sodium Not lower tan 100 mm 2 and following <88> 1. Tickness < 0.5 mm: 120 cm 2 / 20 (size: cm) 2. Tickness mm: 60 cm 2 / Standing 1. Autoclaving 2. Standing 3. Standing RegMed 2015 Vol. 52 2

3 cloride (for plastics class II to VI) 3. Polyetylene glycol 400 (for plastics class III, V and VI) 4. Vegetable oil (for plastics class III, IV, V and VI) 20 (size: cm) 3. Tickness > 1 mm (slabs, tubing, and molded items): 60 cm 2 / 20 (size: cm) 4. Tickness > 1 mm (elastomers): 25 cm 2 / 20 (do not subdivide) 針對此一不足, 美國藥典包裝儲存與運銷專家委員會 (packaging, storage, and distribution expert committee) 正積極討論修訂與增設一般通則 <661: Plastic packaging systems and teir materials of construction> <661.1: Plastic materials of construction> <661.2: Plastic packaging systems for parmaceutical use> <1663: Assessment of extractables associated wit parmaceutical packaging/delivery systems> <1664: Assessment of drug product leacables associated wit parmaceutical packaging/delivery systems> 以及 <1664.1: Orally inaled and nasal drug products> (9), 相關草案已於 2013 年 9 月至 10 月公開其中, 美國藥典 <1663> 草案大幅增列有關可浸出物鑑別與定量的方式, 包含如 UV FT-IR GC NMR MS 等從篩選化合物至定量的各種應用, 並再針對浸出詴驗條件的選擇提供詳盡的說明 (10) 而美國藥典 <1664> 草案則補足了美國藥典在可滲出物的不足, 說明可滲出物的評估方式在溫度與時間的條件上,<1664> 草案建議比照架儲期的條件來評估, 並建議使用藥品本身來評估實際的包材滲出物, 以建立可浸出物與可滲出物的關聯性 (leacables-extractables correlation) 當浸出詴驗出現超出允收標準的狀況, 即可利用兩者關聯性, 評估藥品中可滲出物的風險 (11) 綜上所述, 為了評估可滲出物於藥品中的安全性, 美國藥典建議以 <1663> 草案列出的方法鑑別與定量可滲出物, 再依 <1664> 草案提供之毒理學指標, 如 tresold of toxicological concern (TTC) safety concern tresold (SCT = 0.15 μg/day for orally inaled nasal drug products) 等數值, 確立分析方法的閥值 (analytical evaluation tresold, AET), 以選擇可行的滲出詴驗條件由 SCT 計算 AET 的方式如表二所示 RegMed 2015 Vol. 52 3

4 (11) 表二分析方法閥值計算式 Terms General Liquid dosage forms Solid dosage forms Equations AET (μg / container) = (0.15 μg / day) / (doses / day) (labeled doses) / (container) AET (μg / ) = (μg / container) / ( / container) AET (μg / g) = (μg / container) / (g / container) 除了美國藥典一般通則之外, 美國藥品包材指引 Guidance for industry: container closure systems for packaging uman drugs and biologics 於 Attacment C 所建議的浸出詴驗條件, 亦包含間接食品添加物 (indirect food additives) 之規範 (1) 依 U.S. FDA 管理方式, 食品接觸材料 (food-contact substances) 屬於間接食品添加物之分類範圍, 而美國食品接觸材料管理指引 Guidance for industry: preparation of premarket submissions for food contact substances: cemistry recommendations, 即建議了遷移詴驗 (migration testing) 執行條件, 其中較為常用的詴驗設計條件整理於表三 (12) 在該指引 Appendix II, 尚有依各種食品使用狀況而訂定之詴驗條件可供參考表三 U.S. FDA 食品指引所列之遷移詴驗條件 ( 依食品特性選擇適用條件 ) (12) Parameters Conditions Temperature and time C for 10 days C for C for 30 min C for 2, ten 40 C for 238 (10 days) C for 10 days C for 10 days C for 5 days Food simulants 1. Aqueous & acidic foods: 10% etanol 2. Low and ig alcoolic foods: 10% or 50% etanol 3. Fatty foods: Food oil (e.g., corn oil), HB307 (a mixture of syntetic triglycerides), Miglyol 812 (derived from coconut oil), or oters Sample size Mecanism Tickness at least 0.05 cm Mild agitation 1.2 限量規定目前可滲出物的限量標準並不在 ICH Q3B 規範之內 (13), 但若全面性逐一評估所有可滲出物的風險與限量, 在成本與時間考量上並不可行實務上, 美國藥典 <1664> 草案建議可先以毒理評估方式訂定限量標準, 如利用歐盟 EMA 於 Guideline on te limits of genotoxic impurities 對基因毒性不純物所 RegMed 2015 Vol. 52 4

5 提出之 TTC = 1.5 μg/day total daily intake (TDI) (14), 或 Product Quality Researc Institute (PQRI) 對吸入劑以及鼻用製劑所建議的可滲出物限量 SCT = 0.15 μg/day 以及 qualification tresold (QT) = 5 μg/day TDI (15), 但這些數值並非以個別毒理學研究評估而得的標準, 主要的應用對象為尚未經過鑑別的可滲出物, 如曝露量在 SCT 以下的可滲出物得免除鑑別以及安全性評估 ; 在 QT 以下, 且不含恐具致癌性與刺激性之可疑結構的可滲出物, 得免除個別化合物的安全性評估美國藥典 <1664> 草案有關可滲出物鑑別以及毒理評估決策樹如圖一所示 (11) RegMed 2015 Vol. 52 5

6 圖一可滲出物鑑別與驗證之決策樹 (PNA: polynuclear aromatics; SAR: structure-activity relationsip) (11) RegMed 2015 Vol. 52 6

7 由於美國藥典 <1664> 草案尚未正式生效, 美國法規中類似可滲出物限量規定的部分, 依藥品包裝材料相關之指引 Guidance for industry: container closure systems for packaging uman drugs and biologics, 口服固體與液體製劑的可滲出物規定亦可參考 21CFR parts 之內容 (1,16) 該法規涵蓋了美國食品包裝材料相關的使用限制以及限量標準, 其純度要求與限量規定可作為藥品包裝材料安全性評估之參考依據由於內容相當複雜,U.S. FDA 將 21CFR parts 所提及之材質整理於 List of indirect additives used in food contact substances 資料庫中 (17) 該資料庫為網頁介面, 可供大眾查詢各材料所屬之 21CFR 章節, 其中收集之資料共有 3237 筆 ( 至 2014 年 12 月為止 ), 為國際間食品包裝材料最大之官方資料庫但在應用於藥品包材時, 應注意食品包材的規定並不一定適用於長期投予之口服液態製劑 (1) 2. 歐盟 2.1 檢驗方法在歐盟法規方面, 浸出詴驗條件的參考依據以歐洲藥典為主歐洲藥典 <3.1 Materials used for te manufacture of containers> 記載包裝材質從製程添加物到檢驗規格的相關規定 (18),<3.2 Containers> 則提供容器封蓋系統整體物理性質化學性質與生物學性質之評估方式 (19) 其中與浸出詴驗相關之詴驗條件整理於表四歐洲藥典雖記載了詳盡的浸出詴驗評估方式, 但僅限材質本身, 以及盛裝藥品前的包裝材料, 仍缺少歐盟指引 Guideline on plastic immediate packaging materials 所說明之藥品包裝材料相容性詴驗條件, 包括遷移詴驗 (migration) 以及吸附詴驗 (sorption) 等依指引內容, 原則上遷移詴驗應參考浸出詴驗的結果, 若浸出詴驗所推測而得之可滲出物最大滲出量 (maximum amount of individual leacable substance), 經毒理學評估後認定風險不高, 可藉由說明相關評估過程以免除遷移詴驗 ; 但若無法排除可浸出物的風險, 則應考量藥品之用法用量, 逐一檢視可滲出物對藥品有效性與安定性之影響, 僅以模擬藥品之媒液 (test media) 所執行的詴驗, 並不能作為免除以藥品本身執行之詴驗的依據安定性詴驗的變化則為吸附詴驗的指標, 若於架儲期間藥品產生顯著變化, 應一併執行吸附詴驗評估包裝材料對該變化之影響 (2) RegMed 2015 Vol. 52 7

8 (18,19) 表四歐洲藥典收載之浸出詴驗條件 Monograps Materials based on plasticised poly(vinyl cloride) for containers for uman blood and blood components Temperature and time ± 1 C for 2 (for vinyl cloride) ± 2 C for 20 min ± 1 C for 60 ± 1 min (for extractable di(2-etylexyl ) ptalate) Polyolefines 1. S1: reflux for 5 2. S2: reflux for 90 min 3. S3: reflux for 1 Polyetylene witout additives for containers for parenteral preparations and for optalmic preparations Polyetylene/ polypropylene wit additives for containers for parenteral preparations and for optalmic preparations Poly(etylene-vi nyl acetate) for containers and tubing for total parenteral nutrition preparations 1. S1: reflux for 5 2. S2: reflux for 90 min 3. S3: reflux for 1 1. S1: reflux for 5 2. S2: reflux for 90 min 3. S3: reflux for 1 4. Substances soluble in exane: reflux for 4 1. S1: reflux for 90 min 2. S2: reflux for 5 3. Substances soluble in exane: reflux for 4 Extraction medium 1. Dimetylacetamide R (for vinyl cloride) 2. Water for 3. 96% etanol diluted wit water (relative density: to ) 1. S1: water for s 2. S2: toluene 3. S3: 0.1 M ydrocloric acid 1. S1: water for s 2. S2: toluene 3. S3: 0.1 M ydrocloric acid 1. S1: water for s 2. S2: toluene 3. S3: 0.1 M ydrocloric acid 4. Hexane 1. S1: toluene 2. S2: water for 3. Hexane Surface area / weigt to volume ratio g / 10 (for vinyl cloride) g / Wole container (alf of te nominal value) 1. S1: 25 g / S2: 2.0 g / S3: 100 g / S1: 25 g / S2: 2.0 g / S3: 100 g / S1: 25 g / S2: 2.0 g / S3: 100 g / Hexane: 10 g / S1: 2.0 g / S2: 25 g / Hexane: 5 g / 50 Mecanism 1. Saking 2. Autoclaving 3. Standing Reflux Reflux Reflux Reflux RegMed 2015 Vol. 52 8

9 Monograps Silicone elastomer for closures and tubing Materials based on non-plasticised poly(vinyl cloride) for containers for non-injectable, aqueous solutions Materials based on non-plasticised poly(vinyl cloride) for containers for dry dosage forms for oral administration Materials based on non-plasticised poly(vinyl cloride) for containers for aqueous solutions for intravenous infusion Polyetylene tereptalate for containers for preparations not for parenteral use Sterile plastic containers for uman blood and blood components: abnormal toxicity Temperature and time 1. Reflux for 5 2. Substances soluble in exane: reflux for ± 1 C for 2 (for vinyl cloride) 2. S1: 121 ± 2 C for 20 min 3. S3: reflux for ± 1 C for 2 (for vinyl cloride) 2. S1: 121 ± 2 C for 20 min 3. S3: reflux for ± 1 C for 2 (for vinyl cloride) 2. S2: 121 ± 2 C for 20 min 1. S1: 50 C for 5 2. S2: 50 C for 5 3. S3: 50 C for 5 4. S4: 50 C for 5 Extraction medium 1. Water for 2. Hexane 1. Dimetylacetamide R (for vinyl cloride) 2. Water for M ydrocloric acid 1. Dimetylacetamide R (for vinyl cloride) 2. Water for M ydrocloric acid 1. Dimetylacetamide R (for vinyl cloride) 2. Water for 1. Water 2. 96% etanol M ydrocloric acid M sodium ydroxide 110 C for 30 min Sterile, pyrogen-free 9 g/l solution of sodium cloride R Surface area / weigt to volume ratio g / Hexane: 2.0 g / g / S1: 25 g / S3: 5 g / g / S1: 25 g / S3: 5 g / g / S1: 25 g / g / g / g / g / 50 Wole container / 100 Mecanism Reflux 1. Saking 2. Autoclaving 3. Reflux 1. Saking 2. Autoclaving 3. Reflux 1. Saking 2. Autoclaving Standing Autoclaving RegMed 2015 Vol. 52 9

10 Monograps Empty sterile containers of plasticised poly(vinyl cloride) for uman blood and blood components Sterile containers of plasticised poly(vinyl cloride) for uman blood containing anticoagulant solution Sets for te transfusion of blood and blood components Sterile single-use plastic syringes Rubber closures for containers for aqueous parenteral preparations, for powders and for freeze-dried powders Temperature and time ± 1 C for 60 ± 1 min (for extractable di(2-etylexyl ) ptalate) C for 30 min 37 ± 1 C for 60 ± 1 min (for extractable di(2-etylexyl) ptalate) Extraction medium 1. 96% etanol diluted wit water (relative density: to ) 2. Water for 96% etanol diluted wit water (relative density: to ) Surface area / weigt to volume ratio 1. Wole container (alf of te nominal value) 2. Wole container (full volume) Wole container (alf of te nominal value) 37 ± 1 C for 2 Water for 3 sets for a closed circulation system / C for 24 Water for Total: 50 of solution 121 ± 2 C for 30 min Mecanism 1. Standing 2. Autoclaving Standing Circulation (1 L / ) Standing Water 100 cm 2 / 200 Autoclaving 歐盟藥品塑膠包材指引 Guideline on plastic immediate packaging materials 雖未明確提供遷移詴驗之詴驗條件, 但亦於指引中說明藥品塑膠包材應一併考量食品法規之規定 (2) 歐盟食品法規 Commission Regulation (EU) No 10/2011 of 14 January 2011 on plastic materials and articles intended to come into contact wit food (Commission Regulation No 10/2011) 提出了三項評估塑膠包材內物質釋放量之指標 ( 詳見表五 ), 且於 Annex III 建議了 etanol 10% (v/v) (food simulant A), acetic acid 3% (w/v) (food simulant B) etanol 20% (v/v) (food simulant C) etanol 50% (v/v) (food simulant D1) vegetable oil (food simulant D2) poly(2,6-dipenyl-p-penylene oxide) (particle size mes, pore size 200 nm) (food simulant E) 等六種食品模擬物 RegMed 2015 Vol

11 (food simulants) 作為設計相關詴驗時取代食品之選擇, 並於 Annex III 之 table 2 中提供八大類食品所建議使用之食品模擬物, 再於 Annex V 建議詴驗設計方式 (20) 表六與表七分別簡述詴驗方式之參數選擇 (20) 表五歐盟 Commission Regulation (EU) No 10/2011 訂定之遷移詴驗指標 Terms Definition General limits Overall migration (OML) Specific migration (SML) limit limit Total specific migration limit (SML(T)) Te maximum permitted amount of non-volatile substances released from a material or article into food simulants Te maximum permitted amount of a given substance released from a material or article into food or food simulants Te maximum permitted sum of particular substances released in food or food simulants expressed as total of moiety of te substances indicated Adults:10 mg / dm 2 of food contact surface Cildren: 60 mg / kg of food simulant General SML: 60 mg / kg of food - 表六歐盟 Commission Regulation (EU) No 10/2011 用以評估 SML 之遷移詴驗條 (20) 件 Parameters Temperature Time Conditions Contact temperature in worst foreseeable use Test temperature T 5 C 5 C 5 C < T 20 C 20 C 20 C < T 40 C 40 C 40 C < T 70 C 70 C 70 C < T 100 C 100 C or reflux temperature 100 C < T 121 C 121 C (*) 121 C < T 130 C 130 C (*) 130 C < T 150 C 150 C (*) 150 C < T 175 C 175 C (*) T > 175 C Adjust te temperature to te real temperature at te interface wit te food (*) (*) Tis temperature sall be used only for food simulants D2 and E. Contact time in worst foreseeable use Test time t 5 min 5 min 5 min < t < t < t 2 2 RegMed 2015 Vol

12 Medium Surface area to volume ratio 2 < t < t day < t 3 days 3 days 3 days < t 30 days 10 days Above 30 days Specific conditions ( 詳見 Annex V) Food simulant or food Te material or article sall be treated as described by accompanying instructions or by provisions given in te declaration of compliance. 表七歐盟 Commission Regulation (EU) No 10/2011 用以評估 OML 之遷移詴驗 (20) 條件 Test number Contact temperature and time Intended food contact conditions OM1 10 days at 20 C Any food contact at frozen and refrigerated conditions OM2 10 days at 40 C Any long term storage at room temperature or below, including eating up to 70 C for up to 2 ours, or eating up to 100 C for up to 15 minutes OM3 2 at 70 C Any contact conditions tat include eating up to 70 C for up to 2 ours, or up to 100 C for up to 15 minutes, wic are not followed by long term room or refrigerated temperature storage OM4 1 at 100 C Hig temperature applications for all food simulants at temperature up to 100 C OM5 2 at 100 C or at reflux or alternatively 1 Hig temperature applications up to 121 C at 121 C OM6 4 at 100 C or at reflux Any food contact conditions wit food simulants A, B or C, at temperature exceeding 40 C OM7 2 at 175 C Hig temperature applications wit fatty foods exceeding te conditions of OM5 1. In case it is tecnically not feasible to OM8 perform OM7 wit food simulant D2 te test can be replaced by test OM8 or OM9. Hig temperature applications only 2. Food simulant E for 2 ours at 175 C and food simulant D2 for 2 ours at 100 C RegMed 2015 Vol

13 OM9 1. In case it is tecnically not feasible to perform OM7 wit food simulant D2 te test can be replaced by test OM8 or OM9. 2. Food simulant E for 2 ours at 175 C and food simulant D2 for 10 days at 40 C Hig temperature applications including long term storage at room temperature 2.2 限量規定歐洲藥典在 <3.1 Materials used for te manufacture of containers> 以及 <3.2 Containers> 記載了多項藥品包裝材料之檢驗規格, 並針對浸出詴驗所得之可浸出物, 包括可浸出之重金屬 (extractable eavy metals) 還原物質 (reducing substances) 正己烷浸出物 (substances soluble in exane) 等訂定允收標準而風險較高的化合物, 如 vinyl cloride (maximum 1 ppm) 以及 di(2-etylexyl) ptalate (DEHP; 0.10 mg/ for nominal volume ; 0.13 mg/ for nominal volume ; 0.14 mg/ for nominal volume up to 150 ) 等, 歐洲藥典於製程中會添加相關化合物之包裝材料個論中, 訂定較為嚴格的允收標準另外, 個論中除了包裝材料之檢驗規格, 亦描述包裝材料在製程中可能出現之添加物, 並訂定每批材料於製程中下料之最大容許量 (maximum allowable content) (18,19) 未記載於歐洲藥典之可浸出物與可滲出物, 則可參考其他相關指引, 如 Guideline on te limits of genotoxic impurities (14) 或 ISO (21) 所提供之評估原則 ( 如針對具有基因毒性之不純物 TTC 為 1.5 μg/day) 口服藥品的包裝材料, 除了歐洲藥典所規定的容器封蓋系統規格之外, 亦應符合 Commission Regulation No 10/2011 之規定 (2,20) 該法規之 Annex I 共收錄 885 種在食品塑膠包材合成與製作過程中可能涵蓋的物質, 並列舉其 SML 與 SML(T) 等相關規定 (Annex I 所收錄之 885 種物質規定請參考原文 ), Annex II 則列舉部分包裝材質釋出物之限量規定 ( 表八 ) (20) 表八歐盟 Commission Regulation (EU) No 10/2011 Annex II 限量規定 Substances Barium Cobalt Copper Iron Litium Restrictions (SML) 1 mg / kg food or food simulant 0.05 mg / kg food or food simulant 5 mg / kg food or food simulant 48 mg / kg food or food simulant 0.6 mg / kg food or food simulant RegMed 2015 Vol

14 Manganese Zinc Primary aromatic amines (excluding tose appearing in table 1 of Annex I) 0.6 mg / kg food or food simulant 25 mg / kg food or food simulant 0.01 mg / kg food or food simulant 結論藥品包材可浸出物詴驗條件之規定, 在美國與歐盟均以藥典收載之通則或個論為主, 並在指引中提供詴驗執行之原則以及評估方式另外, 指引中亦引用食品包裝材料相關法規, 以進一步規範藥品口服固體與液體製劑之包裝材料不過, 在藥品與包裝材料相容性詴驗以及可滲出物的評估方面, 美國與歐盟的指引仍僅提供原則性描述為了提供更全面的包裝材料安全性評估方式, 美國藥典草案已著手修訂藥品包裝材料可浸出物與可滲出物之相關章節, 內容不僅包含詴驗設計的考量, 亦包含分析方法的確立以及毒理評估原則未來有待更新之指引或藥典專論提供相關資訊, 藉由各方討論凝聚國際共識, 以形成更完善的管理體制參考文獻 1. Guidance for industry: container closure systems for packaging uman drugs and biologics, U.S. FDA, Guideline on plastic immediate packaging materials, EU EMA, ISO : Evaluation and testing, USP <381: Elastomeric closures for s>, 37t edition, USP <661: Containers plastics>, 37t edition, USP <87: Biological reactivity tests, in vitro>, 37t edition, USP <88: Biological reactivity tests, in vivo>, 37t edition, USP <1151: Parmaceutical dosage forms>, 37t edition, USP Plastic packaging general capters: an overview (stimuli article), Packaging, Storage, and Distribution Expert Committee, USP <1663: Assessment of extractables associated wit parmaceutical packaging/delivery systems> (draft), Packaging, Storage, and Distribution Expert Committee, USP <1664: Assessment of drug product leacables associated wit parmaceutical packaging/delivery systems> (draft), Packaging, Storage, and RegMed 2015 Vol

15 Distribution Expert Committee, Guidance for industry: preparation of premarket submissions for food contact substances: cemistry recommendations, U.S. FDA, ICH Q3B (R2): impurities in new drug products, ICH, Guideline on te limits of genotoxic impurities, EU EMA, Safety tresolds and best practices for extractables and leacables in orally inaled and nasal drug products, Product Quality Researc Institute (PQRI), CFR , US 17. List of indirect additives used in food contact substances (ttp:// U.S. FDA, current version 18. EP <3.1 Materials used for te manufacture of containers>, 8t edition, EP <3.2 Containers>, 8t edition, Commission Regulation (EU) No 10/2011 on plastic materials and articles intended to come into contact wit food, EU, ISO : Establisment of allowable limits for leacable substances, 2002 RegMed 2015 Vol

所 3 學分課程, 及兩門跨領域課程共 6 學分以上課程學生在修課前, 必須填寫課程修課認定表, 經班主任或指導教授簽名後始認定此課程學分 ) 10. 本規章未盡事宜, 悉依學位

所 3 學分課程, 及兩門跨領域課程共 6 學分以上課程學生在修課前, 必須填寫課程修課認定表, 經班主任或指導教授簽名後始認定此課程學分 ) 10. 本規章未盡事宜, 悉依學位 95 年訂定 96 年 11 月修正 97 年 10 月修正 100 年 2 月修正 101 年 4 月修正 102 年 1 月修正 103 年 4 月修正 103 學年度入學新生適用, 舊生可比照適用 1. 研究生須於入學後第二學期開學前選定指導教授, 經課程委員會認定後方得繼續

審 查 考 量 1. 美 國 1.1 檢 驗 方 法 美 國 藥 典 一 般 通 則 (general capters) 所 收 載 之 章 節 <381: Elastomeric closures for s> (4) <661: Containers plastics> (5) <87: Bio

審查考量 1. 美國 1.1 檢驗方法美國藥典一般通則 (general capters) 所收載之章節 <381: Elastomeric closures for s> (4) <661: Containers plastics> (5) <87: Bio