美國與歐盟對藥品包材可浸出物 (extractables) 與可滲出 …€¦ · regmed 2015 vol....

RegMed 2015 Vol. 52 1

美國與歐盟對藥品包材可浸出物 (extractables) 與可滲出物

(leachables) 之審查考量張凱琳/張琳巧1

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 human 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 (leachables)

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


審查考量

1. 美國

1.1 檢驗方法

美國藥典一般通則 (general chapters) 所收載之章節 <381: Elastomeric

closures for injections>(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: Pharmaceutical dosage forms>(8)

提到可滲出物

評估的必要性 (When evidence exists that leachables from the container-closure

systems (e.g., rubber stopper, cap liner, or plastic bottle) have an impact on

safety or efficacy of the drug product, a test is included to evaluate the presence

of leachables.)，尚未收載詳細的可滲出物評估方式。

表一、美國藥典收載之浸出詴驗條件(4,5,6,7)

General

chapters

Temperature and

time

Extraction

medium

Surface area /

weight to volume

ratio

Mechanism

<381> 121 ± 2 °C for 30

min

Purified water or

water for injection

1. Whole, uncut

closures

corresponding

to a surface

area of 100 ±

10 cm2 / 200

mL

2. 1 cm2 / 2 mL

Autoclaving

<661> 70 °C for 24 h Purified water 120 cm2 / 20.0 mL

Size: 3 mm × 5 cm

N/A

<87> 37 °C for 24 h Sodium chloride

injection (0.9%

NaCl) or serum-free

mammalian cell

culture media

Not lower than 100

mm2 and following

<88>

Standing

<88> 1. 121 °C for 60

min

2. 70 °C for 24 h

3. 50 °C for 72 h

1. Sodium

chloride

injection

2. 1 in 20 solution

of alcohol in

sodium

1. Thickness < 0.5

mm: 120 cm2 /

20 mL (size: 5

× 0.3 cm)

2. Thickness 0.5 –

1 mm: 60 cm2 /

1. Autoclaving

2. Standing

3. Standing


chloride

injection (for

plastics class II

to VI)

3. Polyethylene

glycol 400 (for

plastics class

III, V and VI)

4. Vegetable oil

(for plastics

class III, IV, V

and VI)

20 mL (size: 5

× 0.3 cm)

3. Thickness > 1

mm (slabs,

tubing, and

molded items):

60 cm2 / 20 mL

(size: 5 × 0.3

cm)

4. Thickness > 1

mm

(elastomers):

25 cm2 / 20 mL

(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 their materials of construction>、<661.1:

Plastic materials of construction>、<661.2: Plastic packaging systems for

pharmaceutical use>、 <1663: Assessment of extractables associated with

pharmaceutical packaging/delivery systems>、 <1664: Assessment of drug

product leachables associated with pharmaceutical packaging/delivery systems>

以及 <1664.1: Orally inhaled 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 (leachables-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 threshold of toxicological concern (TTC)、safety concern threshold (SCT

= 0.15 μg/day for orally inhaled nasal drug products) 等數值，確立分析方法的

閥值 (analytical evaluation threshold, 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。


表二、分析方法閥值計算式(11)

Terms Equations

General AET (μg / container) = (0.15 μg / day) / (doses / day) × (labeled doses) /

(container)

Liquid dosage

forms AET (μg / mL) = (μg / container) / (mL / container)

Solid dosage forms 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 human drugs and biologics 於

Attachment 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: chemistry 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 1. 40 °C for 10 days

2. 121 °C for 2 h

3. 100 °C for 30 min

4. 66 °C for 2 h, then 40 °C for 238 h (10 days)

5. 40 °C for 10 days



Food simulants 1. Aqueous & acidic foods: 10% ethanol

2. Low and high alcoholic foods: 10% or 50% ethanol

3. Fatty foods: Food oil (e.g., corn oil), HB307 (a mixture of synthetic

triglycerides), Miglyol 812 (derived from coconut oil), or others

Sample size Thickness at least 0.05 cm

Mechanism 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 the limits of genotoxic impurities對基因毒性不純物所


提出之 TTC = 1.5 μg/day total daily intake (TDI)(14)，或 Product Quality

Research 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 threshold (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)。


圖一、可滲出物鑑別與驗證之決策樹 (PNA: polynuclear aromatics; SAR:

structure-activity relationship) (11)


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 human 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 174-186 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 175-178 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 the 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 leachable 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)。


表四、歐洲藥典收載之浸出詴驗條件(18,19)

Monographs Temperature and

time

Extraction

medium

Surface area /

weight to volume

ratio

Mechanism

Materials based

on plasticised

poly(vinyl

chloride) for

containers for

human blood

and blood

components

1. 60 ± 1 °C for 2

h (for vinyl

chloride)

2. 121 ± 2 °C for

20 min

3. 37 ± 1 °C for

60 ± 1 min (for

extractable

di(2-ethylhexyl

) phthalate)

1. Dimethyl-

acetamide R

(for vinyl

chloride)

2. Water for

injection

3. 96% ethanol

diluted with

water (relative

density: 0.9389

to 0.9395)

1. 1.0 g / 10 mL

(for vinyl

chloride)

2. 25 g / 500 mL

3. Whole

container (half

of the nominal

value)

1. Shaking

2. Auto-

claving

3. Standing

Polyolefines 1. S1: reflux for 5

h

2. S2: reflux for

90 min

3. S3: reflux for 1

h

1. S1: water for

injections

2. S2: toluene

3. S3: 0.1 M

hydrochloric

acid

1. S1: 25 g / 500

mL

2. S2: 2.0 g / 80

mL

3. S3: 100 g / 250

mL

Reflux

Polyethylene

without

additives for

containers for

parenteral

preparations and

for ophthalmic

preparations

1. S1: reflux for 5

h

2. S2: reflux for

90 min

3. S3: reflux for 1

h

1. S1: water for

injections

2. S2: toluene

3. S3: 0.1 M

hydrochloric

acid

1. S1: 25 g / 500

mL

2. S2: 2.0 g / 80

mL

3. S3: 100 g / 250

mL

Reflux

Polyethylene/

polypropylene

with additives

for containers

for parenteral

preparations and

for ophthalmic

preparations

1. S1: reflux for 5

h

2. S2: reflux for

90 min

3. S3: reflux for 1

h

4. Substances

soluble in

hexane: reflux

for 4 h

1. S1: water for

injections

2. S2: toluene

3. S3: 0.1 M

hydrochloric

acid

4. Hexane

1. S1: 25 g / 500

mL

2. S2: 2.0 g / 80

mL

3. S3: 100 g / 250

mL

4. Hexane: 10 g /

100 mL

Reflux

Poly(ethylene-vi

nyl acetate) for

containers and

tubing for total

parenteral

nutrition

preparations

1. S1: reflux for

90 min

2. S2: reflux for 5

h

3. Substances

soluble in

hexane: reflux

for 4 h

1. S1: toluene

2. S2: water for

injection

3. Hexane

1. 1. S1: 2.0 g /

80 mL

2. S2: 25 g / 500

mL

3. Hexane: 5 g /

50 mL

Reflux



time

Extraction

medium

Surface area /

weight to volume

ratio

Mechanism

Silicone

elastomer for

closures and

tubing

1. Reflux for 5 h

2. Substances

soluble in

hexane: reflux

for 4 h

1. Water for

injection

2. Hexane

1. 25 g / 500 mL

2. Hexane: 2.0 g /

100 mL

Reflux

Materials based

on

non-plasticised

poly(vinyl

chloride) for

containers for

non-injectable,

aqueous

solutions

1. 60 ± 1 °C for 2

h (for vinyl

chloride)

2. S1: 121 ± 2 °C

for 20 min

3. S3: reflux for 1

h

1. Dimethyl-

acetamide R

(for vinyl

chloride)

2. Water for

injection

3. 0.1 M

hydrochloric

acid

1. 1.0 g / 10 mL

2. S1: 25 g / 500

mL

3. S3: 5 g / 100

mL

1. Shaking

2. Auto-

claving

3. Reflux

Materials based

on

non-plasticised

poly(vinyl

chloride) for

containers for

dry dosage

forms for oral

administration

1. 60 ± 1 °C for 2

h (for vinyl

chloride)

2. S1: 121 ± 2 °C

for 20 min

3. S3: reflux for 1

h

1. Dimethyl-

acetamide R

(for vinyl

chloride)

2. Water for

injection

3. 0.1 M

hydrochloric

acid

1. 1.0 g / 10 mL

2. S1: 25 g / 500

mL

3. S3: 5 g / 100

mL

1. Shaking

2. Auto-

claving

3. Reflux

Materials based

on

non-plasticised

poly(vinyl

chloride) for

containers for

aqueous

solutions for

intravenous

infusion

1. 60 ± 1 °C for 2

h (for vinyl

chloride)

2. S2: 121 ± 2 °C

for 20 min

1. Dimethyl-

acetamide R

(for vinyl

chloride)

2. Water for

injection

1. 1.0 g / 10 mL

2. S1: 25 g / 500

mL

1. Shaking

2. Auto-

claving

Polyethylene

terephthalate for

containers for

preparations not

for parenteral

use

1. S1: 50 °C for 5

h

2. S2: 50 °C for 5

h

3. S3: 50 °C for 5

h

4. S4: 50 °C for 5

h

1. Water

2. 96% ethanol

3. 0.1 M

hydrochloric

acid

4. 0.01 M sodium

hydroxide

1. 10.0 g / 200

mL

2. 10 g / 100 mL

3. 20 g / 50 mL

4. 20 g / 50 mL

Standing

Sterile plastic

containers for

human blood

and blood

components:

abnormal

toxicity

110 °C for 30 min Sterile,

pyrogen-free 9 g/L

solution of sodium

chloride R

Whole container /

100 mL

Autoclaving



time

Extraction

medium

Surface area /

weight to volume

ratio

Mechanism

Empty sterile

containers of

plasticised

poly(vinyl

chloride) for

human blood

and blood

components

1. 37 ± 1 °C for

60 ± 1 min (for

extractable

di(2-ethylhexyl

) phthalate)

2. 110 °C for 30

min

1. 96% ethanol

diluted with

water (relative

density: 0.9389

to 0.9395)

2. Water for

injection

1. Whole

container (half

of the nominal

value)

2. Whole

container (full

volume)

1. Standing

2. Auto-

claving

Sterile

containers of

plasticised

poly(vinyl

chloride) for

human blood

containing

anticoagulant

solution

37 ± 1 °C for 60 ±

1 min (for

extractable

di(2-ethylhexyl)

phthalate)

96% ethanol diluted

with water (relative

density: 0.9389 to

0.9395)

Whole container

(half of the nominal

value)

Standing

Sets for the

transfusion of

blood and blood

components

37 ± 1 °C for 2 h Water for injection 3 sets for a closed

circulation system /

250 mL

Circulation

(1 L / h)

Sterile

single-use

plastic syringes

37 °C for 24 h Water for injection Total: 50 mL of

solution

Standing

Rubber closures

for containers

for aqueous

parenteral

preparations, for

powders and for

freeze-dried

powders

121 ± 2 °C for 30

min

Water 100 cm2 / 200 mL 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 with 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

ethanol 10% (v/v) (food simulant A), acetic acid 3% (w/v) (food simulant B)、

ethanol 20% (v/v) (food simulant C)、ethanol 50% (v/v) (food simulant D1)、

vegetable oil (food simulant D2)、poly(2,6-diphenyl-p-phenylene oxide) (particle

size 60-80 mesh, pore size 200 nm) (food simulant E) 等六種食品模擬物


(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。

表五、歐盟 Commission Regulation (EU) No 10/2011 訂定之遷移詴驗指標(20)

Terms Definition General limits

Overall

migration limit

(OML)

The maximum permitted amount of non-volatile

substances released from a material or article into

food simulants

Adults:10 mg / dm2 of food

contact surface

Children: 60 mg / kg of

food simulant

Specific

migration limit

(SML)

The maximum permitted amount of a given

substance released from a material or article into

food or food simulants

General SML: 60 mg / kg of

food

Total specific

migration limit

(SML(T))

The maximum permitted sum of particular

substances released in food or food simulants

expressed as total of moiety of the substances

indicated

-

表六、歐盟 Commission Regulation (EU) No 10/2011 用以評估 SML 之遷移詴驗條

件(20)

Parameters Conditions

Temperature

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 the temperature to the real temperature

at the interface with the food (*)

(*) This temperature shall be used only for food simulants D2 and E.

Time

Contact time in worst foreseeable

use Test time

t ≤ 5 min 5 min

5 min < t ≤ 0.5 h 0.5 h

0.5 h < t ≤ 1 h 1 h

1 h < t ≤ 2 h 2 h


2 h < t ≤ 6 h 6 h

6 h < t ≤ 24 h 24 h

1 day < t ≤ 3 days 3 days

3 days < t ≤ 30 days 10 days

Above 30 days Specific conditions (詳見 Annex V)

Medium Food simulant or food

Surface area to

volume ratio

The material or article shall be treated as described by accompanying instructions or

by provisions given in the declaration of compliance.

表七、歐盟 Commission Regulation (EU) No 10/2011 用以評估 OML 之遷移詴驗

條件(20)

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 heating up to 70 °C for

up to 2 hours, or heating up to 100 °C for up

to 15 minutes

OM3 2 h at 70 °C

Any contact conditions that include heating

up to 70 °C for up to 2 hours, or up to 100

°C for up to 15 minutes, which are not

followed by long term room or refrigerated

temperature storage

OM4 1 h at 100 °C High temperature applications for all food

simulants at temperature up to 100 °C

OM5 2 h at 100 °C or at reflux or alternatively 1 h

at 121 °C High temperature applications up to 121 °C

OM6 4 h at 100 °C or at reflux

Any food contact conditions with food

simulants A, B or C, at temperature

exceeding 40 °C

OM7 2 h at 175 °C High temperature applications with fatty

foods exceeding the conditions of OM5

OM8

1. In case it is technically not feasible to

perform OM7 with food simulant D2

the test can be replaced by test OM8 or

OM9.

2. Food simulant E for 2 hours at 175 °C

and food simulant D2 for 2 hours at

100 °C

High temperature applications only


OM9

1. In case it is technically not feasible to

perform OM7 with food simulant D2

the test can be replaced by test OM8 or

OM9.

2. Food simulant E for 2 hours at 175 °C

and food simulant D2 for 10 days at 40

°C

High 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 the 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 heavy metals)、還原物質

(reducing substances)、正己烷浸出物 (substances soluble in hexane) 等訂定允

收標準。而風險較高的化合物，如 vinyl chloride (maximum 1 ppm) 以及

di(2-ethylhexyl) phthalate (DEHP; 0.10 mg/mL for nominal volume 300-500 mL;

0.13 mg/mL for nominal volume 150-300 mL; 0.14 mg/mL for nominal volume

up to 150 mL) 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 the limits of genotoxic

impurities(14)或 ISO 10993-17

(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)。

表八、歐盟 Commission Regulation (EU) No 10/2011 Annex II 限量規定(20)

Substances Restrictions (SML)

Barium 1 mg / kg food or food simulant

Cobalt 0.05 mg / kg food or food simulant

Copper 5 mg / kg food or food simulant

Iron 48 mg / kg food or food simulant

Lithium 0.6 mg / kg food or food simulant


Manganese 0.6 mg / kg food or food simulant

Zinc 25 mg / kg food or food simulant

Primary aromatic amines

(excluding those appearing in

table 1 of Annex I)

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 human drugs and

biologics, U.S. FDA, 1999

2. Guideline on plastic immediate packaging materials, EU EMA, 2005

3. ISO 10993-1: Evaluation and testing, 2003

4. USP <381: Elastomeric closures for injections>, 37th edition, 2014

5. USP <661: Containers – plastics>, 37th edition, 2014

6. USP <87: Biological reactivity tests, in vitro>, 37th edition, 2014

7. USP <88: Biological reactivity tests, in vivo>, 37th edition, 2014

8. USP <1151: Pharmaceutical dosage forms>, 37th edition, 2014

9. USP Plastic packaging general chapters: an overview (stimuli article), Packaging,

Storage, and Distribution Expert Committee, 2013

10. USP <1663: Assessment of extractables associated with pharmaceutical

packaging/delivery systems> (draft), Packaging, Storage, and Distribution

Expert Committee, 2013

11. USP <1664: Assessment of drug product leachables associated with

pharmaceutical packaging/delivery systems> (draft), Packaging, Storage, and


Distribution Expert Committee, 2013

12. Guidance for industry: preparation of premarket submissions for food contact

substances: chemistry recommendations, U.S. FDA, 2007

13. ICH Q3B (R2): impurities in new drug products, ICH, 2006

14. Guideline on the limits of genotoxic impurities, EU EMA, 2006

15. Safety thresholds and best practices for extractables and leachables in orally

inhaled and nasal drug products, Product Quality Research Institute (PQRI),

2006

16. 21CFR 174-186, US

17. List of indirect additives used in food contact substances

(http://www.accessdata.fda.gov/scripts/fcn/fcnNavigation.cfm?rpt=iaListing),

U.S. FDA, current version

18. EP <3.1 Materials used for the manufacture of containers>, 8th edition, 2013

19. EP <3.2 Containers>, 8th edition, 2013

20. Commission Regulation (EU) No 10/2011 on plastic materials and articles

intended to come into contact with food, EU, 2011

21. ISO 10993-17: Establishment of allowable limits for leachable substances, 2002

美國與歐盟對藥品包材可浸出物 (extractables) 與可滲出 …€¦ · regmed 2015 vol....

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