-
Guidance for Industry
Container
Closure Systems for Packaging Human Drugs and
Biologics
Chemistry, Manufacturing and
Controls Documentation
行业指南
人用药品及生物制品的包装容器和封装系统：化学，生产和控制文件
指南发布者：美国
FDA
下属的
CDER
及
CBER
发布日期：
May 1999
TABLE OF
CONTENTS
目录
I.
II.
INTRODUCTION
介绍
BACKGROUND
背景
A.
B.
C.
III.
Definitions
定义
CGMP, CPSC and USP Requirements on
Containers and Closures.
CGMP, CPSC
和
USP
对容器和密封的要求
Additional
Considerations
其他需要考虑的事项
QUALIFICATION AND QUALITY CONTROL OF
PACKAGING COMPONENTS
包装组件的合
格要求以及质量控制
A.
B.
C.
D.
E.
F.
G.
H.
IV.
V.
Introduction
介绍
General
Considerations
通常要求
Information That Should Be Submitted in
Support of an Original Application for Any
Drug Product
为支持任何药品的原始申请所必须提供的信息
Inhalation Drug Products
吸入性药品
Drug
Products for Injection and Ophthalmic Drug
Products
注射剂和眼科用药
Liquid-Based Oral and Topical Drug
Products and Topical Delivery Systems
液体口服
和外用药品和外用给药系统
Solid Oral Dosage Forms and Powders for
Reconstitution
口服固体剂型和待重新溶解
的粉末
Other Dosage Forms
其他剂型
POSTAPPROVAL
PACKAGING CHANGES
批准后的包装变更
TYPE III DRUG MASTER FILES
药品主文件
第
III
类
A.
B.
VI.
A.
B.
General
Comments
总体评述
Information in a Type III DMF
第
III
类
DMF
中包括的信息
Containers for
Bulk Drug Substances
用于原料药的容器
Containers for Bulk Drug Products
用于散装药品的容器
BULK
CONTAINERS
大包装容器
ATTACHMENT A
附件
A
REGULATORY REQUIREMENTS
药政要求
ATTACHMENT B
附件
B
COMPLIANCE POLICY GUIDES THAT CONCERN
PACKAGING
关于包装，所适用的政策指
南
ATTACHMENT C
附件
C
EXTRACTION STUDIES
“提取性”研究
ATTACHMENT D
附件
D
ABBREVIATIONS
缩略语
ATTACHMENT E
附件
E
REFERENCES
参考文献
GUIDANCE FOR
INDUSTRY
1
Container Closure Systems for Packaging
Human Drugs and Biologics
Chemistry,
Manufacturing and Controls Documentation
This guidance document represents the
Agency's current thinking on container
closure systems for the packaging of
human drugs and biological products. It
does not create or confer any rights
for or on any person and does not operate to
bind FDA or the public. An alternative
approach may be used if such approach
satisfies the requirements of the
applicable statute, regulations, or both.
本指南代
表了
FDA
目前对于人用
药品和生物制品包装的容器
/
封装系统方面的看法。
本指南不具强
制力。与本指南不相同的替代措施也可采用，前提是能满足相
应法律
/
法规的要求。
I
．
INTRODUCTION
介绍
This document
is intended to provide guidance on general
principles
for submitting information
on packaging materials used for human
drugs and biologics.
This guidance
supersedes the
FDA
Guideline
for Submitting Documentation for Packaging for
Human Drugs and Biologics
,
issued in February 1987 and the
packaging policy statement issued in a letter to
industry dated
June 30, 1995 from the
Office of Generic Drugs.
This guidance
is not intended to describe the
information that should be provided
about packaging operations associated with drug
product
manufacture.
本文件目的是为
递交人用药品和生物制品的包装信息提供总体原则指南。本文件替
代了
< br>FDA
在
1987
年
2
月发布的另一份指南，
以及替代了仿制药办公室
在
1995
年
6
月
30
日向行
业内发布的包装政策声
明信。本指南不描述药品的包装操作。
Approaches
which differ from those described in this guidance
may be followed, but the
applicant is
encouraged to discuss significant variations in
advance with the appropriate CDER
chemistry review staff or CBER review
staff. This is to prevent applicants or sponsors
from
spending unnecessary time and
effort in preparing a submission that the FDA may
later
4
3
2
< br>determine to be unacceptable.
可以采取与本
指南的内容不一致的措施，但是我们建议申请人就
明显的差异预先与
CDER
或
CBER
的审核人员进
行讨论。
这样做的目的是为了避免申请人或发起
人花费不必要的
时间和努力准备申报资料，而这种申报资料经
FDA
认定是不可
接受的。
II
．
BACKGROUND
背景
The Federal
Food, Drug, and Cosmetic Act (the Act) mandates
the need for adequate
information
related to packaging materials. Section 501(a)(3)
of the Act states that a drug is
deemed
to be adulterated
deleterious substance
which may render the contents injurious to
health....
502 of the Act states that a
drug is considered misbranded if there are
packaging omissions.
Also, section 505
of the Act requires a full description of the
methods used in, and the facilities
and
controls used for, the packaging of drugs (see
Attachment A).
联邦食品、药品和化妆品法案
（简称“法案”）要求必须提供包装材料的充分信息。法案的第
501(a)(3)
部分规定，如果某个药
品的包装材料含有有毒、有害的物质，导致药
品损坏健康，那么该药品为劣药。另外，法案的第
502
部分规
定，如果某药品在包装方面有缺失，则被认为是贴错标签。还有，法案第
505
部分要
求详细描述包装药品时所用的方法，所用的设施和控制措施（见附
件
A
）。
Section 505(b)(1)(D) of the Act states
that an application shall include a full
description of the
methods used in, the
manufacturing, processing and packing of such
drug. This includes
facilities and
controls used in the packaging a drug product.
法案的第
505(b)(1)(D)
部分规定
，申
请人必须完整描述该药品的生产、加工和包装。其中包括包装药品时的设施和控制措
施。
A.
Definitions
定义
Materials of
construction
refer to the substances
(e.g., glass, high density polyethylene
(HDPE) resin, metal) used to
manufacture a packaging component.
组成材料
是指用来
生产包装组件的物质（例如玻璃，
HDPE
树脂，金属）
A
packaging component
means
any single part of a container closure system.
Typical
components are containers
(e.g., ampules, vials, bottles), container liners
(e.g., tube
liners), closures (e.g.,
screw caps, stoppers), closure liners, stopper
overseals,
container inner seals,
administration ports (e.g., on large-volume
parenterals (LVPs)),
overwraps,
administration accessories, and container labels.
A
primary packaging
component
means a packaging
component that is or may be in direct contact with
the
dosage form. A
secondary
packaging component
means a packaging
component that is
not and will not be
in direct contact with the dosage form.
包装组件
是指一个容器
/
封装系
统的任何单独部分。通常的组件有容器（例如安瓿，西林瓶，瓶子），容器垫，封装，封
装垫
……
.
等，包
括给药附件和容器标签。
一级包装组件
是指与制剂直接接触的组
件，或
者可能会直接接触的组件。
二级包装组件
是指不会与制剂直接接触的组件。
A
container closure system
refers to the sum of packaging components that
together
contain and protect the dosage
form. This includes primary packaging components
and
secondary packaging components, if
the latter are intended to provide additional
protection to the drug product. A
packaging system
is
equivalent to a container closure
6
5
system.
容器
/
封装系统
是指包装组件
的组合，在一起盛装和保护制剂。这包括一级包装
组件和二级包装组件，后者的目的是为
药品提供额外保护。包装系统就等同于容器
/
封装
系统。
A
package or market package
refers to the container closure system and
labeling,
associated components (e.g.,
dosing cups, droppers, spoons), and external
packaging
(e.g., cartons or shrink
wrap). A market package is the article provided to
a pharmacist
or retail customer upon
purchase and does not include packaging used
solely for the
purpose of shipping such
articles.
包装
或
上市包装
是指容器
/
封装系统，以及标签，相关
组件（例如量杯，滴管，药匙等），以及外包装（例如纸箱或收缩包装）。上市包装是指
提供给药剂师或零售消费者的包装物件，不包括仅仅用于运输目的的包装物件。
Quality
refers to
the physical, chemical, microbiological,
biological, bioavailability, and
stability attributes that a drug
product should maintain if it is to be deemed
suitable for
therapeutic or diagnostic
use. In this guidance, the term is also understood
to convey
the properties of safety,
identity, strength, quality, and purity (see 21
CFR 211.94(a)).
7
质量
是指：一种药品可被看做具有治疗或诊断用途时，它所具有的理化、微生物、生物、
生物利用度以及稳定性方面的品质。在本指南中，此术语还被理解为安全性，等效性，规
格，质量和纯度等性质（见
21 CFR
211.94(a)
）。
An
extraction profile
refers to
the analysis (usually by chromatographic means) of
extracts obtained from a packaging
component. A
quantitative extraction
profile
is one in
which the
amount of each detected substance is determined. <
/p>
提取性特征
是指对从包装
组件中所得提取
物的分析（通常用色谱的方法）。定量提取性特征是指所提取的每种成分
的测得量。
B.
CGMP, CPSC and
USP Requirements on Containers and
Closures
CGMP, CPSC
和
< br>USP
对容器和密封的要求
Current good manufacturing practice
(CGMP) requirements for the control of drug
product containers and closures are
included in 21 CFR Parts 210 and 211. A listing of
the relevant sections is provided in
Attachment A. In addition, a listing of Compliance
Policy Guides that deal with packaging
issues is provided in Attachment B. References
in this guidance to CGMP regulations
are provided for completeness. For additional
information, refer to the
FDA Compliance Program Guidance
Manual
for Pre-Approval
Inspections/Investigations (7346.832)
which describes specific responsibilities for
CDER scientists and for field
investigators.
现行良好生产规范（
CGMP
）关于“药品容
器
/
< br>封装的控制”的要求在
21 CFR
的第
210
和
211
部分。相关部
分的清单请见附件
A
。
另外，关于包装
方面的“
Compliance Policy Guides
达标政策指南”清单请见附件
B
。本
指
南关于
CGMP
的参考文献对本指南有补充作用。更多的信息，
请参考“
FDA
达标项目
指南手册”，
以指导“批准前检查
/
调查
(7346
.832)
”，里面描述了
CDER
科
学家和现场
检查的具体职责。
The
FDA requirement for tamper-resistant closures is
included in 21 CFR 211.132 and
the
Consumer Product Safety Commission (CPSC)
requirements for child-resistant
closures are included in 16 CFR 1700.
An outline of these and other applicable
regulatory requirements is provided in
Attachment A.
FDA
关于防篡改封装的要求请见
21 CFR 211.13
2
，
消费者产品安全委员会
（
CPSC
）
对
“儿童防
护封装”
的要求请见
16 CFR
1
700
。附件
A
提供了这些法规要求和
其他相应法规要求的要点。
The United
States Pharmacopeial Convention has established
requirements for
containers which are
described in many of the drug product monographs
in
The United
States
Pharmacopeia/National Formulary
(USP/NF). For capsules and tablets, these
requirements generally relate to the
design characteristics of the container (e.g.,
tight,
well-closed or light-resistant).
For injectable products, materials of construction
are also
addressed (e.g.,
Type I glass, protected from
light
Notices and
Requirements
the
USP
. The requirements for
materials of construction are defined in the
Chapters
美国药典委员会建立了对容器的要求，这在
“美国药典
/
国家处方集（
USP/NF
）”的各药品专论中进行了描述。对于胶囊和片剂，这
些要求通常与容器的设计特征有关
（例如牢固，
密闭良好，
或者避光）
。
对于注射剂产品，
还有生产材料的要求（例如，“保存在单次给药或多次给药容器中，最好采用
< br>I
型玻璃，
避光”）。这些要求在美国药典的“通则和要
求”（保存，包装，贮存和标签）部分。关
于生产材料的要求在美国药典的“总章”（请
见附件
A
）。
C.
Additional Considerations
其他需要考虑的事项
1.
Submissions of INDs
The packaging information
in the chemistry, manufacturing, and controls
section of an IND usually includes a
brief description of the components, the
assembled packaging system and any
precautions needed to ensure the
protection and preservation of the drug
substance and drug product during their
use in the clinical trials.
For general guidance regarding the
container closure system information to be
submitted for phase 1 studies, refer to
the FDA guidance for industry
Content
and Format of investigational New Drug
Applications(INDs) for Phase 1 Studies
of Drugs, Including Well-Characterized,
Therapeutic, Biotechnology-derived
Products
(November 1995).
General guidance regarding
the container closure system information to be
submitted for phase 2 or phase 3
studies will be provided in the FDA guidance
for industry
INDs for Phase
2 and 3 Studies of Drugs, Including Specified
Therapeutic Biotechnology-Derived
Products, Chemistry, Manufacturing, and
Controls Content and Format,
when finalized (draft guidance published April 21,
1999).
2.
Submissions on Packaging of a Drug
Product by Another Firm
a.
Contract Packager
A contract packager is a
firm retained by the applicant to package a
drug product. The applicant remains
responsible for the quality of the
drug
product during shipping, storage, and packaging.
The information regarding
the container closure system used by a
contract packager that should be
submitted in the CMC section of an
application (NDA, ANDA, or BLA), or in
a DMF which is referenced in
the
application, is no different from that which would
be submitted if the
applicant performed
its own packaging operations. If the information
is
provided in a DMF, then a copy of
the letter of authorization (LOA) for
the DMF should be provided in the
application (see section V.A).
b.
Repackager
A repackager is a firm that
buys drug product from the drug product
manufacturer or distributor and
repackages it for sale under a label
different from that of the
manufacturer. The repackager is responsible
for ensuring the quality and stability
of the repackaged drug prpoduct.
The
repackaging operation is required to e in
compliance with CGMPs
(21 CFR Part
211), and there are limits to the expiration
period that may
be used with the
repackaged product unless the repackager conducts
stability studies.
Packaging
qualification information is not required if
the repackager uses the same container
closure system approved in
the original
application.
All
significant phases of the manufacturing and
processing of a drug
product (including
packaging) should be described as part of the CMC
section of an application (NDA, ANDA or
BLA), or in a DMF referenced
in the
application. The only exception is the repackaging
of solid oral
drug products for which
an approved application already exists.
For
biologics, repackaging is
considered a step in the manufacturing
process for which licensing is required
(21 CFR 600.3(u) and 601)
III.
QUALIFICATION AND
QUALITY CONTROL OF PACKAGING COMPONENTS
包装组件
的合格要求以及质量控制
a)
Introduction
介绍
CDER and CBER
approve a container closure system to be used in
the packaging of a
human drug or
biologic as part of the application (NDA, ANDA or
BLA) for the drug or
biologic. A
packaging system found acceptable for one drug
product is not automatically
assumed to
be appropriate for another. Each application
should contain enough
information to
show that each proposed container closure system
and its components
are suitable for its
intended use.
药品或生物制品的（
NDA,
ANDA
或
BLA
）申请时，作
为其中一部分的容器
/
封装系统也由
CDER
或
CBER
批
准。
某个容器
/
封装系统被批准用于<
/p>
10
9
8
一个药
品，
并不自动被认定为适用于其他药品。
在申请资料中应有充分
的信息显示所采用
的容器
/
封装系统和
其组件适应这个用途。
The type and
extent of information that should be provided in
an application will depend
on the
dosage form and the route of administration. For
example, the kind of information
that
should be provided about a packaging system for an
injectable dosage form or a
drug
product for inhalation is often more detailed than
that which should be provided
about a
packaging system for a solid oral dosage form.
More detailed information
usually
should be provided for a liquid-based dosage form
than for a powder or a solid,
since a
liquid-based dosage form is more likely to
interact with the packaging
components.
申请资料中要提供信息的类型和程度取决于剂型和给药途径。例如，为注
射或吸入剂型的包装系统提供的资料往往比固体口服剂型的包装系统所提供的资料要详
< br>细。
为液体类制剂的包装系统提供的资料要比粉末或固体制剂要多，
因为液体类制剂更容
易与包装组件相互作用。
Table 1 illustrates the correlation
between the degree of concern regarding the route
of
administration with the likelihood
of packaging component-dosage form interactions
for
different classes of drug products.
表
1
说明了“给药途径的受关注程度”
与“各类药品
的包装组件
-
制剂相互作
用”之间的关系。
Table 1
Examples of
packaging Concerns for Common Classes of Drug
Products
Degree of Concern
Associated with
the Route of
Administration
与
给药
途径有关的关注
程度
Highest
最高
Likelihood of Packaging Component-
Dosage Form Interaction
包装组件与制剂相互作用的可能性
High
高
Medium
中
Low
低
Inhalation Aerosols
and
Solutions;
Injections and
Injectable
Suspensions
吸入
性气雾剂和溶液；注
射液和注射性悬浮液
a
Sterile Powders and
Powders for
Injection;
Inhalation
Powders
无菌粉末
和注射用粉末；吸入
性粉末
High
高
Ophthalmic
Solutions and
Suspensions;
Transdermal
Ointments and
Patches; Nasal
Aerosols and
Sprays
眼用溶液和
悬浮液；透皮软膏和
贴剂；鼻腔气雾剂和
喷雾剂
Low
低
Topical Solutions
and
Suspensions;
Topical and Lingual
Aerosols; Oral
Solutions and
Suspensions
外用溶
液和悬
浮液；外用和
口腔气雾剂；口服溶
液和悬浮液
< br>
Topical Powders;
Oral
powders
外用粉
末；口服粉末
Oral Tablets and
Oral (Hard
and Soft
Gelatin) Capsules
口<
/p>
服片剂和口服（硬凝
胶或软凝胶）胶囊
a
For the
purposes of this table, the term
suspension
is used to mean a
mixture of two immiscible phases (e.g., solid
in liquid or liquid in liquid). As
such, it encompasses a wide variety of dosage
forms such as creams, ointments, gels,
and emulsions, as well as suspensions
in the pharmaceutical sense.
For the purpose of this
guidance, container closure systems for the most
common types
of dosage forms will be
discussed in terms of five general categories:
Inhalation Drug
Products (section
III.D); Drug Products for Injection and Ophthalmic
Drug Products
(Section III.E); Liquid-
based Oral and Topical Drug Products and Topical
Delivery
Systems (section III.F); Solid
Oral Dosage Forms and Powders for Reconstitution
(section III.G); and Other Dosage Forms
(section III.H)
在本指南中，绝大多数类型的制
剂的容器
/
封装系统将按照
5
种类型讨论，即：吸入性药品（第
III.D
部分）；注射性药品
和眼用药品（第
III.E
部分）；液体口服和外用药品以及外用给药系统（第
III.F
部分）；
固体口服制剂和待重新溶解的粉末（第
II
I.G
部分）；以及其他剂型（第
III.H
< br>部分）。
b)
General Considerations
通常要求
Suitability
refers to the
tests and studies used and accepted for the
initial qualification of
a component or
a container closure system for its intended use.
Quality control
(QC)
refers to the tests typically used and
accepted to establish that, after the application
is
approved, the components and the
container closure system continue to possess the
characteristics established in the
suitability studies. The subsections on
associated
components
and
secondary components
describe the tests and studies for establishing
suitability and quality control for
these types of components. However, the ultimate
proof
of the suitability of the
container closure system and the packaging process
is
established by full shelf life
stability studies.
适应性
是指：为最初
确定一个组件或容器
/
封装系统是否适用于其用途，所采用和接
受的试验和研究。
质量控制
（
QC
）是指常规使
用的试验和被接受的试验，用来证明（申请被批准后）
组件和容器
/
封装系统继续具有在
适应
性研究中所建立的特征。
“相关组件”和“二级组件”两个部分描述了为建立这种类
型的组件的适应性和质量控制而进行的试验和研究。但是，容器
/<
/p>
封装系统和包装工艺的
适应性的最终证据要靠完整的有效期试验研
究来建立。
i.
Suitability for the Intended Use
关于目的用途的适应性
Every
proposed packaging system should be shown to be
suitable
for its
intended use: it should adequately
protect
the dosage form; it
should be
compatible
with
the dosage form; and it should be composed of
materials that
are considered
safe
for use with the dosage
form and the route of
administration.
If the packaging system has a
performance
feature in
addition to
containing the product, the
assembled container closure system should be
shown to function properly.
每一个拟采用的包装系统都应能显示其目的用途的
适应性：它必须充分的
保护
制剂；必须能与制剂
相容
；在特定的制剂和给药途径
下，其组成材料必须
安全
。如果包装系统除了能盛装产品，还有其
功能
特征
，那
么组装后的容器
/
封装系统应能显
示其功能正常发挥。
Information
intended to establish suitability may be generated
by the applicant,
by the supplier of
the material of construction or the component, or
by a
laboratory under contract to
either the applicant or the firm. An adequately
detailed description of the tests,
methods, acceptance criteria, reference
standards, and validation information
for the studies should be provided. The
information may be submitted directly
in the application or indirectly by
reference to a DMF. If a DMF is used, a
letter authorizing reference (i.e., letter
of authorization (LOA)) to the DMF must
be included in the application (see
section V.A).
用来证明适应性的信息可以由（
药品）申请人提供，也可以由材料
或组件的供应商提供，或者由他们的外协实验室提供。
必须提供以下详细描述资
料：试验，方法，接受标准，标准品，以及验证。这些信息可直
接放入申请资料
递交，
也可以用非直接的方法即
DMF
，
然后由
FDA
审核
DMF
。
如果使
用了
DMF
，
那么必须在申请资料中附
一份授权书（
LOA
），请见
V.A<
/p>
部分。
General issues
concerning protection, compatibility, safety and
performance of
packaging components
and/or systems are discussed below. In this
guidance,
component functionality and
drug delivery will also be addressed in connection
with specific dosage forms and routes
of administration (see sections III.D, III.E,
III.F, III.G, and III.H).
下面
讨论了包装组件和
/
或系统的一些问题，有：保护，相
容性，安全以及功能。本指南中，组件功能和给药系统将与特定剂型和给药途径
< br>一并阐述（请见
III.D, III.E, III.F, III.G,
and III.H
部分）。
1.
Protection
保护
A container closure system should
provide the dosage form with
adequate
protection from factors (e.g., temperature, light)
that can
cause a degradation in the
quality of that dosage form over its shelf life.
Common causes of such degradation are:
exposure to light, loss of
solvent,
exposure to reactive gases (e.g., oxygen),
absorption of water
vapor, and
microbial contamination. A drug product can also
suffer an
unacceptable loss in quality
if it is contaminated by filth.
容器
/
封装系统
应能为制剂提供充足的保护，
保证在有效期内能避免一些因素
（例如温度，
光
线）
造成此制剂的品质降级。
造成这种降级的因素通常有：
暴露在光线
中，溶剂的减失，暴露在活泼性气体中（例如氧气），吸
收水蒸气，微生
物污染。药品还可能因为被污物污染而造成无法接受的品质降低。
Not every drug product is
susceptible to degradation by all of these
factors. Not all drug products are
light sensitive. Not all tablets are
subject to loss of quality due to
absorption of moisture. Sensitivity to
oxygen is most commonly found with
liquid-based dosage forms.
Laboratory
studies can be used to determine which of these
factors
actually have an influence on a
particular drug product.
并非所有药品
< br>都易于受上述因素影响而品质降级。
不是所有的药品都对光线敏感。
不是
所有的片剂会因吸收水蒸气而品质降低。对氧气的敏感最常见于液体制<
/p>
剂。
对于某个特定药品，
可以用实验室研
究的方法确定哪种因素真正会造
成影响。
Light protection
is
typically provided by an opaque or amber-colored
container or by an opaque secondary
packaging component (e.g.,
cartons or
overwrap). The USP test for light transmission
(USP <661>)
11
is an accepted
standard for evaluating the light transmission
properties
of a container. Situations
exist in which solid and liquid-based oral drug
products have been exposed to light
during storage because the
opaque
secondary packaging component was removed,
contrary to the
approved labeling and
the USP monograph recommendation. A firm,
therefore, may want to consider using
additional or alternate measures
to
provide light protection to these drug products
when necessary.
避光
保护通常采用不透明或
棕色容器，
或采用不透明的二级包装组件
（例如纸
箱或外包装纸）。美国药典中的光透过试验（请见
USP<661>
）是一个
被认可的标准，
用来评价一个容器的光
透过性质。
有些情况下，
贮藏中的
固体
和液体口服制剂会暴露在光线中，
原因是不透明的二级包装组件被去
掉了，导致与已经批准的标签不符，与美国药典的专论推荐不符。
Loss of solvent can occur through a
permeable barrier (e.g., a
polyethylene
container wall), through an inadequate seal, or
through
leakage. Leaks can develop
through rough handling or from inadequate
contact between the container and the
closure (e.g., due to the buildup
of
pressure during storage). Leaks can also occur in
tubes due to a
failure of the crimp
seal.
溶剂减失会发生于可透过性屏障（例如聚乙烯
容器
壁），
密封不严，或者泄露。
泄露可能是因为粗暴的操作或者容
器与
封装部分结合不紧密
（例如贮藏期间的压力积累）
。
泄露还可能发生于瓶
子，原因是卷曲密封没有
做好。
Water vapor or reactive
gases (e.g., oxygen) may penetrate a container
closure system either by passing
through a permeable container
surface
(e.g., the wall of a low density polyethylene
(LDPE) bottle) or by
diffusing past a
seal. Plastic containers are susceptible to both
routes.
Although glass containers would
seem to offer better protection,
because glass is relatively
impermeable, glass containers are more
effective only if there is a good seal
between the container and the
closure.
水蒸气或者活泼性气体（例如氧气）可能穿过容器的封装系统，
途径可能是穿过透过性容器表面（例如
LDPE
瓶壁），或者通
过密封口
散播。
塑料容器易于发生上两种情况。
虽然玻璃容器看起来能提供更好的
保护，
因为玻璃是相
对非透过性的，
但是玻璃容器只能在容器和封装密封
严密的情况
下才更为有效。
Protection from
microbial contamination is provided by maintaining
adequate container integrity after the
packaging system has been
sealed. An
adequate and validated procedure should be used
for drug
product manufacture and
packaging.
避免微生物污染，
在于包装系统密
封后保持容器的完整不被破坏。
药品生产和包装中必须使用恰当的、
经过
验证的方法。
2.
Compatibility
相容性
Packaging
components that are compatible with a dosage form
will not
interact sufficiently to cause
unacceptable changes in the quality of
either the dosage form or the packaging
component.
与某制剂相容的包
装组件不会与制剂发
生过多的作用，
以导致制剂或包装组件的质量发生不
可接受的改
变。
Examples of interactions
include loss of potency due to absorption or
adsorption of the active drug
substance, or degradation of the active
drug substance induced by a chemical
entity leached from a packaging
component; reduction in the
concentration of an excipient due to
absorption, adsorption or leachable-
induced degradation; precipitation;
changes in drug product pH;
discoloration of either the dosage form or
the packaging component; or increase in
brittleness of the packaging
component.
相互作用的例子包括：
吸收或者吸附活性药品成分造成的含
量降低，
或者从包装组件上脱落的化学成分引起活性药品成分的分解
；
由
于吸收，吸附，或者脱落物引起的辅料浓度降低；产品
pH
值的改变；制
剂或者包装组件的变色；
或者包装组件脆性增加。
Some
interactions between a packaging component and
dosage form
will be detected during
qualification studies on the container closure
system and its components. Others may
not show up except in the
stability
studies. Therefore, any change noted during a
stability study
that may be
attributable to interaction between the dosage
form and a
packaging component should
be investigated and appropriate action
taken, regardless of whether the
stability study is being conducted for
an original application, a supplemental
application, or as fulfillment of a
commitment to conduct postapproval
stability studies.
有些包装组件和
制剂
之间的相互作用可在容器
/
封装系统及其组件的合格性研究中发
现。
有些则显示不出来，
除非是稳定性试验。
< br>因此，
任何在稳定性试验中发现
的改变如果是由于制剂和
包装组件的相互作用引起的，
那么就必须展开调
查，
并采取合适的措施，
不论这个稳定性试验是为了一个原始申请而正在
进行的，或者是补充申请，或者是履行“批准后的稳定性试验”。
3.
Safety
安全性
Packaging
components should be constructed of materials that
will not
leach harmful or undesirable
amounts of substances to which a patient
will be exposed when being treated with
the drug product. This
consideration is
especially important for those packaging
components
which may be in direct
contact with the dosage form, but it is also
applicable to any component from which
substances may migrate into
the dosage
form (e.g., an ink or adhesive).
包装组件的组
成材料应该是
不脱落有害物质或过量的物质，
而使接受这个药品
治疗的患者暴露于这些
物质。
这一点对于那些直接与制剂接触的
包装组件尤其重要，
不过，
任何
有可能
释放物质进入到制剂中的组件也适用于此要求（例如墨水或粘合
剂）。
< br>
Making the determination that a
material of construction used in the
manufacture of a packaging component is
safe for its intended use is
not a
simple process, and a standardized approach has
not been
established. There is,
however, a body of experience which supports
the use of certain approaches that
depend on the route of
administration
and the likelihood of interactions between the
component and the dosage form (see
Table 1).
判定生产包装组件的材
料相对于其用途是
否安全并不是一个简单的过程，
现在还没有建立一个标
准化的方
法。
不过，
根据给药途径和组件与制剂相互作用的可能性，
有大
量的经验可以支持某些方法的应用（见表
1
）。
For a drug
product such as an injection, inhalation,
ophthalmic, or
transdermal, a
comprehensive study is appropriate. This involves
two
parts: first, an extraction
study
on the packaging component to
determine which chemical species may
migrate into the dosage form
(and at
what concentration); and, second, a toxicological
evaluation of
those substances which
are extracted to determine the safe level of
exposure via the label specified route
of administration. This technique
is
used by the Center for Food Safety and Applied
Nutrition (CFSAN) to
evaluate the
safety of substances that are proposed as indirect
food
additives (e.g., polymers or
additives that may be used in for packaging
foods).
对于一些药品，例如
注射液、吸入性药品、眼科用药或透皮药
品，需要做全面的研究。
包括两个部分：
首先，进行包装组件的提取性试
验，以确定哪
些类型的化学物质会混入制剂（以及混入的数量）；其次，
对提取出的物质进行毒理学评
价，
确定：
按照标签指定的给药途径，
安全
的暴露水平。这是美国食品安全与应用营养学中心（
CFS
AN
）采用的一
种方法，
用来评价一些
被当作间接食品添加剂的物质的安全性
（例如聚合
物或者可用来
包装食品的添加剂）。
The approach for
toxicological evaluation of the safety of
extractables
should be based on good
scientific principles and take into account the
specific container closure system, drug
product formulation, dosage
form, route
of administration, and dose regimen (chronic or
short-term
dosing).
可提取物的毒理性
评价方法应基于良好的科学原则，并考虑到
具体的容器
/
封装系统，药品处方，剂型，给药途径以及给药方案（长期
或短期给药
）。
For many injectable and
ophthalmic drug products (see sections III.E
and III.F), data from the USP
Biological Reactivity Tests and USP
Elastomeric Closures for Injections
tests will typically be considered
sufficient evidence of material safety.
对于许多注射剂和眼科药品（见
13
1
2
III.E
和
III.F
部分），
USP
生物反应试验和
USP
注射用橡胶封
装试验所
获得的数据通常被看作是材料安全性的充分证据。
For many solid and liquid oral drug
products, an appropriate reference
to
the indirect food additive regulations (21 CFR
174-186) promulgated
by CFSAN for the
materials of construction used in the packaging
component will typically be considered
sufficient. Although these
regulations
do not specifically apply to materials for
packaging drug
products, they include
purity criteria and limitations pertaining to the
use
of specific materials for packaging
foods that may be acceptable for the
evaluation of drug product packaging
components. Applicants are
cautioned
that this approach may not be acceptable for
liquid oral
dosage forms intended for
chronic use (see section III.F.1).
对于许多
固
体和液体口服药品的包装组件生产材料，恰当的参考由
CFS
AN
发布的
“间接食品添加剂法规”（
21 CFR 174-186
）通常被认为是充分的。虽
然这
些法规不是专门适用于药品包装材料的，
但是它们包括根据特定食品
包装材料的用途而制订的洁净标准和限制，
可能能被接受用来评价药品的
包装组件。申请人要注意的是：对于长期使用的液体口服制剂（见
III.
F.1
部分），上面的方法不能被接受。
For drug products that undergo clinical
trials, the absence of adverse
reactions traceable to the packaging
components is considered
supporting
evidence of material safety.
如果是正在进行临床试
验的药
品，包装组件没有引起不良反应，即可作为材料安全性的支持证据。
Safety assessments for specific
dosage forms are discussed further in
section III of this guidance.
具体剂型的安全性评价将在本指南的第
III
部
分进一步讨论。
4.
Performance
功能
Performance of the container closure
system refers to its ability to
function in the manner for which it was
designed. A container closure
system is
often called upon to do more than simply contain
the dosage
form. When evaluating
performance, two major considerations are
container closure system functionality
and drug delivery.
容器
/
封装系统
的功能是指其按照设计发挥功能的能力。容器
/
包装系统通常不仅仅用来
包装制剂。在评价功能时，有两个
主要方面要考虑：容器
/
封装系统的功
能性和药品输送。
a)
Container Closure System Functionality
容器
/
封装系统的功能性
The container closure system may
be designed to improve
patient
compliance (e.g., a cap that contains a counter),
minimize waste (e.g., a two-chamber
vial or IV bag), improve
ease of use
(e.g., a prefilled syringe), or have other
functions.
容器
/
封装系
统可被设计成能提高患者适用性
（例如，
包括计量装
置的瓶盖），减少浪费（例如，双腔药瓶或静脉输液袋），方便
使用（例如
，预灌装针），或者其他功能。
b)
Drug Delivery
药品输送
Drug
delivery refers to the ability of the packaging
system to
deliver the dosage form in
the amount or at the rate described
in
the package insert. Some examples of a packaging
system
for which drug delivery aspects
are relevant are a prefilled
syringe, a
transdermal patch, a metered tube, a dropper or
spray bottle, a dry powder inhaler, and
a metered dose inhaler.
药品输送是指包装系统按照药品说
明书的描述输出一定量制剂
或按照一定速度输出制剂的能力。一些和药品输送有关的包装
系
统的例子有：预灌装针，透皮贴剂，定量管，滴管或喷雾瓶，干
粉吸入器，以及定量吸入器。
Container
closure system functionality and/or drug delivery
are
compromised when the packaging
system fails to operate as
designed.
Failure can result from misuse, faulty design,
manufacturing defect, improper
assembly, or wear and tear
during use.
Tests and acceptance criteria regarding dosage
form delivery and container closure
system functionality should
be
appropriate to the particular dosage form, route
of
administration, and design features.
当包装系统达不到设计要
求时，容器
/
封装系统的功能性和
/
或药品输送这两
个方面即不合
格。原因可能是使用不当，设计缺陷，生产缺陷，组装不当，或
者使用时磨损或破裂。容器
/
封装系统的功能性和
/
或药品输送的
检验项目和接受标准应
与特定剂型，给药途径和设计性能相符
合。
5.
Summary
总结
Table 2
summarizes typical packaging suitability
considerations for
common classes of
drug products.
表
2
总结了各常见类型药品要考虑的
包装适应性事项。
Table 2
表
2
Typical Suitability Considerations for
Common Classes of Drug Products
(This table is a general guide, and is
not comprehensive. See sections III.C
through III.H for a more detailed discu
ssion.
本表格只是一个大体指导，不是全面
的。更详细的
内容请见第
III.C~
第
III.H
部分
)
Route of
Administration/
Dosage Form
给药途径
/
剂型
Protection
保护
SUITABILITY
适应性
Compatibility
相容性
Safety
安全
性
< br>
Performance/Drug
Deliver
y
功能性
/
药
品输送
a
Inhalation
Aerosols and
Solutions, Nasal Sprays
吸
入性气雾剂，吸入性液体，
鼻腔喷雾剂<
/p>
Inhalation
Powders
吸入性
粉末
Injections, Injectable
Suspensions
注射液，注射
性悬浮液
Sterile Powders and
Powders
for Injection
无菌
粉末和注射用粉末
Ophthalmic Solutions and
Suspensions
眼科溶液和悬
浮液
Topical Delivery Systems
外用给药系统
Topical
Solutions and
Suspensions, and Topical
and Lingual Aerosols
外用溶
液和悬浮液，外用和舌用喷
雾剂
Topical
Powders
外用粉末
Oral
Solutions and
Suspensions
口服溶液和悬
浮液
Oral Powders
口服粉末
Oral Tablets and Oral (Hard
and Soft Gelatin) Capsules
口服
片剂和口服胶囊（硬凝
b
L, S, M, W,
G
Case 1c
Case 1s
Case 1d
L, W, M
Case 3 c
case 5s
Case 1d
L, S, M, G
Case 1c
Case 2s
Case 2d
L, M, W
Case 2c
Case 2s
Case 2d
L, S, M,
G
Case 1c
Case 2s
Case 2d
L, S
Case 1c
Case 3s
Case 1d
L, S, M
Case 1c
Case 3s
Case 2d
L, M, W
L, S, M
Case 3c
Case 1c
Case 4s
Case 3s
Case 3d
Case 2d
L, W
L, W
Case 2c
Case 3c
Case 3s
Case 4s
Case 3d
Case 3d
胶或软凝胶）
a
If there is a special
performance
function
built
into the drug product (e.g., counter cap), it is
of importance
for any dosage form/route
of administration to show that the container
closure system performs that
function
properly.
如果此药品包装具有特殊功能（例如：具
有计量装置的瓶盖），则
悬浮液的定义请见表
1
注释。
不论是什么剂型或给药途径，都要显示出其能
正常表现此功能，这点很重要。
b
For definition of the term
suspension,
see footnote a
to Table 1.
Explanation of
Codes in Table 2:
表
2
中的符号含义
Protection:
保护
L
(protects from light, if
appropriate)
如有必要，避光
S
(protects from
solvent loss/leakage)
避免溶剂损失
/
泄露
M
(protects sterile products or those with microbial
limits
from microbial contamination)
避免无菌药品或那些具有微生
物限制的药品被微生物污染
W
(protects from water
vapor, if appropriate)
如有必要，避免
水汽
G
(protects
from reactive gases, if appropriate)
如有必
要，避
免活泼性气体
Compatibility:
相容
性
Case 1c:
Liquid-based dosage
form that conceivably could
interact
with its container closure system components (see
examples described in section III.B.1)<
/p>
液体制剂，可能会与容
器
/
封装系统相互作用（见第
III.B.1
部分描述的
例子）
Case 2c:
Solid dosage form until reconstituted; greatest
chance for interacting with its
container closure system
components
occurs after it is reconstituted.
待溶解的固体
制
剂；在溶解后很有可能与容器
/
封装
系统的组件相互作用。
Case
3c:
Solid dosage form with low
likelihood of interacting
with its
container closure system components.
固体制
剂，与
容器
/
封装系统的组件相互作用
的可能性很低
Safety:
安全性
Case
1s:
Typically provided are USP
Biological Reactivity
Test data,
extraction/toxicological evaluation, limits on
extractables, and batch-to-batch
monitoring of extractables.
通常要提供
USP
生物反应性试验数据，提取性
/
毒性评价，可
提取物限度，以及每批的可提取物的监测。
Case 2s:
Typically
provided are USP Biological Reactivity
Test data and possibly
extraction/toxicological evaluation.
通
常提供
USP
生物反应性试验数据，
有可能提供提取性
/
毒性评
< br>价
Case 3s:
Typically, an appropriate reference to the
indirect
food additive regulations is
sufficient for drug products with
aqueous-based solvents. Drug products
with non-aqueous
based solvent systems
or aqueous based systems
containing co-
solvents generally require additional suitability
information (see section III.F).
通常，对于水性液体药品，合
理的参考间接食品添加剂法规就足够了。
非水性液体药品或者
含有助溶剂的水性药品通常需要提供额外的适应性信
息
（见第
III.F
部分）
Case 4s:
Typically,
an appropriate reference to the indirect
food additive regulations is sufficient
.
通常，合理的参考间接
食品添加剂法规就足够了。
Case 5s:
Typically,
an appropriate reference to the indirect
food additive regulations for all
components except the
mouthpiece for
which USP Biological Reactivity Test data is
provided.
通常，除了口部组件要提供
U
SP
生物反应性试验数
据，其他所有组件要合理的参考间接食品
添加剂法规
Performance:
功能
性
Case 1d:
Frequently a
consideration
经常要考虑到
Case 2d:
May be a
consideration
有可能要考虑到
Case 3d:
Rarely a
consideration
很少考虑到
2.
Quality Control of
Packaging Components
包装组件的质量控制
In
addition to providing data to show that a proposed
container closure system
is suitable
for its intended use, an application should also
describe the quality
control measures
that will be used to ensure consistency in the
packaging
components (see section
III.C.3). These controls are intended to limit
unintended postapproval variations in
the manufacturing procedures or
materials of construction for a
packaging component and to prevent adverse
affects on the quality of a dosage
form.
除了提供资料证明拟采用的容器
/
封装系
统适应于其目的用途，申请资料中还应该描述用来保证包装组件的质量一
致性的
质量控制措施（见第
III.C.3
部分）。这些控制措施的目的是限制申请被批准后的
生产工艺变化，或者包装组件的
生产材料的变化，以及防止对制剂的质量造成不
良影响。
Principal consideration is usually
given to consistency in physical characteristics
and chemical composition.
主要
的考虑事项通常是物理特征和化学组成的质量
一致性。
a.
Physical Characteristics
物理特征
The physical
characteristics of interest include dimensional
criteria (e.g.,
shape, neck finish,
wall thickness, design tolerances), physical
parameters critical to the consistent
manufacture of a packaging
component
(e.g., unit weight), and performance
characteristics (e.g.,
metering valve
delivery volume, or the ease of movement of
syringe
plungers). Unintended
variations in dimensional parameters, if
undetected, may affect package
permeability, drug delivery
performance, or the adequacy of the
seal between the container and
the
closure. Variation in any physical parameter is
considered important
if it can affect
the quality of a dosage form.
要关心的物理特征包
括尺寸
标准（例如形状，瓶颈，壁厚，设计公差），包装组件连续生产时的关键
物理参数（例如单位重量），以及功能性特征（例如定量阀输出的体积，
或者注射器推杆的运动的灵活性）
。
如果未能检查出尺寸参数的
过量改变，
有可能会影响包装的渗透性，
药品输出的表现，
或者导致容器与封装的结
合不严密。任何能影响制剂质量的物理参数
的改变都被认为是严重的。
b.
Chemical Composition
化学组成
The chemical
composition of the materials of construction may
affect
the safety of a packaging
component. New materials
may result in
new substances being extracted into the
dosage form or a change in
the amount
of known extractables. Chemical composition may
also
affect the compatibility,
functional characteristics or protective
properties of packaging components by
changing rheological or other
physical
properties (e.g., elasticity, resistance to
solvents, or gas
permeability).
生产材料的化学组成可能影响到包装组件的安全性。采用
新材料可能导致提取出
一些新物质进入制剂，或者改变已知提出物的数
量。
化学组成还
可以通过改变流变学或其他物理特征
（例如弹性，
溶剂抗
性，
或者气体透过性）
而影响相容性、
功能性特征或者包装组件的保护性
能。
A composition change may occur as a
result of a change in formulation
or in
a processing aid (e.g., using a different mold
release agent) or
through the use of a
new supplier of a raw material. A change in the
supplier of a polymeric material or a
substance of biological origin is
more
likely to bring with it an unexpected composition
change than a
change in the supplier of
a pure chemical compound, because
polymeric and natural materials are
often complex mixtures. A
composition
change may also occur with a change in the
manufacturing
process, such as the use
of different operating conditions (e.g., a
significantly different curing
temperature), different equipment, or both.
化学组成的改变可能是由配方的改变所引起，
也可能是加工助剂
（例如采
用不同的脱模剂）
的改变，
或者采用了新供应商的原料。
改变聚合物材料
或生物来
源物质的供应商很可能比改变纯化合物供应商更能导致成分变
化，
因为聚合物和天然物质常常是混合物。
成分的改变也可能由生产工艺
< br>的改变所引起，
例如使用了不同的操作条件
（例如，
固化温度的显著改变）
，
不同的设备，或者
两者都不同。
14
A change
in formulation is considered a change in the
specifications for
the packaging
component. This change in the formulation of a
packaging component by its manufacturer
should be reported to the
firm that
purchases that component and to any appropriate
DMF. The
firm that purchases the
component should, in turn, report the change to
its application as required under 21
CFR 314.70(a) or 601.12.
Manufacturers
who supply a raw material or an intermediate
packaging
component should inform their
customers of any intended changes to
formulations or manufacturing
procedures and update the DMF in
advance of implementing such a change.
Changes which seem
innocuous may have
unintended consequences on the dosage form
marketed in the affected packaging
system.
配方的改变被看作是包装
组件质量标准的改变
。
包装组件的生产商改变了其配方，
则要向购买此组
件的公司报告，并且变更相关的
DMF
。然后，按
照
21 CFR 314.70(a) or
601.12<
/p>
的要求，购买组件的公司就要在其申请资料中报告变更。提供原
材
料或直接包装组件的生产商应当通知他们的客户拟变更的配方或生产
工艺，并且在进行变
更前更新
DMF
。看起来无关紧要的变更可能会对上
市制剂造成坏的影响。
The use of
stability studies for monitoring the consistency
of a container
closure system in terms
of compatibility with the dosage form and the
degree of protection provided to the
dosage form is accepted. Currently
there is no general policy concerning
the monitoring of a packaging
system
and components with regard to safety. One
exception involves
inhalation drug
products for which batch-to-batch monitoring of
the
extraction profile for the
polymeric and elastomeric components is
routine.
采用稳定性研究作为监测容器
/
封装系统的质量一致性（与制剂
的相容性以及对制
剂提供的保护）
是可被接受的。
现在还没有关于监测包
装系统和组件的安全性的通用政策。
一个例外是吸入性药品的每批聚合物
和橡胶组件的提取物监测是例行的。
3.
Associated Components
相关组件
Associated
components
are packaging components
that are typically intended
to deliver
the dosage form to the patient but are not stored
in contact with the
dosage form for its
entire shelf life. These components are packaged
separately
in the market package and
are either attached to the container upon opening
or
used only when a dose is to be
administered. Measuring spoons, dosing cups,
measuring syringes, and vaginal
delivery tubes are examples of associated
components that typically contact the
dosage form only during administration. A
hand pump or dropper combined into a
closure are examples of an associated
component that would contact the dosage
form from the time the packaging
system
is opened until the dosing regimen is completed. <
/p>
相关组件通常是用来
输送制剂给患者的包装组件，但是在整个有效
期内，在存放时都不与制剂接触。
这些组件在上市包装中是独立包装的，
要么是附着在容器上的
（直到打开为止）
，
要么只在给药时才使用。药匙，量杯，定量注射器，以及阴道给药器是典型的一
些直到给药时才接触制剂的例子。与封装部分连在一起的手动泵或滴管是“相关
组件
从打开包装系统到给药方案结束过程中接触制剂”的例子。
The complete and assembled component
and its parts should meet suitability
criteria appropriate for the drug
product and the actual use of the component
(see sections III.B.1 and III.B.2).
Safety and functionality are the most common
factors to be established for
suitability. The length of time that the
associated
component and the dosage
form are in direct contact should also be taken
into
consideration when assessing the
suitability of an associated component.
根据
具体的药品，以及组件在药品中的实际应用，整个组装好的组件和单独组件应符<
/p>
合适应性标准（见第
III.B.1
和第
III.B.2
部分）。安全性和功能性是在确立适应性
时的最常见因素。在评价一个相关组件的适应性时，还应该考虑相关组件与制剂
直接接触的时间长短。
4.
Secondary Packaging Components
二级包装组件
Unlike
primary and associated packaging components,
secondary packaging
components
are not intended
to make contact with the dosage form. Examples
are cartons, which are generally
constructed of paper or plastic, and overwraps,
which may be fabricated from a single
layer of plastic or from a laminate made
of metal foil, plastic, and/or paper. <
/p>
与一级包装组件和相关组件不同，
二级组件不
与制剂接触。例如纸箱（通常由纸或者塑料组成），以及外包装（通常由一层塑
料或
金属箔板，塑料板和
/
或纸板）。
A secondary packaging component
generally serves one or more of the
following additional functions:
二级组件通常行使以下的一个或多个额外功能：
a.
Provides protection from
excessive transmission of moisture or
solvents into or out of the packaging
system
避免湿气或溶剂过多的透
过包装系统
b.
Provides protection from
excessive transmission of reactive gases
(atmospheric oxygen, inert headspace
filler gas, or other organic
vapors)
into or out of the packaging system
避免活
泼性气体（例如空气
中的氧气，
顶端填充的惰性气体，
或者其他有机气体）
过多的透过包装系
统
c.
d.
Provides light protection for the
packaging system
为包装系统提供避光
保护
Provides protection for a packaging
system that is flexible or needs
extra
protection from rough handling
保护易变形的包装
系统，或者为粗
暴操作提供保护
e.
Provides an additional measure of
microbiological protection (i.e., by
maintaining sterility or by protecting
the packaging system from
microbial
intrusion)
避免微生物污染的额外措施
（即维持无
菌状态或者避
免微生物侵入包装系统）
When information on a container closure
system is submitted in an application,
the emphasis would normally be on the
primary packaging components. For a
secondary packaging component, a brief
description will usually suffice unless
the component is intended to provide
some additional measure of protection to
the drug product. In this case, more
complete information should be provided,
along with data showing that the
secondary packaging component actually
provides the additional protection (see
sections III.B.1 and III.B.2).
在提交申请
资料时，
关于容器
/
封装系统的信息重点通常是一级包装组件。
对于二级包装组件，
做个大体描述就足够了，除非这个组件是用来为药品提供保护的额外措施。在这
种情况下
，要提供更详细的信息以及数据，以证明二级包装组件确实能提供额外
保护（见第
III.B.1
和第
III.B.2
部分）。
Because
secondary packaging components are not intended to
make contact
with the dosage form,
there is usually less concern regarding the
materials from
which they are
constructed. However, if the packaging system is
relatively
permeable, the possibility
increases that the dosage form could be
contaminated by the migration of an ink
or adhesive component, or from a
volatile substance present in the
secondary packaging component. (For
example, a solution packaged in a LDPE
container was found to be
contaminated
by a volatile constituent of the secondary
packaging components
that enclosed
it.). In such a case, the secondary packaging
component should
be considered a
potential source of contamination and the safety
of its materials
of construction should
be taken into consideration.
因为二级包装组件不与
制剂
接触，通常较少关心它们的生产材料。不过，如果包装系统是比较有透过性的，
那么制剂被污染的可能性就增加，污染的来源有墨水或者粘合的组件，或者二级
包装组件里的挥发性物质。（例如，曾经发现包装在
LDPE
容器里的溶液被外面
的二级包装组件的挥发性成分污染。）这种情况下，应把二
级包装组件看作潜在
污染源，其生产材料的安全性应被考虑。
B.
Information That Should
Be Submitted in Support of an Original Application
for
Any Drug Product
为支持药品的最初申请而需要提供的信息
Additional discussion and information
regarding the CMC information to be provided in
an application (NDA, ANDA, or BLA) can
be found in the guidances and guidelines
listed in Attachment E.
其他关于药品申请
（
NDA, AND
A
或
BLA
）需要提供的
CMC
信息
的讨论请见附件
E
里面的指南和指导方针。
2.
Description
描述
A general description of the entire
container closure system should be provided
in the CMC section of the application.
In addition, the following information
should be provided by the applicant for
each individual component of the
packaging system:
关于整体容器
/
封装系统的描述应该在申请资料的
CMC
部分
提供。另外，申请人还应提供关于包装系统的每个组件的以下信
息：
15
a.
Identification by product name, product
code (if available), the name
and
address of the manufacturer, and a physical
description of the
packaging component
(e.g., type, size, shape, and color)
组件
的名称，
产品编号（如果有的话），生产商的名称和地址，
描述
包装组件的物理特
征（例如型号，尺寸，形状以及颜色）。
b.
Identification of the
materials of construction (i.e., plastics, paper,
metal,
glass, elastomers, coatings,
adhesives, and other such materials)
should be identified by a specific
product designation (code name
and/or
code number) and the source (name of the
manufacturer).
Alternate
materials of construction should also be
indicated.
Postconsumer recycled
plastic should not be used in the manufacture
of a primary packaging component. If
used for a secondary or
associated
component, then the safety and compatibility of
the material
for its intended use
should be addressed appropriately.
生产材料
的鉴
别（即，塑料，纸，金属，玻璃，橡胶，涂层，黏合剂，以及其他这类材
料）应按照具体产品的名称（代号和
/
或编号）和
来源（生产商名称）。
还应指出替代生产材料。
消费者使用后回
收的塑料不能用于生产一级包装
组件。
如果用于生产二级或相关
组件，
则应恰当的阐述该物料用于目的用
途的安全性和相容性。
16
c.
Description of any operations or
preparations that are performed on a
packaging component by the applicant
(such as washing, coating,
sterilization, or
depyrogenation)
描述应由申请人对包装组件
进行的加
工和准备（例如洗涤，覆层，灭菌或除热原）。
17
3.
Information
About Suitability
关于适应性的信息
a.
To establish safety and
to ensure consistency, the complete chemical
composition should be provided for
every material used in the
manufacture
of a packaging component.
为了确证安全性和保证质量一
致性，生产包装组件的每种材料都要提供其完整的化学组成。
b.
Test results from
appropriate qualification and characterization
tests
should be provided. Adequate
information regarding the tests, methods,
acceptance criteria, reference
standards, and validation information
should be provided.
应提供适当的“合
格要求”和“鉴别”试验的结果。
应提供关于试验，方法，接受标准，标准品和验证的充
分信息。
To address protection,
use of USP tests (see Attachment A) for light
transmission, moisture permeation,
microbial limits, and sterility are
generally considered sufficient.
Testing for properties other than those
described in USP (e.g., gas
transmission, solvent leakage container
integrity) may also be necessary.
关于保护方面，采用
USP
的试验（光
透过性，水透过性，微生物限度，以及无菌）通常被认为是充分的（见附
件
A
）。
USP
规定的其他方面的试验（例如，气体透过性，溶剂泄露，
容器完整性）也可能是必要的。
To address safety and
compatibility, the results of
extraction/toxicological evaluation
studies should be provided for drug
products that are likely to interact
with the packaging components and
introduce extracted substances into the
patient (see Table 1). For drug
products less likely to interact, other
tests (e.g., USP Biological
Reactivity
Test) or information (e.g., appropriate reference
to the
indirect food additive
regulations at 21 CFR 174-186) could be used to
address the issue of safety and
compatibility (see Table 2). For
example, an appropriate reference to an
indirect food additive
regulation is
generally sufficient for a solid oral dosage form
product.
关
于安全性和相容性，
对于那些有可能与包装组件相互作用的药品和把提取
出的物质引入患者体内的药品（
见表
1
）应提供提取性
/
毒理评价研究的
结果。对于相互作用可能性小的药品（见表
< br>2
），可用其他试验（例如
USP
生物反应性试验）或信息（例如适当的参考
21 CFR 174-186
的间
接食品添加剂法规）
来对待安全性和相容性问
题。
例如，
对于固体口服制
剂，通常认
为适当的参考间接食品添加剂法规就足够了。
To
address performance, the results of USP and non-
USP functionality
tests are considered
sufficient if the test and acceptance criteria are
appropriate for the intended purpose. <
/p>
对于功能性，
如果接受标准相对它
的目的
用途是适当的，则
USP
和非
USP<
/p>
功能性试验的结果被认为是充
分的。
Tests described in the USP are
typically considered sufficient standards
for establishing specified properties
and characteristics of specified
materials of construction or packaging
components. USP
规定的试验通
常被认为是充分
的标准，
用来确定生产材料或包装组件的指定性质和鉴别
特征。
For non-USP tests, an
applicant should provide justification for the use
of the test, a complete and detailed
description of how the test was
performed, and an explanation of what
the test is intended to establish.
If a
related USP test is available, comparative data
should be provided
using both methods.
Supporting data should include a demonstration of
the suitability of the test for its
intended use and its validation.
对于非
USP
试验，申请人应提供采用这个试验的合理性，完整并详细的描述
试
验过程，并解释本试验的目的。如果有相应的
USP
试验，应同时提供采
用两种试验方法获得的比较数据。
< br>所提供的支持性数据应包括：
显示此试
验对于其目的用途
的适应性，以及试验方法的验证。
Testing on
an assembled container closure system is usually
performed
by the applicant (or a
testing laboratory commissioned by the applicant)
and the test results provided in the
application. Such tests may include
vacuum leak testing, moisture
permeation, and weight loss or media fill.
组装后的容器
/
封装系统的检验通常由申请人进行（或
者由申请人委托的
检验实验室进行）
，
申请资料中应包括检验结果。
这些检验可能包括真空
泄露试验，
水气透过试验，以及重量减轻或培养基灌装。
Testing
on an individual packaging component is typically
performed by
the manufacturer of the
component and reported via a DMF (see
section V).
单个包装组件的检验通常是由组件的
生产商进行，并且在
DMF
中报告（见第
V
部分）。
4.
Information About Quality Control
关于质量控制的信息
The
fabricator/manufacturer of a packaging component
and the drug product
manufacturer who
uses this firm share the responsibility for
ensuring the quality
of packaging
components. These firms should have a quality
control program in
place so that
consistent components are produced. The drug
product
manufacturer must have an
inspection program for incoming packaging
components and materials (21 CFR
211.22, 211.84 and 211.122). For most
drug products, a drug product
manufacturer may accept a packaging
component lot based on receiving a
Certificate of Analysis (COA) or Certificate
of Certification (COC) from the
component supplier and the performance of an
appropriate identification test,
provided the supplier's test data are periodically
validated (21 CFR 211.84(d)(3)).
Acceptance of a packaging component lot
based on a supplier's COA or COC may
not be appropriate in all cases (e.g.,
some packaging components for certain
inhalation drug products).
包装组件生
产商和药品生产商共同承担保证包装组件的质量的责任。这些公司应该具有恰当
的质量控制程序，以使能生产出合格的组件。药品生产商必须有进厂的包装组件
和材料的
检查程序（依据是
21 CFR 211.22, 211.84
和
211.122
）。对于大多数
药
品，药品生产商可以根据收到的“检验报告书，
COA
”或“合
格证，
COC
”以
及进行恰当的鉴别试
验而认可一批包装组件，前提是供应商的试验数据有定期验
证
（
见
21 CFR 211.84(d)(3)
）
。
不是所有情况下都可以凭供应商的
COA
或
COC
认可一批包装组件（例如有些吸入性药品
的一些包装组件）。
a.
Applicants
申请人
The tests and methods used by the
applicant for acceptance of each
batch
of a packaging component that they receive should
be described.
If a batch is to be
accepted based on a supplier's COA or COC, then
the procedure for supplier validation
should be described. The data
from the
supplier's COA or COC should clearly indicate that
the lot
meets the applicant's
acceptance criteria. Acceptance criteria for
extractables should also be included,
if appropriate.
申请人应描述他们
为接受每
批包装组件而采用的试验及试验方法。如果是根据供应商的
COA
或
COC
接受一批，那么要描述供应商确认的程序。供应商提
高能
够的
COA
或
COC
上面的数据应能明确的显示出符合申请人的接受标准。
如有必要，还应包括可提取物的接受标准。
Dimensional and performance criteria
should be provided. Dimensional
information is frequently provided via
a detailed schematic drawing
complete
with target dimensions and tolerances and may be
provided
via the packaging component
manufacturer's DMF. A separate drawing
may not be necessary if the packaging
component is part of a larger
unit for
which a drawing is provided or if the component is
uncomplicated in design (e.g., a cap
liner).
必须提供尺寸和功能标准。
尺寸信息常常是用
详细的示意图
（包括目标尺寸和公差）
给出的，
可以在
包装组件生产商的
DMF
中提供。
如果某个包装组件是另一个较大组件的
一部分
（已经提供了较大组件的示意图）
，
或者这个
组件的设计并不复杂，
则无须提供单独的示意图。
b.
Manufacturers of
Packaging Components Sold to Drug Product
Manufacturers
卖给药品生产商的包装组件的生产商
Each manufacturer of a packaging
component sold to a drug product
manufacturer should provide a
description of the quality control
measures used to maintain consistency
in the physical and chemical
characteristics of the component. These
generally include release
criteria (and
test methods, if appropriate) and a description of
the
manufacturing procedure. If the
release of the packaging component is
based on statistical process
control,
a complete description of the
process (including control criteria)
and its validation should be provided.
每个向药品生产商卖包装组件的生产商都要提供质量控制措施
（用来保证
组件的物理和化学特征合格）
的描述。
通常包括放行标
准
（如有必要提供
试验方法）
以及生产
过程的描述。
如果某种包装组件的放行是基于统计过
程控制（<
/p>
SPC
），则应完整的描述这个过程（包括控制标准）以及其验<
/p>
证。
The description
of the manufacturing process is generally brief
and
should include any operations
performed on the packaging component
after manufacture but prior to shipping
(e.g., washing, coating, and/or
sterilization). In some cases it may be
desirable for the description to be
more detailed and to include in-process
controls.
对生产过程的描述通
常是概要性的，
而且必须包括包装组件生产出来后直到发运前的任何操作
（例如洗涤
，覆层，和
/
或灭菌）。有些情况下可能需要描述的更具体些，
并且包括中间过程控制。
This
information may be provided via a DMF (see section
V).
这些信息
可以通过
DMF
提供（见第
V
部分）。
c.
Manufacturers of
Materials of Construction or of Packaging
Components Used to Make Other Packaging
Components
材料的生产
商，或者用来生产其他包装
组件的包装组件的生产商
The quality
control procedures of the manufacturer of a
packaging
component may sometimes rely
in whole or in part on the quality control
procedures of a manufacturer who makes
an intermediate packaging
18
component that is used to
create the component. If so, each contributor
to the final packaging system should
provide a description of the quality
control measures used to maintain
consistency in the physical and
chemical characteristics of the
separate components and of the
assembled packaging system that they
provide.
包装组件生产商的质量
控制措施有时可能部
分或全部的依赖中间包装组件（用来生产包装组件）
生产商采取的质量控制措施。
如果是这样，
每个与最终包装系统有关的生
产
商都应该描述他们为保证单独组件和组装后的包装系统的物理和化学
特征合格而采取的质
量控制措施。
The manufacturer of
each material of construction should be prepared
to describe the quality control
measures used to maintain consistency
in the chemical characteristics of
their product.
每个材料生产商都应该
做好准
备：描述他们为保证产品的化学特征的合格而采取的质量控制措
施。
This information may be provided via
a DMF (see section V).
这些信息
可
以通过
DMF
提供（见第
V
部分）。
5.
Stability Data (Packaging Concerns)
稳定性数据（与包装有关系的）
Stability testing of the drug product
should be conducted using the container
closure systems proposed in the
application. The packaging system used in
each stability study should be clearly
identified.
进行药品的稳定性试验，必须采
用申
请资料中提出的容器
/
封装系统。
应明
确确定每个稳定性试验所使用的包装系
统。
The container closure system should be
monitored for signs of instability. When
appropriate, an evaluation of the
packaging system should be included in the
stability protocol. Even when a formal
test for quality of the packaging system is
not performed, the applicant should
investigate any observed change in the
packaging system used in the stability
studies. The observations, results of the
investigation, and corrective actions
should be included in the stability report. If
the corrective action requires a change
in an approved container closure
system, a supplemental application
should be submitted.
试验中应监测容器
/
封
装系统的不稳定迹象。有必要时，在稳定性方案中应评价
包装系统。即使没有对
包装系统的质量做正式试验，申请人也应对观察到的任何包装系统
（用于稳定试
验）的改变做调查。观察到的现象，调查结果，以及改正措施都要在稳定性
报告
中给出。
如果改正措施需要变更已被批准的容器
/
封装系统，
那么应提交补充申请。
For general guidance on
conducting stability studies, refer to the FDA
Guideline
for Submitting
Documentation for the Stability of Human Drugs and
Biologics
(February 1987).
The stability guideline is undergoing revision and
will be
superseded by the FDA's draft
guidance for industry
Stability Testing
of Drug
Substance and Drug
Products
(June 1998), once it is issued
in final form.
关于实
施稳定性研究的指南，<
/p>
请参考
FDA
的
“人用药品及生物制品的稳定性文件递交指
南
Guidelin
e for Submitting Documentation for the Stability
of Human Drugs and
Biologics
”（
1987
年
2
月）。这份稳定性指南目前正被修订，将要被
FDA
的行<
/p>
业指南草案
“原料药及药品的稳定性试验
Stability Testing of Drug Substance and
Drug Products
”（
19
98
年
6
月）取代，一旦最终稿发布，
即取代前稿。
Table 3
表
3
Information
That Should Be Submitted in an Original
Application for Any Drug
Product
任何药品的最初申请资料中应包括的信息
Description
描述部分
Overall general description of the
container closure system, plus:
全面的
概括性描述容器
/
封装系统，以及：
For Each Packaging Component:
对于每个包装组件：
?
?
Name, product code, manufacturer,
physical
description
名称，产品代码，生产商，物理特征描述
Materials of construction (for each:
name,
manufacturer, product code)
生产材料（描述每种生产材料的名
称，生产商，产品代码）
?
Description of any additional
treatments or
preparations
如有任何处理或准备工作，加以描述
Suitability
适应性部分
Protection: (By each component and/or
the container closure system, as
appropriate)
保护：（根据具体情况，描述单个
组件和
/
或容器封装系统）
?
?
气）
?
?
?
Moisture permeation
水气透过
Solvent loss
or leakage
溶剂减失或泄露
Microbial
contamination(sterility/container
integrity, increased bioburden,
microbial limits)
微生物污染（无
菌
/
容器完整性，生物负荷增加，微生物限度）
?
?
Filth
污物
Other
其他
Light exposure
光线
Reactive gases (e.g., oxygen)
活泼性气体
（如氧
Safety:
(for each material of construction, as
appropriate)
安全性：（根
据具体情况，描述每
种材料）
?
成分
Chemical
composition of all plastics,
elastomers, adhesives, etc.
所有塑料，橡胶，黏合剂等的化学
a
?
Extractables, as
appropriate for the material
根
据材料的具体情况，描述可提取物
Extraction/toxicological evaluation
studies, as appropriate
酌情描述提取
/
毒理评价研究
Appropriate USP testing
相应的<
/p>
USP
检验
Appropriate reference to the indirect
food additive
regulations (21 CFR 174-186)
酌情参考间接食品添加
剂法规（
21
CFR 174-186
）
b
?
Other studies as appropriate
酌情进行其他研究
Compatibility: (for each component
and/or the packaging system, as
appropriate)
相容性：（根据具体情况，描述每
种组件和
/
或包装系统）
?
法通常被认可
?
May also be
addressed in post-approval stability
studies
可能还要在批准后的稳定性试验中加以描述
Performance: (for the assembled
packaging system)
功能：（描述组装
后的包装系统）
?
Functionality
and/or drug delivery, as
appropriate
根据具体情况，描述其功能和
/
或药品输送
Component/dosage form
interaction, USP
methods are typically
accepted
组件
/
制剂间相互
作用，
USP
的方
Quality
Control
质量
控制部分
For Each Packaging Component Received
by the Applicant:
申请人收到
的每个包装组件
?
?
?
Applicant's
tests and acceptance criteria
申请
人所进行的检验和接受标准
Dimensional (drawing) and performance
criteria
尺寸（用示意图表示）和功能标准
Method to monitor consistency in
composition,
as appropriate
根据具体情况，成分合格的检测方法。
For Each Packaging Component Provided
by the Supplier:
供应商提供
的每种包装组件
?
?
Manufacturer's acceptance criteria for
release,
as appropriate
根据具体情况，生产商的放行质量标准
Brief description of the manufacturing
process
生产工艺的大体描述
c
Stability
稳定性部分
?
See section
III.C.4
请见第
III.C.4
部分
a
Including
any additives used in the manufacture of a
packaging component
包括生产包装组件过
See Attachment C for further discussion of
extraction studies. Testing of plastics should be
程中使用的任何添加剂。
b
performed on the packaging
component, not on the unformed resin. For a
blow/fill/seal product,
extractables
should be evaluated on the formed drug product
container itself. This also applies to
a container closure system which is
manufactured as part of the drug product
manufacturing
process.
关于提取性研
究的更深入讨论，请见附件
C
。关于塑料，应采用包装组件进行
试验，而不
是采用未成型的树脂。对于吹灌封一体化的产品，应直接对成型的药品容器本
身进行提取物研究。
如果容器
/
封装系
统是在整个药品生产过程中生产出来的，也应对成型的药品容器本身进行研究。
c
Note that an applicant's
acceptance tests may include, among others, test
parameters indicated
under the
description, suitability, and quality control
sections of this table.
注意申请人的接受试验
可能包括但不限于：本表的描述、适应性、质量控制部分下的检验项目。
C.
Inhalation Drug Products
Inhalation drug products
include inhalation aerosols (metered dose
inhalers); inhalation
solutions,
suspensions, and sprays (administered via
nebulizers); inhalation powders
(dry
powder inhalers); and nasal sprays. The CMC and
preclinical considerations for
inhalation drug products are unique in
that these drug products are intended for
respiratory-tract compromised patients.
This is reflected in the level of concern given to
the nature of the packaging components
that may come in contact with the dosage form
or the patient (see Table 1).
Guidance regarding the
container closure system information to support
the approval of
applications for
inhalation drug products will be provided in two
guidance documents
when finalized: the
guidance for industry
Metered Dose
Inhaler (MDI) and Dry Powder
Inhaler
(DPI) Drug Products; Chemistry, Manufacturing and
Controls Documentation
(a
draft was issued in October 1998) and
the guidance for industry
Nasal Spray
and
Inhalation Solution, Suspension,
and Spray Drug Products; Chemistry, Manufacturing
and Controls Documentation,
which is currently under development.
D.
Drug Products for
Injection and Ophthalmic Drug Products
These dosage forms share
the common attributes that they are generally
solutions,
emulsions, or suspensions,
and are all required to be sterile. Injectable
dosage forms
represent one of the
highest risk drug products (see Table 1). Any
contaminants present
(as a result of
contact with a packaging component or due to the
packaging system's
failure to provide
adequate protection) can be rapidly and completely
introduced into the
patient's general
circulation. Although the risk factors associated
with ophthalmics are
generally
considered to be lower than for injectables, any
potential for causing harm to
the eyes
demands caution.
-
-
-
-
-
-
-
-
-
上一篇：离别伤感的句子英语
下一篇：(完整版)大学英语完形填空