Download Guidelines on Container Closure Systems Version 1.3

Guidelines on
Container Closure
Systems
Version 1.3
Draft
[Not for implementation and published for
comment purposes]
Date of publication
27/12/2016
Guidelines on Container Closure
Systems
Version 1.3
Drug Sector
Saudi Food & Drug Authority
Please review and send your comments and suggestions within
60 days of publication to:
[email protected]
Please visit the SFDA’s website at
http://www.sfda.gov.sa/en/drug/drug_reg/Pages/default.aspx
for the latest update.
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Drug Sector
Vision and Mission
Vision
To be the leading regional Drug Regulatory Authority for pharmaceuticals and cosmetic
products, with professional excellence and services that contribute to the protection and
advancement of public health in the Kingdom of Saudi Arabia.
‫الرؤية‬
‫ ويقدم خدماته مبهنية ممتزية تسهم يف حامية‬،‫أن يكون قطاع ادلواء رائد ًا اقلميي ًا يف الرقابة عىل الدوية ومس تحرضات التجميل‬
.‫وتعزيز الصحة يف اململكة العربية السعودية‬
Mission
Protecting public health by ensuring safety, quality, efficacy and accessibility of human,
veterinary drugs and biological products, and safety of cosmetics, through administration of a
national regulatory system which is consistent with international best practice. Through our
mission, we also provide accurate and scientific-based information to the public and healthcare
professionals.
‫الرساةل‬
‫حامية الصحة العامة من خالل ضامن أمان وجودة وفعالية وتوفر الدوية البرشية والبيطرية واملنتجات احليوية وسالمة مواد‬
‫التجميل عرب تطبيق نظام وطين للرقابة متوافق مع أفضل املامرسات ادلولية وتقدمي املعلومات ادلوائية املبنية عىل أسس علمية‬
.‫للعامة واملهنيني الصحيني‬
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Document Control
Version
Author
Date
1.0
Drug Sector
26/1/2016
Initial draft
1.1
Drug Sector
08/02/2016
Initial draft for internal review
1.2
1.3
Drug Sector
06/03/2016
Drug Sector
27/12/2016
4
Comments
Include artwork design
Draft for public review
Contents
1.
Introduction ............................................................................................................................. 9
2.
Qualification and quality control of packaging components ................................................... 9
2.1.
General consideration ........................................................................................................ 10
Suitability for the intended Use ..................................................................................... 10
2.1.1.
2.1.1.1.
Protection:.................................................................................................................. 11
2.1.1.2.
Compatibility ............................................................................................................. 12
2.1.1.3.
Safety ......................................................................................................................... 12
2.1.1.4.
Performance ............................................................................................................... 13
Quality control of packaging components ..................................................................... 14
2.1.2.
2.1.2.1.
Physical characteristics .............................................................................................. 14
2.1.2.2.
Chemical composition ............................................................................................... 15
2.1.3.
Associated components ................................................................................................. 15
2.1.4.
Secondary packaging components................................................................................. 15
2.2.
Requirements for dosage form containers ......................................................................... 16
2.2.1.
Injectable drug products ................................................................................................ 16
2.2.2.
Ophthalmic drug products ............................................................................................. 17
2.2.3.
Inhalation and nasal drug products ................................................................................ 18
2.2.4.
Liquid-Based oral and topical drug products and topical delivery systems .................. 18
2.2.4.1.
Liquid-based oral drug products ................................................................................ 18
2.2.4.2.
Topical drug products ................................................................................................ 18
2.2.4.3.
Topical delivery systems ........................................................................................... 19
2.2.5.
Solid oral dosage forms and powders for reconstitution ............................................... 19
2.2.6.
Other dosage forms........................................................................................................ 20
2.2.7.
Bulk containers: ............................................................................................................. 21
2.2.7.1.
Containers for bulk drug substances:......................................................................... 21
2.2.7.2.
Containers for bulk drug products: ............................................................................ 22
2.3.
Packaging materials and closures ...................................................................................... 23
2.3.1.
2.3.1.1.
Types of material ........................................................................................................... 23
Glass .......................................................................................................................... 23
5
2.3.1.2.
Plastics ....................................................................................................................... 23
2.3.1.3.
Metal .......................................................................................................................... 24
Closures ......................................................................................................................... 24
2.3.2.
2.3.2.1.
Elastomeric closures .................................................................................................. 25
2.3.2.2.
Caps or overseals ....................................................................................................... 25
3.
Information that should be submitted in support of an original file for any drug product .... 26
3.1.
Description ........................................................................................................................ 26
3.2.
Suitability .......................................................................................................................... 26
3.3.
Quality Control .................................................................................................................. 27
3.4.
Stability ............................................................................................................................. 27
4.
Special types of container closure system ............................................................................. 28
Child - resistant closures ................................................................................................... 28
4.1.
List of products:............................................................................................................. 28
4.1.1.
Tamper- evident packaging (TEP) .................................................................................... 33
4.2.
Scope ............................................................................................................................. 33
4.2.1.
4.2.1.1.
Over the counter (OTC) and prescription products ................................................... 33
Acceptable TEP systems ............................................................................................... 34
4.2.2.
4.2.2.1.
Film Wrappers – transparent ..................................................................................... 34
4.2.2.2.
Blister or strip packs .................................................................................................. 35
4.2.2.3.
Heat shrink bands or wrappers .................................................................................. 35
4.2.2.4.
Sachet ........................................................................................................................ 36
4.2.2.5.
Bottle mouth inner seal .............................................................................................. 37
4.2.2.6.
Tape seals .................................................................................................................. 38
4.2.2.7.
Breakable caps ........................................................................................................... 38
TEP labeling statement: ................................................................................................. 39
4.2.3.
5.
Graphic design of the container closure system .................................................................... 40
5.1.
Design Recommendations for Primary Packaging (Blister Packs) ................................... 41
5.1.1.
Blister Packs for Oral Medications................................................................................ 41
5.1.1.1.
Product name and strength ........................................................................................ 41
5.1.1.2.
Blister strips foil ........................................................................................................ 43
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5.1.1.3.
Type and background color ....................................................................................... 44
5.1.1.4.
Type size and font color ............................................................................................ 45
5.1.1.5.
Match the styles of primary and secondary packaging .............................................. 46
5.2.
Design Recommendations for Secondary Packaging ........................................................ 47
Allocate white space for the dispensing label ............................................................... 47
5.2.1.
a.
Brand name, generic name and strength position .............................................................. 47
5.2.2.
Put critical information in the same field of vision on at least three non-opposing faces
(one side for Arabic & one side for English)................................................................................. 49
5.2.3.
Orient text in the same direction.................................................................................... 50
5.2.4.
Use blank space to emphasize critical information ....................................................... 51
5.2.5.
Ensure the generic product name is suitably clear ........................................................ 52
5.2.6.
Differentiate between strengths of the same pharmaceutical product ........................... 53
5.2.7.
Do not add trailing zeros to numbers ............................................................................ 54
5.2.8.
Use the same unit for all different strengths from the same pharmaceutical product ... 55
5.2.9.
Use of leading zero ........................................................................................................ 56
5.2.10.
Critical information size ................................................................................................ 57
5.2.11.
Use upper and lower case lettering ................................................................................ 58
5.2.12.
Use sans serif typefaces ................................................................................................. 59
5.2.13.
Use bold or semi-bold type............................................................................................ 60
5.2.14.
Condensed typefaces ..................................................................................................... 61
5.2.15.
Do not compress lines of text close together or adjust the space between letters ......... 62
5.2.16.
Align text to the left for English & to the right for Arabic ............................................ 63
5.2.17.
Images and logos ........................................................................................................... 64
5.2.18.
Create a strong contrast between type and background color ....................................... 65
5.3.
Using Color ....................................................................................................................... 66
5.3.1.
Use color differentiation to highlight information of the same pharmaceutical
product…. ...................................................................................................................................... 66
Packaging Design Summary.......................................................................................................... 68
5.4.
A Guide to Labeling and Packaging of Injectable Pharmaceutical products .................... 69
5.4.1.
5.4.1.1.
Principal Display Panel for carton (PDP) ...................................................................... 69
Features of front panel ............................................................................................... 69
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5.4.1.2.
Use of color ............................................................................................................... 71
5.4.1.3.
Similar drug name ..................................................................................................... 72
5.4.1.4.
Strength ..................................................................................................................... 73
5.4.1.5.
Concentration ............................................................................................................ 74
5.4.1.6.
Administration route .................................................................................................. 75
5.4.1.7.
Warnings.................................................................................................................... 76
5.4.1.8.
Injectable pharmaceutical products intended for use by patients .............................. 77
5.4.2.
Ampoules....................................................................................................................... 78
5.4.2.1.
Text orientation ......................................................................................................... 78
5.4.2.2.
Labeling methods ...................................................................................................... 79
5.4.2.3.
Labeling methods ...................................................................................................... 80
5.4.2.4.
Plastic ampoules ........................................................................................................ 81
5.4.3.
Vials............................................................................................................................... 82
5.4.3.1.
Critical information panel.......................................................................................... 82
5.4.3.2.
Text orientation ......................................................................................................... 83
5.4.3.3.
Color schemes ........................................................................................................... 84
5.4.4.
Pre-filled syringes .......................................................................................................... 85
5.4.4.1.
Secondary packaging ................................................................................................. 85
5.4.4.2.
Text orientation on syringe ........................................................................................ 86
5.4.5.
Infusion bags ................................................................................................................. 87
5.4.5.1.
Text positioning ......................................................................................................... 87
5.4.5.2.
Font ............................................................................................................................ 88
5.4.5.3.
Bag volume ................................................................................................................ 89
5.4.5.4.
Use of color ............................................................................................................... 90
5.4.5.5.
Bag Unit: ................................................................................................................... 91
5.4.5.6.
Route of administration ............................................................................................. 91
5.4.5.7.
Product differentiation ............................................................................................... 92
5.4.5.8.
Surface finish ............................................................................................................. 93
6.
References: ............................................................................................................................ 94
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1. Introduction
This guideline intended to provide guidance on general principles for submitting
information on the packaging materials, recommendations on the type of materials used
and the accepted presentation of the container closure system. It also reviews the various
elements of the packaging components in order to ensure that the product arrive properly
in the hands of patients.
The guideline describes the following topics:

Qualifications and quality control of packaging components.

Information that should be submitted in support of an original file or a variation
application for any drug product

Special types of container closure system:
o Child resistance closure and list of drugs subjected to this system.
o Types of tamper-evident packing.

Graphic design of the container closure system.
2. Qualification and quality control of packaging components
Each file should contain enough information to show that each proposed container closure
system and its components are suitable for its intended use.
The type and extent of information that should be provided in the file 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 provided about a packaging system
for a solid dosage form.
Table 1 illustrates the correlation between the degree of concern regarding the route of
administration and the likelihood of packaging component-dosage form interactions for
different classes of drug products:
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Table 1 Example of packaging concerns for common classes of drug products
Degree of Concern
Associated with the
Route of
Administration
Highest
High
Low
Likelihood of Packaging Component-Dosage Form Interaction
High
Medium
Inhalation Aerosols and
Solutions;
Injections and Injectable
Suspensions.
Ophthalmic Solutions
and Suspensions;
Transdermal Ointments
and Patches; Nasal
Aerosols and Sprays.
Topical Solutions and
Suspensions; Topical and
Lingual Aerosols Oral
Solutions and
Suspensions.
Sterile Powders and
Powders for
Injection; Inhalation
Powders
Topical Powders;
Oral powders
Low
Oral Tablets and
Oral (Hard and
Soft Gelatin)
Capsules
2.1. General consideration
The aspects of packaging to be considered include:
2.1.1. Suitability for the intended Use
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.
Every proposed packaging system should be shown to be:
-
suitable for its intended use.
-
adequately protect the dosage form.
-
be compatible with the dosage form.
-
composed of materials that are considered safe for use with the dosage form and
the route of administration.
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 company. An adequately detailed description of the
10
tests, methods, acceptance criteria, reference standards, and validation information for the
studies should be provided.
The sections below describe the tests and/or 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 is established by full shelf life stability studies.
2.1.1.1.
Protection
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 or
reactive gases (e.g., oxygen), loss of solvent, absorption of water vapor, and microbial
contamination.

Light protection is typically provided by an opaque or amber-colored container or by
an opaque secondary packaging component (e.g., cartons or overwrap). Test for light
transmission (Pharmacopoeia) is an accepted standard for evaluating the light
transmission properties of a container. This issue can also be evaluated by providing
the photostability studies. Further information regarding photostability studies can be
found in The GCC Guidelines for Stability Testing.

Loss of solvent can occur through a permeable barrier (e.g., a polyethylene (PE)
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.

Water vapor or reactive gases (e.g., oxygen) may penetrate a container closure
system either by passing through a semi-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.
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
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.
2.1.1.2.
Compatibility
There are numerous possibilities of interactions between (primary) packaging materials
and pharmaceutical products, such as:

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.

Release of visible and/or subvisible particles.
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.
2.1.1.3.
Safety
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).
12
For a drug product such as an injection, inhalation, ophthalmic, or transdermal and the
packaging materials are not describe in pharmacopoeias 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.
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).
For drug products that undergo clinical trials, the absence of adverse reactions traceable to
the packaging components is considered supporting evidence of material safety.
2.1.1.4.
Performance
Performance of the container closure system refers to its ability to function in the manner
for which it was designed. When evaluating performance, two major considerations are
container closure system functionality and drug delivery.

Container Closure System Functionality
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), for children protection (e.g., child resistance cap), or have
other functions.

Drug Delivery
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.
13
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.
2.1.2. Quality control of packaging components
Quality Control 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.
These controls are intended to limit unintended variations request in the manufacturing
procedures or materials of a packaging component and to prevent adverse effects on the
quality of a dosage form.
A file should describe the quality control measures that will be used to ensure consistency
in the packaging components. Principal consideration is usually given to consistency in
physical characteristics and chemical composition.
2.1.2.1.
Physical characteristics
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).
14
2.1.2.2.
Chemical composition
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.
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 company that purchases that component and to any appropriate
DMF.
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.
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.
2.1.3. Associated components
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.
The complete and assembled component and its parts should meet suitability criteria
appropriate for the drug product and the actual use of the component 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.
2.1.4. Secondary packaging components
Secondary packaging components are not intended to make contact with the dosage form.
An information in a file for a secondary packaging component is a brief description unless:
15

the component is intended to provide some additional measure of protection to the drug
product (e.g. to provide protection from light, stating the term “Keep in the outer Carton
until ready to use”).
 In this case, more complete information should be provided, along with data
showing that the secondary packaging component actually provides the
additional protection.

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. (e.g. a solution
packaged in a Low-density polyethylene (LDPE) container may be contaminated by a
volatile constituent of the secondary packaging components).
 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.
2.2. Requirements for dosage form containers
2.2.1. Injectable drug products
Injections are classified as small-volume parenterals (SVPs ≤ 100 ml), or as large-volume
parenterals (LVPs > 100 ml). For solids that must be dissolved or dispersed in an
appropriate diluent before being injected, the diluent may be in the same container closure
system (e.g., a two-part vial) or be part of the same market package (e.g., a kit containing
a vial of diluent).
A SVP may be packaged in a disposable cartridge, a disposable syringe, a vial, an ampule
or a flexible bag. A LVP may be packaged in a vial, a flexible bag, a glass bottle or, in
some cases, as a disposable syringe.
The containers for parenteral preparations should be made from a material that is
sufficiently transparent to permit the visual inspection of the contents. They should not
16
adversely affect the quality of the preparation, allow diffusion of any kind into or across
the container, or release foreign substances into the preparation.
Cartridges, syringes, vials, and ampules may be composed of type I, II or III glass, or
polyolefins. Flexible bags are typically constructed with multilayered plastic. Stoppers and
septa in cartridges, syringes, and vials are typically composed of elastomeric materials. The
input (medication) and output (administration) ports for flexible bags may be plastic and/or
elastomeric materials. An overwrap may be used with flexible bags to retard solvent loss
and to protect the flexible packaging system from rough handling.
For all these components data should be provided showing that a component meets the
requirements of pharmacopoeia.
Performance of a syringe to deliver the labeled amount of the drug product should be
demonstrated.
2.2.2. Ophthalmic drug products
These drug products are usually solutions marketed in a LDPE bottle with a dropper built
into the neck (sometimes referred to as droptainer), or ointments marketed in a metal or
plastic tube with an ophthalmic tip. A few solution products use a glass container due to
stability concerns regarding plastic packaging components. Ophthalmic ointments that are
reactive toward metal may be packaged in a tube lined with an epoxy or vinyl plastic
coating.
A large volume intraocular solution (for irrigation) may be packaged in a glass or
polyolefin (polyethylene and/or polypropylene) container.
Although ophthalmic drug products are required to be sterile. The descriptive, suitability,
and quality control information is typically the same as that for an injectable drug product.
Since ophthalmic drug products are applied to the eye, compatibility and safety should also
address the container closure system's potential to form substances which irritate the eye
or introduce particulate matter into the product.
17
2.2.3. Inhalation and nasal 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 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
complete information should be provided on the characteristics of, and acceptance criteria,
test methods, and sampling plans used for each component of the container and closure
system to ensure its suitability for manufacturing the drug product.
Preparations for nasal should be supplied in containers adapted for the appropriate delivery
of the product to the site of application, or should be supplied with a suitable applicator.
2.2.4. Liquid-Based oral and topical drug products and topical delivery
systems
2.2.4.1.
Liquid-based oral drug products
Typical liquid-based oral dosage forms are elixirs, emulsions, extracts, fluid extracts,
solutions, gels, syrups, spirits, tinctures, aromatic waters, and suspensions.
A liquid-based oral drug product typically needs to be protected from solvent loss,
microbial contamination, and sometimes from exposure to light or reactive gases (e.g.,
oxygen).
For glass components, data showing that a component meets the requirements of
pharmacopeia should be provided.
2.2.4.2.
Topical drug products
Topical dosage forms include aerosols, creams, emulsions, gels, lotions, ointments,
pastes, powders, solutions, and suspensions. These dosage forms are generally
18
intended for local (not systemic) effect and are generally applied to the skin or oral mucosal
surfaces. Topical products also include some nasal and otic preparations as well as some
ophthalmic drug products.
Some topical drug products are sterile or may be subject to microbial limits. In these cases,
additional evaluation may be necessary when determining the appropriate packaging.
The packaging system for a liquid-based topical product should deter solvent loss and
should provide protection from light when appropriate. Because these dosage forms may
be placed in contact with mucosal membranes or with skin that has been broken or
otherwise compromised, the safety of the materials of construction for the packaging
components should be evaluated.
2.2.4.3.
Topical delivery systems
Topical delivery systems are self-contained, discrete dosage forms that are designed to
deliver drug via intact skin or body surface. There are three types of topical delivery
systems: transdermal, ocular, and intrauterine.
Each of these systems is generally marketed in a single-unit soft blister pack or a preformed
tray with a preformed cover or overwrap.
2.2.5. Solid oral dosage forms and powders for reconstitution
The most common solid oral dosage forms are capsules and tablets. Oral powders and
granules for reconstitution are also included in this group.
The risk of interaction between packaging components and a solid oral dosage form is
generally recognized to be low. Powders that are reconstituted in their market container,
however, have an additional possibility of an interaction between the packaging
components and the reconstituting fluid. Although the contact time will be relatively short
when compared to the component/dosage form contact time for liquid-based oral dosage
forms, it should still be taken into consideration when the compatibility and safety of the
container closure system is being evaluated.
Solid oral dosage forms generally need to be protected from the potential adverse effects
19
of water vapor. Protection from light and reactive gases may also be needed. For example
the presence of moisture may affect the decomposition rate of the active drug substance or
the dissolution rate of the dosage form. The container should have an intrinsically low
rate of water vapor permeation, and the container closure system should establish a seal to
protect the drug product.
A typical container closure system is a plastic (usually HDPE) bottle with a screw-on or
snap-off closure and a flexible packaging system, such as a pouch or a blister package.
A typical closure consists of a cap, often with a liner, and frequently with an inner seal.
If a filler, desiccant or other absorbent material is used, the composition should be
provided. The component should differ in shape and/or size from the tablets or capsules
with which it is packaged. This will help distinguish between the component and the dosage
form since these are considered primary packaging components.
The most common forms of flexible packaging are the blister package and the pouch.
2.2.6. Other dosage forms
When submitting information for a drug product or dosage form not specifically covered
by the sections above, the following should be taken into consideration:
-
the compatibility and safety concerns raised by the route of administration of the drug
product and the nature of the dosage form (e.g., solid or liquid-based);
-
the kinds of protection the container closure system should provide to the dosage form;
-
the potential effect of any treatment or handling that may be unique to the drug product
in the packaging system.
-
Pharmacopeial requirements.
Quality control procedures for each packaging component should ensure the maintenance
of the safety and quality of future production batches of the drug product.
20
2.2.7. Bulk containers
2.2.7.1.
Containers for bulk drug substances
Drug substances are generally solids, but some are liquids or gases. The container closure
system for storage or shipment of a bulk solid drug substance is typically a drum with
double LDPE liners that are usually heat sealed or closed with a twist tie. A desiccant may
be placed between the bags.
The drum provides protection from light and mechanical strength to protect the liner during
shipment and handling. The majority of the protection from air and moisture is provided
by the liner. Because LDPE is not a particularly good moisture barrier, a drug substance
that is moisture sensitive may need additional protection. An alternative to a LDPE bag is
a heat-sealable laminate bag with a comparatively low rate of water vapor transmission.
Qualification of the packaging system is usually based on establishing compatibility and
safety of the liner but may also include characterization for solvent or gas transmission.
The container closure system for the storage or shipment of a bulk liquid drug substance is
typically plastic, stainless steel, a glass-lined metal container, or an epoxy-lined metal
container with a rugged, tamper-resistant closure. Qualification of the container closure
system may include characterization for solvent and gas permeation, light transmittance,
closure integrity, ruggedness in shipment, protection against microbial contamination
through the closure, and compatibility and safety of the packaging components as
appropriate.
The file should include a detailed description of the complete container closure system for
the bulk drug substance as well as a description of the specific container, closure, all liners,
inner seal, and desiccant (if any), and the composition of each component. The tests,
methods, and criteria for the acceptance and release of each packaging component should
be provided.
21
Stability studies to establish a retest period for bulk drug substance in the proposed
container closure system should be conducted with fillers or desiccant packs in place (if
used). Smaller versions which simulate the actual container closure system may be used.
Stability recommendations for container closure systems of different types are described
in the GCC Guidelines for Stability Testing.
2.2.7.2.
Containers for bulk drug products
A container closure system for bulk drug products may be used for storage prior to
packaging or for shipment to re-packagers or contract packagers.
In all cases, the container closure system should adequately protect the dosage form and
should be constructed of materials that are compatible and safe.
Container closure systems for on-site storage have generally been considered a cGMP
issue. However, if the company plans to hold bulk drug products in storage, then the
container closure system and the maximum storage time should be described and justified
in the file. In addition, stability data should be provided to demonstrate that extended
storage in the described containers does not adversely affect the dosage form. Even when
the storage time before packaging will be short, a company should use a container closure
system that provides adequate protection and that is manufactured from materials that are
compatible and safe for the intended use. A container closure system for the transportation
of bulk drug products to contract packagers should be described in the file. The container
closure system should be adequate to protect the dosage form, be constructed with
materials that are compatible with product being stored, and be safe for the intended use.
The protective properties of the shipping container are verified by the practice of including
annual batches of the packaged product in post-approval stability studies.
A container closure system specifically intended for the transportation of a large volume
of drug product to a re-packager, whether for a solid or liquid dosage form, is considered
a market package. The package should meet the same requirements for protection,
compatibility, and safety as a smaller market package, should be included in the stability
studies for file approval and in the long term stability protocol; and should be fully
22
described in the file. The length of time that the dosage form will spend in the bulk
container may be a factor in determining the level of detail of the supporting information
(including Holding time Studies).
For sterile drug substances, the capability of the container closure system to maintain
sterility during transportation should be demonstrated (e.g. simulated studies).
2.3. Packaging materials and closures
To ensure the efficacy of a product during its total shelf-life, pharmaceuticals must be
regarded as a combination of the medicinal product itself and the packaging.
2.3.1. Types of material
Only the most commonly used packaging materials and containers are described here:
2.3.1.1.
Glass
For a large number of pharmaceuticals, including medicinal products for oral and local
administration, glass containers are usually the first choice (e.g. bottles for tablets, injection
syringes for unit- or multi-dose administration). Different types of glass may be necessary,
depending on the characteristics and the intended use of the medicinal products concerned.
Manufacturers should arrange with their suppliers to obtain the appropriate type of glass
container for the intended use. Classifications of types of glass and relevant testing
protocols are given in the pharmacopoeias.
2.3.1.2.
Plastics
Some containers are now being made of plastics; the main use is for bags for parenteral
solutions. Classifications of types of plastic and relevant testing protocols are given in the
pharmacopoeias.
23
2.3.1.3.
Metal
Metal containers are used solely for medicinal products for non-parenteral administration.
They include tubes, packs made from foil or blisters, cans, and aerosol and gas cylinders.
Aluminium and stainless steel are the metals of choice for both primary and secondary
packaging for medicinal products. They have certain advantages and provide excellent
tamper-evident containers.
Since metal is strong, impermeable to gases and shatterproof, it is the ideal packaging
material for pressurized containers.
The suitability of a particular material for a container is normally established by conducting
stability studies in which the material is in contact with the drug.
2.3.2. Closures
Closures used for the purpose of covering drug containers after the filling process should
be as inert as possible. They should not give rise to undesired interactions between the
contents and the outside environment, and should provide a complete seal. Besides their
protective function, closures must also allow the easy and safe administration of the drug.
Depending on the application, closures may have to be pierced with a needle for
intravenous sets. Such closures are made from elastomeric materials (rubbers), while those
that cannot be pierced are generally made from plastics such as polyethylene (PE) or
polypropylene.
Depending on the type of container, closures may have different shapes and sizes, e.g.
stoppers for infusion or injection bottles or plungers for prefilled syringes. A special design
of stopper may also be required for some pharmaceutical production processes such as
lyophilization.
Closures, as primary packaging components, are of critical importance and must be
carefully selected. They are an essential component of the container and, as such, an
integral part of the drug preparation.
24
A container type which does not require a removable closure at the time of administration
is usually preferred since such a container/ closure system avoids, or at least minimizes,
the risk of biological and other contamination as well as tampering.
For parenteral preparations, the combination of glass containers and elastomeric closures,
usually secured by an aluminum cap, is widely used. Typical examples are infusion bottles,
injection vials and prefilled syringes. The rubber closures used within such a system must
be carefully selected in accordance with the intended purpose. Most often, improper rubber
closures are the cause of incompatibility between the packaging and the drug.
2.3.2.1.
Elastomeric closures
Rubber closures for pharmaceutical use must meet the relevant requirements of the most
important pharmacopoeias. The suitability of a rubber closure for a given application can
only be established by means of stability studies.
Coring studies should be conducted on elastomeric stoppers used in the packaging of multi
dose products, in order to establish its suitability for multiple piercing.
2.3.2.2.
Caps or overseals
Caps or overseals are used to secure the rubber closure to the container in order to maintain
the integrity of the seal under normal conditions of transport, handling and storage during
the intended shelf-life of the product. Such caps are usually made of aluminum and can be
equipped with a plastic top to facilitate opening. Caps also provide evidence of tampering:
once opened or removed they cannot be repositioned. This is especially true for caps with
a plastic top.
25
3. Information that should be submitted in support of an original file
for any drug product
This section applies to primary packaging components and to those associated and
secondary packaging components that provide protection to the drug product or for which
there may be a safety concern.
3.1. Description
Overall general description of the container closure system, plus:
For Each Packaging Component:



Name, manufacturer, physical description.
Materials of construction (for each: name, manufacturer).
Description of any additional treatments or preparations.
3.2. Suitability
Protection: (By each component and/or the container closure system, as appropriate)





Light exposure.
Reactive gases (e.g., oxygen).
Moisture permeation.
Solvent loss or leakage.
Microbial contamination(sterility/container integrity, increased bioburden, microbial
limits).
 Other.
Safety: For each material of construction, as appropriate.



Chemical composition of all plastics, elastomers, adhesives, etc.
Compatibility: (for each component and/or the packaging system, as appropriate).
Component/dosage form interaction .
Performance: (for the assembled packaging system)

Functionality and/or drug delivery, as appropriate.
26
3.3. Quality Control
For Each Packaging Component Received:
 Applicant's tests and acceptance criteria.
 Dimensional (drawing) and performance criteria.
 Method to monitor consistency in composition, as appropriate.
3.4. Stability
Stability testing of the drug product should be conducted using the container closure
systems proposed in the application. The orientation (e.g. inverted, horizontal) should be
carefully selected to ensure maximum contact of the product with all components of the
primary container closure system. The packaging system used in each stability study should
be clearly identified.
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 data should be submitted.
For general guidance on conducting stability studies, refer to the GCC Guidelines for
Stability Testing.
A correlation in table 2 provided to address the location of information in the drug
product’s file:
Table 2 Sections in the submitted file
Requirement
Module Section
Container / closure systems for active
substances
Container closure system for drug products
3.2.S.6
3.2.P.2.4
3.2.P.7
27
4. Special types of container closure system
4.1. Child - resistant closures
Tragic accidents involving the drug intoxication of children has led to new legislation
making it difficult for drug packaging to be opened by young children, while allowing
adults easy access.
Such packaging is designated as child-resistant. The caps also provide evidence of
tampering (tamper proof); where once opened or removed they cannot be repositioned
(section 4.2.2.7).
SFDA categorized the list of drugs to be in a child resistant pack to cover; over the counter
(OTC) and prescribed drugs.
The criterion to determine the list is based on the toxicity of substance contained in the
drug.
Child-resistant packaging is required for liquid or solid dosage form; the closure material
must be in plastic cap.
4.1.1. List of products
This list is subjected to update depending on the toxicity reports received by the SFDA
from hospital and health care professionals:
A. Over the counter drugs (OTC)
1. Non-steroidal anti-inflammatory
Ibuprofen
oral dosage forms containing 1 gm or more of ibuprofen in a
single package.
Naproxen
dosage forms containing 250 mg or more of naproxen in a single
package.
Ketoprofen
dosage forms containing more than 50 mg of ketoprofen in a
single package.
28
2. Paracetamol
oral dosage forms containing more than 1 gm per package.
3. Iron medications
that contain an equivalent of 250 mg or more of elemental iron
per package.
and supplements
4. Cold and cough preparations
5. Loperamide
oral dosage forms containing more than 0.045 mg of loperamide
in a single package.
6. Aspirin
7. Multivitamin preparations
8. Methyl salicylate
liquid
containing more than 5 % by weight, unless packaged in
pressurized spray containers.
preparations
(Wintergreen oil)
9. Diphenhydramine
oral dosage forms containing more than the equivalent of 66 mg
of diphenhydramine base in a single package.
B. Priority list for prescription drugs
1. Any controlled drug
2. Minoxidil (oral)
29
3. Antidepressants( priority for tricyclic antidepressants , selective serotonin reuptake
inhibitors and serotonin /norepinephrine reuptake inhibitors)
Amitriptyline
Dothiepin
Clomipramine
Nortriptyline Impipramine
4. Selective Serotonin Reuptake Inhibitors
Paroxetine
Reboxetine
Sertraline
Escitalopram
Citalopram
Fluoxetine
Fluvoxamine
5. Serotonin / norepinephrine reuptake inhibitor
Desvenlafaxine
Venlafaxine
Duloxetine
6. Cardiovascular drugs (priority for Beta-blockers , Calcium channel blockers and
Cardiac glycosides)
Beta-Blockers
Nadolol
Nebivolol
Propranolol
Carvedilol
Bisprolol
Sotalol
Labetalol
Metoprolol
Atenolol
Calcium Channel Blockers
Amlodipine
Nifedipine
Diltiazem
Felodipine
Nimodipine
Cardiac glycosides:
Digoxin
30
Lercanidipine
Verapamil
7. Antihistamines
Brompheniramine
Cetirizine
Chlorpheniramine
Cyproheptadine
Desloratadine
Dexchlorpheniramine
Dimenhydrinate
Doxylamine
(combination with
paracetamol, caffeine)
Fexofenadine
Hydroxyzine
Ketotifen
Loratadine
Meclozine
Pheniramine
Promethazine
Triprolidine (combination with other
drugs)
8. Anticonvulsants (priority for carbamazepine and valproic acid)
Carbamazepine
Valproic acid
9. Antipsychotics
Amisulpride
Aripiprazole
Chlorpromazine
Clozapine
Flupenthixol
Haloperidol
Pimozide
Prochlorperazine
Promazine
Promethazine
Quetiapine
Risperidone
Sulpiride
Lithium ( citrate,
Olanzapine
Trifluoperazine
sulphate)
10. Antineoplastic
Capecitabine
Cyclophosphamide
Dasatinib
Hydroxyurea
Imatinib
Lapatinib
Levamisole
Melphalan
Mercaptopurine
Methotrexate
Methyl
Nilotinib
aminolevulinate
Sorafenib
Sunitinib
Thioguanine
31
Tretinoin
11. Muscle relaxants
Baclofen
Chlorzoxazone
Dantrolene
Diazepam
12. Oral hypoglycemic (priority for sulfonylurea)
Chlorpropamide
Glibenclamide
Glimepiride
Gliclazide
Glipizide
13. Anticoagulants
Dabigatran
Rivaroxaban
Warfarin
32
Apixaban
4.2. Tamper- evident packaging (TEP)
The design of the packaging must contribute to preventing the tampering of certain
products.
Such tamper-evident packaging can allow the visual inspection of the product before use.
Definition of TEP: Packaging having an indicator or barrier to entry which, if breached or
missing, can reasonably be expected to provide visible evidence to consumers that
tampering has occurred.
TEP may involve in primary and/or secondary packaging.
The visual indication is required to be accompanied by appropriate precautionary label
statements to describe the tamper-evident feature(s) to the consumer and to warn that the
absence of or damage to such feature(s) at the time of purchase is an indication of possible
tampering with the product.
4.2.1. Scope
4.2.1.1.
Over the counter (OTC) and prescription products
The manufacturer and packager should choose to package the product in acceptable form
of TEP as described in this guidance with precautionary label statement.
TEP must not be regarded as replacing the need for Child Resistant Closures for bottles,
since SFDA request the companies for such protection.
33
4.2.2. Acceptable TEP systems
Manufacturers and packagers are free to use any packaging system included in this
guidance. Packaging features must be properly designed and appropriately applied to be
effective TEP.
4.2.2.1.
Film Wrappers – transparent
A transparent colorless film is wrapped securely around the entire product container. The
film must be cut to open the container and remove the product.
A reasonably tight "fit" of the film around the container must be achieved, e.g., by a shrinktype process. A film wrapper sealed with overlapping end flaps must not be capable of
being opened and resealed without leaving visible evidence of entry.
The wrappers should be imprinted with identifying characteristic (such as: product name,
registered or company’s logo) that cannot be readily or easily duplicated and repackaged.

Recommended label statement:
o Do not use if film wrapper is damaged or missing.
Figure
Figure 1
1
34
4.2.2.2.
Blister or strip packs
Dosage units (e.g., tablets or capsules) are individually sealed in plastic or foil. The blister
must be broken to take out the product.
The backing materials cannot be separated from the blisters or replaced without leaving
visible evidence of entry.

Recommended label statement:
o Do not use if blister seal is broken or damaged.
Figure 2
4.2.2.3.
Heat shrink bands or wrappers
The band and wrapper must be cut in order to utilize the product.
The band or wrapper cannot easily be removed and reapplied without visible damage to
the band.
Bands and wrappers should be imprinted with identifying characteristic (such as: product
name, registered or company’s logo) and shrunk by heat to seal the union of the cap and
container.

Recommended label statement:
o Do not use if seal around cap is broken or missing.
o Do not use if tape around cap is damaged.
o
For your protection, this bottle has an imprinted seal around the neck.
35
Figure 3
4.2.2.4.
Sachet
The product is enclosed in an individual sachet that must be broken to obtain the product.
The end seams of the pouches cannot be separated and resealed without showing visible
evidence of entry.
The sachet should be imprinted with identifying characteristic (such as: product
name,registered or company’s logo).

Recommended label statement:
o Do not use if sachet is damaged or broken.
Figure 4
36
4.2.2.5.
Bottle mouth inner seal
Paper, thermal plastic, plastic film, foil, or a combination can be used as a sealed to the
mouth of the bottle under the cap.
The seal must be broken to open the container and remove the product.
The seal cannot be removed and reapplied without leaving visible evidence of entry.
Seals applied by heat induction to containers appear to offer a higher degree of tamper
evidence than those that depend on an adhesive to create the bond.
The seal should be imprinted with identifying characteristic (such as: product name,
registered or company’s logo) that cannot be readily or easily duplicated and reapplied.

Recommended label statement:
o Do not use if inner foil liner is missing or broken.
o Bottle sealed under cap for your protection.
Figure 5
37
4.2.2.6.
Tape seals
Tape seals are acceptable if they contain a feature that makes it obvious if the seals have
been removed and reapplied e.g. a permanent adhesive.
The seal should be imprinted with identifying characteristic (such as: product name,
registered or company’s logo) that cannot be readily or easily duplicated.

Recommended label statement:
o Tape over carton flaps must be unbroken.
o Use only if carton seal is unbroken.
o Do not use if seals over carton ends are missing or broken.
Figure 6
4.2.2.7.
Breakable caps
The container (e.g. bottle) is sealed by a plastic that either breaks away completely when
removed from the container or leaves part of the cap attached to the container.
The cap, or a portion thereof, must be broken in order to open the container and remove
the product. Once opened or removed they cannot be repositioned.
The cap cannot be reapplied in its original state.

Recommended label statement:
o Use only if seal is unbroken.
o Do not use if cap seal is broken.
38
Figure 7
4.2.3. TEP labeling statement
The precautionary label statements are required to be translated into Arabic language.
If the tamper evident feature is on an secondary pack (e.g. caron box), the primary pack
(e.g., bottle) needs to include a statement to inform the consumer that the bottle should be
in a carton at the time of purchase.
If identifying characteristics are required in the tamper evident feature, those characteristics
need to be referenced in the labeling statement.
The label statement is required to be:

Displayed in a prominent place on the primary and secondary pack.

Unaffected if a TEP feature is breached or missing

Described the tamper evident features of the container.
If manufacturer and packager choose to deviate from the recommended label statements
included in this guidance, it is important to choose a statement that deliver the feature of
the TEP.
39
5. Graphic design of the container closure system
This section is complementary to the GCC Guidance for Presenting the SPC (Summary of
Product Characteristics), PIL (Patient Information leaflet), and Labeling Information with
more illustrations and details to minimize medication errors.
It is intended for solid oral dosage forms, which are the most common type of primary
packaging for prescription pharmaceutical products, and secondary packaging used on the
container label attached to secondary packaging. It should also be used for all injectable
pharmaceutical products. The design considerations and principles outlined also can be
applied to other products dosage forms.
40
5.1. Design Recommendations for Primary Packaging (Blister Packs)
5.1.1. Blister Packs for Oral Medications
5.1.1.1.
Product name and strength
The name and strength of the product should appear over each blister pocket. Batch number
and expiry date should be applied on each blister pocket as well. If it is not possible, the
batch number and expiry date should be added at the end of each blister strip, preferably at
both ends.
√
X
Figure 8
41
Optional: If the medication is given every day, print the days of the week on the reverse
side of the blister or capsule.
Figure 9
In certain cases (such as: small blister) it may not be possible to design the packaging
to accommodate all critical information on each blister cell. In such circumstances,
important information can appear multiple times across the back of the blister or the
important information should be displayed in such a manner that it is not destroyed or
eliminated when dosage units are removed.
42
5.1.1.2.
Blister strips foil
Use non reflective, matte material. Reflective foil can cause glare by light reflecting on the
foil which reduces the legibility of any information.
√
X
Figure 10
43
5.1.1.3.
Type and background color
Type color should contrast strongly with background color. Legibility can be reduced by
the combined effect of the foil material, a small font size and a background color that does
not sufficiently contrast with the font color.
√
X
Figure 11
44
5.1.1.4.
Type size and font color
Use bold or semi-bold type and avoid lightweight type. Maximize the font size to a size
that is appropriate for the size of the container. Small type size and a lightweight font on a
foil background impairs legibility.
√
X
Figure 12
45
5.1.1.5.Match the styles of primary and secondary packaging [optional]
A product’s primary and secondary packaging should have an identical or linked visual
style.
Figure 13
Patients taking more than one pharmaceutical product, or the same pharmaceutical product
in two or more strengths, must be able to identify which blister strip belongs to which
packet because the prescription instructions are attached to the secondary packaging.
Mixing up packages and blister strips could lead to the patient taking the wrong medication
or even overdosing.
46
5.2. Design Recommendations for Secondary Packaging
Secondary packaging describes the outer package of a pharmaceutical product. It serves to
hold the primary packaging and is not in contact with the product. The combined impact
of all design elements, such as color and typography, should be evaluated.
5.2.1. Allocate white space for the dispensing label [optional]
Have a clearly designated white space for the dispensing label if possible. Label
dimensions vary but a minimum of 70 x 35 mm is suggested, as this is the most common
size for dispensing. The white space should not interfere or cover the legibility of the
critical information on either side.
Figure 14
a. Brand name, generic name and strength position
The brand name, generic name and strength of the product should be directly above or
beside the space provided for the dispensing label. Pharmacy staff can then easily check
that the product description on the dispensing label correctly matches that on the secondary
packaging.
47
√
X
Figure 15
48
5.2.2. Put critical information in the same field of vision on at least three nonopposing faces (one side for Arabic & one side for English)
A standard packaging container has six faces on which information can be displayed.
Critical information should be in the same field of vision on at least 3 of the non-opposing
faces of the secondary packaging. This means putting the information on the top or bottom
face, one of the side faces, and one of the end faces. If it is feasible, display a product
description (the brand name, generic name and dosage strength of the product) on more
than three non-opposing faces.
Figure 16
49
5.2.3. Orient text in the same direction [optional]
The text on every face, excluding the ends, should be oriented in the same direction in a
way to easily read the information when the product is placed at any side on the shelf.
Figure 17
50
5.2.4. Use blank space to emphasize critical information
Leave sufficient space around critical information, so that it can be easily seen. If the
secondary packaging is cluttered with text and images, it can be difficult to recognize
important information and identify the correct packaging.
Critical information is
1. Brand and generic name of the product.
2. Strength and dosage form.
3. Total volume or concentration of vial and bottle, plus the “per mL” amount (e.g.,
10 mg/2 mL and 5 mg/mL).
4. Warning statements in some cases.
The net quantity number should be moved away from the strength number.
√
X
Figure 18
51
5.2.5. Ensure the generic product name is suitably clear
The generic name should be at least 50% the size of the brand name. Patients can be given
different brands of the same medication which can lead to them confusing brand names
with generic names. This can result in them taking multiple doses of the same medication.
√
X
Figure 19
52
5.2.6. Differentiate between strengths of the same pharmaceutical product
Make pharmaceutical product strengths stand out through typeface, type weight, color and
shape. This is particularly important if all secondary packaging from a manufacturer looks
similar.
√
X
Figure 20
53
5.2.7. Do not add trailing zeros to numbers
Do not add trailing zeros to numbers; always use whole numbers. If numbers have a trailing
zero (a decimal point followed by a zero, for example 5.0 mg) it is easy to miss the decimal
point and dispense a tenfold overdose. For example, a practitioner could administer 50 mg
instead of 5 mg.
√
X
Figure 21
54
5.2.8. Use the same unit for all different strengths from the same
pharmaceutical product
In addition, different strengths of the same pharmaceutical product should be expressed in
the same way, such as 250 mg, 500 mg, 750 mg. (e.g., 500 mg, not 0.5 g)
√
X
Figure 22
55
5.2.9. Use of leading zero
For an amount less than one, always use a leading zero to avoid any confusion in the
concentration (for example use 0.25 not .25).
√
X
Figure 23
56
5.2.10. Critical information size
Use the largest size font possible for that package size so that the information is readable
and clear.
√
X
Figure 24
57
5.2.11. Use upper and lower case lettering
Entire sentences written in upper case letters or italic type are hard to read. Use the lower
case except for the first letter of the generic names, brand names, sentences or paragraphs.
Italic types should not be used where there is an alternative method of emphasis such as
bold type. Mixed case lettering should always be used for sentences.
√
X
Figure 25
58
5.2.12. Use sans serif typefaces
Use a sans serif typeface, such as Arial, Helvetica or Universe. The choice of typeface
influences legibility. Ornate typefaces are difficult to read. They are not suitable for
medication packaging, where clarity, accuracy and legibility must be paramount.
√
X
Figure 26
59
5.2.13. Use bold or semi-bold type
Lightweight type reduces legibility. Patients, especially those who are partially sighted,
find bolder type easier to read. Use bold or semi-bold type and avoid lightweight type for
all critical information.
√
X
Figure 27
60
5.2.14. Condensed typefaces
Do not use condensed typefaces when possible. Condensed typefaces reduce legibility and
increase the chance of error. Condensed typefaces may be necessary on blister packs on
each pocket and on small vials to fit all the required information, but should not be used
when there is adequate space for normal typeface.
√
X
Figure 28
61
5.2.15. Do not compress lines of text close together or adjust the space between
letters
Reducing the space between lines, known as the leading, and reducing the space between
letters, known as the kerning, affects legibility. Do not compress lines of text close
together. Leave enough space between lines and letters.
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X
Figure 29
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5.2.16. Align text to the left for English & to the right for Arabic
An irregular amount of space between words affects legibility. Align text to the left hand
margin and do not center justify text. Align all English text including the critical
information to left side (left justified) and for the Arabic version, it should be aligned to
the right side (right justified).
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X
Figure 30
63
5.2.17. Images and logos
Images or logos should not be near the text, as it could interfere with reading it, or it may
look like it is part of the text. Text should remain unbroken. Fitting text around or over
images or logos breaks the flow of information.
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X
Figure 31
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5.2.18. Create a strong contrast between type and background color
There should be a strong color contrast between the type and background colors. Dark
colored type (e.g. black, dark blue) should be on a light colored background (e.g. white,
pale pink, pale yellow). The reverse is true as well. Insufficient contrast between the
background and the type reduces legibility.
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Figure 32
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5.3. Using Color
Secondary packaging describes the outer package of a pharmaceutical product. It serves to
hold the primary packaging and is not contact with the product. The combined impact of
all design elements, such as color and typography, should be evaluated.
5.3.1. Use color differentiation to highlight information of the same
pharmaceutical product
Use color to distinguish between, for example, different strengths of the same
pharmaceutical product and between similarly named pharmaceutical products.
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Figure 33
66
Do not color code packaging. A color coding system allows people to memorize a color
and match it to a particular product. However, creating a shortcut for identifying a
pharmaceutical product without having to read the label can lead to mistakes. It is important
that practitioners do not rely on color as a means to identify a specific product, as many
manufacturers may use the same color for different products, or different strengths of the
same product.
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Packaging Design Summary
Issue
Recommendation
Primary packaging
Glare caused by light reflecting on the foil Use non-reflective foil
Text damaged when blister strip is cut
Put pharmaceutical product name and
strength clearly on each pocket
Reduced legibility due to combined effect Create a strong contrast between type and
of foil material, small type size and background color
background color
Reduced legibility due to combined effect Use bold or semi-bold type
of a small type size and lightweight font
on a foil background
Blister strip with the wrong secondary Match the styles of primary and secondary
packaging
packaging
Secondary packaging
Pharmaceutical product name and strength
obscured
Dispensing label and pharmaceutical
product name mismatched
Allocate 70 x 35mm white space for
dispensing label
Position the generic name and
pharmaceutical product strength above or
next to the space for the dispensing label
Critical information does not appear in the Put critical information in the same field of
same field of vision
vision on at least three non-opposing faces
Compressing lines of text close together or Do not squash lines of text closer together
reducing the distance between individual or adjust the spaces between letters
letters makes text difficult to read
Irregular amount of space between words Align text to the left for English, and right
for Arabic
Text illegible over an image or logo
Logo should not be placed near text
Insufficient contrast between background Create a strong contrast between type and
and type
background color
Using color
Color
differentiation
inadvertently Use color differentiation to highlight
associated with a particular feature
information
Color does not help distinguish between Use opposing, meaningless colors
products in a manufacturer’s range
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5.4. A Guide to Labeling and Packaging of Injectable Pharmaceutical products
5.4.1. Principal Display Panel for carton (PDP): (in the red box below)
5.4.1.1.
Features of front panel
Create a front panel that features only the critical information. Subsequent (noncritical)
information can be shown on the back panel.
Minimum information consists of:

Trade name

Generic drug name

Concentration of the pharmaceutical product:
 Total quantity in the container (large font)
 Concentration per unit volume (smaller font).

Administration route(s)

Significant Warnings
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Key information becomes
difficult to find when
information is printed on
packaging in a dense block
using text in a small font.
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X
Figure 34
70
5.4.1.2.
Use of color
Use color to highlight key differences in information: the drug name, the quantity
concentration or warning if appropriate.
Apply the color scheme consistently throughout the primary and secondary packaging.
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Figure 35
71
5.4.1.3.
Similar drug name
Highlight the differences between similar generic or brand names from the same company.
This could be done through the use of color, or font sizes.
Change the graphic component to ensure an added element of differentiation; for example
this can be done by using different colors.
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X
Use Different colors or font size to differentiate between generic names of look-alike and sound-alike products
from the same company
Figure 36
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5.4.1.4.
Strength
Include a representation of the full volume strength, i.e. total quantity in total volume, as
well as amount per unit volume (e.g., 25 mg per 5 mL, then directly underneath and in
parentheses 5 mg/mL).
Care should be taken with the spacing between mg and ml. Adjust the kerning so as to
leave sufficient space around the “/” to achieve maximum legibility. It is acceptable to use
the slash mark (/) if the number after the slash is a 1, as in 1 ml. If the number is something
else, then use the “per” (for example, 50 mg per 2 mL, not 50 mg /2 mL). A slash can be
mistaken for the number 1, so the concentration could be misread (for the above example,
could be read as 50 mg in 12 mL, instead of 2 mL)
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Figure 37
73
5.4.1.5.
Concentration
Display concentration in total quantity /total volume, even if other units of concentration
such as percentage and ratios (for example ‘1 in 1,000’) are also present.
When using numbers of 1,000 and above, use commas to help prevent misreading.
Do not superimpose information on other information.
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Figure 38
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5.4.1.6.
Administration route
Make positive statements- use ‘do’s’, rather than ‘do not’s’ as much as possible.
Use specific directions and avoid using technical terms that are not well understood. (e.g.
‘For Parenteral Use’ meaning: For intravenous, intramuscular, intradermal, subcutaneous,
intrathecal).
Routes which should
not be used are stated
rather than routes that
should.
Always use positive
statements regarding
the
route
of
administration.
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Figure 39
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5.4.1.7.
Warnings
Separate warning notices from the main part of the text and highlight the warning.
Proprietary Name
Proprietary Name
Generic Name
500 mg
Generic Name
500 mg
Must be diluted before use.
For injection or infusion as sodium salts.
Read directions for use carefully.
Store below 25°C.
Must be diluted before use.
For injection or infusion as sodium salts.
Read directions for use carefully.
Store below 25°C.
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X
Figure 40
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Warning
about
unusually high doses
or potential allergies,
for example, are often
not highlighted and
become lost in dense
blocks of text
5.4.1.8.
Injectable pharmaceutical products intended for use by patients
[optional]
For injectable pharmaceutical products that are intended for use by patients, leave a clearly
designated blank space for the pharmacy label that is a minimum size of 70 x 35 mm.
Position the drug name and strength near the space.
For injectable pharmaceutical products that come in a multi dose format as insulin, it is
recommended that the drug concentration be represented as strength per unit volume.
Figure 41
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5.4.2. Ampoules
5.4.2.1.
Text orientation
Print the pharmaceutical product name longitudinally, along the length of the ampoule. A
good rule of thumb is: if the visible width of the label is less than the height of the label
then the name should be printed longitudinally.

The information listed below is the minimum and must be present on containers
more than 10 ml (the small container exceptions apply to containers of 10 ml
or less):
1. Pharmaceutical product name (brand name and nonproprietary name)
2. Expression of strength
3. Route of administration
4. Warnings, where important
5. Expiry date
6. Batch number
7. Marketing authorization holder
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Figure 42
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5.4.2.2.
Labeling methods
Use paper labeling where possible, and ensure that the label does not wrap completely
around the ampoule to allow for inspection of contents.
If ceramic or clear plastic labeling must be used, highlight key information by inverting
the text color.
Keep information to a minimum and reduce overlapping with text from the reverse side as
much as possible.
Labels should not come off in use and should be printed with ink that does not run when
sprayed with alcohol to disinfect the ampoule surface in the pharmacy or during clinical
procedures.
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X
Figure 43
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5.4.2.3.
Labeling methods
We recommend the addition of a peel-off label on ampoules or vials, which can be
transferred to a syringe in practice, will help practitioners avoid selection errors. All
syringes containing pharmaceutical products should be labeled if they leave the operator’s
hands.
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X
Figure 44
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5.4.2.4.
Plastic ampoules

Use a clear font size.


Information should be printed on paper label, if possible or direct on the
ampoule with good contrast color.
Use color to help to differentiate between products of the same company.

Eliminate or reduce emphasis on the name of the container type such as ‘PlasAmp’.

Expiry dates and batch numbers should be easy-to-read and printed on the main
body of the container, not on rip-off tabs.

Where concentrations are shown, they should be expressed as total quantity in
total volume (e.g., 20 mg per10 ml) as well as the per unit volume (e.g., 2 mg/
mL).
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X
Figure 45
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5.4.3. Vials
5.4.3.1.
Critical information panel
Create an area, which highlights the critical information. This area should not be wider
than the width of the bottle in order to allow seeing the critical information without the
need to turn the vial (i.e., along a single line of vision).
Use appropriate font size and formatting to enable the generic drug name to be read in one
glance. The generic name should be at least 50% the size of the brand name.
Key information
can be hard to find
in dense text.
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X
Figure 46
82
5.4.3.2.
Text orientation
The drug name should be able to be seen in a single line of vision. If the full drug name
cannot be seen when the vial is upright, then the label should be oriented in a longitudinal
fashion, in order to have the drug name in a single line of vision.
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X
Figure 47
83
5.4.3.3.
Color schemes
Match the design of the vial label to that of the carton.
Where the flip cap is colored, use the predominant differentiating color that has been used
on the label and carton if possible.
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Figure 48
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5.4.4. Pre-filled syringes
5.4.4.1.
Secondary packaging
Vary the design of the secondary packaging of similar products to enable easy
identification. Pre-filled syringes that may be required during a medical emergency can be
easily confused, especially when there is minimal differentiation on the outer packaging.
Consider the use of different colored components, for example, plungers or caps, to
emphasize differences. Pharmaceutical products that come in a wide range of
concentrations and doses can also be mistaken for each other.
Outer packaging, once opened, should not be easily re-sealable and should clearly indicate
that the pre-filled syringe has been removed to prevent a delay in treatment if the empty
pack is placed back into stock.
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Figure 49
85
5.4.4.2.
Text orientation on syringe
Orient text along the length of the syringe so critical information can be read holding it in
the right hand, without rotating the syringe. When text is oriented around the syringe it
necessitates a small font size which can be difficult to read.
Invert text color or use a background color to prevent text showing through.
Volume markings should always be visible and not covered by labels.
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Figure 50
86
5.4.5. Infusion bags
5.4.5.1.
Text positioning
The critical information should be placed at the top of the bag; this information (especially
the drug name and strength/concentration) should be repeated at the bottom of the bag so
that as the bag empties it can still be visualized.
Position the batch number and expiry date close together.
Invert the key information text to draw the eye to it. Key information is lost in dense blocks
of text.
√
√
Figure 51
87
X
5.4.5.2.
Font
The choice of font should be carefully considered to ensure adequate spacing between
letters also the ink should not bleed. Use a san serif font as with other labels.
For multi-ingredients products, list the ingredients in table format if possible.
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Figure 52
88
5.4.5.3.
Bag volume
For fluids that comes in different volume sizes, give emphasis to the volume of infusion.
Vary other elements of the design to increase differentiation between labels.
When listing ingredients on the infusion bags, the strength should be represented as
quantity per container.
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X
Figure 53
89
5.4.5.4.
Use of color
It is important to differentiate between identified high-alert infusions.
Use bold blocks of color that stand out and draw the eye to the critical information and
warnings.
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X
Figure 54
90
5.4.5.5.
Bag Unit
Where the strength of pharmaceutical product is expressed in mmol, it should be
represented as mmol/container volume.
5.4.5.6.
Route of administration
Highlight the route of administration, particularly if it is different from the norm.
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Figure 55
91
5.4.5.7.
Product differentiation
Ensure there is an additional differentiator in addition to the text. For example, use color
or, if this is not possible, vary the graphic components.
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X
Figure 56
92
5.4.5.8.
Surface finish
Use matte materials where possible to improve legibility. If materials used for the fluid
bags and overwraps are reflective, the combination of the two materials can lead to
impaired visibility of key information.
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X
Figure57
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6. References:

WHO Guidelines on packaging for pharmaceutical products, 2002.

FDA Guidance for Industry (Container Closure Systems for Packaging Human Drugs
& Biologics), May 1999.

TGA Guideline for the Tamper-Evident Packaging of Medicines, Complementary
Healthcare Products and Medical Devices, December 2000.

FDA Tamper-Resistant Packaging Requirements for Certain over-the-counter Human
Drug Products, January,1988.

A guide to labeling and packaging injectable medicine , edition 1, 2008 National
patient Safety Agency (NHS)

A guide to the graphic design of medication packaging, 2nd edition , 2007 , National
Patient Safety Agency (NHS)

A guide to the design of dispensed medicines, 1st edition, 2007, National Patient Safety
Agency (NHS)

The US Draft guidance, “Safety Considerations for Container Labels and Carton
Labeling to Minimize Medication Errors ”, April 2014

This guidance was reviewed by the Institute for Safe Medication Practices (ISMP)
subsidiary, Med-ERRS (www.med-errs.com) www.ismp.org.
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