Version 1.3

Draft

[Not for implementation and published for

comment purposes]

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Date of publication 27/12/2016

2

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:

Drug.comments@sfda.gov.sa

Please visit the SFDA’s website at

http://www.sfda.gov.sa/en/drug/drug_reg/Pages/default.aspx

for the latest update.

3

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

قلميياً يف الرقابة عىل ال دوية ومس تحرضات التجميل، ويقدم خدماته مبهنية ممتزية تسهم يف حامية أ ن يكون قطاع ادلواء رائدًا ا

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 أ مان وجودة وفعالية وتوفر ال دوية البرشية والبيطرية واملنتجات احليوية وسالمة مواد

التجميل عرب تطبيق نظام وطين للرقابة متوافق مع أ فضل املامرسات ادلولية وتقدمي املعلومات ادلوائية املبنية عىل أ سس علمية

.لصحينيللعامة واملهنيني ا

4

Document Control

Version Author Date Comments

1.0 Drug Sector 26/1/2016 Initial draft

1.1 Drug Sector 08/02/2016 Initial draft for internal review

1.2 Drug Sector

06/03/2016 Include artwork design

1.3 Drug Sector

27/12/2016 Draft for public review

5

Contents 1. Introduction ............................................................................................................................. 9

2. Qualification and quality control of packaging components ................................................... 9

2.1. General consideration ........................................................................................................ 10

2.1.1. Suitability for the intended Use ..................................................................................... 10

2.1.1.1. Protection:.................................................................................................................. 11

2.1.1.2. Compatibility ............................................................................................................. 12

2.1.1.3. Safety ......................................................................................................................... 12

2.1.1.4. Performance ............................................................................................................... 13

2.1.2. Quality control of packaging components ..................................................................... 14

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. Types of material ........................................................................................................... 23

2.3.1.1. Glass .......................................................................................................................... 23

6

2.3.1.2. Plastics ....................................................................................................................... 23

2.3.1.3. Metal .......................................................................................................................... 24

2.3.2. Closures ......................................................................................................................... 24

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

4.1. Child - resistant closures ................................................................................................... 28

4.1.1. List of products: ............................................................................................................. 28

4.2. Tamper- evident packaging (TEP) .................................................................................... 33

4.2.1. Scope ............................................................................................................................. 33

4.2.1.1. Over the counter (OTC) and prescription products ................................................... 33

4.2.2. Acceptable TEP systems ............................................................................................... 34

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

4.2.3. TEP labeling statement: ................................................................................................. 39

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

5.2.1. Allocate white space for the dispensing label ............................................................... 47

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. Principal Display Panel for carton (PDP) ...................................................................... 69

5.4.1.1. 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

Likelihood of Packaging Component-Dosage Form Interaction

High Medium Low

Highest Inhalation Aerosols and

Solutions;

Injections and Injectable

Suspensions.

Sterile Powders and

Powders for

Injection; Inhalation

Powders

High Ophthalmic Solutions

and Suspensions;

Transdermal Ointments

and Patches; Nasal

Aerosols and Sprays.

Low Topical Solutions and

Suspensions; Topical and

Lingual Aerosols Oral

Solutions and

Suspensions.

Topical Powders;

Oral powders

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

11

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.

12

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).

13

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.

14

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).

15

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:

16

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

17

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.

18

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

19

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

20

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.

21

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.

22

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

23

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.

24

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.

25

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.

26

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.

27

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

3.2.S.6

Container closure system for drug products 3.2.P.2.4

3.2.P.7

28

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.

29

2. Paracetamol oral dosage forms containing more than 1 gm per package.

3. Iron medications

and supplements

that contain an equivalent of 250 mg or more of elemental iron

per package.

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

preparations

(Wintergreen oil)

containing more than 5 % by weight, unless packaged in

pressurized spray containers.

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)

30

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 Citalopram Fluoxetine

Escitalopram 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 Diltiazem Felodipine Lercanidipine

Nifedipine Nimodipine Verapamil

Cardiac glycosides:

Digoxin

31

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,

sulphate)

Olanzapine Trifluoperazine

10. Antineoplastic

Capecitabine Cyclophosphamide Dasatinib Hydroxyurea

Imatinib Lapatinib Levamisole Melphalan

Mercaptopurine Methotrexate Methyl

aminolevulinate

Nilotinib

Sorafenib Sunitinib Thioguanine Tretinoin

32

11. Muscle relaxants

Baclofen Chlorzoxazone Dantrolene Diazepam

12. Oral hypoglycemic (priority for sulfonylurea)

Chlorpropamide Glibenclamide Gliclazide

Glimepiride Glipizide

13. Anticoagulants

Dabigatran Rivaroxaban Warfarin Apixaban

33

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.

34

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 shrink-

type 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 1 Figure 1

35

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.

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.

Figure 2

36

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 3

Figure 4

37

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

38

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.

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.

Figure 6

39

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.

Figure 7

40

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.

41

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

42

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.

43

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

44

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

45

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

46

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.

47

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.

48

√

X

Figure 15

49

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)

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

50

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

51

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.

√ X

Figure 18

The net quantity number should be moved away from the strength number.

52

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

53

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

54

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

55

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

56

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

57

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

58

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

59

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

60

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

61

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

62

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.

√

X

Figure 29

63

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).

√

X

Figure 30

64

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.

√

X

Figure 31

65

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.

√

X

Figure 32

66

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.

√

X

Figure 33

67

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.

68

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

of foil material, small type size and

background color

Create a strong contrast between type and

background color

Reduced legibility due to combined effect

of a small type size and lightweight font

on a foil background

Use bold or semi-bold type

Blister strip with the wrong secondary

packaging

Match the styles of primary and secondary

packaging

Secondary packaging

Pharmaceutical product name and strength

obscured

Allocate 70 x 35mm white space for

dispensing label

Dispensing label and pharmaceutical

product name mismatched

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

same field of vision

Put critical information in the same field of

vision on at least three non-opposing faces

Compressing lines of text close together or

reducing the distance between individual

letters makes text difficult to read

Do not squash lines of text closer together

or adjust the spaces between letters

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

and type

Create a strong contrast between type and

background color

Using color

Color differentiation inadvertently

associated with a particular feature

Use color differentiation to highlight

information

Color does not help distinguish between

products in a manufacturer’s range

Use opposing, meaningless colors

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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

70

√ X

Figure 34

Key information becomes difficult to find when information is printed on packaging in a dense block using text in a small font.

71

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.

Figure 35

√ X

72

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.

Figure 36

√ X

Use Different colors or font size to differentiate between generic names of look-alike and sound-alike products

from the same company

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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

74

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

75

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).

√ X

Figure 39

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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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.

√ X

Figure 40

Warning about unusually high doses or potential allergies, for example, are often not highlighted and become lost in dense blocks of text

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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

√ X

Figure 42

79

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.

√ 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.

√

X

Figure 44

81

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 ‘Plas-

Amp’.

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).

√

X

Figure 45

82

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.

√ X

Figure 46

Key information can be hard to find in dense text.

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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.

√ X

Figure 47

84

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.

√

X

Figure 48

85

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.

√

X

Figure 49

86

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.

√

X

Figure 50

87

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.

√ √ X

Figure 51

88

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

89

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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Figure 53

90

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.

√ X

Figure 54

91

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.

√ X

Figure 55

92

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.

√

X

Figure 56

93

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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Figure57

94

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.