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Guidelines on Container Closure Systems Version 1.3 Draft [Not for implementation and published for comment purposes] Date of publication 27/12/2016 Guidelines on Container Closure Systems Version 1.3 Drug Sector Saudi Food & Drug Authority Please review and send your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. 2 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 3 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 6 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 7 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 8 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: 9 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. 11 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. √ X Figure 29 62 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 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. √ X Figure 31 64 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 65 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 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. 67 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 68 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 69 Key information becomes difficult to find when information is printed on packaging in a dense block using text in a small font. √ 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. √ X 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. √ 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 72 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) √ X 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. √ X Figure 38 74 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. √ X Figure 39 75 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 76 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 77 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 78 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 79 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 80 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). √ X Figure 45 81 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. √ 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. √ 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. √ X Figure 48 84 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 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. √ X 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. √ X 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. √ 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. √ 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. √ X 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. √ 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. √ X Figure57 93 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. 94