INTRODUCTION

The WHO defines packaging as a collection of various components (e.g. bottle, vial, closure, cap, ampoule, blister) which surround the pharmaceutical product from production until its use¹. The US FDA defines the container closure system (CCS) as the combination of packaging components that work together to contain and protect the dosage form. This includes both primary and secondary packaging components, with the latter intended to provide additional protection to the drug product².

Any proposed packaging system must be proven to be suitable for its intended use: it should adequately protect the dosage form (against light, moisture, oxygen, contaminants, etc.); it should be compatible with the dosage form (without adsorption of the active pharmaceutical ingredient, etc.); it should be made from materials considered safe for use with both the dosage form and its route of administration (without migration of potential toxic substances); and it should function as intended (performance features).

Child-resistant closures are designed to make it difficult for young children to open drug packaging while still allowing easy access for adults. The use of child-resistant packaging has been shown to effectively reduce child mortality due to intoxication from oral prescription drugs. The three most common common types of reclosable child-resistant closures are “press–turn”, “squeeze–turn” and a combination lock (WHO TRS 902).

Tamper-evident packaging refers to a system where access is impossible without visible destruction of the seal or some part of the packaging (USP 659) or one that “provides visible evidence to consumers that tampering has occurred” (WHO 902). Examples of packaging technologies capable of meeting the TRP requirements are given in “FDA Compliance Policy Guide, 7132a. 17, CPG Sec. 450.500 Tamper-Resistant Packaging Requirements for Certain Over-the-Counter Human Drug Products”.

¹ WHO, TRS 902 Annex 9

² USFDA, Container Closure Systems for Packaging Human Drugs and Biologics

CONTAINER CLOSURE SYSTEMS FOR SPECIFIC PHARMACEUTICAL FORMS

CONTAINER CLOSURE SYSTEMS FOR PARENTERAL PREPARATIONS (DINJ and DINF)

Parenteral drug products are sterile preparations, typically liquids in the form of solutions, emulsions, suspensions, or dry solids that must be reconstituted with an appropriate vehicle to obtain a solution or suspension. They are classified as small-volume parenterals (SVPs) if the volume is 100 ml, or less, and as large-volume parenterals (LVPs) if the volume exceeds 100 ml.

SVPs (DINJ family) may be packaged in disposable cartridges, disposable syringes, vials, ampoule, flexible bags, or semi-rigid bottles. Only single-ended ampoules are accepted by MSF.

• Cartridges, syringes, vials, and ampoules are usually made of Type I or II glass or polypropylene. Specific glass types for each pharmaceutical form can be found in the European Pharmacopoeia (EP), British Pharmacopoeia (BP), or United States Pharmacopoeia (USP).
• Stoppers and septa used in cartridges, syringes, and vials are typically made from elastomeric materials. Closures for injectable preparations must meet the Type I (for aqueous preparations) or Type II (for non-aqueous preparations) test limits defined in the EP or USP.
• Caps or over seals are used to secure the rubber closure to the container to maintain the integrity of the seal under normal conditions of transport, handling, and storage during the product's shelf-life. These caps are usually made of aluminium may include a plastic top for easier opening. Caps also provide evidence of tampering.

LVPs (DINF family) may be packaged in flexible bags (with or without PVC), semi-rigid bottles, or a glass bottles. MSF's first choice is PVC-free flexible bags or semi-rigid bottles, as those containing are no longer accepted. The containers must have a site suitable for the attachment of an infusion set and a site that allows the administration of drugs.

Flexible bags are typically made of multi-layer plastic.

• Cyclo-olefins offer an alternative to PVC or glass; they are flexible and have low permeability.
• Flexible bag ports (for input of medication and output for administration) are made from plastic and/or elastomeric materials. These bags usually include a hanging part to withstand tension during use.
• Depending on the plastic used, IV fluid bags may have a protective pouch/overwrap that protects against solvent loss (which can lead to increased concentration), oxygen ingress, and dust. The over pouch is made from material with low permeability to water and gases.

Semi-rigid plastic bottles are typically made using Blow-Fill-Seal (BFS) technology and come with a sealed top that can be fitted with various types of closures. Some manufacturers offer open-neck bottles fitted with rubber stoppers and a flip-off caps.

• BFS bottles with a nipple head are not appropriate, as the base of the nipple head is fragile and the small cap does not provide adequate protection, leading to potential fatigue points and micro-holes during transport. Additionally, they lack an injection or administration site, requiring the top of the nipple to be pierced by the IV set or the needle. If alternative is available, experts recommend using larger caps for better head protection.
• Euro head caps are acceptable, but present some risks, including contamination of the top before welding if not done in an aseptic environment, and the potential for the space between the bottle top and cap to remain unsterilised due to insufficient penetration of water vapour.
• Newer generation caps have two access ports for the IV set and admixture, typically protected by an aluminium seal or a plastic cover (Twincap^®, Duocap^®).

CONTAINER CLOSURE SYSTEMS FOR OPHTHALMIC PRODUCTS (DEXO)

Ophthalmic preparations are sterile products, avaiable in liquid, semi-solid, or solid forms, specifically designed for application to the eye. These preparartion can be categorized into eye drops, eye lotions, semi-solid eye preparations, and ophthalmic inserts.

Liquid preparations for ophthalmologic use are typically packaged in sterilised single-dose (often preservative-free) or multi-dose containers. Multi-dose products are most commonly packaged in polyethylene (PE) or polypropylene (PP) bottle with an integrated dropper on the neck, sometimes referred to as "droptainers". For some eye drops, glass containers may be used when there are stability or compatibility concerns with flexible plastics. The container must be tamper-evident and contain a maximum of 15 ml of the preparation. Single-dose containers are generally made from . PP manufactured using the Blow-Fill-Seal (BFS) technique. Some preparations may be indicated for both ophthalmic or otic use (e.g., DEXTCIPR1D- : a preparation for eye and/or ear).

Semi-solid eye preparations are packaged in small, collapsible sterilised tubes, with or without an ophthalmic cannula or tip. These tubes are typically made from metal, though ophthalmic ointments that react with metal may be packaged in tubes with an epoxy or vinyl plastic coating inside. The packaging must be tamper-evident and contains no more than 5 g of the preparation³.

³ USFDA, Container Closure Systems for Packaging Human Drugs and Biologics.

CONTAINERS FOR TOPICAL PRODUCTS⁴ (DEXT)

Topical dosage forms include aerosols, creams, emulsions, gels, lotions, ointments, pastes, powders, solutions, and suspensions. These forms are typically intended for local (non-systemic) effects and are usually applied to the skin or oral mucosa. Topical products also include ceratin nasal and ear preparations, as well as vaginal and rectal pharmaceuticals.

Semi-solid or liquid preparations are commonly packaged in multi-dose containers, such as jars or collapsible tubes.

• Flexible (collapsible) tubes are usually made from metal (or metal-lined), LDPE, or laminated materials. These tubes are classified as closed-ended or open-ended. In closed-ended tubes, the product does not come into contact with the cap during storage.
• Jars are usually made of polypropylene and have a screw cap. The same type of cap liners and inner seals are sometimes used for solid oral dosage forms.
• Nasal, otic, vaginal, and rectal preparations should be packaged in containers suitable for their appropriate administration at the application site, or should be supplied with an appropriate applicator.

The closures of these containers should be designed to minimise the risk of microbial contamination and should be tamper-evident.

Liquid ear preparations⁵ are supplied in multi-dose containers made from glass or suitable plastics. These containers often have an integrated dropper or a screw cap from appropriate materials, which may incorporate a rubber dropper or plastic teat, sometimes provided separately.

Vaginal and rectal products are usually packaged in aluminium/aluminium strips or blisters, or occasionally in tubes (e.g., vaginal gel).

⁴ WHO, TRS 902 Annex 9 ; Handbook of Pharmaceutical Manufacturing Formulations: Liquid Products, Sarfaraz K Niazi, CRC Press, 2009
⁵ Ph Eur monograph 0652, Ear Preparations

CONTAINERS FOR ORAL MEDICINES (DORA)

Liquid oral pharmaceutical products⁶, such as solutions, syrups, or suspensions, require protection from solvent loss, microbial contamination, and sometimes Exposure to light or reactive gases (e.g., oxygen). These liquid dosage forms can be supplied in either multiple-dose (bottles) or single-dose (sachets) containers.

• Bottles are usually made of glass or plastic (e.g., PET, HDPE), often featuring a screw cap (made of aluminium or polypropylene) with a liner, and may include a tamper-resistant seal or an overcap welded to the bottle.
• Each dose from a multi-dose container is administered using a device suited for measuring the prescribed volume, such as a measuring cup, dosing spoon (for volumes of 5ml or more), oral syringe (for other volumes), or a dropper.
• Many of the associated components are graduated for dose administration. Graduations should be legible and indelible.
• Pouches may be made of a single-layer plastic or laminated material.

Solid Oral dosage forms (e.g. tablets and capsules) and powders for reconstitution should generally be protected from the potential adverse effects of water vapour (moisture). Typical container closure systems are bulk containers, strips, blister packs and sachets.

Bulk containers are plastic or glass bottles with a screw or snap closure.

• Glass containers are made of type III glass. Plastic containers are most often made of HDPE, PP or PET. The primary packaging may be a LDPE bag, which is then placed in HDPE/PP bottles and provides additional protection.
• A typical closure consists of a cap (often made of PP), often with a sealed part. The seal is a piece of material that sits between the cap and the bottle. Different liner materials can be used to provide a moisture barriers, chemical resistance, or preventing leakage. Another benefit is tamper evidence; once the sealed part has been removed, it cannot be reapplied to the container.
• A filler material can be added to the container to fill the empty spaces and prevent the tablets from breaking during transport. Fillers can be made of cotton, rayon or polyester.
• Desiccant is used to reduce the amount of moisture in the head space of the bottle, and to protect gelatin capsules or moisture sensitive products/substances. The shape and size of the desiccant should be clearly distinguishable from the shape of the medicine to prevent accidental consumption. The desiccant is usually packed in a small HDPE canister or sachet which should be placed on top of the tablets.
• A bulk container should not contain more than 1000 tablets.

Strips are multi-dose containers consisting of two layers of aluminium, usually provided with perforations, suitable for containing single doses of solid or semi-solid preparations⁷.

Blisters are multi-dose containers consisting of a moulded film insert that contains the product and a cover, which is the material that seals the blister.

For the film blister, different types of materials and many combinations - offering different degrees of protection from water vapour, gas and light - are available on the market ⁸. However, due to the lack of barrier properties of PVC film, multi-layer PVC-based films are often used when better moisture protection is required, e.g. PVC coated with PVDC (polyvinylidene chloride), PVC laminated with PCTFE (polychlorotrifluoroethylene, or Aclar®), triplex laminates made of PVC/PE/PCTFE, etc.

The lid stock is sealed to the moulded blister. Its material is usually a laminate that includes a barrier layer (e.g., aluminium foil).

Sachets are adequate packaging for oral powders in single-dose preparations. Each dose is enclosed in an individual sachet preferably made of laminated aluminium foil, the edges of which are sealed by heat or adhesive.

⁶ USFDA, Container Closure Systems for Packaging Human Drugs and Biologics; USP <659> Packaging and storage requirements

⁷ WHO, TRS 902 Annex 9

⁸ USP <1146> Packaging practice—repackaging a single solid oral drug product into a unit-dose container

PHARMACEUTICAL PRODUCTS FOR INHALATION (DORA)

Preparations for inhalation are intended to be administered as vapours or aerosols into the lung to obtain a local or systemic effect. These products may be supplied in either multi-dose or single-dose containers ⁹.

Inhalation pharmaceuticals include:

• Aerosols in pressurised metered-dose devices: The preparation is released from the container as an aerosol upon activation of an appropriate valve.
• Liquid preparations for inhalation: Administered using nebulizers, these are usually packaged in a PP (polypropylene) single-dose containers.
• Inhalation powders: Delivered by dry powder inhalers, which are loaded with pre-dispensed powders in capsules or other suitable dosage forms, or with a powder reservoir and a metering mechanism
• Nasal sprays: designaded for nasal administration

⁹ Ph Eur monograph 0671: Preparations for inhalation; USFDA, Container Closure Systems for Packaging Human Drugs and Biologics.