Packaging aspects

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Container closure system
Hua YIN

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References
This presentation make reference to:
Pharmaceutical packaging - an overview including some considerations
for paediatrics
Dr. Simon Mills .Training workshop: pharmaceutical development with
focus on paediatric formulations, Beijing June 2010.)
Container closure system and product labels
Wondifraw Z. Worku. WHO workshop on assessment of interchangeable
multisource medicines, April 2010. Addis Ababa

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References
 Generic guidance
 Guidelines on packaging for pharmaceutical products (TRS 902, Annex 9)
 Container closure systems for packaging human drugs and biologics (FDA,
may 1999)
 Guideline on Plastic immediate packaging materials – specific to plastics
only
 USP /EP

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Overview
 The role of packaging
 Types of containers and closures
 Moisture permeation
 Oxygen permeation
 Light protection
 Information of packaging to be submitted and reviewed in the dossier
 Suitability (compatibility, safety, protection)
 Specification
 Dosing device
 Labeling (pharmaceutical issues)

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Packaging Terminology
Immediate (Primary) Pack
 Contains and protects the dosage form so is normally in contact with it.
 It bears appropriate label(s) providing content and usage information.
 Immediate pack components are considered essential to the stability of their contents,
whether or not in contact with them.
Secondary Pack
 A pack component with no product contact but may add protection to that provided by the
immediate pack.
Container Closure System
 The sum of packaging components that together contain and protect the dosage form. This
includes primary packaging components and secondary packaging components, if the latter
are intended to provide additional protection (e.g. light barrier) of the drug product.
Marketing Pack
 Combination of primary and secondary packaging, labeling, associated components (e.g.,
dosing cups, droppers, spoons), and external packaging (e.g., cartons or shrink wrap).

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The role of packaging
 Protecting the product from the environment and vice versa
 being an effective barrier to light, moisture, oxygen, bacteria, volatiles,
etc. as appropriate)
 protection from damage
 Providing all necessary information for...
 Identification , preparation if required (e.g. reconstitution, dilution), use
of the medicine including precautions
 Storage and shelf-life of in-use product
 Appropriate disposal of any unused medicine and the packaging itself
Labelling and Product Inserts/Patient Information Leaflets

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The role of packaging
 Enabling accurate dosing and compliance
e.g. Spoons, cups or syringes for oral dose measurement and delivery
 Ensuring supply-chain integrity of the medicine
e.g. “Track-and-Trace” systems assuring “chain of custody”, Anti-
counterfeiting measures

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Types of containers
 Primary containers including fillers, absorbents, and desiccants
 Secondary functional (e.g, fibre drums, HDPE bottles for products which
are immediately packaged with LDPE bag etc).
 Secondary non functional
 Accessories such as measuring cap

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Types of containers: Bottles
 Glass
 Type 1: borosilicate, most inert and preferred for solutions to be
autoclaved
 Type 2: treated soda lime, more susceptible to leaching than type 1
glass. Useful for solutions buffered to maintain pH below 7
 Type 3: traditional soda lime glass. Has more leachable oxides than type
2 glass. Mainly used for dry products (solids)

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Types of containers: Bottles
 HDPE bottle
 (-CH2 –CH2 -) n or copolymer with other olefins
 in general considered highly protective, common in pharma
 has good safety profile
 has stronger intermolecular forces and tensile strength than lower-density PE
 permeability also depends on thickness
 semi permeable for liquid preparations
 naturally translucent
 PET (Polyethylene Terephthalate or Polyester) bottle
 consists of polymerized units of the monomer ethylene terephthalate
 usually for liquid preparations
 has good gas and fair moisture barrier
 has good safety profile

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Types of containers: Bottles
 Polypropylene (PP) is used primarily for jars and closures and provides a
rigid package with excellent moisture barrier.
 Closures
 polypropylene screw /CRC caps
 inner seal-eg Inductions seal/heat sealed
 aluminium cap
 Fillers, absorbents and moisture adsorbents
 absorbent Cotton
 rayon fibres
 silica gel desiccant (efficient at high relative humidities) or molecular
sieve (efficient at low relative humidities)

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Types of containers--Bags
 LDPE bag
 as primary container for bulk packs which is further placed in
HDPE/PE bottles
 as primary container for bulk product or intermediates
 as primary container for API and excipients, which is further placed in
Alu, fiber or steel drum
 considered safe
 less protective than HDPE and PET
 Triple laminated LDPE/PET/Al bag
 three layers 'sandwiched', LDPE film as inner layer
 Protection from oxygen, water vapor, UV
 Protection from other contaiminants, e.g. oils, acid, alkalines

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Types of containers - Thermoform Blister Packs

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Types of containers - Cold Form Blister Packs

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Types of containers - Tropicalised Blister Packs

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Types of containers: Blisters
 Blisters and strips
 Alu/Alu > Al/PVC/PE/Aclar > Al/PVC/PVDC > Aluminim/PVC
 in general safe

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Comparative moisture barrier properties
of blister pack

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Oxygen permeation

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Light protection
 Plastic materials, e.g. HDPE bottles, opacified with titanium dioxide
pigment can still allow significant light to be transmitted through because
light scatters internally as well as externally
 Brown glass is a barrier to the more damaging short wave-length light but
is transparent at longer wavelengths
 Aluminium foil provides the best option for assured protection from light
 A secondary pack component can augment light protection

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Secondary packaging components
 Are not intended to make contact with the dosage form (eg.
outer cartons)
 provide additional protection from excessive moisture and reactive
gases
 provide additional protection against light
 provide additional protection against microbial and dirt contamination
 may protect the product from rough handling

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Information to be submitted and reviewed
 Detailed description of the packaging system
 Suitability information should be located in 3.2.P.2
 compatibility, e.g. extraction/leaching/sorption (packaging-product
interaction)
 Safety
 Protection (from moisture, oxygen, light)
 Quality control--Specifications
 Dose delivery accuracy and reproducibility
 Labels

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Detailed description of the packaging system
 Identification of the materials of construction specially for primary
containers.
 Physical description, including type, size, shape, and colour
 Including fillers, absorbents and desiccants
 Secondary packaging
 Pack size
 Dosing device, if applicable

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Detailed description of the packaging system
Examples:
 2ml clear solution in 3ml USP type I tubular glass vial with 13 mm reformulated grey
colour rubber stopper and 13 mm aluminium red coloured flip-off tear off seals externally
lacquered by colourless lacquer. Pack size: box of 5 vials.
 Al/Al strip pack of 10 tablets. Such 3 or 10 strips per box. Pack size: 30 (3x10), 100
(10x10) tablets.
 White opaque, round HDPE bottle fitted with white opaque polypropylene screw cap
closure, aluminium sealed, and containing molecular sieve canister 2 gm (CAN
TRISORB 2G) as desiccant. Pack size: 30 tablets
 Transparent LDPE bag, containing 500 or 1000 tablets, packed in a triple laminated
aluminium sachet which is further packed in an HDPE bottle along with a leaflet. Each
bottle is sealed with an aluminium tagger and closed with a screw cap.

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Suitability
 Suitability information should be located in 3.2.P.2. One time tests usually
performed at the stage of packaging development:
 Compatibility, e.g. Extraction/leaching/Sorption (packaging-product
interaction)
 Safety
 Protection (from moisture, oxygen, light, etc.)
 performance
 The type and extent of information that should be provided will depend on
the dosage form and the rout of administration

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Safety (Contd)

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Suitability--Compatibility
 The container closure system should be compatible with the product
components, not cause unacceptable changes in the quality due to
 adsorption/absorption of the API/excipients
 leachables / extractables
 precipitation
 pH changes
 discoloration of the product or the packaging
 Likelihood of interaction depends on the type of the dosage form to be
packaged with

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Suitability--Compatibility
 Demonstration of compatibility
 For plastic components: USP <661>, physicochemical tests
 For glass components: USP <660>, chemical resistance
 For elastomeric components: USP <381> elastomeric closures for
injections, evaluation of swelling effects
 Some interactions will be detected during qualification studies on the
container closure system. Others may not show up except in the
stability studies (may be addressed by stability studies).

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Suitability--Safety
 Packaging materials should not leach harmful or undesirable amounts of
substances
 for example, unreacted monomers and process impurities such as
antioxidants in plastics
 particularly for those containers which are in direct contact with the
product
 in some cases, substances may migrate from secondary components
( eg. Ink and adhesives)
 Concern for safety depends on the type of dosage form

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Suitability--Safety (Contd)
 Demonstration of safety
 For injectables, inhalations
• Extraction studies and toxicological evaluation on leachables and
extractables
• USP biological reactivity tests <87> and Elastomeric losures for
injections tests <381> are acceptable for many injectable and
ophthalmic products
 for oral solid and liquid dosage forms – a declaration by the supplier
that the material of construction complies with the USFDA or EU
requirements for packaging of food items is acceptable.

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Suitability--Protection
 The container closure system should protect the product from factors that
cause deterioration
 exposure to light
 exposure to reactive gases such as oxygen
 absorption of water vapour
 loss of solvent
 microbial contamination
 exposure to other contamination sources such as dirt
 Demonstration of protection
 depends on the product (sensitivity of the product to the particular degradation
factor)
 usually general pharmacopoeial test procedures are used (eg USP<661>, <671>)
 Validation of packaging procedure, such as leak testing (for seal integrity)

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Suitability

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Specification
Signed and dated specification for each packaging component specially for
primary containers and functional secondary containers
 identity of primary packaging components is an essential routine test
• HDPE, LDPE, PE: IR
• Al: IR of the coating is acceptable. Titration (pharmacopoeial)
• PVC/PVDC: IR
• Glass: Pharmacopoeial (powdered glass test)
 dimensional criteria (eg, area weight for film and foil materials, wall
thinkness, shape, neck finish, capacity for bottles,)
 performance characteristics (eg, ease of movements of syringe plunger)
 The FPP manufacturer must have their own specs (to be tested upon
receipt at the site of packaging) with at least identity, dimensions, and
thickness/area weight (for blisters).

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Dosing Devices
 Devices: Required for oral solutions, emulsions, suspensions (or liquid
API) and powders/granules for multiple doses
 Required collaboration between Q and WHOPAR experts
 Quality part:
 Specification of the material (with IR identification)
 Data to demonstrate the uniformity of mass of doses delivered– at the
lowest intended dose (weigh 20 doses, not more than 2 of the
individual masses deviate by more than 10% from the average mass,
and none deviates by more than 20%.)
 A sample of device to be reviewed (may consult with WHOPAR
experts)

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Labelling
Pharmaceutical issues to be reviewed by quality assessor: refer to internal
labelling guideline "Quality review of labelling"
• Check the information of Labels (immediate container and Outer labels)
• Confirm the name, product description, excipients, packaging, pack size,
storage condition, shelf life, MA holder for PIL/SmPC (Items 1, 2, 3, 6 of
SmPC).
• Copy the Section 6 (composition) into the assessment report is highly
encouraged, as it allows subsequent assessors to ensure that all the
necessary elements are included.

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Labelling
Pay attention to:
• Scoreline –check uniformity of half dosing if appropriate
• Pack size—clearly state the number of each blister, each box
• SmPC composition should include ink solids, opadry components
The considerations from clinical, what should be discussed with clinical
assessors in the quality review…., will be presented separately

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Thank you!