Container Closure System: Hua Yin

Container closure system
Hua YIN
1|
CPH training | January 2012
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
2|
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
3|
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)
4|
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).
5|

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
6|

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, Anticounterfeiting measures
7|
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
8|
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)
9|

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
10 |
consists of polymerized units of the monomer ethylene terephthalate

usually for liquid preparations
has good gas and fair moisture barrier
has good safety profile

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)
11 |
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
12 |
Types of containers - Thermoform Blister Packs
13 |
Types of containers - Cold Form Blister Packs
14 |
Types of containers - Tropicalised Blister Packs
15 |
Types of containers: Blisters

Blisters and strips
Alu/Alu > Al/PVC/PE/Aclar > Al/PVC/PVDC > Aluminim/PVC
in general safe
16 |
Comparative moisture barrier properties

of blister pack
17 |
Oxygen permeation
18 |
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
19 |
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
20 |
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
21 |

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
22 |

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.
23 |
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
24 |
Safety (Contd)
25 |
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
26 |
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).
27 |
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
28 |
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.
29 |
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)
30 |
Suitability
31 |
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).
32 |
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)
33 |
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.
34 |
Labelling
Pay attention to:
Scoreline check uniformity of half dosing if appropriate
Pack sizeclearly 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
35 |
Thank you!
36 |

Container Closure System: Hua Yin

Încărcat de

Informații document

Descriere originală:

Titlu original

Drepturi de autor

Formate disponibile

Partajați acest document

Partajați sau inserați document

Opțiuni de partajare

Vi se pare util acest document?

Este necorespunzător acest conținut?

Drepturi de autor:

Formate disponibile

Container Closure System: Hua Yin

Încărcat de

Drepturi de autor:

Formate disponibile

Container closure system

CPH training | January 2012

CPH training | January 2012

CPH training | January 2012

Information of packaging to be submitted and reviewed in the dossier

Labeling (pharmaceutical issues)

CPH training | January 2012