2-1 Packaging – overview and tips
for assessment
Andrew Chemwolo, Technical Officer,
WHO Prequalification Team – Medicines
Assessment
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CPH training | May 2014
References
This presentation makes 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
Yin Hua. CPH Training, January 2012.
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References
 WHO Quality guideline (WHO TRS 970, Annex 4)
 Guidelines on packaging for pharmaceutical products (WHO TRS 902,
Annex 9)
 Container closure systems for packaging human drugs and biologics
(FDA Guidance for Industry, May 1999)
 Guideline on Plastic immediate packaging materials EMEA/CVMP/205/04
 ICH quality guidelines
 USP /Ph. Eur.
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Overview
 Packaging Terminology
 The role of packaging system
 Types of containers and closures
 Information on packaging to be submitted and reviewed in the
dossier
 Suitability
 Quality controls
 Dosing devices
 Packaging assessment Tips
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Packaging Terminology
 WHO TRS 902 Annex 9 defines packaging as ' the collection of
different components (e.g. bottle, vial, closure, cap, ampoule, blister)
which surround the pharmaceutical product from the time of
production until its use.'
 US FDA defines container closure system as '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 to the drug product.'
 A packaging component: is any part of the container closure system.
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Packaging Terminology
 Immediate (Primary) pack:
 is or may be in direct contact with the product
 It bears appropriate label(s) providing content and usage
information.
 Immediate pack components are considered essential to the
stability of their contents.
 Secondary Pack
 A pack component with no contact with the product but may
provide additional protection to that provided by the
immediate pack.
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Packaging Terminology
 Marketing Pack
 Combination of container closure system, labelling,
associated components (e.g. dosing cups, droppers, spoons),
and external packaging (e.g. cartons or shrink wrap).
 Materials of construction
 substances used to manufacture a packaging component
(e.g. HDPE resin, glass, metal).
 Refer to USP <659> and Glossary to WHO TRS 902 Annex 9
for more packaging definitions.
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The role of packaging system
 Containment of the product e.g. no leaking or permeation of
contents, hold contents in during normal handling etc.
 Protection of the product
 forming an effective barrier to light, moisture, gases, (e.g.
oxygen), microbial contaminants, dirt, other degradants etc. as
appropriate
 protection from mechanical damage e.g. breakages, cracks etc.
 under the proposed conditions of storage of the product
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The role of packaging system
 Providing all necessary information for...
 Identification, preparation if required (e.g. reconstitution,
dilution), use of the medicine etc.
 Storage conditions and shelf-life
 Handling
 Appropriate disposal of any unused medicine and the
packaging itself
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The role of packaging system
 Enabling accurate dosing and compliance by patient
e.g. spoons, cups or syringes for oral dose measurement and
delivery
 Ensuring supply-chain integrity of the medicines e.g. inclusion
of anti-counterfeiting measures, use of tamper-evident closures
etc.
 Ensuring product is not exposed to children i.e. use of childresistant closures
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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
 Packaging accessories such as dosing devices e.g. measuring
cup or syringe
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Types of containers: Bottles
 Glass
 Type 1: borosilicate, most inert, has high hydrolytic and
thermal shock resistance
 Type 2: treated soda lime glass, more susceptible to leaching
than type 1 glass, moderate to high hydrolytic resistance
 Type 3: traditional soda lime glass. Has more leachable
oxides than type 2 glass and moderate hydrolytic resistance
 May be coloured to provide light protection
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Types of containers: Bottles
 HDPE bottle
 in general considered highly protective
 has good safety profile
 Semi-permeable for liquid preparations
 permeability also depends on wall thickness
 naturally translucent
 PET (Polyethylene Terephthalate or Polyester) bottle
 usually for liquid preparations
 has good gas and fair moisture barrier properties
 has good safety profile
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Types of containers: Bottles
 Polypropylene (PP):
 used primarily for jars and closures
 provides a rigid package with excellent moisture barrier
 Closures
 polypropylene screw /CRC caps
 inner seal – e.g. Induction seal/heat seal
 aluminium cap
 Fillers, absorbents and moisture adsorbents
 absorbent cotton
 rayon fibres
 silica gel desiccant or molecular sieve
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Types of containers: Bags
 LDPE bag
 as primary container for bulk packs which is further placed in
HDPE/PP 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
 Provides additional protection
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Types of containers: Bags
 Triple laminated LDPE/Alu/PET bag
 three layers, LDPE film as inner layer
 as primary container for bulk packs which is further placed
in HDPE/PP bottles
 Protection from oxygen, water vapour, UV
 Protection from other contaminants e.g. oils, acid, alkalines
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Types of containers: Blisters
 Blisters and strips
 Cold-form
 Alu/Alu
 Alu/PVC/PE/Aclar* (* poly-chloro-trifluoro-ethylene, PCTFE)
 Alu/PVC/PVDC
 Alu/PVC
 Generally safe
 Moisture and gas permeation of the blisters also depends on the
sealing integrity
 Alu/Alu provides protection from light
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Secondary packaging components
 Are not intended to make contact with the dosage form (e.g.
outer cartons)
 provide additional protection from excessive moisture and
reactive gases
 provide additional protection against light
 provide additional protection against microbial and dirt
contamination e.g. carton box
 may protect the product from rough handling
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Information to be submitted
 3.2.S.6: Detailed description of the container closure system
including identity of materials of construction, appearance etc.
 Quality controls: specifications of critical packaging
components
 Include description and identification
 Demonstration of suitability of packaging – pursued only where
necessary e.g. APIs in liquid form & for sterile APIs (Tips to
follow)
 Product labels: conditions of storage & use
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Information to be submitted
 3.2.P.2.4: Discussion of the suitability of the container closure
system with respect to:
 Choice of materials
 Compatibility with product e.g. extraction/leaching/sorption
(packaging-product interaction) for liquid dosage forms
 Safety of materials used
 protection of product (from moisture, oxygen, light)
 Performance e.g. dose delivery accuracy and reproducibility
 transportation/shipping of product (Tip to follow)
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Information to be submitted
 3.2.P.7: Detailed description of the container closure system
e.g. identity of materials of construction, appearance, pack sizes
etc.
 Proposed quality controls: specifications of critical packaging
components
 Include description, identification, thickness or area weight
for film and foil materials, etc.
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Detailed description of the packaging system
 Identification of the materials of construction especially for
primary containers.
 Physical description e.g. component type, size, shape and colour
 Fillers, absorbents and desiccants used
 Secondary packaging (functional, non-functional)
 Pack sizes
 Dosing devices, if applicable
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Detailed description of the packaging system
Examples of description of different types of packs:
 Vial: 2ml clear solution in 3ml USP type I tubular glass vial with 13 mm grey
rubber stopper and 13 mm red aluminium flip-off seal. Pack size: box of 5 vials.
 Blister: Alu/Alu strip pack of 10 tablets. Such 3 or 10 strips per box. Pack size:
30 (3x10), 100 (10x10) tablets.
 HDPE: 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
 HDPE: 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 of packaging
 Suitability information should be located in 3.2.P.2. Data usually
generated during packaging development:
 Compatibility i.e. packaging-product interaction
– Extraction/leaching/sorption: required for liquid dosage forms
 Safety of materials used
– Considering dosage form, route of administration, etc.
 Protection (from moisture, oxygen, light, etc.)
 Performance – functions properly
 The type and extent of information that should be provided will
depend on the dosage form and the route of administration.
 Next 2 slides: PQ & US FDA guidance for risk-assessment
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PQ Guidance: P.2.4
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US FDA Guidance
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Examples of pharmacopoeial standards
 Plastic components: USP <661>
 Glass components: USP <660>
 Elastomeric components: USP <381> elastomeric closures for
injections
 Biological reactivity tests: USP <87>/<88> e.g. for elastomers
 Container performance testing: USP <671>
 Ph. Eur. 3.2 (Containers)
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Suitability - Compatibility
 The container closure system including associated components
should be compatible with the product
 Components should not cause unacceptable changes in the quality
of product due to
 adsorption/absorption of the API/excipients
 leachables / extractables
 precipitation
 pH changes
 discoloration of the product or the packaging
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Suitability - Compatibility
 Likelihood of interaction depends on the type of the dosage form to
be packaged and type of packaging materials used
 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).
 Extraction & interaction studies may need to be carried out based
on a risk-assessment (route of administration, dosage form)
 Extraction, leaching & adsorption: required for liquid preparations.
 Compatibility may need to be monitored during stability testing
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Suitability - Safety
 Packaging materials including for associated components should
not leach harmful or undesirable amounts of substances
 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 ( e.g. Ink and adhesives)
 Concern for safety depends on the type of packaging material, type
of dosage form and route of administration
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Suitability - Safety
 Demonstration of safety
 For injectables, inhalations, ophthalmic products
• Extraction studies and toxicological evaluation on
leachables and extractables
• USP biological reactivity tests <87>/<88> and USP
Elastomeric closures for injections tests <381> may
provide sufficient evidence of safety
 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 may
be acceptable (exception: liquid preps for chronic use).
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Suitability - Protection
 The container closure system should protect the product from
factors that can cause degradation of product such as
 exposure to light
 exposure to reactive gases (e.g. oxygen)
 absorption of water vapour
 loss of solvent
 microbial contamination
 exposure to other contaminants such as dirt
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Suitability - Protection
 Demonstration of protection
 depends on the product (sensitivity of the product to the
particular degradation factor, for example light)
 usually general pharmacopoeial test procedures are used
(e.g. USP <671>)
 Validation of packaging procedure for seal integrity; leak
testing
 Packaging must be demonstrated to protect the product from
what it is susceptible to e.g. light, moisture etc.
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Suitability - Performance
 Functionality and drug delivery aspects of the container closure
system should be evaluated, if applicable.
 A device is required to be included with the container closure
system for oral liquids or solids (e.g. solutions, emulsions,
suspensions and powders/granules), any time the package provides
for multiple doses.
 Results of a study should be provided demonstrating the
reproducibility of the device (e.g. consistent delivery of the
intended volume), generally at the lowest intended dose.
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Suitability - Performance
 Packaging should ideally be child-resistant
 Packaging should be tamper-proof/tamper-evident
 Packaging should accommodate patient needs – ability of the
elderly to open without exposing a risk to children
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Quality controls
 An applicant should have in place quality controls for critical
packaging components – to ensure consistency in quality
 Signed and dated specifications for each packaging component
especially for primary containers and functional secondary
containers.
 Are a combination of physical, chemical & microbiological tests
 Chemical composition should be controlled/monitored
 Performance characteristics (e.g. deliverable volume, ease of
movements of syringe plunger, etc.) also controlled
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Quality controls
 Identity of primary packaging components is an essential routine
test
• HDPE, LDPE, PE, PVC/PVDC : IR
• Al: IR of the coating; Chemical test for Aluminium.
• Glass: Pharmacopoeial (powdered glass test)
 Dimensional criteria (e.g. area/weight for film and foil materials,
wall thickness, shape, neck finish, capacity for bottles, design
tolerances, etc.)
 Having good specifications is meaningless if not supported by
stability studies.
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Dosing Devices
 Devices: Required for oral solutions, emulsions, suspensions and
powders/granules for multiple doses e.g.
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Dosing devices: Examples
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Dosing Devices
 Quality part:
 Specification of the material (with IR identification)
 Data to demonstrate the uniformity of doses delivered– at
the lowest intended dose
 A sample of device to be reviewed (may consult with
WHOPAR experts)
 Compatibility/safety with product, if applicable (Tip to
follow)
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Packaging assessment Tips
Due consideration should be given to:
 Characteristics of the API – its sensitivity to different factors
 Light, moisture, oxygen etc.
 Dosage form – liquid/semi-solid vs solid
 Route of administration – ophthalmic, injection or oral
 Packaging materials used – plastic, paper, glass, metal,
rubber/elastomer
 Results of stability studies: provide ultimate proof of suitability
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Packaging assessment Tips
 Consider API sensitivity from:
 forced degradation and photostability studies for the API and
product.
• Photostability: As per ICH Q1B. Tests on API, then FPP, then
FPP in pack, stopping when photostability is established
 Pharmacopoeial monographs
 Literature review
 Consider Dosage form:
 Liquid and semi-solid preparations considered critical
 Solid dosage forms not considered very critical
Qualification: route of administration, packaging material & sterility
requirements important
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Packaging assessment Tips
 Route of administration: Expected level of attention:
 Injections & inhalation products > ophthalmic preparations &
nasal sprays > topical and oral preparations
Qualification: Dosage form and packaging material important
 A risk assessment should be carried out to determine the nature of
the information that needs to be provided
 Applicant must demonstrate the suitability of proposed packaging
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Tips - Suitability data: P.2.4
 Packaging suitability must be established during product
development process
 Susceptibility of the API: Must be familiar with the results of
forced degradation studies and photostability studies.
 Note: ICH Q1B photostability studies are required in the dossier.
 Transportation of bulk: Check whether the bulk product is
packed on the same site or transported/shipped to another site:
check suitability of packaging for bulk product
 transportation studies provided where appropriate
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Tips - Suitability data P.2.4
 Proposed packaging should be suitable/appropriate for
transportation/shipping of the product e.g. protect the product
from breakage or damage or exposure.
 Check whether the product requires presence of a dosing
device: may need to consult the clinical assessors.
 Choice of packaging materials must be appropriate: consult
pharmacopoeias, review literature, refer to SRA guidelines
 Proposed packaging must be appropriate for the dosage
form, route of administration, nature of the API
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Tips - Suitability data for injectables
 Considered high risk
 Rubber stoppers:
 compatibility studies (nature and levels of
extractables/leachables, sorption, etc.).
 Demonstration of safety: Compliance with USP <87>/<88>
or other equivalent requirements; attestation that it is free
from nitrosamines and 2-mercapto benzothiazole
 evidence of physicochemical testing as per USP <381>
 Supplier name & article details (type, code/model number)
 Stability study includes samples kept in inverted orientation
(product in contact with rubber stopper)
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Tips - Suitability data (injectables)
 Glass vials/ampoules: data to demonstrate that the glass meets
the requirements of USP <660> or other equivalent
requirements.
 Type III glass must be demonstrated to be suitable, if used
 Sterility: demonstration of seal integrity (microbial ingress, dye
ingress)
 Diluents/solvents: compatibility with packaging
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Other Tips
 Compatibility with dosing devices only required if dose is not
administered immediately.
 Stability study must cover the proposed pack (ICH Q1A): check
description of packaging for stability samples to confirm this
 Safety of materials: Declaration of compliance with food
regulations, where applicable (US, EU). Consider duration of use.
 Applicant must have own specifications: not enough to rely on
supplier testing. Adequate vendor qualification, as appropriate.
 Demonstration of satisfactory performance of packaging, as
appropriate
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Other Tips
 Packaging components must maintain same quality as used for
suitability testing: adequate QCs
 Quality aspects of PIL & SmPC: description of container
closure system; storage conditions, shelf life, instructions for
use & disposal
 Labels: storage conditions, shelf life, instructions for use &
disposal must be clearly indicated
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Summary
 Proposed container closure system should be fully described in the
application.
 Proposed container closure system should be demonstrated to be
suitable for the product under the proposed conditions of storage.
 Stability studies useful in further demonstrating suitability of
proposed packaging
 Characteristics of critical packaging components confirmed during
suitability testing should be maintained through adequate QC
measures put in place.
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Thank you for your attention
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CPH training | May 2014