CPH training | January 2012 1 |1 | Container closure system Hua YIN.

CPH training | January 20121 |

Container closure system

Hua YIN


ReferencesReferences

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


ReferencesReferences

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


OverviewOverview

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)


Packaging TerminologyPackaging 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).


The role of packagingThe 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


The role of packagingThe 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


Types of containersTypes 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


Types of containers: BottlesTypes 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)



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



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)


Types of containers--BagsTypes 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


Types of containers - Thermoform Blister PacksTypes of containers - Thermoform Blister Packs


Types of containers - Cold Form Blister PacksTypes of containers - Cold Form Blister Packs


Types of containers - Tropicalised Blister PacksTypes of containers - Tropicalised Blister Packs


Types of containers: BlistersTypes of containers: Blisters

Blisters and strips Alu/Alu > Al/PVC/PE/Aclar > Al/PVC/PVDC > Aluminim/PVC in general safe


Comparative moisture barrier properties of blister pack

Comparative moisture barrier properties of blister pack


Oxygen permeationOxygen permeation


Light protectionLight 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


Secondary packaging componentsSecondary 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


Information to be submitted and reviewedInformation 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


Detailed description of the packaging systemDetailed 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


Detailed description of the packaging systemDetailed 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.


SuitabilitySuitability

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


Safety (Contd)Safety (Contd)


Suitability--CompatibilitySuitability--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


Suitability--CompatibilitySuitability--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).


Suitability--SafetySuitability--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


Suitability--Safety (Contd)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.


Suitability--Protection 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)


SuitabilitySuitability


SpecificationSpecification

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).


Dosing DevicesDosing 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)


LabellingLabelling

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.


LabellingLabelling

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


Thank you!

CPH training | January 2012 1 |1 | Container closure system Hua YIN.

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