Guidelines - WHO/OMS: Extranet Systems€¦ · PPT file · Web view · 2016-06-13Types of...

CPH training | May 20141 |

2-1 Packaging – overview and tips for assessment

Andrew Chemwolo, Technical Officer,

WHO Prequalification Team – Medicines Assessment


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.


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.


Overview

Packaging Terminology

The role of packaging system

Types of containers and closures

Information on packaging to be submitted and reviewed in the dossierSuitabilityQuality controlsDosing devices

Packaging assessment Tips



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.



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.



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.



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



Providing all necessary information for... Identification, preparation if required (e.g. reconstitution,

dilution), use of the medicine etc. Storage conditions and shelf-lifeHandling Appropriate disposal of any unused medicine and the

packaging itself



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 child-resistant closures


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


Types of containers: Bottles

GlassType 1: borosilicate, most inert, has high hydrolytic and

thermal shock resistanceType 2: treated soda lime glass, more susceptible to leaching

than type 1 glass, moderate to high hydrolytic resistanceType 3: traditional soda lime glass. Has more leachable

oxides than type 2 glass and moderate hydrolytic resistanceMay be coloured to provide light protection



HDPE bottle in general considered highly protectivehas good safety profileSemi-permeable for liquid preparationspermeability also depends on wall thicknessnaturally translucent

PET (Polyethylene Terephthalate or Polyester) bottleusually for liquid preparationshas good gas and fair moisture barrier propertieshas good safety profile



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 adsorbentsabsorbent cotton rayon fibressilica gel desiccant or molecular sieve


Types of containers: Bags

LDPE bagas primary container for bulk packs which is further placed in

HDPE/PP bottlesas primary container for bulk product or intermediatesas primary container for API and excipients, which is further

placed in Alu, fiber or steel drumconsidered safe less protective than HDPE and PETProvides additional protection


Types of containers: Bags

Triple laminated LDPE/Alu/PET bag three layers, LDPE film as inner layeras primary container for bulk packs which is further placed

in HDPE/PP bottlesProtection from oxygen, water vapour, UVProtection from other contaminants e.g. oils, acid, alkalines


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


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 gasesprovide additional protection against lightprovide additional protection against microbial and dirt

contamination e.g. carton boxmay protect the product from rough handling


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

Information to be submitted



3.2.P.2.4: Discussion of the suitability of the container closure system with respect to:Choice of materialsCompatibility with product e.g. extraction/leaching/sorption

(packaging-product interaction) for liquid dosage formsSafety of materials usedprotection of product (from moisture, oxygen, light)Performance e.g. dose delivery accuracy and reproducibility transportation/shipping of product (Tip to follow)



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.


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


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.


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


PQ Guidance: P.2.4


US FDA Guidance


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)


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 / extractablesprecipitationpH changesdiscoloration of the product or the packaging


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


Suitability - Safety

Packaging materials including for associated components should not leach harmful or undesirable amounts of substancesunreacted monomers and process impurities such as

antioxidants in plasticsparticularly 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


Suitability - Safety

Demonstration of safetyFor 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).


Suitability - Protection

The container closure system should protect the product from factors that can cause degradation of product such asexposure to lightexposure to reactive gases (e.g. oxygen)absorption of water vapour loss of solventmicrobial contaminationexposure to other contaminants such as dirt


Suitability - Protection

Demonstration of protectiondepends 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.


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.


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


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


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.


Dosing Devices

Devices: Required for oral solutions, emulsions, suspensions and powders/granules for multiple doses e.g.


Dosing devices: Examples


Dosing Devices

Quality part:Specification of the material (with IR identification)Data to demonstrate the uniformity of doses delivered– at

the lowest intended doseA sample of device to be reviewed (may consult with

WHOPAR experts)Compatibility/safety with product, if applicable (Tip to

follow)



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



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 establishedPharmacopoeial monographsLiterature review

Consider Dosage form:Liquid and semi-solid preparations considered criticalSolid dosage forms not considered very critical

Qualification: route of administration, packaging material & sterility requirements important



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


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


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 guidelinesProposed packaging must be appropriate for the dosage

form, route of administration, nature of the API


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)


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


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


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


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.


Thank you for your attention

Guidelines - WHO/OMS: Extranet Systems€¦ · PPT file · Web view · 2016-06-13Types of...

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