Presentation on theme: "2-1 Packaging – overview and tips for assessment"— Presentation transcript:
1 2-1 Packaging – overview and tips for assessment Andrew Chemwolo, Technical Officer,WHO Prequalification Team – Medicines Assessment
2 References This presentation makes reference to: Pharmaceutical packaging - an overview including some considerations for paediatricsDr. Simon Mills.Training workshop: Pharmaceutical development with focus on paediatric formulations, Beijing June 2010.Container closure systemYin Hua. CPH Training, January 2012.
3 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/205/04ICH quality guidelinesUSP /Ph. Eur.
4 Overview Packaging Terminology The role of packaging system Types of containers and closuresInformation on packaging to be submitted and reviewed in the dossierSuitabilityQuality controlsDosing devicesPackaging assessment Tips
5 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.
6 Packaging Terminology Immediate (Primary) pack:is or may be in direct contact with the productIt bears appropriate label(s) providing content and usage information.Immediate pack components are considered essential to the stability of their contents.Secondary PackA pack component with no contact with the product but may provide additional protection to that provided by the immediate pack.
7 Packaging Terminology Marketing PackCombination of container closure system, labelling, associated components (e.g. dosing cups, droppers, spoons), and external packaging (e.g. cartons or shrink wrap).Materials of constructionsubstances 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.
8 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 productforming an effective barrier to light, moisture, gases, (e.g. oxygen), microbial contaminants, dirt, other degradants etc. as appropriateprotection from mechanical damage e.g. breakages, cracks etc.under the proposed conditions of storage of the product
9 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-lifeHandlingAppropriate disposal of any unused medicine and the packaging itself
10 The role of packaging system Enabling accurate dosing and compliance by patiente.g. spoons, cups or syringes for oral dose measurement and deliveryEnsuring 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
11 Types of containersPrimary containers including fillers, absorbents, and desiccantsSecondary functional (e.g. fibre drums, HDPE bottles for products which are immediately packaged with LDPE bag etc.)Secondary non-functionalPackaging accessories such as dosing devices e.g. measuring cup or syringe
12 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
13 Types of containers: Bottles HDPE bottlein general considered highly protectivehas good safety profileSemi-permeable for liquid preparationspermeability also depends on wall thicknessnaturally translucentPET (Polyethylene Terephthalate or Polyester) bottleusually for liquid preparationshas good gas and fair moisture barrier properties
14 Types of containers: Bottles Polypropylene (PP):used primarily for jars and closuresprovides a rigid package with excellent moisture barrierClosurespolypropylene screw /CRC capsinner seal – e.g. Induction seal/heat sealaluminium capFillers, absorbents and moisture adsorbentsabsorbent cottonrayon fibressilica gel desiccant or molecular sieve
15 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 safeless protective than HDPE and PETProvides additional protection
16 Types of containers: Bags Triple laminated LDPE/Alu/PET bagthree 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
17 Types of containers: Blisters Blisters and stripsCold-formAlu/AluAlu/PVC/PE/Aclar* (* poly-chloro-trifluoro-ethylene, PCTFE)Alu/PVC/PVDCAlu/PVCGenerally safeMoisture and gas permeation of the blisters also depends on the sealing integrityAlu/Alu provides protection from light
18 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
19 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 componentsInclude description and identificationDemonstration 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
20 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 reproducibilitytransportation/shipping of product (Tip to follow)
21 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 componentsInclude description, identification, thickness or area weight for film and foil materials, etc.
22 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 colourFillers, absorbents and desiccants usedSecondary packaging (functional, non-functional)Pack sizesDosing devices, if applicable
23 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 tabletsHDPE: 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.
24 Suitability of packaging Suitability information should be located in 3.2.P.2. Data usually generated during packaging development:Compatibility i.e. packaging-product interactionExtraction/leaching/sorption: required for liquid dosage formsSafety of materials usedConsidering dosage form, route of administration, etc.Protection (from moisture, oxygen, light, etc.)Performance – functions properlyThe 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
27 Examples of pharmacopoeial standards Plastic components: USP <661>Glass components: USP <660>Elastomeric components: USP <381> elastomeric closures for injectionsBiological reactivity tests: USP <87>/<88> e.g. for elastomersContainer performance testing: USP <671>Ph. Eur. 3.2 (Containers)
28 Suitability - Compatibility World Health OrganizationSuitability - Compatibility13 April, 2017The container closure system including associated components should be compatible with the productComponents should not cause unacceptable changes in the quality of product due toadsorption/absorption of the API/excipientsleachables / extractablesprecipitationpH changesdiscoloration of the product or the packaging
29 Suitability - Compatibility Likelihood of interaction depends on the type of the dosage form to be packaged and type of packaging materials usedSome 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
30 Suitability - SafetyPackaging 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 productin 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
31 Suitability - Safety Demonstration of safety For injectables, inhalations, ophthalmic productsExtraction studies and toxicological evaluation on leachables and extractablesUSP biological reactivity tests <87>/<88> and USP Elastomeric closures for injections tests <381> may provide sufficient evidence of safetyfor 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).
32 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 vapourloss of solventmicrobial contaminationexposure to other contaminants such as dirt
33 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 testingPackaging must be demonstrated to protect the product from what it is susceptible to e.g. light, moisture etc.
34 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.
35 Suitability - Performance Packaging should ideally be child-resistantPackaging should be tamper-proof/tamper-evidentPackaging should accommodate patient needs – ability of the elderly to open without exposing a risk to children
36 Quality controlsAn applicant should have in place quality controls for critical packaging components – to ensure consistency in qualitySigned and dated specifications for each packaging component especially for primary containers and functional secondary containers.Are a combination of physical, chemical & microbiological testsChemical composition should be controlled/monitoredPerformance characteristics (e.g. deliverable volume, ease of movements of syringe plunger, etc.) also controlled
37 Quality controlsIdentity of primary packaging components is an essential routine testHDPE, LDPE, PE, PVC/PVDC : IRAl: 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.
38 Dosing DevicesDevices: Required for oral solutions, emulsions, suspensions and powders/granules for multiple doses e.g.
40 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)
41 Packaging assessment Tips Due consideration should be given to:Characteristics of the API – its sensitivity to different factorsLight, moisture, oxygen etc.Dosage form – liquid/semi-solid vs solidRoute of administration – ophthalmic, injection or oralPackaging materials used – plastic, paper, glass, metal, rubber/elastomerResults of stability studies: provide ultimate proof of suitability
42 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 establishedPharmacopoeial monographsLiterature reviewConsider Dosage form:Liquid and semi-solid preparations considered criticalSolid dosage forms not considered very criticalQualification: route of administration, packaging material & sterility requirements important
43 Packaging assessment Tips Route of administration: Expected level of attention:Injections & inhalation products > ophthalmic preparations & nasal sprays > topical and oral preparationsQualification: Dosage form and packaging material importantA risk assessment should be carried out to determine the nature of the information that needs to be providedApplicant must demonstrate the suitability of proposed packaging
44 Tips - Suitability data: P.2.4 Packaging suitability must be established during product development processSusceptibility 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 producttransportation studies provided where appropriate
45 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
46 Tips - Suitability data for injectables Considered high riskRubber 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 benzothiazoleevidence 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)
47 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 usedSterility: demonstration of seal integrity (microbial ingress, dye ingress)Diluents/solvents: compatibility with packaging
48 Other TipsCompatibility 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 thisSafety 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
49 Other TipsPackaging components must maintain same quality as used for suitability testing: adequate QCsQuality aspects of PIL & SmPC: description of container closure system; storage conditions, shelf life, instructions for use & disposalLabels: storage conditions, shelf life, instructions for use & disposal must be clearly indicated
50 SummaryProposed 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 packagingCharacteristics of critical packaging components confirmed during suitability testing should be maintained through adequate QC measures put in place.