2-1 Packaging – overview and tips for assessment Andrew Chemwolo, Technical Officer,

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 paediatrics Dr. Simon Mills.Trainingworkshop: Pharmaceutical development with focus on paediatric formulations, Beijing June 2010. • Container closure system Yin 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/205/04 • ICH quality guidelines • USP /Ph. Eur.

4. 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

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 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.

7. 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.

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 product • forming an effective barrier to light, moisture, gases, (e.g. oxygen), microbial contaminants, dirt, other degradantsetc. as appropriate • protection 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-life • Handling • Appropriate disposal of any unused medicine and the packaging itself

10. 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 child-resistant closures

11. 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

12. 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 glassand moderate hydrolytic resistance • May be coloured to provide light protection

13. 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

14. 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

15. 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

16. 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

17. 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

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 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

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 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

20. 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)

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 components • Include 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 colour Fillers, absorbents and desiccants used Secondary packaging (functional, non-functional) Pack sizes Dosing devices, if applicable

23. Detailed description of the packaging system Examplesof 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 aluminiumflip-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.

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 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 guidancefor risk-assessment

25. PQ Guidance: P.2.4

26. US FDA Guidance

27. 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)

28. 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

29. 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

30. 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

31. 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).

32. 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

33. 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.

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-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

36. 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

37. 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.

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

39. Dosing devices: Examples

40. 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)

41. 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

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 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

43. 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

44. 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

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 guidelines • Proposed packaging must be appropriate for the dosage form, route of administration, nature of the API

46. 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)

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 used • Sterility: demonstration of seal integrity (microbial ingress, dye ingress) • Diluents/solvents: compatibility with packaging

48. 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

49. 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

50. 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.