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

CPH training | January |2 | References 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 Addis Ababa

CPH training | January |3 | References  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

CPH training | January |4 | Overview  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)

CPH training | January |5 | Packaging 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).

CPH training | January |6 | The 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

CPH training | January |7 | The 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

CPH training | January |8 | 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  Accessories such as measuring cap

CPH training | January |9 | Types 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)

CPH training | January | Types of containers: Bottles  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

CPH training | January | Types of containers: Bottles  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)

CPH training | January | Types 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

CPH training | January | Types of containers - Thermoform Blister Packs

CPH training | January | Types of containers - Cold Form Blister Packs

CPH training | January | Types of containers - Tropicalised Blister Packs

CPH training | January | Types of containers: Blisters  Blisters and strips  Alu/Alu > Al/PVC/PE/Aclar > Al/PVC/PVDC > Aluminim/PVC  in general safe

CPH training | January | Comparative moisture barrier properties of blister pack

CPH training | January | Oxygen permeation

CPH training | January | Light 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

CPH training | January | Secondary 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

CPH training | January | Information 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

CPH training | January | Detailed 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

CPH training | January | Detailed 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.

CPH training | January | Suitability  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

CPH training | January | Safety (Contd)

CPH training | January | Suitability--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

CPH training | January | Suitability--Compatibility  Demonstration of compatibility  For plastic components: USP, physicochemical tests  For glass components: USP, chemical resistance  For elastomeric components: USP 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).

CPH training | January | Suitability--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

CPH training | January | Suitability--Safety (Contd)  Demonstration of safety  For injectables, inhalations Extraction studies and toxicological evaluation on leachables and extractables USP biological reactivity tests and Elastomeric losures for injections tests 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.

CPH training | January | 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, )  Validation of packaging procedure, such as leak testing (for seal integrity)

CPH training | January | Suitability

CPH training | January | Specification 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).

CPH training | January | Dosing 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)

CPH training | January | Labelling 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.

CPH training | January | Labelling 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

CPH training | January | Thank you!