NSF packaging Flashcards
2011/62/EU Falsified Medicines Directive
- Safety features – a unique identifier and an anti‐tampering device on the outer packaging of medicines
- A common, EU‐wide logo to identify legal online pharmacies
- Tougher rules on import of active pharmaceutical ingredients
- Strengthened record‐keeping requirements for wholesale Distributors
Anti counterfeiting goals
Add at least one overt and one covert feature to all primary packaging
Add overt and covert features to secondary packages where applicable
Upgrade covert technologies to invisible encrypted graphics for all printed components
Develop and Implement “track and trace” technology on all priority packs
Overt features
Holograms
Ink colour changes when viewed at different angles
Component corner radius
Varnish pattern with intentional errors
Dot varnish void
Temperature sensitive ink
Aphrodite
Covert features
Micro dots/text
Coin reactive – reveals hidden code
Scrambled Ink – opens web link when scanned
Hidden ink – text changes through viewing lens
Luminescent inks
Use of taggants
DNA Presence
Indicators of instability
Loss of drug substance
Loss of efficacy
Loss of content uniformity
Inappropriate dosing
Reduction in safety profile
Increase in concentration
Evaporation / drying out
Safety concerns
Microbial contamination
Safety questionable
Loss of efficacy
Production of toxic impurities
Reduction in safety profile
NITROSAMINES!..
Loss of pharmaceutical elegance
Loss of acceptability in use
Types of stability test
- Stress testing
Establish the degradation pathways
and the intrinsic stability of the molecule
and validate the stability indicating power of the analytical procedures used.
Studies include:
Temperature
Humidity
Oxidation
Hydrolysis
Photostability- Accelerated testing
Increase the rate of degradation or physical change
Can also be used for extrapolation - Long term (real time) testing
Evaluation of real time physical, chemical, biological and microbiological characteristics
- Accelerated testing
Types of stability study
Long term (Real time) studies
Required for all products
Requires a single label for all markets
Accelerated studies
To support shelf-life
To demonstrate effects of
High/low temperatures, humidity, light
Analytical methods for stability testing need to be:
Specific
Sensitive
Validated
Capable of detecting degradation
Certain variations may require supporting stability data
Change in formulation
Change in packaging material (less protective)
6 months, pilot x3
There is Specific Guidance on this!
EU guideline
ICH Q12 Section 9
Glass key facts
Super cooled liquid
Primary constituent silica (silicon dioxide SiO2)
Pure silica forms a glass when heated
SiO2 molecules polymerise with strong covalent Si-O bonds
Great strength (approx. 2.5 x tensile strength of steel)
Thermal resistance
Transparent to visible and some UV light
Resistant to acid
High softening point
Difficult material to work
Attacked by alkali
Addition of soda (Na2CO3) dramatically reduces softening point but high
sodium content produces low chemical resistance – susceptible to degradation
Addition of lime greatly improves chemical resistance, by replacing
some Na+ by Ca++ and closing up the matrix
Borosilicate glass has improved thermal resistance
Pharmacopeia tests
If a type II glass container is tested and is intact, it will pass the
Pharmacopoeial hydrolytic test
* The test then requires glass to be crushed and repeated
* Type II glass fails the test when untreated surfaces are exposed
* Type I glass continues to pass the test, even when crushed
Advantages
* Clear/strong/stable
* Impermeable
* Acid resistant
* Surface treatable
* Hygienic
* Sterilisable by heat
* Economical
Disadvantages
* Not malleable/ductile
* Breakable
* Difficult to work
* Attacked by alkalis
* Sensitive to handling
* Heavy
* Limited colours
* Transparent to visible light and some UV
Plastic Key Facts
Many applications – flexible
PE and PP included in pharmacopoeias
Adhesives and inks can migrate through plastics… labels!
Additives – sorption and leaching
Sorption
General term used to cover drug binding to a container when the
mechanism (i.e. adsorption or absorption) is unclear
Overall, glass is not a threat (cf Insulin)
Rubber closure – problem with Lipophilics
PVC is particularly bad (pH dependent for some drugs)
Leaching
Problems with both plastic and glass
Polyethylene and polypropylene do not pose a hazard
PVC is a problem due to additives in formulation
Rubber key facts
Synthetic Rubber widely used in pharmaceuticals
* Butyl rubber
* Halobutyl rubbers
* Silicone rubber
Complex formulations – high development costs
Drug master files can be used to protect commercially sensitive information
Finishing and pre-treatment
Washing
* Surface contamination
* Lubricants
* Rubber
Atmospheric contaminants
Sterilisation
* Autoclaving
* Irradiation
Aluminium, film, tubes
Strong, rigid
Impermeable at thicknesses greater than 25μ approximately
Lightweight
May need coating/lacquer to prevent reaction with products
General term covering the steps from plain foil to the finished material
(e.g. foil with heat seal lacquer and printing)
* Application of Adhesive Layer – Laquer/Melt
* Laminate
* Printing
Adhesive process
Lacquer
* Solvent solutions of plastic(s) sprayed onto surface
* Solvent dried off resulting in thin film of plastic, which acts as heat seal
* Typical 4-10gsm coating
* Lacquer coating may be needed to act as ‘key’ for printing
Melt
* Extrusion and rolling method
* Roller coating
* Higher film thickness
* E.g. polythene 30gs
Lamination
Produces multiple layer laminate
Paper/foil/poly – often 9μ used
Cold forming laminates
* E.g. nylon/foil/poly
‘Cocktail’ of adhesives used
* E.g. PVA, Urethane
Container closure information is a critical component of the eCTD.
Within 3.2.S.6 (drug substance) and 3.2.P.7 (drug product):
* Description
* Details on the primary components
Identity of materials of construction of each packaging component
Component specifications
Description
Critical dimensions
Drawings
Non-compendial methods, where appropriate
* Secondary packaging components
Brief details of non-functional components
Additional information for functional components
.. and ALSO within 3.2.P.2 (Pharmaceutical Development): Information on the
suitability of the container-closure for its intended purpose.
PACKAGING SUITABILITY FOR INTENDED USE:
- PROTECTION from factors that can cause degradation in the quality of the dosage form
- COMPATIBILITY – that the container closure will not cause unacceptable changes in
the quality of either the dosage form or the packaging component - SAFETY from leaching harmful or undesirable amounts of substance to which a
patient might become exposed during treatment with the dosage form - Do not forget the ink printing and label adhesives (on plastic and other permeable
components)!! - PERFORMANCE – where the container meets the functionality for which it was
designed. Providing appropriate levels of:
System functionality (where a delivery system is designed to help patient
compliance – such as calendar packs, packs with counters etc.)
Drug delivery (where the container-closure system is designed to deliver
specific dosages – such as transdermal patches, dry powder inhalers,
metered dose inhalers etc.)
CONTROL OF PACKAGING COMPONENTS
PHYSICAL CHARACTERISTICS
* Dimensional criteria (shape, wall thickness, design tolerances)
* Physical parameters (unit weight)
* Performance characteristics (metering valve delivery volume, ease of movement of
syringe plungers)
CHEMICAL COMPOSITION
* Extractables (extraction profiles for polymeric and elastomeric components of
inhalation products)
* Leachables
* Change in formulation of a packaging component
Secondary components are packaging items that are not intended to come into contact with
the dosage form. They include cartons, aluminium over-pouches, paper or plastic
overwraps etc. These must provide one or more of the following functions:
* Protection from moisture ingress or egress
* Protection from gaseous ingress or egress
* Protection from light
* Protection from rough handling
* Protection from microbiological spoilage (e.g., maintaining sterility)
WHAT SHOULD I PUT IN MY REGULATORY SUBMISSION?
- Description
- General description of the container-closure system
- Specific information for each component:
Product name and code
Name and address of the manufacturer
Physical description of the component (type, size, shape, colour) - Materials of construction:
Plastics, paper, metal glass etc
Identified by code and source
Alternative materials - Operations of preparations prepared on the packaging components (washing,
coating, sterilisation etc.)
Information about the suitability
* Complete chemical composition for every material used in the manufacture of a
packaging component
* Test results from qualification and characterisation studies:
Protection: USP tests
Safety and compatibility: extraction / toxicological evaluations (e.g.,
USP Biological Reactivity Test)
Performance: USP and Non-USP functionality tests
Tests on the assembled container-closure system
Information about the quality control
* Information on the quality controls applied by the component suppliers
* Certificates of Conformity or Analysis
* Tests and methods applied to components on receipt, including:
Acceptance criteria for extractables
Dimensional and performance criteria
Appropriate diagrams must always accompany information on container-closure
components. The extent of detail required depends upon the type of component, but
these typically include diagrams of:
* Bottles
* Tamper-evident and child-resistant closures
* Multiple-layered materials (e.g., transdermal patches)
* Metered dose valves
* Actuators
* Component manufacturers
* Materials manufacturers
* Stability data
CONTAINER-CLOSURE SYSTEMS FOR “HIGH-RISK” DRUG PRODUCTS
Inhalation drug products
These include inhalation aerosols (MDIs), inhalation solutions, suspensions and sprays
(administered via nebulisers), inhalation powders (DPIs) and nasal sprays.
These are considered “high risk” because they are intended for patients with compromised
respiratory function, and specific additional requirements are applied to the packaging
components used for these types of products.
There are three important US guidances on these types of products which we will look at
below (note that US guidances can be draft for many years):
* Metered dose inhaler (MDI) and Dry Powder Inhaler (DPI) Drug Products; CMC
Documentation (updated 2018) – draft
* Nasal Spray and Inhalation Solution, Suspension and Spray Drug Products; CMC
Documentation (2002) – final
* Inhalation Drug Products Packaged in Semi-permeable Container-Closure Systems
(2002) – draft
Nasal spray and inhalation solution products
Here the administered dose is directly dependent on the design, reproducibility, and
performance characteristics of the container-closure system. The selection of the suitable
pump for a given set of formulation characteristics (viscosity, density, surface tension,
rheological properties etc) is of considerable importance.
Information is needed on:
* Fabricators of the container, closure and the assembled pump
* Fabricators for each part of the pump
* Unique identifiers for different parts of the pump
* Unique identifiers of the container, closure and the assembled pump
* Engineering drawings of the container, closure and pump components
* Precise dimensional measurements of the container, closure and pump components
* Composition and quality of materials of the container, closure, pump, and pump
components
* Composition and quality of materials of the container, closure, and pump
components
* Control extraction methods and data for elastomeric and plastic components.
* Toxicological evaluation of extractables.
* Acceptance criteria, test procedures and analytical sampling plans:
Physicochemical parameters and dimensional measurements of the
container, closure and pump components
Qualitative and quantitative extractable profiles from the container,
closure, and pump components
Performance characteristics of the pump
Inhalation products in semi-permeable containers
For these types of container-closure systems, the same basic information as for nasal
products is required. An additional concern for these containers is the integrity of the
container – and the need to include more detailed information on the SECONDARY
packaging components than would normally be required for other types of products.
The reason for this is that semi-permeable primary container-closure systems (such as LDPE
vials) need to be protected by secondary packaging to minimise and control the entry of
chemical contaminants from the local environment into the drug product. The secondary
packaging therefore plays a crucial role in assuring the reproducibility of batch-to-batch
quality.
Injectable and ophthalmic drug products
INJECTABLES
Considerations for injectable products include:
* The potential for haemolytic effects
* Protection from microbial contamination
* Protection from light and gases
* Protection from solvent loss
* Protection from exposure to water vapour
The type of materials chosen must be clearly justified:
* Elastomeric components:
Ph Eur /USP Elastomeric Closures for Injections
* Plastic components:
USP Biological Reactivity tests
* Glass components:
USP Containers: Chemical Resistance – Glass Containers
Ph Eur Glass Containers for Pharmaceutical Use
OPHTHALMICS
These are usually solutions in an LDPE bottle with a built-in dropper (often referred to as
“droptainers”), or ointments supplied in metal tubes with an ophthalmic tip.
Considerations for these products include:
* The potential for the container-closure to form substances that irritate the eye
* Potential for particulate contamination
* Reactivity of the dosage form with the metal container
* Maintenance of sterility
* Seal integrity
* Reactive gases
Standard labelling - outer
Name, Strength, Pharmaceutical form
Tradename – INN / avoid confusion
Dosage form – EDQM standard terms
Braille
Qualitative and Quantitative statement
Per dosage unit or e.g. mg/ml
Number of doses
Excipients
Those known to have a recognised effect - e.g. Sucrose
Note that there is specific EU guidance on certain substances
E.g. All products containing ethanol
ALL EXCIPIENTS for injectable, topical, ocular preparations
Method / route of administration
“Keep out of the reach and sight of children”
Special warnings
Expiry date
Storage precautions
Precautions for disposal of unused product
Basic information
MA holder
MA number
Batch number
Instructions for use (non-Rx)
Authenticity and tamper evidence
Labelling Exemptions
Blister packs and small packs
Blister packs and small packs
Name
MAH
Lot no.
Expiry date
Plus for small immediate packaging units
Route of administration
Contents by weight, volume or unit
