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
Variations for labelling can come from
These can come from:
Upgrades to the product / substance e.g. new stability data – longer shelf-life.
New indications / further patient groups
SAFETY MONITORING
“PRAC variations”
see example for ibuprofen in your notes.
Sometimes as URGENT SAFETY RESTRICTION variations.
PACK
Module 3.2.P, Drug Product
P.1 Description and Composition
Concise information on integral medicinal products, and brief information on any additional medical
device (part)/accessories provided and intended for use with the medicinal product, should be submitted,
and their identity (e.g. type/version), description and function should be stated.
P.2 Pharmaceutical Development
This section of the dossier should summarise the information relevant to development of the specific
medical device (part) integrated into the medicinal product, including the rationale for its selection in the
specific sections of 3.2.P.2. A risk assessment summary for the medicinal product, aligned with relevant
risk management principles in ICH Q9, should be presented.
P.2.2 Drug Product
P.2.3 Manufacturing Process Development
P.2.4 Container Closure System (CCS)
P.2.5 Microbiological Attributes
P.2.6 Compatibility
P.3 Manufacture
P.3.1 Manufacturers
P.3.3 Description of manufacturing process and process controls
P.3.4 Controls of critical steps and intermediates
P.3.5 Process validation and/or evaluation
P.5 Control of drug product
P.5.1 Specification(s)
P.7 Container closure system (CCS)
P.8 Stability
Module 3.2.A.2, Adventitious Agents Safety Evaluation
Module 3.2.R, Regional Information, Medical Device
Artwork approval process
Artwork preparation
Transfer to supplier
Generate proof
Customer approval
Plate preparation and control
Printing
Supply of component
Prepare artwork
Design Requirements
- Regulatory
- Mandatory Text
- Marketing
- Branding
- Anti-counterfeit Measures
- Overt
- Covert
Artwork Origination
- Software
- Secure Storage
- Naming conventions
- Folder structures
- In-Process
- Final Approved
- Obsolete
- Rejected
- Revision Control
- Archiving
Outsourced? - Approved Supplier
Artwork process controls
- Converters Code
- Item Number Allocation
- Pharmacode Allocation
- Version/Revision Control
- Colours – Pantone ref
- Translation
- Who Checks…?
- Pack Development
- Packaging
- Regulatory
- QA
- Secure Storage of Final Copy
Artwork transfer
Electronic
* Email
* Secure Server
* Encryption
* Transfer Errors
Manual Hard Copy
* Converted at Printers
Artwork Proof generation and approval
Final Check
* Artwork Dept
* vs Original
* Colour match
* Layout
* Dimensions accurate
Artwork Copy change and proof reading
Oral liquid
* Antihistamine
* Antiemetic
* Sedative
Instruction for dosage changed
* From mls
* To xx 5ml spoonful’s
Artwork - print plates
Preparation
* Unique Identification
* Version Control
* Traceable to Original Artwork
* Secure Storage
Use
* Multi-Use
* Authorised Issue and Return
* Rotation of plates within set (wear)
Destruction
* Secure
Artwork printing
Specification
* Paper/card/labels
* Colours
* Dimensions
* Splices
* Artwork unique referenced
Automated Devices
* Print presence/absence – camera systems
* Double sheets
* Bar codes/pharmacode readers
* Splices
In Process Checks
* Device challenges
* Colour checks
* Dimensional checks
* Quality
Artwork common challenges
Multiple markets supplied
* 1000 of artworks to manage and update
* Different regulatory requirements pack (even in EU… Blue Box information)
Multi-language packs
* Space
* Proof reading
Implementation date for regulatory approvals
* When should the new artwork be placed onto the market?
* Good link with regulatory required
Artwork supplier considerations
Due Diligence – financially sound and ethical
Facility capacity, location, supply chain and back up
Standards for manufacture
* Technical capability
* Operating to recognised standards (PQS)
* Quality culture
* Facility design
* Hygiene and cleanliness
* Process controls and security
Artwork standards for manufacture
Depend upon:
* Use of the component
* Criticality of component
* Further processing e.g. cleaning
Aim should be GRADUAL IMPROVEMENT in standards to that of the
dosage form manufacturer
Artwork - Key areas of interest for the QP
Change control systems
Artwork management
* Control of printing plates
* Digital artwork management
Line clearance
Opportunities for mix-ups
Contamination (primary materials)
Artwork - Product security
Use, control and verification of security codes
Unique controlled numbering systems
Secure storage and documented issues/returns
Avoidance of processing products with similar appearance in close proximity
Controlled set up procedures
Digital file control and access on-line
No composite gang printing
Verification of replacement print media during runs
Verification and control of splices
No replacement of missing labels
Accurate counts
* Control of rejects, scrap and over run
* Labels may be sequentially numbered
Running the web to plain print if possible
Packaging vision systems
Missing or wrong characters
Missing parts of a character
Filled in letters
Missing accents or symbols
Missing graphical elements
Wrong barcodes
Wrong colours
Wrong font
Braille
Packing Supplier management
Audit
* Risk-based (determine need and frequency/duration)
* ‘Desk top’ vs physical audit
* Periodic re-evaluation
Quality/technical agreement
Material specifications
* Agreed quality standards
* Agreed sampling plans
Ongoing performance monitoring/reviews
Specific guidance for the manufacture of these materials is provided however by the following
documents:
ISO 15378 (2017): Primary packaging materials for medicinal products – particular
requirements for the application of ISO 9001:2015, with reference to Good Manufacturing
Practice (GMP)
PS 9000 (2016): Chartered Quality Institute of Quality Assurance/Pharmaceutical Quality
Group in a Code of Practice Pharmaceutical Packaging Materials – the application of ISO
9001:2015 to pharmaceutical packaging materials
Goods receipts checks
Typical checks
* Condition and security of delivery vehicle
* Cleanliness
* Transit damage
* Identity
* Quantity
* Purchase order (authenticity of delivery)
The different items should be
* Separated – to avoid mix-up!
* Labelled
* Stored pending sampling
Stock inventory records will also need to be updated
Packing - Sampling
The Sampling Plan for packaging materials should take account of at least the following
* The agreed quality standard
* The nature of the material (e.g. primary and/or printed packaging material)
* The production method
* The knowledge of the QA system of the packaging material supplier based on audit
* The quantity received
The number of samples taken should be determined statistically and specified in a sampling plan
The typical plans adopted
* The well known n + 1 rule
* Statistical plans e.g. IS0 2859
Packing component specs
Specifications for starting, primary or printed packaging materials should include, if applicable
* A description of the materials including
* The designated name and the internal code of reference
* The reference, if any, to a pharmacopoeial monograph
* The approved suppliers and, if possible, the original producer of the products
* A specimen of printed materials
* Directions for sampling and testing or reference to procedures
Qualitative and quantitative requirements with acceptance limits
Storage conditions and precautions
The maximum period of storage before re-examination
Packing line validation
Feeder design
Tablet feed rate
Line dwell time
Forming temperature
Sealing temperature
Sealing pressure
Line speed
Product security certification - correct product, correct fill, blister sealed
Packing line start up checks
Key to using the packing process is the start‐up checks:
* Line clearance
* Incoming bulk and components visual check for condition
* Critical processes validation
* Calibrations complete and in date
* The name and batch number of the product being handled should be displayed at
* each packing line or station.”
* All products and packing materials checked on delivery to the packing department
* for quantity, identity and conformity with the packing instructions.
Packing line in process controls
Once the process is underway, it is necessary to confirm continued acceptable operation through a
series of controlled in‐process checks.
On‐line control of the product during packaging should include at least checking the
following:
(a) General appearance of the packages;
(b) Whether the packages are complete;
(c) Whether the correct products and packaging materials are used;
(d) Whether any over‐printing is correct;
(e) Correct functioning of line monitors.
Samples taken away from the packaging line should not be returned.
There may be other product or process specific checks introduced by the company for example
integrity test, torque tests, blister seal checks etc.
Products which have been involved in an unusual event should only be reintroduced
into the process after special inspection, investigation and approval by authorised
personnel. Detailed records should be kept of this operation.
Packing line end of run checks
The final stage in the process is the end of run check, covering:
Reconciliation
Line clearance
Retained samples
Returns to warehouse
Packing line IPCs
On-line control of the product during packaging should include at
least checking the following:
a. General appearance of the packages
b. Whether the packages are complete
c. Whether the correct products and packaging materials are used
d. Whether any over-printing is correct
e. Correct functioning of line monitors”
Packing line visual IPCs
Routine visual checks to ensure the quality of the product during the
packaging process
Visual verification that the correct materials are being used, printed,
information applied online is correct, the pack is assembled correctly
and there is no physical damage occurring
* Collations and shipper
* Tamper evident labels
* Carton and leaflets
* Blister
Packing line challenge tests
Splice detection
Vision System
Blister seal
On-line verification
* Printed foil
* Leaflets
* Cartons
Checkweigher
Packing line test frequencies
How often must these checks be carried out?
* Challenge tests
* Start and end of batch
* After machine has been switched off
* After engineering activity
* Visual tests
* Start and end of batch
* Every 30mins – 2 hours
* After machine stoppages as above
Record all tests in Packaging Batch Record
Packing line rejects
Clearly labelled reject bins for empty blisters and partially filled blisters
Reject bins for cartons
* Missing blisters
* Missing leaflets
* Incorrect code
Reprocess, when… how?
Control
Pack Breakdown
Inspection
Reintroduction before Verification system
EOB or specific times during batch (recorded)
Clear approved procedures
Rework
Documented procedure
* How and when? During or at end of batch?
* How many times is allowable?
* Rework due to coding error?
* Rework into another market pack due to commercial need?
Activity recorded – batch record or log book
Appropriate and validated equipment used
Authority requirements
* E.g. Russia expect a validated process
