10.1 Explain factors influencing choice of containers.
The selection of pharmaceutical containers involves balancing multiple factors to ensure
product integrity and safety:
Product-related factors:
• Physical state (solid, liquid, semi-solid, gas) determines container requirements
• Chemical properties, including pH, reactivity, and oxidation sensitivity
• Moisture sensitivity necessitates appropriate barrier properties
• Light sensitivity may require opaque or amber containers
• Stability profile and degradation pathways impact material selection
Administration and usage factors:
• Dosage requirements (single vs. multiple dose)
• Route of administration influences container design
• Patient demographics (elderly, pediatric) affect closure systems
• Compliance needs may dictate specialized packaging
• Healthcare setting considerations (hospital vs. home use)
Manufacturing factors:
• Filling process compatibility (hot filling, aseptic processing)
• Sterilization method compatibility (autoclave, EtO, radiation)
• Container closure system integrity throughout production
• Scale of production and equipment requirements
• Container dimensional consistency
Regulatory and commercial factors:
• Pharmacopoeial requirements (USP, EP, JP)
• Child-resistant and senior-friendly needs
• Cost considerations and market positioning
• Environmental impact and sustainability
• Tamper-evidence requirements
These factors must be systematically evaluated during development to select optimal
container materials and designs that maintain product quality throughout shelf life.
10.2 Discuss the factors influencing choice of containers for pharmaceuticals.
Selection of pharmaceutical containers requires careful consideration of multiple
interrelated factors:
Product Characteristics:
• Physical form (solid, liquid, semi-solid) dictates basic container type
• Chemical properties, including pH extremes, oxidation potential, and reactivity
• Sensitivity to environmental factors (moisture, light, oxygen, temperature)
• Volatility of components and potential for absorption/adsorption
• Intended shelf life and stability requirements
Protection Requirements:
• Barrier properties against moisture, oxygen, and light
• Microbial contamination prevention
• Physical protection during transport and storage
• Temperature excursion tolerance
• Extractables and leachables potential
Administration Considerations:
• Dosage accuracy needs (calibrated droppers, unit-dose systems)
• Frequency of access (single vs. multiple use)
• Patient population (child-resistant, senior-friendly designs)
• Self-administration requirements and compliance features
• Professional vs. home use environment
Manufacturing and Processing:
• Filling technology compatibility
• Sterilization method tolerance (heat, radiation, gas)
• Closure application parameters
• Production scale economics
• Supply chain reliability
Regulatory and Market Factors:
• Pharmacopoeial standards compliance
• Child-resistant packaging requirements
• Tamper-evidence needs
• Labeling space requirements
• Marketing considerations and brand identity
The optimal container balances these factors while maintaining product quality
throughout shelf life.
10.3 Write a brief note on stability aspects of packing.
Packaging stability aspects directly impact pharmaceutical product quality and must be
carefully evaluated during development and throughout shelf life:
Container-Drug Interactions:
• Adsorption: Surface binding of active ingredients or preservatives to container
materials, resulting in potency loss
• Absorption: Migration of components into packaging materials, particularly
problematic with plastic containers
• Permeation: Transmission of gases (oxygen, water vapor) through container walls
affecting moisture-sensitive or oxidation-prone products
• Chemical reactions: Container components catalyzing degradation or interacting
with formulation ingredients
Extractables and Leachables:
• Extractables: Compounds that can be extracted under exaggerated conditions
(potential leachables)
• Leachables: Compounds that actually migrate into the product under normal
conditions
• Sources include plasticizers, antioxidants, monomers, catalysts, and processing
aids
• Toxicological evaluation required for safety assessment
Physical Stability Considerations:
• Dimensional changes during storage (expansion, contraction)
• Mechanical integrity throughout shelf life (impact resistance, seal strength)
• Stress cracking in plastic materials
• Delamination in glass containers
• Closure system functionality and integrity maintenance
Environmental Effects:
• Temperature effects on container properties and container-drug interactions
• Humidity impact on moisture barriers and material properties
• Light transmission characteristics affecting photosensitive products
• Transportation stresses and their effect on container closure integrity
Stability studies must evaluate these aspects under various conditions to ensure
packaging performance throughout the product's shelf life.
10.4 Classify primary, secondary, and tertiary packaging materials with example.
Pharmaceutical packaging is organized in a hierarchical structure based on product
contact and function:
Primary Packaging:
• Definition: Materials in direct contact with the product
• Functions: Containment, protection, stability, identification, dispensing
• Examples:
o Glass: Vials, ampoules, bottles, prefilled syringes
o Plastics: Blisters (PVC, PVDC, COC), bottles (HDPE, PET), tubes
(polyethylene, aluminum laminates)
o Metals: Aluminum tubes, foil blisters, aerosol canisters
o Elastomers: Rubber stoppers, gaskets, plungers
o Combination systems: Prefilled devices, transdermal patches
Secondary Packaging:
• Definition: Contains primary package(s), no direct product contact
• Functions: Identification, protection, tampering evidence, marketing, patient
information
• Examples:
o Paperboard cartons for blister packs, vials, bottles
o Setup boxes for high-value medications
o Labels and package inserts (PIL)
o Plastic trays or inner dividers
o Shrink wrap groupings
Tertiary Packaging:
• Definition: Facilitates handling, storage, and transportation of multiple secondary
packages
• Functions: Physical protection, distribution efficiency, handling
• Examples:
o Corrugated shipping cases
o Pallets and pallet wraps
o Shrink-wrapped bundles
o Plastic crates
o Shipping containers
Each packaging level serves specific functions in the overall product protection and
delivery system.
10.5 Describe materials used for packaging of pharmaceuticals.
Pharmaceutical packaging employs various materials selected for their protective
properties and compatibility with specific products:
Glass:
• Types: Type I (borosilicate), Type II (treated soda-lime), Type III (soda-lime), Type
NP (non-parenteral)
• Applications: Ampoules, vials, bottles, prefilled syringes
• Advantages: Chemical inertness, transparency, impermeability
• Limitations: Breakage risk, weight, potential for delamination
Plastics:
• Polyethylene (LDPE/HDPE): Bottles, bags, tubes; flexible to rigid applications
• Polypropylene (PP): Containers, closures; good chemical resistance
• Polyethylene terephthalate (PET): Bottles, blisters; excellent clarity
• Polyvinyl chloride (PVC): Blisters; often laminated with PVDC for enhanced barrier
• Cyclic olefin polymers (COP/COC): High-barrier vials, prefilled syringes
• Advantages: Lightweight, shatter-resistant, design flexibility
• Limitations: Permeability, leachables, less inert than glass
Metals:
• Aluminum: Foil blisters, tubes, aerosol containers
• Tin-plated steel: Aerosol containers
• Applications: Barrier packaging, light-sensitive products
• Advantages: Excellent barrier properties, recyclability
• Limitations: Corrosion potential, product compatibility issues
Elastomers:
• Types: Butyl rubber, chlorobutyl, bromobutyl, silicone, thermoplastic elastomers
• Applications: Closures, gaskets, plungers, septums
• Selection based on: Product compatibility, moisture/gas permeability,
extractables profile
Combination materials:
• Laminates: Multiple layers for enhanced properties
• Strip/blister packaging: Aluminum-polymer combinations
• Child-resistant packaging: Specialized polymer-based designs
Material selection requires comprehensive evaluation of product requirements,
regulatory compliance, and performance characteristics.
10.6 Describe different types of glass as a packaging material for parenteral. Explain
water attack test.
Glass for parenteral packaging is classified based on hydrolytic resistance into four
types:
Type I (Borosilicate Glass):
• Highest chemical resistance due to boric oxide content (8-12%)
• Low alkali release and thermal expansion
• Applications: High-value parenterals, pH extremes, sensitive drugs
• Identifiable by USP/EP/JP hydrolytic resistance tests
Type II (Treated Soda-Lime Glass):
• Soda-lime glass with sulfur treatment creating surface sulfate layer
• Improved chemical resistance compared to untreated soda-lime
• Applications: Most buffered aqueous injections
• Note: Surface treatment can be compromised by high temperatures
Type III (Regular Soda-Lime Glass):
• Moderate chemical resistance, higher alkali content
• Applications: Non-aqueous parenterals, powders, less sensitive products
• More economical than Types I and II
Type NP (Non-Parenteral):
• General purpose soda-lime glass
• Not suitable for parenteral products
• Applications: Oral and topical preparations
Water Attack Test:
• Purpose: Determines hydrolytic resistance classification
• Procedure:
1. Glass is crushed to specific particle size (300-500 μm)
2. Washed sample (10g) is heated with purified water (50mL) at 121°C for 30
minutes
3. Cooled solution is filtered and titrated with 0.01N HCl using methyl red
indicator
4. Volume of acid consumed correlates to alkali released from glass
• Classification:
o Type I: ≤1.0 mL HCl per 10g glass
o Type II: ≤8.5 mL HCl per 10g glass
o Type III: ≤15.0 mL HCl per 10g glass
This test is critical for ensuring appropriate glass selection for parenteral products.
10.7 Elaborate powder glass and water attack test.
The powder glass test and water attack test are standardized procedures used to
determine the hydrolytic resistance of glass containers for pharmaceutical use.
Powder Glass Test:
• Purpose: Evaluates total extractable alkali released from the entire glass mass
• Sample preparation: Glass is crushed and sieved to obtain particle size 300-500
μm
• Washing: Particles are washed with acetone, then purified water to remove fines
• Pre-drying: 100-140°C for 20-30 minutes
• Test procedure:
o Weigh 10g of prepared glass powder into a high-quality borosilicate flask
o Add 50mL of high-purity water
o Autoclave at 121°C for 30 minutes
o Cool and filter solution
• Analysis:
o Titrate filtrate with 0.01N hydrochloric acid using methyl red indicator
o Calculate volume of acid consumed per gram of glass
Water Attack Test:
• Purpose: Evaluates hydrolytic resistance of interior surfaces
• Sample preparation: Empty, clean containers
• Test procedure:
o Fill containers to 90% capacity with purified water
o Cover with neutral glass or suitable material
o Autoclave at 121°C for 60 minutes
o Cool and combine contents if using multiple containers
• Analysis:
o Titrate with 0.01N hydrochloric acid using methyl red indicator
o Express results as mL of 0.01N HCl per 100mL of leachate
Classification criteria based on these tests determine glass type (I, II, III, or NP), ensuring
appropriate container selection for pharmaceutical products.
10.8 Discuss the powder glass test and water attack test for packaging in
Pharmaceuticals.
The powder glass test and water attack test are critical pharmacopoeial methods for
determining glass container suitability for pharmaceutical products:
Powder Glass Test: This test assesses the inherent hydrolytic resistance of the entire
glass composition:
• Glass containers are crushed to specified particle size (300-500 μm)
• Samples are washed with acetone followed by water to remove fine particles
• Precisely 10g of prepared glass particles are placed in a Type I glass flask
• 50mL of purified water is added
• The mixture is heated at 121°C for 30 minutes in an autoclave
• After cooling, the solution is filtered
• The filtrate is titrated with 0.01N hydrochloric acid using methyl red indicator
• Results are expressed as volume of acid consumed, indicating released alkali
• Classification criteria:
o Type I: ≤1.0mL of 0.01N HCl per gram
o Type II: ≤8.5mL of 0.01N HCl per gram
o Type III: ≤15.0mL of 0.01N HCl per gram
Water Attack Test: This test evaluates the surface hydrolytic resistance of intact
containers:
• Clean, empty containers are filled to 90% capacity with purified water
• Containers are covered and heated at 121°C for 60 minutes
• After cooling, the water extract is titrated with 0.01N HCl
• Results are expressed as mL of acid per 100mL of extract
• Classification limits vary by container volume and intended use
These complementary tests ensure appropriate glass selection for specific
pharmaceutical applications, particularly for parenteral products.
10.9 Describe the hydrolytic resistance test for classification of glass containers as
per IP.
The Indian Pharmacopoeia (IP) employs hydrolytic resistance tests to classify glass
containers based on their resistance to water attack, which directly relates to their
chemical stability and suitability for pharmaceutical products:
Glass Grains/Powder Test (for Glass Mass):
1. Sample preparation:
o Glass containers are crushed and sieved to obtain 300-500 μm particles
o Particles are washed with acetone to remove fines
o Further washed with purified water and dried at 140°C
2. Test procedure:
o 10.0g of prepared glass grains are placed in a Type I glass flask
o 50mL of carbon dioxide-free water is added
o The flask is autoclaved at 121 ± 1°C for 30 minutes
o After cooling, the solution is filtered through a membrane filter
3. Titration:
o The filtrate is titrated with 0.01M hydrochloric acid using methyl red
o A blank determination is performed for correction
4. Classification criteria:
o Type I: ≤1.0mL of 0.01M HCl per gram of glass
o Type II: ≤8.5mL of 0.01M HCl per gram of glass
o Type III: ≤15.0mL of 0.01M HCl per gram of glass
Surface Hydrolytic Resistance Test (for Container Interior):
1. Containers are rinsed with purified water and filled to 90% capacity
2. Containers are covered, autoclaved at 121°C for 60 minutes
3. Extracts are titrated with 0.01M HCl
4. Results are expressed as mL of acid per 100mL of extract
5. Limits vary by container volume and intended use
These tests ensure appropriate glass selection for different pharmaceutical applications,
with Type I being suitable for most parenteral preparations.
10.10 Discuss different methods for evaluation of packaging.
Pharmaceutical packaging evaluation encompasses multiple testing methodologies to
ensure product protection and regulatory compliance:
Physical Integrity Testing:
• Container closure integrity testing (CCIT): Dye ingress, vacuum/pressure decay,
helium leak detection
• Burst/pressure testing: Container resistance to internal pressure
• Drop/impact testing: Resistance to physical damage during handling
• Seal strength: Measurement of force required to separate sealed surfaces
• Torque testing: Application and removal forces for threaded closures
Barrier Property Evaluation:
• Moisture vapor transmission rate (MVTR): Weight gain/loss method or
instrumental techniques
• Oxygen transmission rate (OTR): Coulometric or optical sensor methods
• Light transmission: Spectrophotometric measurement across UV/visible
spectrum
• Gas/volatile permeation: Specialized instrumental methods for specific gases
Chemical Compatibility Assessment:
• Extractables studies: Controlled extractions using multiple solvents and
conditions
• Leachables testing: Migration studies under normal and accelerated conditions
• Sorption evaluation: Measurement of active ingredient loss to container materials
• Compatibility screening: Visual, physical, and chemical evaluation of packaging-
product interaction
Performance Testing:
• Functional testing: Delivery systems (sprays, pumps, valves) performance
• Child-resistant/senior-friendly testing: Protocol-driven human factors studies
• Actuation force: Measurement of force required to operate delivery mechanisms
• Dispensing accuracy: Consistency of delivered volume/dose
Stability Studies:
• Long-term stability in final packaging
• Accelerated stability under stressed conditions
• Photostability in packaging
• Temperature cycling effects
• Transportation simulation testing
These complementary evaluation methods ensure packaging systems meet quality,
safety, and performance requirements throughout product shelf life.
10.11 What are the quality control tests for pharmaceutical packaging?
Quality control tests for pharmaceutical packaging ensure integrity, safety, and
functionality throughout shelf life:
Glass Containers:
• Hydrolytic resistance (powder and surface tests)
• Dimensional accuracy and consistency
• Thermal shock resistance
• Internal pressure resistance
• Visual inspection for defects
• Light transmission (for photosensitive products)
• Chemical resistance for specialized applications
Plastic Containers:
• Identification testing (IR spectroscopy)
• Physicochemical tests: Non-volatile residues, heavy metals
• Water vapor and oxygen permeation rates
• Extractables/leachables profile
• Light transmission characteristics
• Biological reactivity (USP <87>, <88>)
• Environmental stress crack resistance
Rubber/Elastomeric Components:
• Identification
• Hardness (Shore A durometer)
• Penetrability and fragmentation testing
• Self-sealing properties for closures
• Extractable sulfides and heavy metals
• Biological reactivity testing
Metal Containers:
• Corrosion resistance
• Coating integrity
• Internal pressure resistance
• Crimp quality (for aerosols)
Functional Performance Tests:
• Container closure integrity testing (dye ingress, helium leak)
• Seal strength (for flexible packaging)
• Torque testing (for screw caps)
• Child-resistant/senior-friendly testing
• Actuation consistency (for delivery systems)
• Dispensing accuracy
Stability-Indicating Tests:
• Package integrity throughout shelf life
• Interaction with product under storage conditions
• Protection efficacy (moisture, light, oxygen)
• Mechanical performance after aging
These tests are selected based on container type, route of administration, and specific
product requirements to ensure quality and safety.
10.12 Explain tamper proof packaging.
Tamper-proof (more accurately termed "tamper-evident") packaging provides visible
evidence to consumers when a package has been opened or compromised, thereby
protecting against deliberate tampering and contamination.
Key Features of Tamper-Evident Packaging:
• Requires irreversible physical alteration to access contents
• Provides clear visual indication of tampering attempt
• Cannot be easily replicated or restored after opening
• Includes prominent labeling to identify tamper-evident features
Common Tamper-Evident Technologies:
1. Film wrappers: Transparent film with distinctive designs that cannot be removed
without visible damage
2. Shrink bands/sleeves: Heat-shrunk plastic covering closure, requiring
breaking/cutting for access
3. Breakable caps: Components that break upon opening (plastic rings on bottle
caps)
4. Sealed inner-liners: Foil or paper seals bonded to container opening
5. Blister/strip packaging: Individual dose units in sealed cavities requiring physical
destruction to access
6. Tape seals: Special tapes with "void" or "opened" messages appearing upon
tampering
7. Bubble packs: Products sealed between two layers requiring cutting/tearing to
access
Regulatory Requirements:
• FDA requires at least one tamper-evident feature for OTC drugs
• Feature must be distinctive by design or use of identifying characteristics
• Packaging must include description of tamper-evident feature
• Evidence of tampering should remain after feature is breached
Effective tamper-evident packaging balances security with user convenience, providing
visible assurance of product integrity while remaining accessible to legitimate users,
including those with physical limitations.
10.13 Differentiate: 1. Blister packaging and Strip packaging.
Blister and strip packaging are both unit-dose pharmaceutical packaging systems, but
they differ in several important aspects:
Blister Packaging:
• Structure: Consists of a thermoformed plastic cavity or pocket (blister) heat-
sealed to a backing material
• Materials: Typically PVC, PVC/PVDC, PVC/Aclar, COC, or PET for forming film;
aluminum foil or paper/foil laminate for backing
• Manufacturing: Involves thermoforming process creating cavities in plastic sheet,
followed by filling and sealing
• Barrier properties: Moderate to excellent moisture/oxygen barrier depending on
materials
• Visibility: Product visible through transparent forming film
• Child-resistance: Can incorporate push-through resistance or peel-open designs
• Applications: Higher-value medications, moisture-sensitive products
• Advantages: Better protection, product visibility, tamper-evidence
• Disadvantages: Higher cost, larger package size, more complex machinery
Strip Packaging:
• Structure: Two flat sheets of material sealed together around the product
• Materials: Typically aluminum foil or paper/aluminum/plastic laminates
• Manufacturing: Horizontal form-fill-seal process without thermoforming step
• Barrier properties: Excellent moisture/oxygen barrier when using aluminum foil
• Visibility: Product not visible unless transparent film is used
• Child-resistance: Generally not child-resistant
• Applications: Cost-sensitive markets, tropical climates requiring moisture
protection
• Advantages: Economical, compact, excellent barrier, simpler machinery
• Disadvantages: Limited product visibility, less physical protection, difficult to
implement child-resistance
Both systems provide unit-dose convenience, tamper-evidence, and product
identification, but selection depends on specific product requirements, market needs,
and cost considerations.
