harmaceutical Packaging Materials – Short Notes (GPAT Focus)

Importance of Packaging:

• Protects drug from environmental factors: Gases, moisture, light, solvents, and
microbial contamination.

• Ensures safety: Non-toxic, no taste/odor imparted, compatibility with drug.

• Must be economical, eco-friendly, tamper-resistant, and adaptable to high-speed

machines.

Packaging Layers:

1. Primary Packaging: In direct contact with drug (e.g., glass vials, blister films, desiccants).

2. Secondary Packaging: Cartons, blister overwraps (no direct contact).

3. Types of Containers:

o Single-unit container: Single dose.

o Unit-dose container: For solid oral forms.

o Multiple-unit container: Multiple doses.

Glass Packaging:

• Chemically inert, rigid, impermeable.

• Types of Glass (USP/NF):

1. Type I – Borosilicate Glass

→ Highly resistant, suitable for parenterals.

2. Type II – Treated Soda-Lime Glass

→ Surface-dealkalized, good for acidic/neutral parenterals.

3. Type III – Regular Soda-Lime Glass

→ Not for parenterals.

4. Type NP – General Purpose Soda-Lime Glass

→ Non-parenteral use.
• Colored Glass (Amber) protects from UV (290–450 nm).

• Flaws: Alkali leaching, insoluble flake formation.

Plastic Packaging:

• Advantages: Lightweight, impact-resistant, design flexibility.

• Polymers Used:

o Polyethylene (HDPE)
→ Good moisture barrier, poor oxygen barrier, low cost.

o Polypropylene (PP)
→ High melting point, sterilizable, good chemical resistance, brittle at low temp.

o Polyvinyl Chloride (PVC)

→ Clear, rigid, good barrier properties, but less chemical resistance.

Additives in Plastic Packaging:

• Antioxidants: Butylated hydroxy toluene (BHT).

• Antistatic Agents: Polyethylene glycols, fatty amides (0.1–0.2%).

• Plasticizers, Stabilizers, Colors.

Special Packaging Requirements:

• Moisture-sensitive drugs → Hermetic or tight containers.

• Photo-sensitive drugs → Amber glass.

• Tamper-evident packages → OTC, ophthalmic products.

• High-potency drugs → Buffered solution to minimize pH changes due to alkali release.

Key GPAT Point Summary:

• Type I glass → Parenterals, most inert.

• Amber glass → UV protection, prevents degradation.

 • HDPE → Common, low-cost, but oxygen permeable.

• PP → Sterilizable, no stress cracking.

• Plastic additives → Avoid leaching & toxicity.

• Plastic over glass → Safer (non-breakable), but inferior chemical barrier.

Pharmaceutical Packaging Materials – Detailed Short Notes

Polyvinyl Chloride (PVC):

• Fair oxygen barrier, good stiffness, but poor impact resistance → softened with
plasticizers.

• Stabilizers used: Tin compounds (good clarity, some not food/drug approved),
calcium/zinc salts (yellowish tint).

• Excellent barrier for oils, alcohols, petroleum solvents.

• Amber glass better for light-sensitive drugs; PVC often used in blister packs (may be
coated with PVdC or PCTFE).

• Concern: Vinyl chloride monomer (VCM) suspected carcinogen, not PVC itself.

Polymonochlorotrifluoroethylene (PCTFE) – Trade Name: Aclar

• Excellent moisture barrier, poor O₂, N₂, CO₂ barrier compared to PVdC.

• Very expensive, used as thin layer in blister packs.

• Homopolymers (Rx 160, UltRx 2000, SupRx 3000) offer cost/performance advantages.

Polystyrene (PS):

• Crystal clear, low cost, but poor water and oxygen barrier.

• Not for liquids; used for solid dosage forms.

• High oxygen & water vapor permeability.

• Static charge build-up, low melting point (190°F).

• Impact polystyrene improved by rubber, acrylic blends → classified as intermediate,

high, super impact.

Nylon (Polyamide):

• Strong, autoclave-resistant, chemically resistant.

• Highly impermeable to O₂, poor moisture barrier → lamination used.

• FDA-approved types: Nylon 6, Nylon 6/6, Nylon 6/10, Nylon 11.

• Interaction possible with drugs → limit long-term storage.

Polycarbonate (PC):

• Clear, FDA-approved, rigid, sterilizable.

• Moderate chemical resistance and moisture barrier.

• High impact strength, dimensional stability.

• Used in specialty containers (vials, syringes).

Acrylic Multipolymers (Nitrile Polymers):

• Good gas barrier, chemical resistance, oil/grease resistance.

• Less brilliant than styrene.

• FDA standard: Residual acrylonitrile <11 ppm; migration <0.3 ppm.

Polyethylene Terephthalate (PET):

• Biaxially oriented PET bottles widely used (carbonated drinks).

• Excellent impact strength and barrier properties.

• FDA-approved for food contact >25 years.

Acetal (Polyoxymethylene – POM):

• High tensile strength, stiffness, fatigue resistance.

• Used in engineering components (e.g., aerosol valves).

• Less hygroscopic than nylon.

Regenerated Cellulose (Cellophane):

• Uncoated: Hygroscopic, permeable to water, poor stability.

• Coated film: Transparent, grease-resistant → used for strip packs, laminations.

Coextruded Resins:

• Combine properties of multiple polymers (e.g., PP/EVOH/PP).

• High-barrier properties, substitute for glass.

• New tech: Nylon in polyolefin matrix → great O₂, hydrocarbon barrier.

Drug-Plastic Interactions – Key Concepts:

1. Permeation – Gases/liquids passing into/out of container → affects shelf-life.

o Example: Penicillin degraded in polystyrene due to moisture.

2. Leaching – Additives migrating into drug → toxic risk.

3. Sorption – Drug components binding to plastic → loss of drug efficacy.

o Example: Loss of preservatives (e.g., Vioform lotion).

4. Chemical Reaction – Ingredients in plastics may react with drug.

5. Physical Alteration (Modification) – Plastic may deform (softening, hardening).

Metal Packaging:

• Nearly impermeable, shatterproof, strong.

• Common metals: Tin, Aluminum, Lead, Steel.

➔ Tin: Preferred for purity, inertness, coated to improve corrosion resistance.
➔ Aluminum: Lightweight, used in foils, tubes, and blister packs; reacts at extreme pH unless
lined.
➔ Lead: Only used with internal linings (e.g., fluoride toothpaste).
➔ Linings (Epoxy, Phenolic, Vinyl): Prevent metal-drug interaction.

Rubber:

• Used in stoppers, cap liners, dropper assemblies.

• Natural Rubber: Resistant to acids, attacked by oxidizing agents.

• Synthetic Rubbers (Neoprene, Silicone, Buna N): Superior resistance to oxidation,

chemicals.

Pharmaceutical Packaging – Short Notes (GPAT Focus)

Rubber Closures – Key Points:

• Leaching Effect: Rubber closures can leach extractives into vial solutions during
autoclaving (115°C, 10 psi, 30 min) and storage → may interfere with drug analysis,
cause toxicity, loss of preservative stability, and particulates.

• Epoxy Lining: Reduces extractive leaching but does not affect preservative sorption.
 • Teflon-Coated Rubber Stoppers: Prevent leaching and sorption → best for sensitive
formulations.

• Example Data:
- At 60°C, 12 weeks → Neoprene closure: 8.5% residual chlorobutanol vs Ampul:
72.4%.

Collapsible Tubes:

• Advantages:
1. Controlled dispensing
2. Minimal contamination risk
3. Lightweight & unbreakable
4. Suitable for creams, gels, ointments.

• Materials:

1. Metal (Tin, Aluminum, Lead):

- Tin: Most ductile, expensive.
- Aluminum: Lightweight, may develop leaks due to hardening.
- Lead: Cheaper, alloyed with antimony.

2. Plastic (LDPE, HDPE, PP, Vinyl):

- LDPE: Widely used, cheap, flexible.
- HDPE: Stiffer, better protection.
- Suck-back feature prevents ooze but can cause dispensing issues.
- Neck compatibility important for sealing.

3. Laminated Tubes:
- Layers of plastic, paper, foil.
- Good barrier properties.
- Insert of urea-formaldehyde in head reduces permeation.
- Used for pharmaceuticals, dentifrices, adhesives.

Closures – Basic Designs:

1. Screw-on (Threaded):
- Metal (tinplate/aluminum) or plastic caps.
- Plastisol inner gasket for sealing.
 2. Lug Cap:
- Quarter-turn operation.
- Used in food industry; good for sterilization.

3. Crown Cap:
- Friction-fit, crimped (21 flutes).
- Common for beverage bottles.

4. Roll-on Closures:
- Aluminum; thread formed during filling.
- Tamper-proof versions available.

5. Pilfer-proof Closures:
- Breakable bridges indicate tampering.

6. Non-reusable Roll-on Closures:

- Tear-off tabs; no reuse.

Plastic Closures:

• Two types:
1. Thermosetting Resins (Phenolic, Urea):
- Permanent chemical change during molding.
- Resistant to heat, chemicals.
- Phenolics: Black/brown, sturdy, chemical-resistant.
- Urea: Translucent, more expensive, elegant colors, not steam sterilizable.

2. Thermoplastics (Polystyrene, Polyethylene, Polypropylene):

- Widely used (90%+).
- Cost-effective, chemically inert, easier molding.

Closure Liners – Important Factors:

• Chemically inert.

• Resilient to fit irregular surfaces.

• Adhesive or snap-in design.

• Common Facing Materials & Permeation Rates:

Liner Facing Water Permeation Alcohol Permeation

Polyethylene, 2 mil 0.07 0.06

Saran, 75 gauge 0.07 0.08

Aluminum foil, 1 mil 0.04 0.12

Polyester, 50 gauge 0.12 0.10

Vinylite 0.20 0.03

Yellow oil 0.28 0.85

• Homogeneous Liners: Single-material disks → uniform, sterilizable.

• Composite Liners: Face (chemical resistance) + back (cushioning/sealing).

Stoppers – Summary:

• Used for multiple-dose vials & syringes.

• Common polymers: Natural rubber, neoprene, butyl rubber.

• Ingredients: Rubber, vulcanizing agent, fillers, plasticizers, pigments, antioxidants, waxes.

• Issues:
1. Drug sorption → Loss of drug potency.
2. Extractives leaching → Toxicity & interference in analysis.
3. Interaction with preservatives → Inactivation.

Tamper-Resistant Packaging:

• Regulation: FDA (21 CFR parts 211, 314, 700).

• Definition: Indicator/barrier providing visible evidence of tampering.

• Examples of Tamper-Resistant Systems:

1. Film wrappers (end-folded, fin seal, shrink)
2. Blister packs
3. Strip packages
4. Bubble packs
 5. Shrink seals & bands
6. Foil, paper, plastic pouches
7. Bottle seals
8. Tape seals
9. Breakable caps
10. Sealed tubes
11. Aerosol containers
12. Sealed cartons

• Key Requirement: Visual indicator + appropriate labeling.

harmaceutical Packaging – Short Notes (GPAT Focus)

Overwrapped Packaging

• May include heat-sensitive varnish → permanently bonds overwrap to carton →

prevents reuse.

Fin Seal Wrapper

• Seals created by compressing two inner surfaces → “fin” seal.

• Advantages:
• High seal integrity
• Allows use of stronger sealants (Polyethylene, Surlyn).

• Widely used when protective packaging is critical.

• Opened by tearing wrapper.

Shrink Wrapper

• Thermoplastic film shrinks upon heating → tightly wraps product.

• Materials: Heat-shrinkable Polypropylene, Polyethylene, PVC.

• Key Advantage: Low cost, flexible equipment.

• Heat tunnel used to shrink film.

Blister Package

• Thermoplastic sheet vacuum-formed → filled and lidded.

• Lidding types:
1. Push-through: Aluminum foil (heat-seal coated).
2. Peelable: Polyester/paper + foil → Child-resistant.

• Materials: PVC, PVC/PE, Polystyrene, Polypropylene, PVC/Aclar (high moisture barrier).

• Barrier Properties Example:

• Saran/PVC: Oxygen 0.6 cc/24hr; Water vapor 0.092 g/24hr
• Aclar/PVC: Oxygen 1.1 cc/24hr; Water vapor 0.035 g/24hr

Strip Package

• Two webs of heat-sealable film form pockets → tablet/capsule inserted → sealed by

heated platen or rollers.

• Good for moisture-sensitive products.

• Materials: Paper/PE/foil/PE laminate, Cellophane, Heat-sealable Polyester.

Bubble Pack

• Product sandwiched between thermoformable film and rigid backing (e.g., heat-seal-
coated paperboard).

• May involve heat-shrink process → film shrinks tightly over product.

Shrink Banding

• Heat-shrinkable PVC tube shrunk over cap & neck → prevents cap removal without
destroying band.

• Tear perforations possible for ease of opening.

Foil, Paper, Plastic Pouches

• Formed by vertical or horizontal form/fill/seal (f/f/s) machines.

• Vertical f/f/s → liquid, powder, granular products.

• Horizontal f/f/s → smaller volume products → 3-sided perimeter seal.

• High-barrier materials: Paper/PE/foil/PE, Metallized polyester.

Bottle Seals

• Inner seals: Glassine, Foil laminations.

• Types of application:
1. Friction fit.
2. Wax application.
3. Pressure-sensitive adhesives.
4. Heat-seal via induction (requires aluminum foil).

• Printed designs required for tamper-resistance.

Tape Seals

• Pressure-sensitive or glue-applied labels.

• Self-destructing paper used → tears upon attempt at removal.

• Perforations added to enhance destruction during removal.

Breakable Caps

• Roll-on Aluminum caps → perforated → break on opening.

• Ratchet-style Plastic caps → tear-away strip engages ratchet → irreversible opening.

Sealed Tubes

• Metal (Aluminum), Plastic (Polypropylene, Polyethylene), or Laminated

(Foil/Paper/Plastic).

• Puncture inserts seal tube opening → pried out to access product.

• Head designs prevent reuse; crimped or induction-sealed.

 Aerosol Containers

• Made of aluminum → specially coated inside if needed.

• Propellant (hydrocarbon) + spray nozzle + dip tube for controlled metered dose.

• Inherently tamper-resistant.

Sealed Cartons

• Folding cartons as secondary packaging.

• Tuck-end closure no longer recommended alone → must include tamper-proof method

(overwrap, tape, glue).

• Seal-end cartons use glue or hot-melt sealing → better tamper-resistance.

Product-Pack Validation

1. Nonsterile Products (e.g., Tablets in Polypropylene Bottle):

- Test water vapor permeability.
- Test light transmission (daylight & artificial).
- Stability tests (taste, smell, appearance over time).

2. Sterile Products (e.g., Parenteral in Glass Vial):

- Wash & sterilize all pack components.
- Store upright & inverted → monitor glass vial–product, rubber plug–product
interactions.
- Seal integrity (Immersion Test):
• Fill vials with broth → immerse in microbial suspensi

Pharmaceutical Packaging – Regulatory Requirements (GPAT Focus)

Seal Integrity Test (Immersion Test)

• Used to verify tamper-resistant seals of sterile products.

• Process:
• Product-filled packages sterilized → immersed in microorganism suspension (e.g., P.
 aeruginosa, E. coli).
• Incubation at microorganism growth temperature.
• Microbial growth detected by visual/cloudiness or instrumentation.
• Nonsterile packages: Aseptic filtration + filter plating → Microorganism
identification.
• Confirms integrity of seals.

FDA Regulatory Requirements

• Objective: Ensure efficacy, purity, identity, strength, and quality of the drug throughout
shelf life.

• Regulation:
“No packaging component shall be reactive, additive, or absorptive in a way that
affects the drug’s identity, strength, quality, or purity.”

Key Regulatory Submissions

1. New Drug Application (NDA):

• Submitted before marketing a drug.
• Includes:
- Component formulation & drawings.
- Artwork (Labels, cartons).
- Component quality standards & test methods.
- Product-pack validation data.
- Process details of filling & packaging.
- List of primary component manufacturers.

2. Supplemental NDA Type I:

• Major process changes requiring FDA approval before implementation:
- Critical spec relaxation.
- Testing method change.
- New packaging facility (without prior cGMP inspection).

3. Supplemental NDA Type II:

• Minor changes implemented before FDA approval:
- New testing methods.
 - Artwork improvements.
- Small process changes (within cGMP).

4. Annual NDA Reports:

• Document minor, no-supplemental-needed changes in a year.

5. Drug Master File (DMF):

• Detailed info about manufacturing, packaging, storage process.
• Types:
- Type I: Manufacturing site & facility details.
- Type III: Data supporting component suitability.
• Maintained by packaging material manufacturers → FDA uses as reference for NDAs.

GPAT Key Takeaways

• Seal integrity crucial for sterility → Immersion test.

• NDA required before drug marketing → Contains component details & validation data.

• Supplemental NDAs:
• Type I → Major changes.
• Type II → Minor changes.

• DMF Type III → Most important for packaging component suitability.