PRIMARY PACKAGING SELECTION IN

PHARMACEUTICAL INDUSTRY

DEVESH KUMAR
GM-MANUFACTURING
INTAS PHARMACEUTICALS LTD. SIKKIM
 TOPICS TO BE DISCUSSED
• What is primary packaging?
• Types of Primary Packaging.
• Selection criteria of primary pack mat for oral solid dosage
form.
• Packaging materials variables.
• Packaging process variables & troubleshooting.
• Anti-counterfeit packaging.
• Global strategy & Regulatory requirements.
 DEFINITION OF PRIMARY PACKAGING

Refers to packaging that immediately envelopes a product. It

provides most of the strength and barrier needed to safeguard a
product’s purity, potency and integrity from the time it leaves the
assembly line until it’s used by the consumer.

Examples of primary packaging include Bottles, blister packs, etc.

 HEALTHCARE PACKAGING & PRODUCTS

✔ Bottles
✔ Blister Films and Foils Closure Liners
✔ Aerosol/Pump System Components
✔ Pharma Rubber Components
TYPES OF PRIMARY PACKAGING

GLASS BOTTLES (COLOURED /

TRANSPARENT)
POLYMER BOTTLES &
CLOSURES E.G. PET, HDPE ETC.

TUBES & PUMP SYSTEM

COMPONENTS.
TYPES OF PRIMARY PACKAGING

Blisters
• PVC film with Aluminium foil
• PVC/PVDC film with Aluminum foil
• Aclar/ PVC or Aclar/PVC/PE with
Al. Foil
• Cold Form Foil (CFF)
• COC (PVC free barrier film)
• Aluminium / Aluminium blisters
 SELECTION CRITERIA
Company Strategy & Goal (global or National?)
• Trouble free global submissions (USA, EU, Japan)
• Global acceptance of supplier (DMF) & materials

Product stability & Required Barrier

• ICH conditions for zone-I to II or Zone I-IV

Regulatory & Patient Compliance

• Child resistant, Senior friendly etc.

Cost & Benefit

• Price, Advantages & Compliances of the specific packaging system.
BOTTLES &
CONTAINER
 PROPERTIES & ADVANTAGES OF BOTTLES

Glass Bottles
• Convenience:
• Glass is a perfect barrier to atmospheric oxygen, avoiding rancidness, changes of colour & taste.
• Glass is inert. No migration of components
• Inconvenience: Fragile & heavy weight

PET bottles
• Convenience: Light weight & not fragile
• Inconvenience: Not a good barrier & migration of components may happen.

HDPE Bottles
• Convenience:
• Light weight & Unbreakable Comparatively better barrier
• Inconvenience:
• Migration of components may happen & may affect on product stability,
 TYPES OF POLYMER BOTTLES
*Type 1 - PETE Polyethylene Terephthalate (PET)

*Type 2 - HDPE High-Density Polyethylene

*Type 3 - Polyvinyl Chloride (PVC) e.g. blisters

*Type 4 - LDPE Low-Density Polyethylene,

*Type 5 - PP Polypropylene e.g. Most bottles caps.

*Type 6 - PS Polystyrene e.g. Throwaway utensils,.

*Type 7 - OTHER Usually layered or mixed plastic.

• The number indicates the class of resin. Types 1 and 2 are commonly recycled. Type 4 is less commonly recycled.
• The ``Other`` types are generally not recycled because of harmful chemicals, except perhaps in small test programs.
• Common plastics polycarbonate (PC) and acrylonitrile- butadiene-styrene (ABS) do not have recycling numbers.
 IDENTIFICATION SYMBOLS
SYM NAME PROPERTIES
BOL

PET Clarity, strength, toughness, barrier to gas and moisture.

e.g. Soft drink, water, peanut butter etc.

HDPE Stiffness, strength, toughness, resistance to moisture,

permeability to gas. e.g. widely used for pharmaceuticals

PVC Versatility, ease of blending, strength, toughness.

e.g. widely used for blister film

LDPE Ease of processing, strength, toughness, flexibility, ease

of sealing, barrier to moisture. e.g. squeezable bottles & etc.

PP Strength, toughness, resistance to heat, chemicals,

grease and oil, versatile, barrier to moisture e.g. bottle
caps,

PS Versatility, clarity, easily formed

e.g. Egg cartons, disposable cup & plates etc.

OTHER Dependent on polymers or combination of polymers

e.g. Beverage bottle , baby milk bottles etc
Non packaging uses: Compact disc.
 COMPARISON OF POLYMER BOTTLE PROPERTIES
Density Impact Hot Fill
Resin MVTR1 Oxygen2 Stiffness3
(g/ml) Resist Max (F)
PET-G 1.33 4.0 100 300 Fair 160
O-PET 1.36 2.0 75 450 Excellent 160
PET
(hot fill)
1.37 1.8 55 550 Excellent 188
PP
(polypropylene)
0.91 0.5 3,500 200 Fair 200
O-PP
(oriented)
0.91 0.3 2,500 250 Good 220
PVC
polyvinylchloride
1.35 3.0 150 300 Fair 160
HDPE
(high density 0.96 0.5 4,000 150 Excellent 160
polyethylene)

1
g/mil/100 sq in - 24 hrs, 2
cc/mil/sq m - 24 hrs, 3
Flexural modulus (jpsi x
BLISTER FILMS
 BLISTER FILMS AND FOILS

Mono PP , Mono PVC

PVDC-coated PVC PCTFE Lamination , COC co-extrusions

PETG/PCTFE Lamination

CFF Cold Form Foil (Alu / Alu)

PTA film for aggressive liquids (Tekniflex) Lidding foil

 FILM LAYERS VS PRODUCT CONTACT
• Same product contact layer:
• Mono PVC
• PVdC-coated PVC
• PCTFE laminations (Aclar or Vaposhield) Cold-Form Foil
PVC

PVDC PCTFE OPA ALU

 PROPERTIES & ADVANTAGES OF PVC
Pharmaceutical and Food grade only

Homopolymer type (more inert).

Gauge range 125µ - 500µ

Common gauges: 200µ - 250µ

Colors: Clear, UV-blocker, White, Amber

Better adhesion with lidding foil

Cheapest packaging option

Limited barrier
 PROPERTIES & ADVANTAGE OF PVDC

PVDC Coated Film:

• PVC Gauges 200µ & 250µ
• PVDC coatings: 40gsm, 60gsm, 90gsm & 120gsm.
• Duplex or Triplex (25µ PE)
• Colours: Clear and White
• Medium barrier for moisture and oxygen
 DUPLEX & TRIPLEX PVDC COATINGS

• Triplex (example: PVDC 250-25-60)

PVDC 60gsm
PE 25 micron

PVC 250 micron

• Duplex (example: PVDC 250-40

PVDC 40gsm

PVC 250micron
 PROPERTIES OF PCTFE FILM
Homopolymer PCTFE film
- 100% PCTFE (additive free)
- Less shrinkage
- More cost effective

“Copolymer” PCTFE film

- Historically first
- ~ 40 - 50 % less barrier (vs.
Homopolymer)
- ~95% PCTFE content
 ADVANTAGE OF PCTFE LAMINATION

Triplex lamination • More forgiving in thermoforming

• Historically material of choice
(PVC/PE/PCTFE )
• Higher yield (more area per unit
weight)
Duplex lamination • Lower cost (source reduction)
• Better clarity
(PVC/PCTFE ) • Used widely outside North America
• Gaining greater acceptance
 PVDC OR PCTFE BARRIER ?
40gsm and 60gsm
PVDC are best in class
15µ PCTFE is better
than 90gsm PVDC
PCTFE: long shelf life,
does not yellow
PVDC: provides
Oxygen barrier
 PROPERTIES & ADVANTAGES OF CFF
60µ PVC / 45µ Aluminum / 25µ oPA.
100µ PVC / 45µ Aluminium / 25µ oPA.
Near absolute barrier for moisture and oxygen.
Larger blister packs,
Not transparent,
Slower processing compared to thermoforming.
Adhesive

PVC 60 micron
 PROPERTIES OF COC

•COC (Cyclic Olefin Copolymer) Film

Standard range starts at 190 µm COC up to 300 µm COC
COC core starts at 120 µm COC up to 350 µm of COC
The skin layers can
be 20, 30 or 40 µm
thick, depending on
the customers’
requirements.

❑ MVTR barrier: depends on the thickness of the COC

core
❑ Production Process: Coextrusion (most cost effective)
 ADVANTAGES OF COC FILMS
• Properties & Advantages
• COC: Cyclic Olefin Copolymer
• A halogen free & PVC free copolymer
• Totally amorphous offering excellent clarity
• Highest Moisture Barrier Polyolefin
• Excellent Thermoform ability
• Compatible with standard olefin lidding foil

• Remarks:
• Not the best oxygen barrier
• Sensitive to non polar solvents (haze) Need a skin of a PP
or PE Need a skin of a PP or PE…
•Conclusions:
• COC films are a viable alternative to PVdC (90 g up) or PCTFE high moisture
barrier films (0.35 to 0.23 g/m2/day at 38ºC/90%RH)
• COC films are suitable for containing polar liquids
. MVTR BEFORE & AFTER FORMING-COC

0.045 Flat Sheet WVTR

0.040 Formed Blister WVTR
0.035
0.030
0.025
0.020
0.015
0.010
0.005
0.000
m
gs
90
C
D
PV
E/
/P
C
PV
BLISTERING PROCESS
 PROCESS VARIABLES
♦ Bottling Critical Process Variables
￭ Torque Pressure / Induction seal
￭ Tablet counter & Line speed

• Blistering Critical Process Variables

Machine Speed (Dwell time)
Forming Temperature
Sealing Temperature
• Blistering Minor Process Variables:
Cooling Temperature
Perforation Temperature

♠ Packaging Trial Strategy:

Identify critical SKUs: based on unique size, shape & impact by the critical parameters
Establish critical parameters range: Low speed Vs High temperatures and Vice versa.
 PROCESS VARIABLE

☺ • In case of multiple packaged

Packaging SKUs, take a matrix approach to
select the number of batches or
Process run of each SKU.
Validation • Validate the range of each critical process
parameter during the run
Strategy:
 FILM VS BLISTERING PROCESS

Variables PVC PVDC PCTFE

Film heating Upper & Lower Lower than PVC Lower than
same face PVC face

Cavity At any cooling Require Teflon Teflon avoided. RT

Formations temp. coated. Cold tools & Plug assist
may cause PVDC recommended
cracking
Sealing Lidstocks seals Lidstocks seals Lidstocks seals
Properties very well adequately poorly except
Novel lidstock
Sealing Generally 100- Generally 150- Higher temp
Temperature (°C) 150 200 may cause
curling
LAMINATION, WINDING & PRODUCT CONTACT
 TROUBLESHOOTING OF ACLAR BLISTERING
Easily thermoformed on all conventional thermoforming lines
e.g. Uhlmann, IMA, Romaco etc.
Slightly more heat required to form cavities than with mono PVC film
Machine speed comparable with mono PVC film
Appropriate gap between cavity & edge to avoid any partial leakage
Appropriate blister sealing by maintaining uniform sealing & cooling temp
Use plug assist for deep draw ratio if depth >6 mm to avoid malformation.
Proper mold design- draft angle of 5° to avoid non-uniform forming
Shrinkage
3-5% TD shrinkage for copolymer PCTFE
1-3% TD shrinkage for homopolymer PCTFE
Curl
Towards PCTFE side of blister
Causes
Higher TD shrinkage of raw PCTFE compared to PVC film (Up to 15% Vs~0)
Recommendations
Decrease heat applied to PCTFE side of lamination
KEY FACTOR
LIDDING FOIL
 PHARMACEUTICAL LIDDING FOILS

20µ hard or soft temper & 25µ hard or soft temper

“push-through” foils
• Paper/Foil – “push-through” structure.
• Paper/PET/Foil – CR “peel-push” structure.
• Paper/PET/Foil – CR “peelable” structure.

Other lidding foils available with a variety of heat sealable layers & CR
technology.
 ANTI-COUNTERFEIT
• Anti-Counterfeiting Technology in Blister Films:

• ACF films and foils incorporate “UV Markers” to protect

against counterfeiting.

• Company logo or product brand logo can be combined in the

film and foil such that when exposed under a standard UV
light, the logo and blister film illuminate to verify authenticity.

• Variable QR codes are also helpful for Anti counterfeiting

technology
• Child Parent relationship technology

• Authentication technology concept is also helpful for Anti

counterfeiting
 ANTI-COUNTERFEIT
• Digital Imaging:
‘on-packaging’ protection on folding cartons, blisters, labels
and leaflets
A unique pattern made by printed dots, invisible to naked
eye
Using existing holes on the varnish layer and Camouflaged
within the natural imperfections of the varnish layer
Unique characters camouflaged within the structures of
the aluminum foil

• Fingerprints:
‘on-dosage’ or ‘on-product’ protection
Use of existing anti-counterfeit feature on
• molded caps, Vial flip-off tops, bottle closures etc.
 PACKAGING VENDOR INTERCHANGEABILITY

Strategy • Compliance to different parts of the world

Stability study at the early development stage
for • Assurance of protection against different
climatic zones
packaging • Target markets requirement & their most
popular SKU
materials • Cost-effectiveness: Barrier (MVTR), Availability,
Price, Yield and Ease of thermoforming.
based on
 REGULATORY COMPLIANCE VERIFICATION

• USA food contact: 21CFR EU

food contact: 2020/72/EC
• Japanese Food and Sanitation
Worldwide Law, Ministry of Health and
Welfare Notification 20.
compliance • USP: <661>
• Ph.Eur. 3.1.11 and Ph.Eur. 3.2.
For Film : max VCM levels
• Heavy Metal Directives
• CDER approval for oral solid
dosage forms
 REGULATORY GUIDELINES
Web site of FDA guidelines for • http://www.fda.gov/cder/guidance/package.htm
submitting documentation for • FDA guideline “Container Closure Systems for Packaging
human drugs & Biologics. Human Drugs and Biologics”.

• US CPSC (UEU guideline 3AQ10A “Plastic Primary

Child resistant packaging:
Packaging Materials”.

EU guideline 3AQ10A “Plastic

Primary Packaging Materials”.
 RECAPPING
Select cost-effective pack mat at early stage of development
• Appropriate barrier (MVTR) required for product in target market
• HDPE bottle can be the best & cheapest choice if target market allows Appropriate thickness &
thermoforming yield for blister
• PVC/PCTFE blister can be cost effective than PVC/PVDC & CFF Availability from multiple vendors to keep
purchasing flexibility & control Compliance to global regulatory requirements & interchange ability

Critical issues to consider for blister packaging development

• Designing the blister card, Forming mold design, Blister machine operation, Sealing, Die cutting, Lid stock,
• Seal failure may not be seen in leak test but through ICH accelerated condition.

Anti-counterfeit Packaging
• Select cost-effective anti-counterfeit packaging based on the need