CRITICAL SELECTION OF

PRIMARY PACKAGING

Shams Rustom
Labopharm
Sr. Director, Product Development & Manufacturing

Outlines
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
Packaging process validation strategy
Anti-counterfeit packaging
Global strategy & Regulatory requirements

Primary Packaging Definition

Refers to packaging that immediately
envelopes a product. It provides most of the
strength and barrier needed to safeguard a
products purity, potency and integrity from
the time it leaves the assembly line until its
used by the consumer.
Examples of primary packaging include Bottles,
blister packs, etc.

Healthcare Packaging & Products

Pharmaceutical Packaging
Bottles
Blister Films and Foils
Closure Liners
Aerosol/Pump System
Components
Pharma Rubber Components

Types of Primary Packaging

Glass Bottles (colored / transparent)
Polymer Bottles & Closures e.g. PET,
HDPE etc
Tubes & Pump System components
Blisters

PVC film with Aluminum 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)
Aluminum / Aluminum 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.

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 acrylonitrilebutadiene-styrene (ABS) do not have recycling numbers.

Identification Symbols
SYM
BOL

NAME

PROPERTIES

PET

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

HDPE

Stiffness, strength, toughness, resistance to moisture,

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

PVC

Versatility, ease of blending, strength, toughness.

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

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

e.g. widely used for blister film

caps,

PS

Versatility, clarity, easily formed

OTHER

Dependent on polymers or combination of polymers

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

e.g. Beverage bottle , baby milk bottles etc

Non packaging uses: Compact disc.

Comparison of Polymer Bottle properties

Resin

Density
(g/ml)

MVTR1

Oxygen2

Stiffness3

Impact
Resist

Hot Fill
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
polyethylene)

0.96

0.5

4,000

150

Excellent

160

g/mil/100 sq in - 24 hrs,

cc/mil/sq m - 24 hrs,

Flexural modulus (jpsi x 1000)

Source : Westbridge
3

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 Puretherm 1001 LHD

PVDC

PCTFE

Alu
oPA

Properties & Advantages of PVC

Pharmaceutical and Food grade only
Homopolymer type (more inert).
Gauge range 125 - 500 (5mil to 20mil).
Common gauges: 200 - 250 (7.5mil & 10mil).
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 200 & 250 (7.5mil & 10mil).

PVDC coatings: 40gsm, 60gsm, 90gsm &
120gsm.
Duplex or Triplex (25 PE)
Colors: Clear and White
Medium barrier for moisture and oxygen

Duplex & Triplex PVDC coatings

Triplex (example: VDC 250-25-60)
PVDC 60gsm
Adhesive

PE 25 micron
PVC 250 micron

Duplex (example: VDC 250-40)

PVDC 40gsm

PVC 250micron

Properties of PCTFE Film

PCTFE is a flexible thermoplastic film made from
(polychlorotrifluoroethylene) fluoropolymer resin
Homopolymer PCTFE film

Cl

- 100% PCTFE (additive free)

- Less shrinkage
- More cost effective

Copolymer PCTFE film

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

PCTFE Laminations
Triplex Lamination
PCTFE
Adhesive

PE
PVC or
alternative

Duplex Lamination
PCTFE
Adhesive
PVC, PETG, BAREX, PP
Or even LDPE

Advantage of PCTFE Lamination

Triplex lamination (PVC/PE/PCTFE )

More forgiving in thermoforming

Historically material of choice

Duplex lamination (PVC/PCTFE )

Higher yield (more area per unit weight)

Lower cost (source reduction)
Better clarity
Used widely outside North America
Gaining greater acceptance

PVDC or PCTFE barrier ?

40gsm and 60gsm PVDC are best in class
15 PCTFE is better than 90gsm PVDC
PCTFE: long shelf life, does not yellow
PVDC: provides Oxygen barrier
0.045

Flat Sheet
Formed Blister

0.040
0.035
0.030
0.025
0.020
0.015
0.010
0.005
0.000
PVC/PE/PVDC 90gsm

PVC/PCTFE 15

Properties & Advantages of CFF

oPA 25 micron
Adhesive

ALU 45 micron
PVC 60 micron

60 PVC / 45 Aluminum / 25 oPA.

100 PVC / 45 Aluminum / 25 oPA.
Near absolute barrier for moisture and oxygen.
Larger blisterpacks,
Not transparent,
Slower processing compared to thermoforming.

Properties of COC
COC (Cyclic Olefin Copolymer) Film

Standard range starts at 190 m COC up to 300 m COC

COC core starts at 120 m COC up to 350 m of COC

The skin layers can

be 20, 30 or 40 m
thick, depending on
the customers
requirements.

Polyolefine skin
layer: PP, PE,

COC
Polyolefine skin
layer: PP, PE,

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 Polyolefine
Excellent Thermoformability
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
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 38C/90%RH)
COC films are suitable for containing polar liquids

MVTR before & after Forming-COC

New & Improved COC Film Structures
Performance evaluation (before & after) forming.
0.045

Flat Sheet WVTR

Formed Blister WVTR

0.040
0.035
0.030
0.025
0.020
0.015
0.010
0.005

PV

C
/P
E/
P

VD
C

90
gs
m

0.000

Process Variables & Validation Strategy

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.

Packaging Process Validation Strategy:

In case of multiple packaged SKUs, take a matrix approach to select the number of
batches or run of each SKU.
Validate the range of each critical process parameter during the run

Film Vs Blistering Process

Variables

PVC

Film heating

Upper & Lower Lower than PVC

same
face

Lower than
PVC face

Cavity
Formations

At any cooling Require Teflon

temp.
coated. Cold tools
may cause PVDC
cracking

Teflon avoided.
RT & Plug
assist
recommended

Sealing
Properties

Lidstocks
seals very well

Lidstocks seals
adequately

Lidstocks seals
poorly except
Novel lidstock

Generally 1702200

Higher temp
may cause
curling

Sealing
Temperature
(C)

PVDC

PCTFE

Lamination, Winding & Product Contact

Troubleshooting of Aclar Blistering

Easily thermoformed on all conventional thermoforming lines
e.g. Uhlmann, Noack, Klockner, IMA, Romanco 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

Film Cost Vs Performance Analysis

Product

Yield (sq. in./lb.)

Avg. $/lb. at 5M lbs.

Avg. $/msi (1,000 sq

in)

1,866

$11.90

$6.38

0.31

0.020

2,028

$9.50

$4.68

0.23

0.015

1,860

$9.75

$5.24

0.15

0.010

1,730

$10.75

$6.21

0.11

0.007

1,528

$14.00

$9.16

0.07

0.005

1,355

$15.50

$11.44

0.05

0.003

PRODUCT

MVTR - g/m/24 hrs.

MVTR - g/100 in./24 hrs.

MVTR (g/100in/24 hrs)

PRICE IN US$

X: 7.5mil PVC/2.0 mil PE/ 1.5 mil PCTFE

0.020

~ $ 40 / Kg

Y: 7.5mil PVC/2.0 mil PE/ 0.9 mil PCTFE

0.015

~ $ 27 / Kg

M: 10.0 mil PVC/ 2.0 mil PE/ 1.5 mil PCTFE

0.020

~ $ 33 / Kg

N: 10.0 mil PVC/ 2.0 mil PE/ 0.9 mil PCTFE

0.015

~ $ 23 / Kg

Pharmaceutical Lidding Foils

20 hard or soft temper & 25 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.

Covert Marker Technology for Product:

Available form of Indicia containing logos or unique
mark, batch no, text etc can be embedded on the
product which are not easily visible

Anti-Counterfeit
Digital Imaging: e.g. Cryptoglyph

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
aluminium foil

Fingerprints:

on-dosage or on-product protection

Use of existing anti-counterfeit feature on
molded caps, Vial flip-off tops, bottle closures etc.

Several companies from USA & Europe have their patented technology

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

Packaging Vendor Interchangeability

For FDA approval follow the 4 steps:

Step-1: Classification of Change ( Major / Moderate or

Minor ? )
Step-2: Is the packaging Material CDER approved?
Step-3: Does the new package provide the same or
better protective properties ?
Step-4: If the answer of the step-3 yes, then make the
Change Control and include in the Annual Report

Packaging Vendor Interchangeability

Step-1: Classification of the Change in a reporting
Category: Major / Moderate / Minor
The changes of supplier/material can be classified as
Minor Change since : A change in the container
closure system of unit dose packaging (e.g., blister
packs) for non-sterile solid dosage form products, as
long as the new package provides the same or better
protective properties and any new primary packaging
component materials have been used in and been in
contact with CDER-approved products of the same type
(e.g., solid oral dosage form, rectal suppository).

Packaging Vendor Interchangeability

Step 2: Is the Packaging CDER approved ?

If Yes for relevant product, then this

certificate is to be included in the Annual
Report.

Packaging Vendor Interchangeability

Step 3: Does the new package provide the
same or better protective properties ?

Light Transmission: applicable for opaque blisters

only.
Moisture Transmission: to be documented via the
official compendial test: USP <671> Containers Permeation.
Use the test "Single Unit Containers and Unit-Dose
Containers for Capsules and Tablets".
Use Method II for blisters with multiple unit dose containers.
The new blisters should have equal or better WVTR
compared to the current blister.
A tolerance of +/-10% is industry accepted as variation on the
method. The WVTR data is to be included in the Annual
Report.

Packaging Vendor Interchangeability

Step 4: Change Control and Annual Report

If the results from step 3 show the new blister

offers equal (+/-10%) or better protection from
moisture compared to the current blister the
change can be made.
Document the changes in the next Annual
Report to the FDA for each Drug Product.

Example of Interchangeability
FDA Change Protocol

Example-1: Change from PVC/PVDC to Copolymer Aclar.

Changing between the group based on MVTR & availability
The MVTR of PVC/PVDC is 0.65 g/m/day & MVTR of PVC/PE/Aclar is
0.11 g/m/day.

Eample-2: Change from Co-polymer to Homo-polymer Aclar

Changing within the group based on MVTR & price.
The MVTR for 7.5mil PVC/2.0 mil PE/ 1.5 mil PCTFE is 0.020 and for
10.0 mil PVC/ 2.0 mil PE/ 0.9 mil PCTFE is 0.015 g/m/day

Justification for minor change:

The PVC/PE/Aclar offers 5 times more barrier protection

than that of the PVC/PVDC, classified as a minor change.
Same justification applies on other example.
Product contact (PVC) is also remain same

Regulatory Compliance Verification

Worldwide compliance For Film :
USA food contact: 21CFR
EU food contact: 2002/72/EC
Japanese Food and Sanitation Law, Ministry
of Health and Welfare Notification 20.
USP: <661>
Ph.Eur. 3.1.11 and Ph.Eur. 3.2.
max VCM levels
Heavy Metal Directives
CDER approval for oral solid dosage forms

Regulatory Guidelines
Web site of FDA guidelines for submitting
documentation for human drugs & Biologics.

http://www.fda.gov/cder/guidance/package.htm
FDA guideline Container Closure Systems for Packaging
Human Drugs and Biologics.

Child resistant packaging:

US CPSC (US Consumer Product Safety Commission)

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

Packaging Process validation strategy

Perform packaging trials & establish parameters range prior to validation
Select cost-effective validation strategy by taking matrix approach

Comments & Questions ??