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
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
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 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, 3Flexural modulus (jpsi x 1000)

Source : Westbridge
 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

PCTFE Alu
PVDC oPA
Properties & Advantages of PVC
Pharmaceutical and Food grade only
Homopolymer type (more inert).
Gauge range 125µ - 500µ (5mil to 20mil).
Common gauges: 200µ - 250µ (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 200µ & 250µ (7.5mil & 10mil).
„ PVDC coatings: 40gsm, 60gsm, 90gsm &
120gsm.
„ Duplex or Triplex (25µ 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

F F - 100% PCTFE (additive free)
- Less shrinkage
C C - More cost effective

F Cl “Copolymer” PCTFE film

n - 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
15µ PCTFE is better than 90gsm PVDC
PCTFE: long shelf life, does not yellow
PVDC: provides Oxygen barrier
0.045 Flat Sheet
0.040 Formed Blister

0.035

0.030

0.025

0.020

0.015

0.010

0.005

0.000
PVC/PE/PVDC 90gsm PVC/PCTFE 15µ
 Properties & Advantages of CFF
oPA 25 micron
Adhesive ALU 45 micron

PVC 60 micron

– 60µ PVC / 45µ Aluminum / 25µ oPA.

– 100µ PVC / 45µ Aluminum / 25µ 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 µm COC up to 300 µm COC
„ COC core starts at 120 µm COC up to 350 µm of COC

Polyolefine skin
The skin layers can layer: PP, PE, …
be 20, 30 or 40 µm
thick, depending on COC
the customers’
requirements. 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 38ºC/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
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
VD
P
E/
/P
C
PV
 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 PVDC PCTFE

Film heating Upper & Lower Lower than PVC Lower than
same face PVC face
Cavity At any cooling Require Teflon Teflon avoided.
Formations temp. coated. Cold tools RT & Plug
may cause PVDC assist
cracking recommended
Sealing Lidstocks Lidstocks seals Lidstocks seals
Properties seals very well adequately poorly except
Novel lidstock
Sealing Generally 170- Higher temp
Temperature 2200 may cause
(°C) curling
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
Avg. $/msi (1,000 sq
Product Yield (sq. in./lb.) Avg. $/lb. at 5M lbs. in) MVTR - g/m²/24 hrs. MVTR - g/100 in.²/24 hrs.

A 1,866 $11.90 $6.38 0.31 0.020

B 2,028 $9.50 $4.68 0.23 0.015

C 1,860 $9.75 $5.24 0.15 0.010

D 1,730 $10.75 $6.21 0.11 0.007

E 1,528 $14.00 $9.16 0.07 0.005

F 1,355 $15.50 $11.44 0.05 0.003

PRODUCT MVTR (g/100in²/24 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

• 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.

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/m²/day & MVTR of PVC/PE/Aclar is
0.11 g/m²/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/m²/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 ??