How Strong is Your Cold Chain?
P. Andrew Malcolm, P.E.
P. Andrew Malcolm Consulting, Inc.
Thermal Packaging Solutions, LLC
TPS
THERMAL PACKAGING SOLUTIONS, LLC
September 15, 2009
Takeaways from Today
Today’s
s Presentation
Presentation…
• Cold Chain Issues and Environmental
Profiles
• Package Design: Materials
Materials,
Refrigerants, and Monitoring Options
• Validation,
Validation Documentation
Documentation, and
Regulatory Considerations
2
September 15, 2009
Who is Andy Malcolm and why is he
here?
• Consulting Packaging Engineer
• President of P. Andrew Malcolm Consulting, Inc.
• Packaging
g g since 1985
• Thirteen Years in Bio-Pharm
• Ten Years with Own Company
• Affiliated with Thermal Packaging Solutions
Solutions, LLC
• Cold Chain Consultants based in New Jersey
• Over 30 years of experience in environmentally
controlled packaging and logistics
• Published in Pharmaceutical Engineering and elsewhere
• Multiple
p p
patents on p
packages
g and p
packaging
g g systems
y
3
September 15, 2009
Cold
C
ld Chain
Ch i Issues
I
and
d
Environmental Profiles
4
September 15, 2009
What is the “Cold Chain”?
OVER THE ROAD
43o C
WAITING ON THE TARMAC
32o C,, 98% Humidityy
AIR CARGO
-20o C
OCEAN FREIGHT
43o C
5
September 15, 2009
Maintaining Temperature / Humidity
through Product-Specific Environmental
Conditions
6
September 15, 2009
Route-Specific
p
Temperature
p
Profile
E.g.: United States to Europe
Temperature Profile - U.S. to NL
Via AIR
WARM
TEMPERATUR
E
35
HOURS
30
20
15
10
5
HOURS
7
127
121
115
109
97
91
85
103
-5
79
73
67
61
55
49
43
37
31
25
19
7
13
0
1
Degrees C .
25
1
2
3
4
5
6
7
8
9
10
11
12
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
WARM
COLD
6:00 PM
UPS (PIT)
Trans to
JFK
12:00 AM
6
12:00 PM
6
20
20
20
20
20
20
20
20
20
20
20
20
20
20
20
22
21
20
20
21
21
22
22
23
24
24
25
26
26
27
28
28
29
28
28
27
26
26
25
24
24
HUMIDITY
DAY
NIGHT
79
79
79
79
79
79
79
79
79
79
79
69
64
59
59
59
59
59
59
59
59
59
71
72
74
75
75
75
75
75
75
75
75
75
75
70
64
59
59
59
59
COLD
TEMPERAT
URE
10
10
10
10
10
10
10
10
10
10
10
10
10
20
20
0
-1
-1
-2
-2
-3
-2
-2
-1
-1
0
0
1
2
2
3
3
4
3
3
2
2
1
1
0
-1
HUMIDITY
DAY
NIGHT
79
79
79
79
79
79
79
79
79
79
79
67
64
60
60
60
60
60
60
60
60
60
60
64
67
71
71
71
71
71
71
71
71
71
71
September 15, 2009
67
64
60
60
60
60
Ocean Freight Temperatures
ON DECK
Outer level temperatures = 140OF
Second level
= 115OF
Third thru Seventh level = 90OF (note 4)
ON DECK
Levels
1od
2 d
2od
3od
4od
5od
BELOW DECK
6od
7od
Levels
1bd
2bd
3bd
4bd
5bd
6bd
7bd
BELOW DECK
All level temperatures will
hold at their loading
temperatures.
H t loss/gain
Heat
l
/ i will
ill b
be att
equilibrium due to their
insulated positions i.e.: the
day/night temperature swings
do not have a chance to
overcome each other.
NOTES:
1 – Refrigerated containers are stored on deck
2 – Positioning of container is dependent upon content
weights,
g , and destination
3 – Max container levels, 7 above and 7 below
4 – It should be understood that containers may be exposed
to heat load / cooling (day/night) for a few days prior to
ship loading. The 90 degree internal temperature is
contingent upon container temperature at time of ship
loading.
8
September 15, 2009
Why is it so important
and why use special packaging?
Soggy Tablets
Frozen Liquids
9
September 15, 2009
Packaging
P
k i Design:
D i
Materials,, Refrigerants,
g
,
and Monitoring Options
10
September 15, 2009
First: A refresher on some Physical
F d
Fundamentals
t l
• Heat Transfer
• Phase Change
11
September 15, 2009
Heat Transfer
The science of predicting energy transfer in materials
as a result of temperature difference.
T pes of heat transfer:
Types
transfer
Conduction
Convection
Radiation
The transfer of heat from
partt off a body
b d to
t another
th
part or to another body by
short range interaction of
molecules or electrons.
The transfer of heat
b th
by
the combined
bi d
mechanisms of fluid
mixing and conduction.
The emission of energy
i th
in
the fform off
electromagnetic waves.
Examples:
• Hand on a hot plate
• Spoon in a cup of coffee
warms
• Damage to skin tissue
after contacting dry ice or
flame
Examples:
• Cooled air circulating in
a warm room
• Hot water added to a
cooling tub to increase
overall temperature
Examples:
• Sun shining through
window glass
• Interior of a black car
heating up
• Drying clothes in front of
a fireplace
12
September 15, 2009
Transmission of Heat
13
September 15, 2009
Phase Change
Example: Water
Phase Change Periods
Solid
Liquid
Vapor
(Steam)
Phasing:
Ph
i
Phasing rate affected by temperature
or energy transfer.
14
September 15, 2009
100o C
VAPOR PHASE
Phase Chart
o
30 C
SENSIBLE HEAT
LIQUID PHASE
TEM
MPERATU
URE
SOLID PHASE
0o C
o
-20
20 C
Remains at 0oC while melting
SENSIBLE HEAT
PHASE TIME α MASS / ENERGY
TIME Æ
15
September 15, 2009
Phase Change
High Temperature Phasing
Not all “frozen solid” materials are cold
16
September 15, 2009
Design
g Aid for Temperature
p
/ Humidity
y
Controlled Shipping and Packaging
General Questions
• IIn what
h t form
f
is
i the
th product
d t to
t be
b shipped?
hi
d?
Powder, liquid, solid, or some combination?
• At what temperature is the product packed?
Are packaging materials preconditioned?
• At what temperature must the product remain during
shipment?
Is there a tolerance? Ex: 2-8 degrees
g
C for 72 hours,, but may
y
be +2 or -2 degrees for up to a total of 10 hours.
• Where will the shipment originate?
Is the environment hot? Cold? Excessively humid?
• How will it be shipped?
Ex: Truck (refrigerated or not), air cargo, ocean freight?
• How long is each stage?
17
September 15, 2009
Design
What size container is required?
• Measure the product dimensions
• Add space for Refrigerants or Dry Ice
Ice.
• Refer to vendor’s list of standard box sizes or
specify a custom size.
Note: Box dimensions are for inside measurement
18
September 15, 2009
Design
Will the product be shipped Refrigerated
or Frozen?
How long is the shipping cycle?
• The answers determine the best container
specifications
f
for
f the product:
• Overnight shipments do well in boxes with a
standard wall thickness (1 ½”)
• Consider
C
id a greater
t wallll thi
thickness
k
ffor ffrozen
products and/or longer shipping cycles.
19
September 15, 2009
Design
24 HOUR SHIPPING PROFILE
50
De
egrees C
40
30
20
10
0
-10
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
Hours
-20
Summer
Winter
•NOTE: REPEAT PROFILE CYCLE AS NEEDED
20
September 15, 2009
Packaging Materials
21
September 15, 2009
M t i l
Materials
EPS
Urethane
Vacuum Panels
Air Box
22
September 15, 2009
M t i l
Materials
Vacuum Panel
V
P
l
Container Design
• High insulation values
• Package vulnerable to damage
Vacuum Panel System Design
23
September 15, 2009
Pack-Out Example
LID
PCM 18 OZ.
FROZEN
(7 REQU.)
CORRUGATED
PAD
PRODUCT
INSULATED
SHIPPER
24
September 15, 2009
M t i l
Materials
Bubble Wrap
• Provide layers of protection
between refrigerants (PCM’s)
and
d product.
d t
25
Laminates
Foil - Bubble or
Foil – Bubble - Foil
September 15, 2009
Refrigerants
26
September 15, 2009
Design
How much Refrigerant*
Refrigerant or Dry Ice is
needed?
• Consider the following factors:
• Insulation value of the container
• Temperature differentials (∆T)
• Length
L
th off shipping
hi i cycle
l
• Perform preliminary calculations to arrive at a
reasonably close starting point.
• Perform actual package testing and validation.
* Typically Phase Change Material (PCM)
27
September 15, 2009
R fi
Refrigerants
t
Refrigerant Gels
Phase Change Materials
( PCMs )
28
September 15, 2009
Phase Chart
o
O
150 C
o
Options to 2 to 8 C PCMs
TEMP
PERATURE
Phase change
temperature ranges
available with salt
ratios above 30%
100OC
Phase change
temperature range
available through
careful compounding
of various new
chemical materials
50OC
4OC O
0 C
-25OC
Phase change
temperature ranges
available with salt
ratios
ti under
d 30%
-50OC
29
September 15, 2009
Temperature Monitoring
30
September 15, 2009
M th d off Measurement
Methods
M
t
• M
Mercury or Alcohol
Al h l
Thermometer
• Thermo
Thermo-mechanical
mechanical Device
• Resistance Temperature
Detector (RTD)
• Platinum Resistance
Temperature Detector (PRT
or PRTD)
31
•
•
•
•
•
Solid
S
lid St
State
t D
Device
i
Thermistor
Thermocouple
Chemical Device
Infrared Device
September 15, 2009
C
Current
tT
Technology
h l
– Shipping
Shi i
Ti
Time-Temperature
T
t
Integrators
I t
t
• Chemical-Physical-Based TTI
• Chemical Polymerization-Based
y
TTI
• Diffusion-Based TTI
• Enzyme
Enzyme-Based
Based TTI
32
Temperature Recorders
• Graphic (Chart) Recorders
Electronic Temperature
Monitoring Devices
• Temperature Logger
• Temperature + Humidity
Loggers
September 15, 2009
Temperature Loggers – Details
~ Interfaces ~
U
User
IInterfaces
t f
D t Transfer
Data
T
f
•
•
•
Light Emitting Diodes (LED)
Liquid Crystal Display (LCD)
•
•
•
•
Computer Interfaces
•
•
•
Serial or Parallel Ports
Infrared
f
Optical
Real Time
•
•
Hubs or ‘Gateways’
Gateways
End-of-the-Line
•
•
•
33
Satellite
C ll l
Cellular
Wi-Fi
RFID (Active and Passive)
Hardwire
Docking
g
RFID
September 15, 2009
Temperature
p
Loggers
gg
– Details ((cont.))
~ Hardware Considerations ~
Microprocessor
Internal Data Storage
•
•
•
Nonvolatile Memory (no data loss)
(potential data
Volatile Memoryy (p
loss)
Sample Rate – function of
memory
Thermistor
•
•
•
Accuracy
Drift
Temperature
p
Range
g
Alarms
•
•
Event
Cumulative
Calibration Issues
• Resistance
• Single Point
• Certificates
Single Use / Multiple Use
Temperature + Humidity
• Need Reference = Both
• Problem Areas
•
•
Battery Characteristics
34
High Humidity + Low Temperature
High Temperature + Low Humidity
September 15, 2009
Temperature
p
Loggers
gg
– Details ((cont.))
~ Software Considerations ~
O
Operating
ti System
S t
R
Record
dK
Keeping
i
•
•
•
•
•
Microsoft
Palm
Windows CE
Export Capabilities
DB Maintenance and Back-Up
Validation
21 CFR Part 11
Software Verification of
Calibration
Resolution
History Analysis
35
September 15, 2009
Validation, Documentation,
and Regulatory Considerations
36
September 15, 2009
Objective:
483
… or Worse
37
September 15, 2009
Validation Considerations
38
September 15, 2009
Strategies for Validation
Establish Current State of Shipping Validation
•
•
•
Define current shipping methods across product lines
Evaluate effectiveness of current shipping performance
Gather available product stability data to support current shipping
methods
Risk Assessment
•
•
Identify vulnerabilities in validation
Prioritize products requiring shipping validation
Develop Program Plan
•
•
•
•
Define Distribution Environment
Gather Product Stability Data
Define Shipping Qualification Requirements
Document Program Plan
39
September 15, 2009
Strategies for Validation (cont.)
Define Distribution Environment
•
Map Current Distribution Environment
•
•
•
•
Establish Time / Temperature
p
External Data Collection Plan
•
•
Shipping Methods
Warehouse Procedures
Seasonal Variation
Geographic Destinations
Understand capabilities of current shipping containers/methods, if
applicable
Gather Product Stability Data
•
Gather existing product stability data
•
•
•
Ensure documentation exists
Ensure documentation is defendable
Implement Product Stability Program
•
•
Supply input and guidance to R&D/Product Support Department
Ensure product stability data was taken out to expiration
40
September 15, 2009
Strategies for Validation (cont.)
Define Shipping Qualification Requirements (test profiles)
•
Field Data
•
Profiles may be based on extreme temperatures seen during external data collection
Document Program Plan
•
•
•
•
Develop Guideline for Program
Establish SOP for field data collection
Establish SOP for shipping qualifications
Set project plan to accomplish shipping qualifications for all products
41
September 15, 2009
Documentation
Considerations
42
September 15, 2009
D
Documentation
t ti
• Protocols
• S.O.P.s
• Signed Reports
• Data on Signed, Tamperproof Data CDs
• Independent Laboratory Testing Results
• Packaging & Distribution System
Qualifications
43
September 15, 2009
44
September 15, 2009
45
September 15, 2009
Regulatory Considerations
46
September 15, 2009
R
Regulatory
l t
Considerations
C
id ti
A
According
di tto FDA
FDA:
•
A drug is adulterated if the facilities or controls used for its
manufacture, processing, packaging or holding do not conform
t /
to/are
nott operated
t d or administered
d i i t d in
i conformity
f
it with
ith currentt good
d
manufacturing practice (cGMP).
FD&C Act [501 (a)(2)(B)]
What it means to manufacturers:
•
•
FDA demands appropriate conditions.
The manufacturer must define and defend its methods of
handling the product to ensure it is not adulterated.
47
September 15, 2009
R
Regulatory
l t
C
Considerations
id ti
((cont.)
t)
G
Governing
i R
Regulations:
l ti
•
21CFR211.142 and 211.150 (Storage and Distribution)
•
•
USP Chapter 1079: Good Storage and Shipping Practices
21 CFR Part 210 – cGMP in Manufacturing, Processing, Packing, or
Holding of Drugs
21 CFR Part 211 – cGMP for Finished Pharmaceuticals
• 211.142 – Warehousing procedures
• 211.150 – Distribution procedures
• 211.196
211 196 – Distribution records
USP General Guidance Chapter <1079>
Individual countries have their own shipping guidelines.
•
•
•
48
September 15, 2009
R
Regulatory
l t
C
Considerations
id ti
((cont.)
t)
What happens:
•
•
•
•
If the Pharmaceutical Manufacturer is out of compliance and does
not maintain the required temperature, FDA issues:
• 483
• Warning Letter
• Consent Decree
FDA demands a detailed corrective action plan with timing
timing.
FDA maintains the right to accept or reject the proposed corrective
action plan.
FDA maintains
i t i the
th right
i ht tto STOP product
d t shipments
hi
t
until the quality is restored and can demand a recall of shipped
product .
49
September 15, 2009
Example:
FDA Inspection – Warning Letter
Rockville, MD (Apr
Rockville
(Apr. 5
5, 2007)—The US Food and Drug
Administration (FDA, www.fda.gov) concluded its reinspection of
Wyeth’s manufacturing facility... Conditions at the Guayama
facility prompted a Warning Letter in May 2006.
The 2006 Warning Letter cited several violations of current good
manufacturing practice (CGMP) regulations stated in 21 CFR
Parts 210 and 211.
Ref: http://www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=418827
http://www pharmtech com/pharmtech/article/articleDetail jsp?id=418827
50
September 15, 2009
Example:
FDA Inspection – Warning Letter
Irvine,, CA (Mar.
(
11,, 2005)) (American
(
Red Cross Transplant
p
Services) - The US Food and Drug Administration …during an
inspection… determined that your firm manufactures and
distributes cryopreserved heart valves…deviations cause your
device to be adulterated
adulterated…You
You failed to ensure that the device
packaging and shipping containers are designed and
constructed to protect the device from alteration or damage
g the customary
y conditions of p
processing,
g storage,
g
during
handling and distribution….[21 CFR…
Source: http://www.fda.gov/foi/warning_letters/g4586d.htm
51
September 15, 2009
Example:
FDA Inspection – 483
Atlanta,, GA,, Mar. 22 to Mayy 15,, 2006 (Bausch
(
& Lomb Inc.)) Observations made by FDA during facility inspection.
“Temperature conditions within the aseptic processing area are
not being documented…
…trucking company does not have a climate control system in
the trailer to monitor temperature conditions.
…no procedures indicating the amount of time finished products
are allo
allowed
ed to remain stored in trailers before finding a location
in the warehouse for storage.”
Source: http://www.fda.gov/ora/frequent/483s/1032500_baushlomb/greenville_sc.html
52
September 15, 2009
C
Conclusions
l i
•
•
•
•
FDA is
i increasing
i
i its
it scrutiny
ti off the
th processes and
d
procedures used for thermally controlled shipping, storing,
and distributing of pharmaceutical products.
M
Manufacturers
f t
are being
b i required
i d tto supportt th
their
i shipping
hi i
methods ‘from dock to doc’.
Designers must consider all external conditions when
d i i th
designing
the package
k
and
d material
t i lh
handling
dli methods.
th d
In order to avoid 483s, Warning Letters, and / or Consent
Decrees, manufacturers must be able to demonstrate that a
robust,
b t validated
lid t d Cold
C ld Chain
Ch i M
Managementt S
System
t
iis iin
place.
53
September 15, 2009
Q
Questions…?
ti
?
Thank You for your time and attention.
P Andrew Malcolm,
P.
Malcolm P.E.
PE
54
September 15, 2009
Q
Questions…?
ti
?
Additional questions may be e-mailed to
andy@malcolmconsulting.com.
Or visit…
www.malcolmconsulting.com
www.thermalpackagingsolutions.com
TPS
THERMAL PACKAGING SOLUTIONS, LLC
Note: The copyright to this presentation and written materials are the property of P. Andrew Malcolm
Consulting, Inc. and Thermal Packaging Solutions, LLC. This presentation and associated written
materials may be reproduced only in their entirety
entirety.
55
September 15, 2009