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Approach for Performance

Qualification of Cold Rooms
and Chambers
B Y F R A N C I S F E R N A N D E S A N D D R . S U B H A S H PA N D E

Cold storage is a relatively simple cold room that is

commonly used to store material between 2 to 8C.
Such cold rooms are now available commercially as
walk-in chambers and are used for the storage of critical
pharmaceutical products, samples, and raw materials
where excursions in temperature conditions may affect
the quality of stored material(s) in terms of their appearance (color), consistency, potency, and impurity levels.
Hence it is essential to qualify cold storage chambers
under the worst-case scenarios.
Some pharmaceutical manufacturers perform only Installation Qualification (IQ) and Operational Qualification
(OQ) of cold rooms, but the Performance Qualification (PQ)
is also essential because data-based conclusions should be
arrived at by challenging the system for all the attributes that
may have bearing on the performance of the chamber for
maintaining the desired temperature conditions.

OFFICIAL AND STANDARD

REFERENCES
USA
21CFR 211.142 and 211.150: Storage and
Distribution
USP Chapter 1079: Good Storage and Shipping
Practices
Qualification of cold equipment or stores - On a
regular basis, qualification procedures should be independently conducted on equipment in cold stores to guarantee their suitability and proper functioning. The
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procedure should demonstrate the temperature profile for

both air and product temperatures when chambers are
empty as well as when loaded. The procedure should also
demonstrate the time taken for temperatures to exceed
the maximum temperature in the event of a power failure.
Qualification should consider thermal fluctuations that
occur during stock replenishment and order removal. The
results of the qualification should demonstrate the ability
of the equipment to maintain the required temperature
range in all areas, defining any zones which should not be
used for storage such as those areas in close proximity to
cooling coils, doors, or cold air streams from equipment
ventilation. The variability of the system can be characterized by using the relative standard deviation. Thermal
monitoring should establish that the system is rugged in
that its temperature profile is consistent and reliable.
Medicines and Healthcare Products Regulatory
Agency (MHRA)
Rules and Guidance for Pharmaceutical Manufacturers
and Distributors 2007, Section IV Guidance on Wholesale Distribution Practice pg 358:
Large commercial refrigerators and walk-in cold
rooms should be monitored with an electronic temperature - recording device that measures load temperature in
one or more locations, depending on the size of the
unit. Internal air temperature distribution should be
mapped on installation in the empty and full state, and
annually thereafter, under conditions of normal use.

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Francis Fernandes and Dr. Subhash Pande

Irish Republic
Irish Medicines Board: Guide to Control and Monitoring
of Storage and Transportation Temperature Conditions for
Medicinal Products and Active Substances
PDA Technical Report No. 39
Cold chain guidance for medicinal products: maintaining the quality of temperature-sensitive products
through the transportation environment.
World Health Organization
Guidelines on Good Distribution Practices (GDPs)
are incorporated into volume 2, good manufacturing
practices and inspections, in Quality Assurance of Pharmaceuticals.
Canada
Food and Drug Regulations, Section C.02.015
Guidelines for Temperature Control of Drug Products
during Storage and Transportation (Guide - 0069)
Storage is a critical parameter in maintaining the
quality, safety, and efficacy of a medical product.
Storage condition is an important parameter to
maintaining the stability of the product.
Product must be stored in accordance with the requirements of its marketing authorization.

QUALIFICATION PARAMETERS
Normally, the Design Qualification (DQ), Installation
Qualification (IQ), and Operational Qualifications (OQ)
of the cold room are performed prior to the Performance
Qualification (PQ). The IQ/OQ of the chamber are easy
to perform and document, and a majority of pharmaceutical manufacturers comply with this requirement. The
supplier of the equipment also helps in performing these
qualification tests for IQ and OQ.
Now the question arises as to why and how the performance of the cold storerooms or chambers should be
qualified.
The purpose of the PQ of the cold room is to establish

sufficient data to ensure that the cold room is capable of:

Maintaining the desired temperature range throughout
the cold room under extremes of external temperature.
Identifying potential hot spot(s) or cold spot(s) in
the chamber.
Determining the time required for conditions to return to specified parameters (as desired) in case of
excursions.
Determining the effects of electrical or refrigeration
source fluctuations or power failure - especially
where back-up units are employed.
While designing the validation study (protocol), understanding the design of the cold room is helpful. A cold
room or chamber is a room in the shape of a cubical,
made with prefabricated Polyurethane Foam (PUF) insulated panels or of brick and mortar with insulation to
maintain the desired conditions of temperature and humidity within. Knowing that the seal between any two
panels is integral, and that there are no openings, other
than the door, which may disturb the conditions of the
chamber. Understanding of the design of the chamber is
needed to decide on the number of probes and their locations for temperature monitoring.
Parameters that may affect the Condition
of the Cold Room
It is desired that the cold room chamber provide controlled temperature conditions. There are several parameters that may have an impact on the condition of the cold
room. These include:
External temperature conditions
Door opening time during handling of material in
and /or out of the Cold Room
Power breakdown
Air flow velocity through fans (not less than 2400
CFM (cubic feet per minute))

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Too much material stored in the room (thermal load)

Therefore, during the PQ study the above listed parameters should be subjected as simulated worst-case conditions because these parameters may have an impact on
the performance of the cold room.

TEMPERATURE MAPPING
The temperature mapping is accomplished by using
temperature indicating probes coupled with a data logger
for data accusation. Questions may be asked regarding
the number of probes to be utilized and their placement
in the cold room for temperature mapping in the empty
room and the loaded room. The basic consideration
should be that the probes are distributed uniformly in the
room and should cover all the vertical planes. A minimum of fifteen (15) probes were considered adequate for
mapping of the temperature of the cold room to verify its
performance1.
Justification for Probe Locations
Probe location should be decided logically, strategically, and scientifically. The following locations cover
the entire room:

but not at the extreme corners

Probe No 13:
In mid-region between the door and Probe No 4
Probe No 14:
In mid-region between back of wall and Probe No 4
Probe No 15:
In mid-region between floor and Probe No 4
By placing the probes in these positions, you will
completely cover the room and all the planes of the
cuboid (chamber). Such mapping is also conducted as an
operational qualification to check whether the components or utilities are capable of providing the desired conditions.

PERFORMANCE QUALIFICATION
STUDIES

Probe No 3:
Near to the door opening

For performance qualification, two separate studies

are required to be performed. One study should be completed for the temperature distribution in an empty room
or chamber running continually for 24 hours. The second
would be a temperature distribution study in a loaded
room or chamber. Load the boxes with material that simulates a thermal load, such as starch, lactose, or water in
bottles (in case liquid is to be stored in the chamber)
record the temperature intermittently for 75 hours each,
for three seasons (i.e., peak Summer, Monsoon (as applicable), and Winter) to demonstrate that there is no effect of seasonal variations on the temperature controls in
the cold room.

Probe No 4:
At the centre of the room

STUDY METHODOLOGY

Probe No 1:
External environment outside the cold room
Probe No 2:
To calibrate along with the in-built temperature
and humidity probe of the room

Probes No 5, 6, 7, 8:
Top layer four corners of the room, but not at
the extreme corners
Probes No 9, 10, 11, 12:
Bottom layer four corners of the room,
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For Blower Performance

The CFM of the blower should be checked and
recorded at each prequalification (PQ) test point. This information shall help to decide whether the air circulation
from the blower is the cause, if the condition is not
achieved at one or more locations, or it is the cause of the

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Figure 1
Optimum Probe Placement in a Cold Room

Blower

2
6

14

Inbuild Probe

4
10

7
12

15

13
3
11

loading pattern of the materials in the chamber, where the

temperature is being monitored.
For Empty Room or Chamber
Set the temperature of the cold room at the desired
temperature and operate the cold room according to Standard Operating Procedure (SOP). Perform temperature
mapping for 24 hours with five minute sampling intervals. After completion of the study, review the data to
identify the hot spot and cold spot areas in the cold room.
For Loaded Room or Chamber
Load the entire room with dummy boxes (as described earlier under PERFORMANCE QUALIFICA-

Door

TION STUDIES) on the pallets or racks up to its 80%

capacity, maintaining gaps between boxes for uniform
circulation of air. Set the temperature of the cold room at
the desired temperature and operate the cold room according to SOP. Perform the temperature mapping for 72
hours with five minute recording intervals. After completion of the study, review the data and identify the hot
spots and cold spots in the loaded cold room.

SIMULATIONS
The following worst-case conditions should be simulated:
For Power Failure Condition
A power failure study should be conducted at a peak
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temperature hour in summer. When the cold room is in

operation and within the set temperature level, switch the
power off from the mains. Record the temperature at intervals of one minute for simulation of conditions of
power outage.
Continue recording the temperature until the temperature within the chamber falls outside the acceptance criteria. When the temperature is out of limit at the hot spot
area identified earlier in the study, switch ON the mains
and continue recording at intervals of one minute until
the desired temperature is achieved. Record the time required for conditions to go beyond the limits from normal
under the simulated situation of power failure, and again,
the time required for regaining the desired conditions
upon power resumption.
For Open Door Condition
The open door condition study should be conducted at
a peak temperature hour in summer. When the cold room
is in operating condition and the temperature is within the
set value, open the door and record the temperature at intervals of one minute. With door open, continue recording the temperature until the temperature within the cold
room is out of acceptance criteria.
When the temperature is out of limit at the hot spot
identified earlier in the study, close the door and continue
recording until the desired conditions are regained.
Record the time required for conditions to go beyond the
limits, from normal under the simulated situation of the
door being opened and the time required to regain the desired conditions upon closure of the chamber's door.

The PQ should be conducted annually under normal

usage.

CONCLUSION
The temperature for the cold room or chamber is the
critical parameter, since excursions in temperature conditions may affect the quality of stored material(s). It is essential, therefore, to qualify cold room performance
under worst-case scenarios. The approach described
above for conducting the performance qualification of
such cold rooms or chambers, with the consideration of
all possible challenges that may have a bearing on the desired acceptance criteria addresses each potential issue.
Conducting the studies following the methodology outlined, the impact of situations such as opening the door,
or power failure for a given period can be known. Further,
through these procedures, it is possible to identify the hot
spot and cold spot and the time required to regain the desired temperature conditions if disturbed because of adverse conditions.

REFERENCES
1. Michael J.A., Anderson N.R., Sterilization Validation. In
R.A.Nash, A.H.Wachter, eds., Pharmaceutical Process
Validation 3rd Ed. New York: Marcel Dekker, PP. 100(2003).
2. Food and Drug Administration, 21CFR 211.142 and
211.150 (Storage and Distribution).
3. The United States Pharmacopeia, Chapter 1079: Good
Storage and Shipping Practices.
4. Medicines and Healthcare Products Regulatory Agency,

RE-QUALIFICATION

Rules and Guidance for Pharmaceutical Manufacturers and

Distributors 2007, Section IV Guidance on Wholesale Distribution Practice pg 358.

Performance Qualification of cold room to be requalified for:

Replacement of existing room component with a
new one, which can have a direct impact on the performance of the cold room.
Any major modification in a key machine (such as
the compressor) which can affect the performance of
the cold room.

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ABOUT THE AUTHORS

Francis Fernandes is Quality Assurance Manager of
Glenmark Pharmaceuticals Ltd, Colvale, Goa, India. He
has over eight years in the pharmaceutical industry in areas
that include manufacturing, technical services, and Quality
Assurance. Mr. Francis Fernandes specializes in the validation of equipment, utilities, manufacturing, cleaning,
and product processes. He can be reached by e-mail at
fransha.ape@gmail.com, francisf@glenmarkpharma.com
Dr. Subhash Pande is Vice President Corporate Quality
Assurance, in Glenmark Pharmaceutical Limited, Mumbai.
Having over 20 years of experience in manufacturing,
Quality Assurance of APIs, Sterile, Oral, and Semi-solid
Oral dosage forms, Teaching and Research. A life member
of Indian Pharmaceutical Congress and ISPE, he has more
than twelve research papers published in National and International journals. He is also associated with IBC Asia,
for training. He also is involved in academic activities in the
capacity of Guest Lecturer and as Examiner. He can be
reached by email at subhashp@glenmarkpharma.com or
subhashp@gmail.com.

Article Acronym Listing

CFR

Code of Federal Regulations

DQ

Design Qualification

GDP

Good Distribution Practice

IQ

Installation Qualification

MHRA

Medicines and Healthcare Products

Regulatory Agency

OQ

Operational Qualification

PDA

Parenteral Drug Association

PQ

Performance Qualification

PUF

Polyurethane Foam

SOP

Standard Operating Procedure

USP

United States Pharmacopeia

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