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Hold Time Studies:
A Lost Parameter for Cleaning
Validation
B Y T R O Y F U G AT E
❖
INTRODUCTION
With all of the work and focus on cleaning validation,1-7
one facet of the process often overlooked or not understood
is the aspect of Hold Time Studies. So, what exactly are
Hold Time Studies? There are two aspects of “hold times”
generally evaluated for validated cleaning processes in
pharmaceutical manufacturing:
• Clean Hold Times:
The time elapsed from the end of the cleaning
process until the beginning of the use of the cleaned
equipment for manufacture of the next product
• Dirty Hold Times:
The time elapsed from the end of manufacturing
until the beginning of the cleaning process
Either of these two time periods can have a significant
impact upon the cleaning process. Keep in mind that a
cleaning validation study is a reflection of the process(es)
used for cleaning and maintaining items in a cleaned state.
An investigator may note two different types of situations during an audit. One is that equipment is stored with a
status of “Clean – Ready for Use” for perpetuity. That is, no
time limit has been placed on when the item is to be recleaned. Questions that are asked include:
• Is this equipment really clean now?
• Do Standard Operating Procedures (SOPs) indicate
how long the cleaned equipment can be stored prior
to re-cleaning?
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• Does adequate data exist to support the storage of
the cleaned equipment?
A second observation regards dirty equipment held over
a period of days – sometimes longer – prior to cleaning.
This can be problematic for cleaning – especially if you deal
with liquids, which dry and crystallize onto the surface, or
if you handle powder, which is hygroscopic and soon transforms into a paste. Questions for these situations include:
• What is the impact on the surface of the equipment
being held for that period of time?
• How is the dirty equipment held so as to not contaminate other items?
• Is there data to support the cleaning of the dirty
equipment after it has been held for long periods of
time? (To illustrate: cleaning off a powder or liquid
is handled much differently from cleaning off a
paste or a crystallized substance.)
This article is presented as a guide to understanding the
approach to conducting validation studies which compile
data in support of typical operational practices.
CLEANED EQUIPMENT HOLD TIME
VALIDATION
This section covers issues related to the “Cleaned Equipment Hold Time” (which will be abbreviated CEHT).
CEHT is sometimes called the expiration or expiry period
for the cleaned equipment.
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Why CEHT Is Important for the Control of a Cleaning
Process
Essentially, the best reason to conduct such a study is
that nothing stays clean forever, no matter how well protected it is in storage. Re-contamination of the equipment
may be an event-related phenomenon. Heating, Ventilation,
and Air Conditioning (HVAC), personnel, storage areas,
etc., may all have an impact upon the clean status of equipment. In dealing with possible ways the equipment could be
re-contaminated, one should consider both endogenous
sources (such as the growth of microorganisms already
within the equipment) and exogenous sources (such as the
entry of external contaminants into the equipment).
Three Important Issues for the CEHT Include:
1) The characteristics of the cleaned equipment
2) The nature of possible re-contaminants
3) The storage conditions of the equipment
NOTE: These three factors are interrelated in
terms of effects on re-contamination
of cleaned equipment.
Equipment Storage Concerns
A major issue related to the characteristics of the cleaned
equipment is whether the equipment is stored wet or in a
manner such that microbial proliferation is a possibility. This
is covered in the Food and Drug Administration's (FDA's)
Cleaning Validation Guidance1. If the equipment is stored
wet for a sufficient length of time, there is reasonable probability that microbes will grow to an unacceptable level.
Another issue related to the characteristics of the equipment involves possible routes of entry for external contaminants. For small pieces of equipment (scoops, for example),
this involves exposure of the item itself. For larger pieces of
equipment (such as tanks), this involves any opening in the
equipment.
For possible re-contamination, the two major sources are
as follows:
• Microbes that may already be in the cleaned equipment
• External “dust” which is in the storage atmosphere
Residues, such as product residue and cleaning agent
residue, which are in the equipment at trace levels, are generally not expected to change over time.
NOTE: The only exception to this may involve an
active, which is present in the cleaned
equipment at an acceptable level at the end
of the cleaning process, but which, over
time, degrades to a point that would make
the equipment unacceptable for use.
Storage conditions include any steps taken to protect the
equipment, such as: wrapping equipment in a plastic film or
covering openings in the equipment with a bonnet of plastic
film. Consideration of storage conditions includes the room
in which equipment is stored. Conditions of the room include temperature, humidity, air quality (i.e., viable and
non-viable particles), and external access.
Establish the Holding Time for Clean Equipment
Helpful Hint:
It is recommended that the Validation Group contact the Manufacturing (or Scheduling) Group to
determine, under normal conditions, the longest
holding time interval that might be used for the
equipment after cleaning.
Objective of CEHT
The purpose of the CEHT is to adequately protect the
equipment during the designated time period including a
conservative safety margin. Another purpose is to provide
ample justification that equipment remains safe to use
throughout that time period.
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Analyze the Storage Situation
Study the storage situation closely and consider factors
such as:
• Characteristics of the cleaned equipment
• The nature of possible re-contaminants
• The storage conditions
Be Proactive
While considering the situation and factors unique to
your storage circumstances, verify what can be done to adequately protect the equipment from re-contamination.
Justify the Holding Time of Cleaned Equipment
A professional judgment should be made based on an
analysis of the storage situation. If equipment is adequately cleaned and then stored dry, all external ports or
openings to the storage room environment are closed or
covered with a plastic film, and the storage room is controlled, it is feasible to justify a CEHT of several weeks or
months. It should be noted that this approach has its limits; for example, justifying a CEHT of one year by this
method would be unreasonable.
➣
Develop Data
This involves holding the cleaned equipment for
the maximum CEHT and then sampling surfaces
and analyzing those samples for possible re-contaminating residues. The possible re-contaminating
species or material must be determined. As a general rule, these are limited to bioburden and dust.
Testing procedures for bioburden are relatively
straightforward using accepted microbiological
techniques. For dust, consider either a particle
counter, Total Organic Carbon (TOC), or perhaps an
enhanced visual inspection, such as a white or black
wipe cloth.
For sampling sites, do not automatically sample the
same sites that were sampled in the cleaning validation protocol. Consider which sites are most
likely to be re-contaminated during storage. For example, for agitator blades, the bottom of the agitator blade (a worst-case cleaning location) may be
the appropriate sampling point as part of the cleaning validation protocol; however, for determination
of the CEHT, the top of the agitator blade may be
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the appropriate sampling point for dust, since dust
is more likely to settle on the top of the blades.
DIRTY EQUIPMENT HOLD TIME
VALIDATION
This section covers issues related to the “Dirty Equipment Hold Time” (which will be abbreviated DEHT).
Why DEHT Is Important for the Control of a Cleaning
Process
The nature of the “dirt” on the equipment surfaces may
change over time. This may include drying of the dirt and/or
microbial proliferation. Such changes may make the dirt
more difficult to remove by the standard cleaning process.
The cleaning process should be designed to adequately
clean the equipment under the worst cases of normal operating conditions. A demonstration of effectiveness under the
worst-case, usually the longest, DEHT should be conducted. It should be noted that there may be some cases
where the hold time will have no effect on the ease or difficulty of cleaning. In such cases, establishing a maximum
DEHT, and demonstrating effectiveness at that maximum
time is recommended.
Establish a Dirty Equipment Hold Time Limit
The most important considerations are that holding
times be achievable and practical for the manufacturing environment and its capabilities. For the maximum DEHT, ask
the operations departments about the longest time the equipment would be dirty before the cleaning process would be
started. Be conservative and add some extra time to what the
Manufacturing and Production Department specified.
For the minimum DEHT, a similar approach is used.
Operations should be asked for the shortest time practical
between the end of manufacturing and the beginning of
cleaning.
Documentation
If a DEHT is specified for a cleaning process, and that
DEHT is critical for control, then it is important to document that time. The term, documenting, means that the time
of the end of the manufacturing procedures and the time of
the beginning of the cleaning procedures are to be recorded.
The beginning of cleaning time should be defined based on
the cleaning process. It should not be based on a Quality
Control (QC) release time. The end of the manufacturing
time is defined based on the manufacturing process.
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NOTE: If it is important to control the DEHT, then
it needs to be measured in some way, and
it should be defined.
CONCLUSION
Once the data is compiled and analyzed, two new parameters will emerge with regard to cleaning:
• A time limit for holding clean equipment
• A time limit for holding dirty equipment
Procedures should be amended to reflect this new paradigm. It is highly recommended that stickers or tags used on
equipment be altered to indicate an “expiration” date that reflects these hold times. ❏
ABOUT THE AUTHOR
Troy Fugate, Vice President for Compliance Insight,
Inc, located near Cincinnati, Ohio, is a worldwide
compliance consultant in the areas of pharmaceutical quality, operations, packaging, laboratory, and
construction activities. Troy has worked around the
globe on a variety of projects and specializes in
quality systems, audits, investigations, FDA issue
resolution and training. Troy is an active, participating Member of the Editorial Advisory Board for
the Journal of GXP Compliance and can be
reached through his professional email address:
troy@compliance-insight.com.
Article Acronym Listing
REFERENCES
1. FDA, “Guide to Inspections of Validation of Cleaning
Processes, “Office of Regulatory Affairs, July 1993, July
2004.
2. Health Canada, “GMPs-Cleaning Validation Guidelines,”
Health Products and Food Branch Inspectorate, Spring
2000.
3. Gil Bismuth and Shosh Neumann, “Cleaning Validation:
A Practical Approach,” Interpharm Press, 2000.
4. Bill Hall, “The Essentials of Cleaning Validations,”
in Pharmaceutical Process Validation by Robert A. Nash
& Alfred Wachter, Marcel Dekker, Inc. New York Third
Edition 2003.
5. José A. Morales Sanchez, “Road Map for Equipment
Cleaning Validation within a Multi-Products Manufacturing
Facility,” Journal of Validation Technology, Vol.11, No.3,
May 2005.
6. Mowafak Nassani, “Cleaning Validation in the Pharmaceutical Industry,” Journal of Validation Technology, Vol.11, No.4,
August 2005.
7. Praful D. Bharadia & Jignyasha A. Bhatt, “A Review of
Current Implementation Strategies for Validation of
Cleaning Processes in the Pharmaceutical Industry,”
Journal of Validation Technology, Vol.12, No.3, May 2006.
CEHT
DEHT
FDA
GMP
HVAC
QC
SOP
TOC
Cleaned Equipment Hold Time
Dirty Equipment Hold Time
Food and Drug Administration
Good Manufacturing Practice
Heating, Ventilation, and Air
Conditioning
Quality Control
Standard Operating Procedure
Total Organic Carbon
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