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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 Does adequate data exist to support the storage of
the cleaned equipment?
With all of the work and focus on cleaning validation,1-7
one facet of the process often overlooked or not understood A second observation regards dirty equipment held over
is the aspect of Hold Time Studies. So, what exactly are a period of days sometimes longer prior to cleaning.
Hold Time Studies? There are two aspects of hold times This can be problematic for cleaning especially if you deal
generally evaluated for validated cleaning processes in with liquids, which dry and crystallize onto the surface, or
pharmaceutical manufacturing: if you handle powder, which is hygroscopic and soon trans-
forms into a paste. Questions for these situations include:
Clean Hold Times:
The time elapsed from the end of the cleaning What is the impact on the surface of the equipment
process until the beginning of the use of the cleaned being held for that period of time?
equipment for manufacture of the next product How is the dirty equipment held so as to not conta-
minate other items?
Dirty Hold Times: Is there data to support the cleaning of the dirty
The time elapsed from the end of manufacturing equipment after it has been held for long periods of
until the beginning of the cleaning process time? (To illustrate: cleaning off a powder or liquid
is handled much differently from cleaning off a
Either of these two time periods can have a significant paste or a crystallized substance.)
impact upon the cleaning process. Keep in mind that a
cleaning validation study is a reflection of the process(es) This article is presented as a guide to understanding the
used for cleaning and maintaining items in a cleaned state. approach to conducting validation studies which compile
An investigator may note two different types of situa- data in support of typical operational practices.
tions during an audit. One is that equipment is stored with a
status of Clean Ready for Use for perpetuity. That is, no CLEANED EQUIPMENT HOLD TIME
time limit has been placed on when the item is to be re- VALIDATION
cleaned. Questions that are asked include:
This section covers issues related to the Cleaned Equip-
Is this equipment really clean now? ment Hold Time (which will be abbreviated CEHT).
Do Standard Operating Procedures (SOPs) indicate CEHT is sometimes called the expiration or expiry period
how long the cleaned equipment can be stored prior for the cleaned equipment.
to re-cleaning?

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Why CEHT Is Important for the Control of a Cleaning For possible re-contamination, the two major sources are
Process as follows:
Essentially, the best reason to conduct such a study is
that nothing stays clean forever, no matter how well pro- Microbes that may already be in the cleaned equip-
tected it is in storage. Re-contamination of the equipment ment
may be an event-related phenomenon. Heating, Ventilation, External dust which is in the storage atmosphere
and Air Conditioning (HVAC), personnel, storage areas,
etc., may all have an impact upon the clean status of equip- Residues, such as product residue and cleaning agent
ment. In dealing with possible ways the equipment could be residue, which are in the equipment at trace levels, are gen-
re-contaminated, one should consider both endogenous erally not expected to change over time.
sources (such as the growth of microorganisms already
within the equipment) and exogenous sources (such as the NOTE: The only exception to this may involve an
entry of external contaminants into the equipment). 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
Three Important Issues for the CEHT Include: the equipment unacceptable for use.

1) The characteristics of the cleaned equip- Storage conditions include any steps taken to protect the
ment equipment, such as: wrapping equipment in a plastic film or
2) The nature of possible re-contaminants covering openings in the equipment with a bonnet of plastic
3) The storage conditions of the equipment film. Consideration of storage conditions includes the room
in which equipment is stored. Conditions of the room in-
NOTE: These three factors are interrelated in clude temperature, humidity, air quality (i.e., viable and
terms of effects on re-contamination non-viable particles), and external access.
of cleaned equipment.
Establish the Holding Time for Clean Equipment

Equipment Storage Concerns Helpful Hint:

A major issue related to the characteristics of the cleaned It is recommended that the Validation Group con-
equipment is whether the equipment is stored wet or in a tact the Manufacturing (or Scheduling) Group to
manner such that microbial proliferation is a possibility. This determine, under normal conditions, the longest
is covered in the Food and Drug Administration's (FDA's) holding time interval that might be used for the
Cleaning Validation Guidance1. If the equipment is stored equipment after cleaning.
wet for a sufficient length of time, there is reasonable prob-
ability that microbes will grow to an unacceptable level.
Another issue related to the characteristics of the equip-
ment involves possible routes of entry for external contami- Objective of CEHT
nants. For small pieces of equipment (scoops, for example), The purpose of the CEHT is to adequately protect the
this involves exposure of the item itself. For larger pieces of equipment during the designated time period including a
equipment (such as tanks), this involves any opening in the conservative safety margin. Another purpose is to provide
equipment. ample justification that equipment remains safe to use
throughout that time period.

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Analyze the Storage Situation the appropriate sampling point for dust, since dust
Study the storage situation closely and consider factors is more likely to settle on the top of the blades.
such as:
DIRTY EQUIPMENT HOLD TIME
Characteristics of the cleaned equipment VALIDATION
The nature of possible re-contaminants
The storage conditions This section covers issues related to the Dirty Equip-
ment Hold Time (which will be abbreviated DEHT).
Be Proactive
While considering the situation and factors unique to Why DEHT Is Important for the Control of a Cleaning
your storage circumstances, verify what can be done to ad- Process
equately protect the equipment from re-contamination. The nature of the dirt on the equipment surfaces may
change over time. This may include drying of the dirt and/or
Justify the Holding Time of Cleaned Equipment microbial proliferation. Such changes may make the dirt
A professional judgment should be made based on an more difficult to remove by the standard cleaning process.
analysis of the storage situation. If equipment is ade- The cleaning process should be designed to adequately
quately cleaned and then stored dry, all external ports or clean the equipment under the worst cases of normal oper-
openings to the storage room environment are closed or ating conditions. A demonstration of effectiveness under the
covered with a plastic film, and the storage room is con- worst-case, usually the longest, DEHT should be con-
trolled, it is feasible to justify a CEHT of several weeks or ducted. It should be noted that there may be some cases
months. It should be noted that this approach has its lim- where the hold time will have no effect on the ease or diffi-
its; for example, justifying a CEHT of one year by this culty of cleaning. In such cases, establishing a maximum
method would be unreasonable. DEHT, and demonstrating effectiveness at that maximum
time is recommended.
Develop Data
This involves holding the cleaned equipment for Establish a Dirty Equipment Hold Time Limit
the maximum CEHT and then sampling surfaces The most important considerations are that holding
and analyzing those samples for possible re-conta- times be achievable and practical for the manufacturing en-
minating residues. The possible re-contaminating vironment and its capabilities. For the maximum DEHT, ask
species or material must be determined. As a gen- the operations departments about the longest time the equip-
eral rule, these are limited to bioburden and dust. ment would be dirty before the cleaning process would be
started. Be conservative and add some extra time to what the
Testing procedures for bioburden are relatively Manufacturing and Production Department specified.
straightforward using accepted microbiological For the minimum DEHT, a similar approach is used.
techniques. For dust, consider either a particle Operations should be asked for the shortest time practical
counter, Total Organic Carbon (TOC), or perhaps an between the end of manufacturing and the beginning of
enhanced visual inspection, such as a white or black cleaning.
wipe cloth.
Documentation
For sampling sites, do not automatically sample the If a DEHT is specified for a cleaning process, and that
same sites that were sampled in the cleaning vali- DEHT is critical for control, then it is important to docu-
dation protocol. Consider which sites are most ment that time. The term, documenting, means that the time
likely to be re-contaminated during storage. For ex- of the end of the manufacturing procedures and the time of
ample, for agitator blades, the bottom of the agita- the beginning of the cleaning procedures are to be recorded.
tor blade (a worst-case cleaning location) may be The beginning of cleaning time should be defined based on
the appropriate sampling point as part of the clean- the cleaning process. It should not be based on a Quality
ing validation protocol; however, for determination Control (QC) release time. The end of the manufacturing
of the CEHT, the top of the agitator blade may be time is defined based on the manufacturing process.

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Troy Fugate

NOTE: If it is important to control the DEHT, then ABOUT THE AUTHOR

it needs to be measured in some way, and
it should be defined. Troy Fugate, Vice President for Compliance Insight,
Inc, located near Cincinnati, Ohio, is a worldwide
CONCLUSION compliance consultant in the areas of pharmaceuti-
cal quality, operations, packaging, laboratory, and
Once the data is compiled and analyzed, two new para- construction activities. Troy has worked around the
meters will emerge with regard to cleaning: globe on a variety of projects and specializes in
quality systems, audits, investigations, FDA issue
A time limit for holding clean equipment resolution and training. Troy is an active, participat-
A time limit for holding dirty equipment ing Member of the Editorial Advisory Board for
the Journal of GXP Compliance and can be
Procedures should be amended to reflect this new para- reached through his professional email address:
digm. It is highly recommended that stickers or tags used on [email protected].
equipment be altered to indicate an expiration date that re-
flects these hold times.
Article Acronym Listing
REFERENCES CEHT Cleaned Equipment Hold Time
DEHT Dirty Equipment Hold Time
1. FDA, Guide to Inspections of Validation of Cleaning FDA Food and Drug Administration
Processes, Office of Regulatory Affairs, July 1993, July GMP Good Manufacturing Practice
2004. HVAC Heating, Ventilation, and Air
2. Health Canada, GMPs-Cleaning Validation Guidelines, Conditioning
Health Products and Food Branch Inspectorate, Spring QC Quality Control
2000. SOP Standard Operating Procedure
3. Gil Bismuth and Shosh Neumann, Cleaning Validation:
TOC Total Organic Carbon
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. Jos 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 Pharmaceuti-
cal 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.

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