Equipment Hold Time for Cleaning
Article
Validation: Time to Come 'Clean' for a
'Dirty' Little Secret?*
Richard J. Forsyth
Director in Worldwide GMP Quality with Merck & Co., Inc,
Abstract
Regulatory agencies expect companies to establish and monitor 'clean' and 'dirty' hold times for manufacturing equipment
as part of a cleaning validation program. If hold times are validated under properly defined and controlled conditions
the requirement to monitor either or both hold times might not be necessary, resulting in savings of time and resources
as well as potential regulatory exposure.
Q Introduction
The concepts of clean hold time and dirty hold
time have been part of cleaning validation since
its inception. Clean hold time is generally
considered to be the time between the completion
of cleaning and the initiation of the subsequent
manufacturing operation. Dirty hold time can
begin when the clean equipment is initially soiled,
but more often is defined as the time between the
end of manufacturing and the beginning of the
cleaning process. Intuitively it makes sense to
be concerned about both hold times. Dirty
equipment should be harder to clean the longer
the hold time and clean equipment has a greater
chance of becoming soiled as hold time increases.
In its Guide to Inspection of Validation of
Cleaning Processes, the FDA considers identifying
and controlling the length of time between the end
of processing and each cleaning step an often
critical element of cleaning processes1. The FDA
also expects some evidence that routine cleaning
and storage of equipment does not allow microbial
proliferation. The EU wants to see the key
elements of a validation program clearly defined
and documented in a validation master plan2 .
Health Canada looks for the interval between the
end of production and the beginning of the
cleaning procedures as well time frames and
conditions for the storage of cleaned equipment
that do not allow microbial proliferation3. Finally,
the PICS guideline looks for documentation of both
*Reprinted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA © 2008, Merck & Co., Inc.
Corresponding author: Richard J. Forsyth
WP53C-307, West Point, Pa. 19486, Phone: 215-652-7462, Fax: 215-652-7106, E-mail: richard_forsyth@merck.com.
dirty and clean hold times4. The practice developed that
for established hold times, routine documentation track the
equipment hold times to assure ongoing compliance.
Although the regulatory agencies expect that hold times
are addressed, they do not describe the process to how to
establish hold times. In our own validation study, dirty hold
time was established but the ongoing implications were not
examined5. Several articles define both clean and dirty
hold times and how to establish them, but mention nothing
about a strategy to guide the experiments6,7. A more recent
article, which referred to hold time studies as the lost
parameter for cleaning validation, did explore a number of
issues associated with hold time studies8. Issues included
storage conditions, test locations, testing methodology and
the length of hold time studies.
The concern with clean hold times is that clean
equipment will not stay clean indefinitely despite the use of
appropriate storage conditions. The concerns with holding
soiled equipment are that it will become more difficult to
remove the pharmaceutical soil and biological
contamination will proliferate. To address these potential
issues in our validation process, clean hold time testing
extended for over two years, while dirty hold time studies
extended for up to nine days.
After completion of the clean and dirty hold time
identification, ongoing control of the hold times became an
issue. Every time a piece of equipment is used, the operator
needs to confirm and document that the clean hold time
does not exceed the established clean hold time. And prior
to washing a piece of equipment the equipment washer
needs to confirm and document that the dirty hold time does
not exceed the established dirty hold time.
Pharma Times - Vol 40 - No. 6 - June 2008 15
 However, if the clean and dirty hold time issues are
addressed during the validation study, then the severity of
exceeding the established hold times diminishes to a level
making the risk potentially acceptable.
Q Validation Studies
As part of the cleaning validation study in our pilot plant5,
soiled equipment was held after processing for an extended
period of time before cleaning. The hold times for the three
validation trials ranged from 2 hours to 217 hours or 9 days.
Data from the validation study including dirty hold times
are shown in Tables I, II and III. The results include data
from a typical dry granulation equipment train and a wet
granulation equipment train respectively. The majority of
the data (187 of 231 swabs) showed no detectable residue
and all results were far below the acceptable Residue Limit
(ARL) of 100 μg/swab. The conclusion from the validation
study was that over the time span examined, the dirty hold
time had no discernable impact on the ability of the cleaning
process to effectively remove the soil from the
manufacturing equipment.

Table I
Dry Granulation Equipment Train - Dirty Hold Validation
Acceptable residue Limit (ARL) = 100 μg/swab
API (μg/swab) Detergent (μg/swab)
Equipment Swab Trial 1 Trial 2 Trail 3 Trial 1 Trial 2 Trail 3
Encapsulator 1 1.0 0.5 ND – – –
Encapsulator 2 ND ND ND ND ND ND
Encapsulator 3 0.8 ND ND ND ND ND
Encapsulator 4 ND ND ND – – –
Sieve 1 ND ND ND – – –
Sieve 2 ND 0.8 ND – – –
Sieve 3 ND ND ND ND ND ND
Sieve 4 ND ND ND ND ND ND
Sieve 5 6.1 11.3 1.9 – – –
Ribbon Blender 1 ND ND ND – – –
Ribbon Blender 2 ND ND ND ND ND ND
Ribbon Blender 3 ND ND ND – – –
Ribbon Blender 4 ND ND ND – – –
Ribbon Blender 5 ND ND ND – – –
Ribbon Blender 6 ND ND ND – – –
Ribbon Blender 7 ND <0.3 ND ND ND ND
Ribbon Blender 8 ND ND ND – – –
Roller Compactor 1 ND ND ND ND ND ND
Roller Compactor 2 0.8 ND 0.7 – – –
Roller Compactor 3 4.8 ND ND ND ND ND
Roller Compactor 4 ND ND ND – – –
Scoops/Spatulas 1 ND ND ND ND ND ND
Scoops/Spatulas 2 0.3 ND ND – – –
Scoops/Spatulas 3 ND <0.3 ND – – –
Drums & Pots 1 ND ND ND – – –
Drums & Pots 2 ND ND 0.4 ND ND ND
ND - None detected
Limit of Quantitation (LOQ) - API 0.3 μg/swab, Detergent 12.5 μg/swab
Limit of Detection (LOD) - API 0.1 μg/swab, Detergent 3 μg/swab

16 Pharma Times - Vol 40 - No. 6 - June 2008

 Table II
Wet Granulation Equipment Train - Dirty Hold Validation
Acceptable residue Limit (ARL) = 100 μg/swab

API (μg/swab) Detergent (μg/swab)

Equipment Swab Trial 1 Trial 2 Trail 3 Trial 1 Trial 2 Trail 3
Granulator 1 0.5 ND 0.3 ND ND ND
Granulator 2 ND ND ND – – –
Granulator 3 ND 0.3 ND ND ND ND
Granulator 4 ND ND ND – – –
Granulator 5 0.1 0.1 ND – – –
Fluid Bed Dryer 1 0.2 ND ND ND ND ND
Fluid Bed Dryer 2 0.5 ND ND ND ND ND
Fluid Bed Dryer 3 ND ND ND – – –
Fluid Bed Dryer 4 0.7 0.1 1.9 – – –
Mill #1 1 <0.1 ND ND ND ND ND
Mill #1 2 ND 0.1 ND – – –
Mill #1 3 6.0 3.7 5.7 ND ND ND
Mill #1 4 ND ND ND – – –
Mill #2 1 ND ND ND – – –
Mill #2 2 ND 0.1 ND – – –
Mill #2 3 ND ND ND ND ND ND
Mill #2 4 ND 0.2 0.6 ND ND ND
Mill #2 5 ND 0.3 0.1 – – –
Mill #2 6 ND ND ND – – –
Blender 1 ND 1.2 0.3 – – –
Blender 2 ND ND ND – – –
Blender 3 ND ND ND 11 ND ND
Blender 4 0.4 8.1 8.1 – – –
Press 1 ND ND ND ND ND ND
Press 2 ND ND ND ND ND ND
Press 3 ND ND ND – – –
Pan Coater 1 <0.1 <0.1 ND ND ND ND
Pan Coater 2 ND <0.1 ND ND ND ND
ND - None Detected
Limit of Quantitation (LOQ) - API 0.1 μg/swab, Detergent 12.5 μg/swab
Limit of Detection (LOD) - API 0.03 μg/swab, Detergent 3 μg/swab

The clean hold time validation study was conducted
independently. After cleaning, the equipment is wiped
or sprayed with alcohol to remove residual water, dried
and covered to prevent any dust or particulate
accumulation. The validation study consisted of three
trials with a least one trial including an extended clean
hold time. The clean hold times for the three trials
ranged from same day cleaning to a hold time of 2 years
and 5 months. Storage conditions included both the
clean equipment hold area in the pilot plant and a
storage room outside the pilot plant but in the same
building as the pilot plant. Data from the clean hold

Pharma Times - Vol 40 - No. 6 - June 2008 17

 Table III time study are shown in Tables IV, V and VI. The majority
Equipment Dirty Hold Time of the data (128 of 180 swabs) showed no detectable
Equipment Hold Time (hrs) bioburden and all results were far below the acceptable
Dry Train Trial 1 Trial 2 Trial 3 Residue Limit (ARL) of 100 cfu/swab. The results include
Encapsulator 166 72 92 data from a typical dry granulation equipment train and a
Sieve 171 75 3
wet granulation equipment train respectively. The
conclusion from the clean hold time validation study was
Ribbon Blender 171 75 2
that bioburden was not present immediately after cleaning
Roller Compactor 172 75 3
and was not a cause for concern during storage of properly
Scoops/Spatulas 174 76 4 cleaned, dried and covered equipment.
Drums & Pots 174 76 4
Wet Train Q Discussion
Granulator 26 7 196
Cleaning validation studies established equipment dirty
Fluid Bed Dryer 49 55 217
hold times and clean hold times for pharmaceutical
Mill #1 7 7 192 manufacturing equipment. The ongoing expectation is that
Mill #2 8 5 216 equipment cleaning documentation verifies compliance with
Blender 7 4 174 the validated hold times. A conservative approach uses
Press 47 25 171 either the established time for each group of equipment,
Film Coater 26 144 25
which makes record keeping difficult, or the shortest
established extended hold time for all equipment. Using
Table IV
Dry Granulation Equipment Train - Clean Hold Validation
Acceptable residue Limit (ARL) = 100 cfu/swab
Bioburden (cfu/swab)
Equipment Swab Trial 1 Trial 2 Trail3
Encapsulator 1 0 0 0
Encapsulator 2 0 0 0
Encapsulator 3 0 2 0
Encapsulator 4 0 0 0
Sieve 1 0 0 0
Sieve 2 2 0 0
Sieve 3 0 0 0
Sieve 4 0 0 0
Sieve 5 0 0 0
Ribbon Blender 1 0 0 0
Ribbon Blender 2 0 0 0
Ribbon Blender 3 0 0 0
Ribbon Blender 4 0 0 0
Ribbon Blender 5 1 0 3
Ribbon Blender 6 0 0 0
Ribbon Blender 7 1 1 0
Ribbon Blender 8 0 2 5
Roller Compactor 1 0 0 0
Roller Compactor 2 1 0 0
Roller Compactor 3 1 0 0
Roller Compactor 4 0 0 0
Scoops/Spatulas 1 0 0 0
Drums & Pots 1 0 0 0
Drums & Pots 2 0 0 0
Mixers 1 5 1 1
Mixers 2 16 1 4

18 Pharma Times - Vol 40 - No. 6 - June 2008

 Table V
Wet Granulation Equipment Train - Clean Hold Validation
Acceptable residue Limit (ARL) = 100 cfu/swab
Bioburden (cfu/swab)
Equipment Swab Trial 1 Trial 2 Trail 3
Granulator 1 13 0 0
Granulator 2 0 1 0
Granulator 3 2 0 1
Granulator 4 0 0 0
Granulator 5 0 – –
Granulator 6 1 – –
Fluid Bed Dryer 1 4 5 0
Fluid Bed Dryer 2 0 2 1
Fluid Bed Dryer 3 0 0 2
Fluid Bed Dryer 4 8 0 0
Mill #1 1 3 9 0
Mill #1 2 7 8 5
Mill #1 3 2 0 0
Mill #1 4 0 1 0
Mill #2 1 0 0 0
Mill #2 2 0 0 0
Mill #2 3 0 0 0
Mill #2 4 0 0 0
Mill #2 5 1 0 0
Mill #2 6 0 0 0
Blender #1 1 0 47 1
Blender #1 2 3 0 13
Blender #1 3 0 1 0
Blender #1 4 10 21 0
Blender #2 1 0 11 –
Blender #2 2 0 0 –
Blender #2 3 0 1 –
Blender #2 4 0 0 –
Blender #2 5 1 0 –
Blender #2 6 15 0 –
Press 1 0 0 0
Press 2 0 0 0
Press 3 11 37 0
Press 4 0 0 0
Press 5 5 1 0
Press 6 – 0 –
Pan Coater 1 0 0 1
Pan Coater 2 0 1 0

Pharma Times - Vol 40 - No. 6 - June 2008 19

 Table VI
Equipment Clean Hold Time
Equipment Hold Time
Dry Train Trial 1 Trial 2 Trial 3
Encapsulator 1d 1d 2 wk 0 d
Sieve 5 mo 3 wk 1 wk 0 d 0d
Ribbon Blender 8 mo 4 d 4 wk 6 d 0d
Roller Compactor 4d 0d 0d
Scoops / Spatulas NA NA NA
Drums & Pots NA NA NA
Mixer NA NA NA
Wet Train
Granulator 8 wk 1 d 4d 1 wk 0 d
Fluid Bed Dryer 0d 0d 2d
Mill #1 4d 4d 1d
Mill #2 2 yrs 5 mo 8 mo 2 d 0d
Blender #1 2 wk 3 d 4d 1d
Blender #2 5d --- 2d
Press 4 wk 5 d 6d 6d
Film Coater 3 wk 5 d 4d 1d
d - days w - weeks mo - months yrs - years
NA - hold time not applicable for common use equipment

this approach, the dirty hold time is limited to 7 days and
the clean hold time to several weeks. A more aggressive
approach uses the longest hold time data. This gives
a maximum dirty hold time of 9 days and a clean hold time
of over 2 years.
An examination of the clean hold time data supports
the more aggressive approach. The data was consistent
for both the wet and dry granulation equipment. The
average bioburden level for the 180 samples taken was
1.1 colony forming units (cfu)/swab. There were 128
samples with no detectable bioburden and only 9 with a
bioburden greater than 10 cfu/swab. Although the majority
of samples were taken shortly after cleaning, samples were
taken at 1, 2, 5, and 8 months and at 2 years, 5 months
with no discernable increase in bioburden. With a bioburden
limit of 100 cfu/swab, it can be reasonably concluded that
clean hold time is not an issue for cleaned equipment that
is dried, covered and stored appropriately.
The dirty hold time study needed to answer two
concerns. Does the soil become harder to clean the longer
it sits and what is the possibility of microbial proliferation
on the soiled equipment? Soils can become harder to clean
if they are wet and then dry onto the surface or if the soil is
hygroscopic and transforms into a pasty material or
subsequently dries. The high-shear granulator is the only
equipment with a wet granulation at the conclusion of the
unit operation. The dirty hold time for the high-shear
granulator (196 hours) was lengthy enough to allow any
wet material to dry. The controlled humidity of the pilot
plant prevented any moisture uptake by residual
granulation. All other equipment in the validation studies
resulted in a dry granulation at the conclusion of the unit
operation. Microbial proliferation was not a realistic
possibility, which was corroborated by the clean hold time
data.
Subsequent to the validation studies, the gross cleaning
of the equipment including scraping and vacuuming the
equipment was shifted from the equipment cleaning process
to the manufacturing process, which effectively shortened
dirty hold times. Because of the environmental
considerations for residue disposal, equipment operators
scrape and vacuum accumulated residue from the
equipment surfaces. Operators then wipe the equipment
surfaces with alcohol to remove as much of the residue as
possible in order to minimize the amount of residue
discharge to the municipal sewer system. An example of a
typical soiled equipment surface prepared for cleaning is
shown in Figures 1 and 2. The steps taken for
environmental concerns effectively shorten the dirty hold
time. The alcohol wipe dries within minutes leaving no wet
material to subsequently dry and become harder to clean.
The dry soiled surfaces do not have sufficient water activity
to support microbial proliferation. There is not sufficient
residue remaining for hygroscopic residues to be a concern.

20 Pharma Times - Vol 40 - No. 6 - June 2008

 Q References
1. FDA, "Guide to Inspection of Validation of Cleaning Processes,"
(Division of Field Investigations, Office of Regional Operations,
Office of Regulatory Affairs, July 1993).
2. Annex 15 to the EU Guide to GMP, Brussels, July 2001
3. Cleaning Validation Guidelines, Health Canada, May 2000.
4. Recommendations on Validation Master Plan Installation and
Operational Qualification; Non-Sterile Process Validation;
Cleaning Validation, Pharmaceutical Inspection Convention,
Pharmaceutical Inspection Co-Operation Scheme, July 2004.
5. R. J. Forsyth and D. Haynes, "Cleaning Validation in a
Pharmaceutical Research Facility," Pharm. Technol. 22 (9), 104-
112 (1998).
6. J. A. Morales Sanchez, "Equipment Cleaning Validation Within
a Multi-Product Manufacturing Facility," BioPharm Inter . 31 (2),
38- 49 (2006).
7. A. H. Mollah, "Risk-Based Cleaning Validation in
Biopharmaceutical API Manufacturing," BioPharm Inter .30 (11),
Fig. 1: Fielder High-Shear Granulator mixing bowl. 54- 68 (2005).
8. T. Fugate, "Hold Time Studies: A Lost Parameter for Cleaning
Validation," J. Val. Technol. 13 (3), 206-209 (2007).
O O O

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Q Conclusion Mr. Ramesh Shah

If clean and dirty equipment hold times are established
during validation and maintained under properly defined
and controlled conditions the need to monitor either hold
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702, Corporate House, Nr. Dinesh Hall, Opp. Torrent House,
Income Tax, Ashram Road, Ahmedabad - 380009, GUJARAT.
Ph : 079-30023754, 079-27540493 Mobile : +91 93777 46368
E-mail : kns_98@yahoo.com

time is not necessary, resulting in savings of time and Payment advance for every issue in the name of
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Pharma Times - Vol 40 - No. 6 - June 2008 21