Equipment-hold time for cleaning validation

Regulatory agencies expect companies to establish and monitor clean equipment- and dirty
equipment-hold times for manufacturing equipment as part of their cleaning validation
program. If hold times are validated under properly defined and controlled conditions, it is
possible that monitoring either or both hold times may not be necessary.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

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 is harder
to clean the longer the hold time, and clean equipment has a greater chance of becoming
soiled as hold time increases.

Background

In its Guide to Inspection of Validation of Cleaning Processes, the US Food and Drug
Administration considers identifying and controlling the length of time between the end of
processing and each cleaning step to be critical elements of the cleaning processes (1). FDA
also expects pharmaceutical companies to demonstrate that routine cleaning and storage of
equipment does not allow for microbial proliferation. The European Union expects companies
to provide a validation master plan with clearly defined and documented validation program
elements (2). Health Canada looks for companies to describe the interval between the end of
production and the beginning of the cleaning procedures as well timeframes and conditions for
the storage of clean equipment that do not allow for microbial proliferation (3). Finally, the
Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme
(PIC/S) guideline looks for documentation of both dirty- and clean-hold times (4). The general
practice among industry is to routinely document and track equipment-hold times to ensure
ongoing compliance.

Although regulatory agencies expect manufacturers to document and address hold times, they
do not describe a process for establishing hold times. In this validation study, a dirty-hold time
was established but ongoing implications were not examined (5). Several articles define both
clean- and dirty-hold times and how to establish them but do not mention a strategy to guide
the experiments (6, 7). A more recent article, which referred to hold-time studies as "the lost
parameter for cleaning validation," explored several issues associated with hold-time studies
(8). 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 using appropriate storage conditions. Holding soiled equipment makes it more difficult
to remove pharmaceutical soil and allows biological contamination to proliferate. To address
these concerns, the author extended clean-hold time testing for more than 2 yrs and extended
dirty-hold time studies for up to 9 days. After identifying clean- and dirty-hold time, ongoing
control of the hold times became difficult. Every time a piece of equipment is used, the
operator needs to confirm and document that the actual clean-hold time does not exceed the
established clean-hold time. And before washing a piece of equipment, the washer needs to
confirm and document that the actual dirty-hold time does not exceed the established dirty-
hold time.

This study suggests that if clean- and dirty-hold time issues are addressed during the
validation study that the severity of exceeding the established hold times diminishes to a
near-acceptable level.

Validation studies

As part of the cleaning-validation study in a pilot plant (5), soiled equipment was held after
processing for an extended period of time before cleaning. The hold times for the three
validation trials held ranged from 2 h-217 h 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. The majority
of the data (187 of 231 swabs) showed no detectable residue. All results were far below the
acceptable residue limit (ARE) of 100 tag/swab. The tests showed 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.

The clean-hold time validation study was conducted independently. After cleaning, the
equipment was 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;
one trial extended the clean-hold time. The clean-hold times for the three trials ranged from
same-day cleaning to a hold time of 2 yrs and 5 mo. 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. Data from the clean-hold time study are shown in Tables IV, V, and VI. The
majority of the data (128 of 180 swabs) showed no detectable bioburden and all results were
far below the ARL of 100 colony forming units (cfu)/swab. The results include data from a
typical dry-granulation equipment train and a wet granulation equipment train. The results
demonstrate that bioburden was not present immediately after cleaning and was not a cause
for concern during storage of properly cleaned, dried, and covered equipment.

Discussion

Cleaning-validation studies have established equipment dirty-hold times and clean-hold times
for pharmaceutical manufacturing equipment. The ongoing expectation is that equipment
cleaning documentation verifies compliance with the validated hold times. A conservative
approach uses either the established time for each group of equipment, which makes
recordkeeping difficult, or the shortest established extended hold time for all equipment. Using
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 more than 2 yrs.

An examination of the clean-hold time data supports the more aggressive approach. The data
were consistent for both the wet- and dry-granulation equipment. The average bioburden level
for the 180 samples taken was 1.1 cfu/swab. There were 128 samples with no detectable
bioburden and only nine 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 mo and at 2
yrs, 5 mo with no discernable increase in bioburden. With a bioburden limit of 100 cfu/swab,
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 questions. Does the soil become harder to
clean the longer it sits, and what is the possibility of microbial proliferation on soiled
equipment? Soils can be more difficult to clean when they are wet and allowed to dry onto the
surface, or when the soil is hygroscopic and transforms into a pasty material or subsequently
dries. A high-shear granulator is the only equipment that carries out wet granulation at the
conclusion of unit operation. The dirty-hold time for the high-shear granulator (196 h) 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 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
environmental considerations for residue disposal, equipment operators scrape and vacuum
accumulated residue from equipment surfaces. Operators then wipe equipment surfaces with
alcohol to remove as much of the residue as possible 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 dry and become harder to clean. The dry soiled surfaces do not have sufficient
water activity to support microbial proliferation. There is no sufficient residue remaining for
hygroscopic residues to be a concern. The dirty-hold time data, which measured cleaning
effectiveness out to 9 days, demonstrated a worst-case scenario for the pilot plant facility. The
dirty-hold time is not of significant concern for soiled equipment awaiting cleaning.

Under the operating conditions tested as part of the cleaning validation studies, the clean- and
dirty-hold times have little impact on the ongoing operations of the pilot-plant facility. In
addition, routine verification of adherence to these parameters adds little value to a firm's
ability to produce quality formulations. The risk, therefore, tied to not monitoring hold times
should be low for validated cleaning and storage conditions.

Conclusion

If clean- and dirty-equipment hold times are established during validation and maintained
under properly defined and controlled conditions, the need to monitor clean- or dirty-hold
times is not necessary. Avoiding these steps can result in savings of time and resources as
well as potential regulatory exposure.

* What would you do differently? Email your thoughts about this paper to
ptweb@advanstar.com and we may post them on pharmtech.com.

Submitted: Nov. 16, 2007. Accepted: Dec. 20, 2007.

References

(1.) FDA, Guide to Inspection of Validation of Cleaning Processes, Division of Field

Investigations, Office of Regional Operations, Office of Regulatory Affairs (Rockville, MD), July
1993.

(2.) EU, Annex 15, European Union Guide to Good Manufacturing Practice, Working Party on
Control of Medicines and Inspections, European Commission (Brussels, Belgium), July 2001.

(3.) Health Canada, Cleaning Validation Guidelines (Guide-0028), Drug GMP Inspection Unit
(Ottawa, Ontario) May 2000.

(4.) "Recommendations on Validation Master Plan Installation and Operational Qualification;

Non-Sterile Process Validation; and Cleaning Validation," in proceedings of the PIC/S (PIC/S,
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), 54-68, 2005.

(8.) T. Fugate, "Hold Time Studies: A Lost Parameter for Cleaning Validation," J. Val. Technol.
13 (3), 206-209, 2007.

Richard J. Forsyth is an associate director of worldwide GMP quality with Merck & Co., Inc,
WP53C307, West Point, PA. 19486, tel. 215.652.7462, fax 215.652.7106,
Richard_forsyth@merck.com

Table I: Dry granulation equipment train--dirty-hold validation

(Acceptable residue limit [ARL] =100 [micro]g/swab)

API ([micro]g/swab)

Equipment Swab Trial t Trial 2 Trial 3

Encapsulator 1 1.0 0.5 ND

Encapsulator 2 ND ND ND
Encapsulator 3 0.8 ND ND
Encapsulator 4 ND ND ND
Sieve 1 ND ND ND
Sieve 2 ND 0.8 ND
Sieve 3 ND ND ND
Sieve 4 ND ND ND
Sieve 5 6.1 11.3 1.9
Ribbon blender 1 ND ND ND
Ribbon blender 2 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
Ribbon blender 8 ND ND ND
Roller compactor 1 ND ND ND
Roller compactor 2 0.8 ND 0.7
Roller compactor 3 4.8 ND ND
Roller compactor 4 ND ND ND
Scoops/spatulas 1 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

Detergent ([micro]g/swab)

Equipment Trial 1 Trial 2 Trial 3

Encapsulator -- -- --
Encapsulator ND ND ND
Encapsulator ND ND ND
Encapsulator -- -- --
Sieve -- -- --
Sieve -- -- --
Sieve ND ND NQ
Sieve ND ND ND
Sieve -- -- --
Ribbon blender -- -- --
Ribbon blender ND ND ND
Ribbon blender -- -- --
Ribbon blender -- -- --
Ribbon blender -- -- --
Ribbon blender -- -- --
Ribbon blender ND ND ND
Ribbon blender -- -- --
Roller compactor ND ND ND
Roller compactor -- -- --
Roller compactor ND ND ND
Roller compactor -- -- --
Scoops/spatulas ND ND ND
Scoops/spatulas -- -- --
Scoops/spatulas -- -- --
Drums & pots -- --
Drums & pots ND ND ND

ND is no detection of residue. AN is active pharmaceutical ingredient.

Hyphen(-) is point not taken. Limit of quantitation is API 0.3
[micro]g/swab, detergent 12.5 [micro]g/swab. Limit of detection
is API 0.1 [micro]g/swab, detergent 3 [micro]g/swab.
Table II: Wet granulation equipment train--dirty-hold validation
(Acceptable residue limit [ARL] = 100 [micro]g/swab)

API([micro]g/swab)

Equipment Swab Trial 1 Trial 2 Trial 3

Granulator 1 0.5 ND 0.3

Granulator 2 ND ND ND
Granulator 3 ND 0.3 ND
Granulator 4 ND ND ND
Granulator 5 11.0 0.1 ND
Fluid bed 1 0.2 ND ND
dryer
Fluid bed 2 0.5 ND ND
dryer
Fluid bed 3 ND ND ND
dryer
Fluid bed 4 0.7 0.1 1.9
dryer
Mill 1 1 <0.1 ND ND
Mill 1 2 ND 0.1 ND
Mill 1 3 6.0 3.7 5.7
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
Mill 2 4 ND 0.2 0.6
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
Blender 4 0.4 8.1 8.1
Press 1 ND ND ND
Press 2 ND ND ND
Press 3 ND ND ND
Pan coater 1 <0.1 <0.1 ND
Pan coater 2 ND <0.1 ND

Detergent ([micro]g/swab)

Equipment Trial 1 Trial 2 Trial 3

Granulator ND ND ND
Granulator -- -- --
Granulator ND ND ND
Granulator -- -- --
Granulator
Fluid bed ND ND ND
dryer
Fluid bed ND ND ND
dryer
Fluid bed -- -- --
dryer
Fluid bed -- -- --
dryer
Mill 1 ND ND ND
Mill 1 -- -- --
Mill 1 ND ND ND
Mill 1 -- -- --
Mill 2 -- -- --
Mill 2 -- -- --
Mill 2 ND ND ND
Mill 2 ND ND ND
Mill 2 -- -- --
Mill 2 -- -- --
Blender -- -- --
Blender -- -- --
Blender 11.0 ND ND
Blender -- _ _
Press ND ND ND
Press ND ND ND
Press -- -- --
Pan coater ND ND ND
Pan coater ND ND ND

ND is no detection of residue. API is active pharmaceutical

ingredient. Hyphen (-) is point not taken. Limit of quantitation
is API 0.1 [micro]g/swab, detergent 12.5 [micro]g/swab. Limit
of detection is API 0.03 [micro]g/swab, detergent 3-[micro]g/swab.

Table III. Dirty-hold time

Equipment Holdtime (hrs)

Dry train Trial 1 Trial 2 Trial 3

Encapsulator 166 72 92
Sieve 171 75 3
Ribbon blender 171 75 2
Roller compactor 172 75 3
Scoops/spatulas 174 76 4
Drums and pots 174 76 4
Wet train
Granulator 26 7 196
Fluid bed dryer 49 55 217
Mill 1 7 7 192
Mill 2 8 5 216
Blender 7 4 174
Press 47 25 171
Film coater 26 144 25

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 Trial 3

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 0 1
Mixers 2 16 1 4
CFU is colony forming unit.

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 Trial 3

Granulator 1 13 0 0
Granulator 3 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

CFU is colony forming unit. Hyphen (-) is point not taken.

Table VI: Equipment clean-hold time

Equipment Hold time

Dry train Trial 1 Trial 2 Trial 3

2 wk,
Encap- 1 d 1 d
sulator 0 d

Sieve 5 mo, 1 wk, 0 d

3wk 0d

Ribbon 8 mo, 4 wk, 0 d

blender 4 d 6 d

Roller 4 d 0 d 0 d
compactor

Scoops/ N/A N/A N/A

spatulas

Drums N/A N/A N/A

and pots

Mixer N/A N/A N/A

Wet train

Granulator 8 k, 4 d 10 d
1 d

Fluid bed 0 d 0 d 2 d
dryer

Mill 1 4 d 4 d 1 d
Mill 2 2 yr, 8 mo, 0 d
5 mo 2 d

Blender 1 2 wk 4 d 1 d

Blender 2 5 d -- 2 d

Press 4 wk, 6 d 6 d
5 d

Film 3 wk, 4 d 1 d
coater 5 d

d is days. wk is weeks. mo is months. yr is

years. N/A is hold time not applicable for
common use equipment. Hyphen (-) is point
not taken.