article-equipmentholdtimeforcleaning

Pharma Times - Vol 40 - No. 6 - June 2008 15

Art

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IntroductionThe concepts of clean hold time and dirty hold

time have been part of cleaning validation sinceits inception. Clean hold time is generallyconsidered to be the time between the completionof cleaning and the initiation of the subsequentmanufacturing operation. Dirty hold time canbegin when the clean equipment is initially soiled,but more often is defined as the time between theend of manufacturing and the beginning of thecleaning process. Intuitively it makes sense tobe concerned about both hold times. Dirtyequipment should be harder to clean the longerthe hold time and clean equipment has a greaterchance of becoming soiled as hold time increases.

In its Guide to Inspection of Validation ofCleaning Processes, the FDA considers identifyingand controlling the length of time between the endof processing and each cleaning step an oftencritical element of cleaning processes1. The FDAalso expects some evidence that routine cleaningand storage of equipment does not allow microbialproliferation. The EU wants to see the keyelements of a validation program clearly definedand documented in a validation master plan2.Health Canada looks for the interval between theend of production and the beginning of thecleaning procedures as well time frames andconditions for the storage of cleaned equipmentthat do not allow microbial proliferation3. Finally,the PICS guideline looks for documentation of both

dirty and clean hold times4. The practice developed thatfor established hold times, routine documentation track theequipment hold times to assure ongoing compliance.

Although the regulatory agencies expect that hold timesare addressed, they do not describe the process to how toestablish hold times. In our own validation study, dirty holdtime was established but the ongoing implications were notexamined5. Several articles define both clean and dirtyhold times and how to establish them, but mention nothingabout a strategy to guide the experiments6,7. A more recentarticle, which referred to hold time studies as the lostparameter for cleaning validation, did explore a number ofissues associated with hold time studies8. Issues includedstorage conditions, test locations, testing methodology andthe length of hold time studies.

The concern with clean hold times is that cleanequipment will not stay clean indefinitely despite the use ofappropriate storage conditions. The concerns with holdingsoiled equipment are that it will become more difficult toremove the pharmaceutical soil and biologicalcontamination will proliferate. To address these potentialissues in our validation process, clean hold time testingextended for over two years, while dirty hold time studiesextended for up to nine days.

After completion of the clean and dirty hold timeidentification, ongoing control of the hold times became anissue. Every time a piece of equipment is used, the operatorneeds to confirm and document that the clean hold timedoes not exceed the established clean hold time. And priorto washing a piece of equipment the equipment washerneeds to confirm and document that the dirty hold time doesnot exceed the established dirty hold time.

Equipment Hold Time for CleaningValidation: Time to Come 'Clean' for a'Dirty' Little Secret?*

Richard J. ForsythDirector in Worldwide GMP Quality with Merck & Co., Inc,

*Reprinted with permission of Merck & Co., Inc., Whitehouse Station, New Jersey, USA © 2008, Merck & Co., Inc.

Corresponding author: Richard J. ForsythWP53C-307, West Point, Pa. 19486, Phone: 215-652-7462, Fax: 215-652-7106, E-mail: [email protected].

Abstract

Regulatory agencies expect companies to establish and monitor 'clean' and 'dirty' hold times for manufacturing equipmentas part of a cleaning validation program. If hold times are validated under properly defined and controlled conditionsthe requirement to monitor either or both hold times might not be necessary, resulting in savings of time and resourcesas well as potential regulatory exposure.

Pharma Times - Vol 40 - No. 6 - June 200816

However, if the clean and dirty hold time issues areaddressed during the validation study, then the severity ofexceeding the established hold times diminishes to a levelmaking the risk potentially acceptable.

Validation StudiesAs part of the cleaning validation study in our pilot plant5,

soiled equipment was held after processing for an extendedperiod of time before cleaning. The hold times for the threevalidation trials ranged from 2 hours to 217 hours or 9 days.

Data from the validation study including dirty hold timesare shown in Tables I, II and III. The results include datafrom a typical dry granulation equipment train and a wetgranulation equipment train respectively. The majority ofthe data (187 of 231 swabs) showed no detectable residueand all results were far below the acceptable Residue Limit(ARL) of 100 μg/swab. The conclusion from the validationstudy was that over the time span examined, the dirty holdtime had no discernable impact on the ability of the cleaningprocess to effectively remove the soil from themanufacturing 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 7 ND <0.3 ND 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


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 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 – – –


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 part iculate

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


Table III

Equipment Dirty Hold Time

Equipment Hold Time (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 & 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

time study are shown in Tables IV, V and VI. The majorityof the data (128 of 180 swabs) showed no detectablebioburden and all results were far below the acceptableResidue Limit (ARL) of 100 cfu/swab. The results includedata from a typical dry granulation equipment train and awet granulation equipment train respectively. Theconclusion from the clean hold time validation study wasthat bioburden was not present immediately after cleaningand was not a cause for concern during storage of properlycleaned, dried and covered equipment.

DiscussionCleaning validation studies established equipment dirty

hold times and clean hold times for pharmaceuticalmanufacturing equipment. The ongoing expectation is thatequipment cleaning documentation verifies compliance withthe validated hold times. A conservative approach useseither the established time for each group of equipment,which makes record keeping difficult, or the shortestestablished extended hold time for all equipment. Using

Table IV

Dry Granulation Equipment Train - Clean Hold ValidationAcceptable residue Limit (ARL) = 100 cfu/swab

Bioburden (cfu/swab)

Equipment Swab Trial 1 Trial 2 Trail3

Encapsulator 1 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








Roller Compactor 1 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


Table VWet 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




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


Table VI

Equipment Clean Hold Time

Equipment Hold Time

Dry Train Trial 1 Trial 2 Trial 3

Encapsulator 1 d 1 d 2 wk 0 d

Sieve 5 mo 3 wk 1 wk 0 d 0 d

Ribbon Blender 8 mo 4 d 4 wk 6 d 0 d

Roller Compactor 4 d 0 d 0 d

Scoops / Spatulas NA NA NA

Drums & Pots NA NA NA

Mixer NA NA NA

Wet Train

Granulator 8 wk 1 d 4 d 1 wk 0 d

Fluid Bed Dryer 0 d 0 d 2 d

Mill #1 4 d 4 d 1 d

Mill #2 2 yrs 5 mo 8 mo 2 d 0 d

Blender #1 2 wk 3 d 4 d 1 d

Blender #2 5 d --- 2 d

Press 4 wk 5 d 6 d 6 d

Film Coater 3 wk 5 d 4 d 1 d

d - days w - weeks mo - months yrs - yearsNA - hold time not applicable for common use equipment

this approach, the dirty hold time is limited to 7 days andthe clean hold time to several weeks. A more aggressiveapproach uses the longest hold time data. This givesa maximum dirty hold time of 9 days and a clean hold timeof over 2 years.

An examination of the clean hold time data supportsthe more aggressive approach. The data was consistentfor both the wet and dry granulation equipment. Theaverage bioburden level for the 180 samples taken was1.1 colony forming units (cfu)/swab. There were 128samples with no detectable bioburden and only 9 with abioburden greater than 10 cfu/swab. Although the majorityof samples were taken shortly after cleaning, samples weretaken at 1, 2, 5, and 8 months and at 2 years, 5 monthswith no discernable increase in bioburden. With a bioburdenlimit of 100 cfu/swab, it can be reasonably concluded thatclean hold time is not an issue for cleaned equipment thatis dried, covered and stored appropriately.

The dirty hold time study needed to answer twoconcerns. Does the soil become harder to clean the longerit sits and what is the possibility of microbial proliferationon the soiled equipment? Soils can become harder to cleanif they are wet and then dry onto the surface or if the soil ishygroscopic and transforms into a pasty material orsubsequently dries. The high-shear granulator is the onlyequipment with a wet granulation at the conclusion of theunit operation. The dirty hold time for the high-shear

granulator (196 hours) was lengthy enough to allow anywet material to dry. The controlled humidity of the pilotplant prevented any moisture uptake by residualgranulation. All other equipment in the validation studiesresulted in a dry granulation at the conclusion of the unitoperation. Microbial proliferation was not a realisticpossibility, which was corroborated by the clean hold timedata.

Subsequent to the validation studies, the gross cleaningof the equipment including scraping and vacuuming theequipment was shifted from the equipment cleaning processto the manufacturing process, which effectively shorteneddirty hold times. Because of the environmentalconsiderations for residue disposal, equipment operatorsscrape and vacuum accumulated residue from theequipment surfaces. Operators then wipe the equipmentsurfaces with alcohol to remove as much of the residue aspossible in order to minimize the amount of residuedischarge to the municipal sewer system. An example of atypical soiled equipment surface prepared for cleaning isshown in Figures 1 and 2. The steps taken forenvironmental concerns effectively shorten the dirty holdtime. The alcohol wipe dries within minutes leaving no wetmaterial to subsequently dry and become harder to clean.The dry soiled surfaces do not have sufficient water activityto support microbial proliferation. There is not sufficientresidue remaining for hygroscopic residues to be a concern.


The dirty hold time data, which measured cleaningeffectiveness out to nine days, was a worst case for thepilot plant facility. Therefore it can also be reasonablyconcluded that dirty hold is not an issue for soiled equipmentawaiting cleaning.

Under the operating conditions tested as part of thecleaning validation studies, the clean and dirty hold timeshave little impact on the ongoing operations of the pilotplant facility. Additionally, routine verification of adherenceto these parameters adds little value to a firm's ability toproduce quality formulations. Therefore the risk associatedwith not monitoring hold times should be low for validatedcleaning and storage conditions.

ConclusionIf clean and dirty equipment hold times are established

during validation and maintained under properly definedand controlled conditions the need to monitor either holdtime is not necessary, resulting in savings of time andresources as well as potential regulatory exposure.

Fig. 1: Fielder High-Shear Granulator mixing bowl.

References1. 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 andOperational 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 aPharmaceutical Research Facility," Pharm. Technol. 22 (9), 104-112 (1998).

6. J. A. Morales Sanchez, "Equipment Cleaning Validation Withina Multi-Product Manufacturing Facility," BioPharm Inter . 31 (2),38- 49 (2006).

7. A. H. Mollah, "Risk-Based Cleaning Validation inBiopharmaceutical API Manufacturing," BioPharm Inter .30 (11),54- 68 (2005).

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

Fig. 2: Fielder High-shear Granulator exit chute.

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