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Equipment Hold Time for Cleaning Validation: Time to Come 'Clean' for a 'Dirty' Little Secret?

*
Richard J. Forsyth
Director in Worldwide GMP Quality with Merck & Co., Inc,

Article

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.

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

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.

*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.

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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.

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 g/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 g/swab API (g/swab) Equipment Encapsulator Encapsulator Encapsulator Encapsulator Sieve Sieve Sieve Sieve Sieve Ribbon Blender Ribbon Blender Ribbon Blender Ribbon Blender Ribbon Blender Ribbon Blender Ribbon Blender Ribbon Blender Roller Compactor Roller Compactor Roller Compactor Roller Compactor Scoops/Spatulas Scoops/Spatulas Scoops/Spatulas Drums & Pots Drums & Pots Swab 1 2 3 4 1 2 3 4 5 1 2 3 4 5 6 7 8 1 2 3 4 1 2 3 1 2 Trial 1 1.0 ND 0.8 ND ND ND ND ND 6.1 ND ND ND ND ND ND ND ND ND 0.8 4.8 ND ND 0.3 ND ND ND Trial 2 0.5 ND ND ND ND 0.8 ND ND 11.3 ND ND ND ND ND ND <0.3 ND ND ND ND ND ND ND <0.3 ND ND Trail 3 ND ND ND ND ND ND ND ND 1.9 ND ND ND ND ND ND ND ND ND 0.7 ND ND ND ND ND ND 0.4 Detergent (g/swab) Trial 1 ND ND ND ND ND ND ND ND ND ND Trial 2 ND ND ND ND ND ND ND ND ND ND Trail 3 ND ND ND ND ND ND ND ND ND ND

ND - None detected Limit of Quantitation (LOQ) - API 0.3 g/swab, Detergent 12.5 g/swab Limit of Detection (LOD) - API 0.1 g/swab, Detergent 3 g/swab

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Table II Wet Granulation Equipment Train - Dirty Hold Validation Acceptable residue Limit (ARL) = 100 g/swab API (g/swab) Equipment Granulator Granulator Granulator Granulator Granulator Fluid Bed Dryer Fluid Bed Dryer Fluid Bed Dryer Fluid Bed Dryer Mill #1 Mill #1 Mill #1 Mill #1 Mill #2 Mill #2 Mill #2 Mill #2 Mill #2 Mill #2 Blender Blender Blender Blender Press Press Press Pan Coater Pan Coater Swab 1 2 3 4 5 1 2 3 4 1 2 3 4 1 2 3 4 5 6 1 2 3 4 1 2 3 1 2 Trial 1 0.5 ND ND ND 0.1 0.2 0.5 ND 0.7 <0.1 ND 6.0 ND ND ND ND ND ND ND ND ND ND 0.4 ND ND ND <0.1 ND Trial 2 ND ND 0.3 ND 0.1 ND ND ND 0.1 ND 0.1 3.7 ND ND 0.1 ND 0.2 0.3 ND 1.2 ND ND 8.1 ND ND ND <0.1 <0.1 Trail 3 0.3 ND ND ND ND ND ND ND 1.9 ND ND 5.7 ND ND ND ND 0.6 0.1 ND 0.3 ND ND 8.1 ND ND ND ND ND Trial 1 ND ND ND ND ND ND ND ND 11 ND ND ND ND Detergent (g/swab) Trial 2 ND ND ND ND ND ND ND ND ND ND ND ND ND Trail 3 ND ND ND ND ND ND ND ND ND ND ND ND ND

ND - None Detected Limit of Quantitation (LOQ) - API 0.1 g/swab, Detergent 12.5 g/swab Limit of Detection (LOD) - API 0.03 g/swab, Detergent 3 g/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
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Table III Equipment Dirty Hold Time Equipment Dry Train Encapsulator Sieve Ribbon Blender Roller Compactor Scoops/Spatulas Drums & Pots Wet Train Granulator Fluid Bed Dryer Mill #1 Mill #2 Blender Press Film Coater 26 49 7 8 7 47 26 7 55 7 5 4 25 144 196 217 192 216 174 171 25 Trial 1 166 171 171 172 174 174 Hold Time (hrs) Trial 2 72 75 75 75 76 76 Trial 3 92 3 2 3 4 4

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 acceptable Residue Limit (ARL) of 100 cfu/swab. The results include data from a typical dry granulation equipment train and a wet granulation equipment train respectively. The conclusion from the clean hold time validation study was 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 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 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 Encapsulator Encapsulator Encapsulator Encapsulator Sieve Sieve Sieve Sieve Sieve Ribbon Blender Ribbon Blender Ribbon Blender Ribbon Blender Ribbon Blender Ribbon Blender Ribbon Blender Ribbon Blender Roller Compactor Roller Compactor Roller Compactor Roller Compactor Scoops/Spatulas Drums & Pots Drums & Pots Mixers Mixers

Swab 1 2 3 4 1 2 3 4 5 1 2 3 4 5 6 7 8 1 2 3 4 1 1 2 1 2

Trial 1 0 0 0 0 0 2 0 0 0 0 0 0 0 1 0 1 0 0 1 1 0 0 0 0 5 16

Trial 2 0 0 2 0 0 0 0 0 0 0 0 0 0 0 0 1 2 0 0 0 0 0 0 0 1 1

Trail3 0 0 0 0 0 0 0 0 0 0 0 0 0 3 0 0 5 0 0 0 0 0 0 0 1 4

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Table V Wet Granulation Equipment Train - Clean Hold Validation Acceptable residue Limit (ARL) = 100 cfu/swab Bioburden (cfu/swab) Equipment Granulator Granulator Granulator Granulator Granulator Granulator Fluid Bed Dryer Fluid Bed Dryer Fluid Bed Dryer Fluid Bed Dryer Mill #1 Mill #1 Mill #1 Mill #1 Mill #2 Mill #2 Mill #2 Mill #2 Mill #2 Mill #2 Blender #1 Blender #1 Blender #1 Blender #1 Blender #2 Blender #2 Blender #2 Blender #2 Blender #2 Blender #2 Press Press Press Press Press Press Pan Coater Pan Coater Swab 1 2 3 4 5 6 1 2 3 4 1 2 3 4 1 2 3 4 5 6 1 2 3 4 1 2 3 4 5 6 1 2 3 4 5 6 1 2 Trial 1 13 0 2 0 0 1 4 0 0 8 3 7 2 0 0 0 0 0 1 0 0 3 0 10 0 0 0 0 1 15 0 0 11 0 5 0 0 Trial 2 0 1 0 0 5 2 0 0 9 8 0 1 0 0 0 0 0 0 47 0 1 21 11 0 1 0 0 0 0 0 37 0 1 0 0 1 Trail 3 0 0 1 0 0 1 2 0 0 5 0 0 0 0 0 0 0 0 1 13 0 0 0 0 0 0 0 1 0 19

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Table VI Equipment Clean Hold Time Equipment Dry Train Encapsulator Sieve Ribbon Blender Roller Compactor Scoops / Spatulas Drums & Pots Mixer Wet Train Granulator Fluid Bed Dryer Mill #1 Mill #2 Blender #1 Blender #2 Press Film Coater 8 wk 1 d 0d 4d 2 yrs 5 mo 2 wk 3 d 5d 4 wk 5 d 3 wk 5 d 4d 0d 4d 8 mo 2 d 4d --6d 4d
mo - months

Hold Time Trial 1 1d 5 mo 3 wk 8 mo 4 d 4d NA NA NA Trial 2 1d 1 wk 0 d 4 wk 6 d 0d NA NA NA Trial 3 2 wk 0 d 0d 0d 0d NA NA NA 1 wk 0 d 2d 1d 0d 1d 2d 6d 1d


yrs - years

d - days w - weeks 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
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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.

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). Annex 15 to the EU Guide to GMP, Brussels, July 2001 Cleaning Validation Guidelines, Health Canada, May 2000. 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. R. J. Forsyth and D. Haynes, "Cleaning Validation in a Pharmaceutical Research Facility," Pharm. Technol. 22 (9), 104112 (1998). J. A. Morales Sanchez, "Equipment Cleaning Validation Within a Multi-Product Manufacturing Facility," BioPharm Inter . 31 (2), 38- 49 (2006). A. H. Mollah, "Risk-Based Cleaning Validation in Biopharmaceutical API Manufacturing," BioPharm Inter .30 (11), 54- 68 (2005). T. Fugate, "Hold Time Studies: A Lost Parameter for Cleaning Validation," J. Val. Technol. 13 (3), 206-209 (2007).

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7. Fig. 1: Fielder High-Shear Granulator mixing bowl. 8.

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The dirty hold time data, which measured cleaning effectiveness out to nine days, was a worst case for the pilot plant facility. Therefore it can also be reasonably concluded that dirty hold is not an issue 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. Additionally, routine verification of adherence to these parameters adds little value to a firm's ability to produce quality formulations. Therefore the risk associated with not monitoring hold times should be low for validated cleaning and storage conditions.

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Conclusion
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 time is not necessary, resulting in savings of time and resources as well as potential regulatory exposure.

Mr. Ramesh Shah


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