CLEANING HOLD TIME STUDIES

APIC Cleaning Validation guideline states, “For both dedicated and multi-product facilities, the frequency with which the cleaning procedure should be performed should be validated to assess the risks related to potential degradation and microbiological contamination’’.

Eudralex Annex 15 states, “The influence of the storage time before cleaning and the time between cleaning and use taken into account to define (dirty and clean) hold times should be assessed during cleaning validation.

The World Health Organization (WHO) states, “The period and conditions for storage of unclean equipment before cleaning, and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures”.

Health Canada states, “Time-frames for the storage of unclean equipment, prior to commencement of cleaning, as well as time frames and conditions for the storage of cleaned equipment should be established”

PICS states, “The period and when appropriate, conditions of storage of equipment before cleaning and the time between cleaning and equipment reuse, should form” part of the validation of cleaning procedures. This is to provide confidence that routine cleaning and storage of equipment does not allow microbial proliferation”.

The US FDA Guide to Inspections Validation of Cleaning Process states, “Always check for the presence of an often critical element in the documentation of the cleaning processes; identifying and controlling the length of time between the end of processing and each cleaning step. This is especially important for topicals, suspensions, and bulk drug operations. In such operations, the drying of residues will directly affect the efficiency of a cleaning process”.

Dirty Equipment Hold Time (DEHT):

DEHT is defined as the time between end of use of the equipment and the start of equipment cleaning.

The purpose of validating the dirty equipment hold time is to provide evidence that the length of time equipment may sit idle prior to cleaning and the condition under which this storage occurs will not challenge the ability of the cleaning process to remove process or microbial residues.

Keeping residues on equipment surfaces prolonged time may make them harder to remove and thus challenge the ability of the cleaning process to clean the residuals. Also, permitting process residues, media, or solutions to settle in equipment or open to environment may allow to occur microbial proliferation that challenges the capability of the cleaning cycle to successfully remove microbial contamination.

Methodology for Validation:

Held dirty equipment after processing for an extended period of time (for example 24 hrs.) before cleaning and monitor chemical & microbial contaminants at specified periods (for example 0 hrs., 8 hrs., 12 hrs., 16 hrs., and 24 hrs.)

• It would be ideal to discuss with manufacturing team to identify longest time interval that equipment would be uncleaned after usage.
• It would be ideal to use worst case approach to select equipment / equipment train for the study.
• Rinse & swab sampling techniques to be used for monitoring of both active and cleaning agent contents along with total microbial count from swab samples.

Clean Equipment Hold Time (DEHT):

CEHT is defined as the time between completion of the cleaning of the equipment and the equipment re-use.

The purpose of validating the clean equipment hold time is that nothing stays clean forever. There are possibilities for re-contamination of cleaned equipment through endogenous sources (growth of microorganism already present in equipment) as well as exogenous sources (such as entry of external contamination in to equipment)

If equipment is stored wet for a sufficient time, there is a reasonable probability microbes will readily grow to an unacceptable level and that make equipment unsuitable for manufacturing usage.

Methodology for Validation:

Held Clean equipment for an extended period of time (for example 7 days) before re-use and monitor chemical & microbial contaminants at specified periods (for example 1^st day, 2^nd day, 3^rd day, 4^th day, 5^th day, 6^th day and 7^th day.)

• It would be ideal to discuss with manufacturing team to identify longest time interval that equipment would be unused after cleaning.
• It would be ideal to use worst case approach to select equipment / equipment train for the study.
• Rinse & swab sampling techniques to be used for monitoring of both active and cleaning agent contents along with total microbial count from swab samples.

Refer below for other details.

a) CLEANING VALIDATION – ORIGIN

b) CLEANING VALIDATION – ACCEPTANCE LIMITS

c) CLEANING VALIDATION – BRACKETING – WORST CASE RATING