A Clean Hold Time Study (CHT) determines how long cleaned equipment can stay clean and unused. Establishing the clean hold time is an integral part of cleaning validation as it identifies the necessary storage conditions plus the kind of protection from contamination that is needed in order to keep the equipment clean for the period of Clean Hold Time.
In fact, simply cleaning equipment is not sufficient to assure that it will be properly cleaned and ready for use again after an indefinite period of time. Depending on the level of moisture left in the equipment, the environmental conditions and the handling conditions, the microbiological quality may be compromised again.
Dirty hold time refers to the amount of time between the end of manufacturing and the beginning of cleaning. It studies if the residual product can become more difficult to clean or not before cleaning begins.
The two studies cannot be considered the same because the dirty hold time studies how bad the delaying cleaning process may be while clean hold time looks at how to keep the equipment in good condition.
To illustrate, the residue of a thick cream will become harder to remove if the equipment is uncleaned for a long time. As for the clean hold time it may be important to check gene processes of microbial contamination.
The risks involved depend on the equipment, manufacturing process, product and storage environment. Risk factors can include:
manufacturing processes that necessitate strict contamination control, microbiological factors are especially relevant. In sterile manufacturing, clean hold time must be differentiated from validated hold time.
The experiment should indicate a regular operation of equipment. If the equipment is usually kept dry and under the protection of cover, then in this experiment the conditions present should be copied. On the contrary, if the equipment is usually stored in the certain position, the experiment should indicate this fact.
The period of storage must be based on operational requirements.
The procedure should identify sampling method and method of testing, criteria for testing and fundamental scientific basis for the protocol. Depending on the needs, the type of testing can include microbiological sampling, visual inspections or any other relevant scientific evaluation of cleanliness.
To undertake microbiological testing one needs to apply suited approach and sampling tools. The research should consider whether the chosen sampling and recovery techniques will allow one to detect contamination at the chosen location. A negative result obtained through unsuited and/or poorly conducted sampling does not prove cleanliness of the equipment.
Sampling time and amount of samples should be specified in the approved protocol according to risk section, equipment characteristics, intended purposes and the evidence to be provided regarding the planned limit. A single sample taken at the end may be insufficient in case the risk evaluation results in the identification of changes during preservation process.
The protocol should mention whether the equipment will remain untouched during the whole sampling period or whether the sampling process as such may cause any disturbances in the process.
During the actual conduction of the study it is very important to document the time of the actual cleaning completion, time of sampling, conditions of storing, equipment condition and any unusual incident. If any protective cover has been displaced, equipment has moved from its position or the condition of the storing area has changed unexpectedly, it is necessary to document it instead of concluding that it would not have any influence.
It is the responsibility of QA to confirm that protocols are being followed and that any instances of deviation are investigated. On the other hand, QC or the microbiology lab must ensure that the specifications have been met, so the test can only be considered valid if the required documents can be traced back to the record of the protocol's development. For the assessment of equipment assembly, drainage, drying or storage set-up, it is often necessary for Engineering and Production to be consulted as well.
For instance, in case microbial results show that maximum allowable storage time exceeded predetermined limits, it should be considered if residual moisture, compromised lids, sampling technique or storage condition were to blame for this issue and the results earlier showing that the samples complied with the specifications should not be disregarded.
Final report should contain:
The approved clean hold time should be incorporated in the necessary SOPs and the records of equipment marking or status and operating activities. In case the equipment is maintained for a longer period than indicated in the proposed duration, the site approved protocol should be adapted, requiring re-cleaning, rechecking or otherwise justified actions prior to the use of such equipment.
Reviewing the appropriate deviations, microbiological trends, storing equipment and cleaning process performance is useful for evaluating the justification for the period set. If new evidence shows that the original assumptions ceased to be true, the validation process or further study may become necessary.
Clean Hold Time and Dirty Hold Time Are Different
Clean hold time refers to the amount of time from the end of cleaning until the next usage of equipment. The analysis may require checking if the equipment was dried, protected, stored or sanitized or sterilized prior to being used depending on the process.Dirty hold time refers to the amount of time between the end of manufacturing and the beginning of cleaning. It studies if the residual product can become more difficult to clean or not before cleaning begins.
The two studies cannot be considered the same because the dirty hold time studies how bad the delaying cleaning process may be while clean hold time looks at how to keep the equipment in good condition.
To illustrate, the residue of a thick cream will become harder to remove if the equipment is uncleaned for a long time. As for the clean hold time it may be important to check gene processes of microbial contamination.
Why a Clean Hold Time Study is Needed
The main purpose of conducting clean hold time studies is to demonstrate that cleaned equipment will remain in its required condition for its intended purpose for the duration of the specified storage period in the defined environmental conditions.The risks involved depend on the equipment, manufacturing process, product and storage environment. Risk factors can include:
- Microbial growth due to presence of moisture on surfaces coming in contact with products
- Recontamination due to manufacturing environment or handling
- Loss of barrier due to damage of covers, failure in closure of connections or inappropriate storage
- Loss of clean condition due to prolonged storage
- Misidentification of clean/dirt and released for use equipment.
manufacturing processes that necessitate strict contamination control, microbiological factors are especially relevant. In sterile manufacturing, clean hold time must be differentiated from validated hold time.
Designing a Scientifically Justified Study
The initial phase of a clean hold time study involves a documented risk assessment to begin the study. It is important to ensure that the study represents the real equipment being used in the study, the actual cleaning method and the way it was sterilized rather than being based on an imaginary premise, about some hypothetical conditions of the study being conducted.1. Select representative equipment
The first step is to know what equipment is to be studied, which includes both product-contact surfaces, ones that should be cleaned and stored and other physically connected elements of the equipment. Take into special consideration the areas which are hard to reach and to be cleaned.2. Define storage conditions and the proposed duration
The protocol should state the suggested time in which the held equipment must be kept clean between use and the conditions for storing the equipment. Such conditions could include the place of storage, environmental aspects of the location orientation of equipment, drying conditions, usage of covers for protection and supervision of various openings and connections.The experiment should indicate a regular operation of equipment. If the equipment is usually kept dry and under the protection of cover, then in this experiment the conditions present should be copied. On the contrary, if the equipment is usually stored in the certain position, the experiment should indicate this fact.
The period of storage must be based on operational requirements.
3. Establish sampling locations and test methods
Locations for sampling need to be chosen based on the risk of contamination and characteristics of the equipment. These may be areas that are hard to reach, moisture-retaining surfaces in the equipment and areas that are subject to contamination from the environment.The procedure should identify sampling method and method of testing, criteria for testing and fundamental scientific basis for the protocol. Depending on the needs, the type of testing can include microbiological sampling, visual inspections or any other relevant scientific evaluation of cleanliness.
To undertake microbiological testing one needs to apply suited approach and sampling tools. The research should consider whether the chosen sampling and recovery techniques will allow one to detect contamination at the chosen location. A negative result obtained through unsuited and/or poorly conducted sampling does not prove cleanliness of the equipment.
4. Specify sampling times
Sampling should demonstrate that the equipment remains appropriate throughout the expected interval. A study may consist of an initial analysis, post-cleaning, followed by periodic assessments based on justifiable intervals, including the anticipated maximum interval.Sampling time and amount of samples should be specified in the approved protocol according to risk section, equipment characteristics, intended purposes and the evidence to be provided regarding the planned limit. A single sample taken at the end may be insufficient in case the risk evaluation results in the identification of changes during preservation process.
The protocol should mention whether the equipment will remain untouched during the whole sampling period or whether the sampling process as such may cause any disturbances in the process.
Execution: What QA and Validation Teams Should Verify
In order to make the execution effective, it is essential to ensure that the cleaning methodology is approved, personnel is trained adequately, identification of the equipment is correct and sampling techniques are ready to be used before execution is done. The study is supposed to start only after the equipment has passed the agreed cleaning process.During the actual conduction of the study it is very important to document the time of the actual cleaning completion, time of sampling, conditions of storing, equipment condition and any unusual incident. If any protective cover has been displaced, equipment has moved from its position or the condition of the storing area has changed unexpectedly, it is necessary to document it instead of concluding that it would not have any influence.
It is the responsibility of QA to confirm that protocols are being followed and that any instances of deviation are investigated. On the other hand, QC or the microbiology lab must ensure that the specifications have been met, so the test can only be considered valid if the required documents can be traced back to the record of the protocol's development. For the assessment of equipment assembly, drainage, drying or storage set-up, it is often necessary for Engineering and Production to be consulted as well.
For instance, in case microbial results show that maximum allowable storage time exceeded predetermined limits, it should be considered if residual moisture, compromised lids, sampling technique or storage condition were to blame for this issue and the results earlier showing that the samples complied with the specifications should not be disregarded.
Acceptance Criteria and Final Report
Acceptance criteria should be defined prior to study implementation and justified in a documented manner. They may relate to microbiological limits, visual cleanliness and other standards because of both the type of equipment used and study procedure; therefore, they need to be relevant instead of blindly borrowed from information on other studies.Final report should contain:
- Protocol that has been approved together with amendments made to the initial version.
- Information on equipment used in the study, with justification for its relevance.
- Documents confirming completion of cleaning, as well as sampling process.
- Information on sampling process, locations, method used and results of sampling.
- Reports on deviations, as well as on investigation conducted for identifying those deviations and their influence on the study.
The approved clean hold time should be incorporated in the necessary SOPs and the records of equipment marking or status and operating activities. In case the equipment is maintained for a longer period than indicated in the proposed duration, the site approved protocol should be adapted, requiring re-cleaning, rechecking or otherwise justified actions prior to the use of such equipment.
Maintaining the Validated State
A clean hold time is relevant only if the conventional practices reflect the study. Alterations in storage methods, cleansing techniques, equipment configuration, protective shields or control of the environmental conditions can influence the conclusion reached and need to be evaluated in the context of the change control.Reviewing the appropriate deviations, microbiological trends, storing equipment and cleaning process performance is useful for evaluating the justification for the period set. If new evidence shows that the original assumptions ceased to be true, the validation process or further study may become necessary.
Get ready to use editable Validation Protocols in MS-Word FormatView List
No comments:
Post a Comment
Please don't spam. Comments having links would not be published.