Guidance 021 – Establishing and Extending Clean Equipment Hold Times

Background and Risks

The clean equipment hold time is defined as the time between the last step of the cleaning procedure (e.g. drying or sanitization) to the start of next equipment use for manufacturing. This includes, a pre-rinsing step, if used.

A recent international guide has stated that risk approaches are acceptable in differentiating efforts and decisions for cleaning equipment.

There are two main risks associated with CEHT:

1) The risk of contamination of clean equipment with dust, etc due to exposure to the environment. For this risk, it is required that equipment either be held clean in a controlled clean environment or protected from the environment. This type of potential contamination may or may not be visible during visual inspection;

2) The potential for microbiological proliferation. This is only a risk with equipment stored under conditions favourable to microbial growth (e.g. water wet or non-protected under non-controlled storage conditions such as high humidity). Therefore “environmental exposure” may not always result in microbiological risk (e.g. if equipment is not water wet and if the clean equipment is held in a controlled clean environment).

Because of the above two risks, It requires that equipment be protected from the environment and not stored water wet for the API and Drug Product.

Since equipment is cleaned to acceptable active ingredient residues as part of the cleaning process, degradant formation would be expected to be none or negligible, and of low risk.

Factors to Consider in Evaluating the Risks

The following factors should be considered to determine the level of risk for clean equipment hold times:

1) Considerations for the risk of contamination of clean equipment with non-viable particulates (e.g. dust) due to exposure to the environment. Conditions of equipment storage, such as protection from an uncontrolled unclean environment.

Protecting equipment such as with plastic sheaths or bags, closing lids, storing in clean areas, etc. are methods of minimizing negative effects of storage with respect to potential non-viable particulate contamination.

2) Considerations for evaluating the potential for microbiological risk Storage of clean equipment without water present:

If the equipment is either completely dried (including dead legs that may be drained, blown or heated dry) after cleaning, and/or flushed with organic solvent as last rinse, then microbiological risk is considered low and justification may be made for not performing testing for microbes.

Use of organic solvents and/or conditions not conducive to microbiological survival/growth (e.g. high temperature, high or low pH, etc) during subsequent processing of an intermediate, crude API or drug product could be justification for low risk with respect to microbial contamination.

However endotoxins (resulting from killed gram negative bacteria) could still be a risk for APIs that may go into subsequent parenteral DP dosage forms. The risk from endotoxins in these cases should be evaluated.

Nature of the materials manufactured in the equipment.

Drug Products that are susceptible to and tested for microbial limits or endotoxins (e.g. parenterals), would be considered higher risk than non-sterile products.

For example, non-sterile drug product may have a limit of up to 100 CFU per gram of product, in which case the equipment would have to have extremely high levels of bioburden to transfer that level of bioburden to the next product.

3) Considerations for both types of risk (non-viable and microbiological):

The step in an API process (i.e. whether the material is an intermediate or a final API)

Intermediates that will undergo further purification are considered lower risk than final API steps where no further opportunities for purification exist.

Use of single-service utensils (i.e. disposable) may lower the risk if purchased in sanitary containers.

Equipment Groups

If CEHT must be monitored (i.e. tracked) and/or validated, establishing or extending the clean equipment hold time for a group of equipment may be done by obtaining data for one representative item in the group.

For example, data generated for 1 of 5 coating pans, 1 of 4 tablet presses, or 1 of 4 centrifuges would apply to the other pieces in the group, if the pieces are documented to be equivalent with respect to cleanability.

This may be independent of the equipment grouping used for cleaning validation of the cleaning procedure if the hold time conditions for equivalent equipment are the same. For example, if several different cleaning procedures are being validated on the same type of equipment (i.e. multiple product cleaning procedure protocols), they may still have the same clean equipment hold time conditions. For this reason,

CEHT may be performed as part of the cleaning validation for the equipment, or it may be performed independently as a separate protocol study.

Recommended Data -Clean Equipment Hold Times: Establishing or Extending

For product contact equipment that is at high risk due to potential microbial contamination, to establish or extend the CEHT, a single occurrence of evaluating microbiological levels by sampling the equipment should be performed to validate the CEHT. The rationale for one run of data is that this is considered current industry standard based on external benchmarking data.

Visual inspection of equipment after the completion of cleaning, and before use of the next product are also required by the quality standards.

Sampling locations may be designated as most likely to contain contamination upon storage. Locations may or may not necessarily be the same locations as those most likely to contain residual product residue.

A rationale for sampling locations for CEHT is suggested. If an established CEHT is exceeded the equipment should be cleaned or rinsed prior to next use. Additional sampling after the extended CEHT canalsobe considered.

Documentation of Risk Assessment and Conclusions

Documentation of the risk analysis, the conclusions and any corresponding rationale(s) that includes approval by the site Technical, Production and Quality Team is recommended. It should be included in the site cleaning documentation. If no CEHT is established, this should also be documented with rationales and the same level of approval as previously described.

If it is determined that CEHT needs to be established and/or validated, the approach to how the CEHT will be controlled, the data to collect (if any), and the validation approach (e.g. equipment grouping) should also be documented and approved in site cleaning documentation.