Introduction
The recommendations to evaluate if the time between equipment use and cleaning needs to be established and controlled are described for Active Pharmaceutical Ingredients (APIs) and Drug Products. When they are determined to be critical, recommendations on how to establish and extend existing hold times are also described.
This guidance outlines considerations and risks associated with hold times between equipment use and cleaning.
Information used to determine if a study is necessary, and if so the amount of sampling, sampling approach (e.g. grouping of products and equipment) and number of replicate runs for a potential validation study are described.
Recommendations and Rationale for Recommendations
The non-cleaned equipment hold time period is defined from the “end of manufacturing” to the start of cleaning. The end of manufacturing is when the individual equipment piece is emptied of the material contained within (e.g. when no additional product is removed for further processing).
The beginning of cleaning is defined when a cleaning activity is initiated on the equipment. Examples include pre-rinsing initiation or post campaign flush, placing an item into solution for soaking, or a CIP cycle is started.
Maximum allowable time intervals for periods between API equipment use and cleaning (non-cleaned or “dirty” hold time) are required to be specified unless there is an approved documented rationale or data demonstrating the time interval is non-critical. (1,2). For drug products the intervals must be demonstrated in at least one cycle of use and cleaning, and it must be documented in the validation.
Non-cleaned equipment hold times for APIs are not required to be validated. A recent international guide has stated that risk approaches are acceptable in differentiating efforts in cleaning of equipment based on intended use.
Factors in the Consideration of Establishing Hold Times
Consideration of the hold time of equipment after manufacturing use and before cleaning is important because it may impact the equipment cleaning.
The following considerations should be evaluated in a documented and approved risk analysis:
Drying of product on the surface.
Certain organic compounds, APIs, waxes, or polymeric formulations may harden on drying or standing, making it more difficult to remove. Example is polymethylacrylates as coating polymers.
In some cases, it is possible that after drying of the residue during normal manufacturing, further increase in hold time will have no effect on the difficulty of cleaning to remove product residue. For example, this may be the case when processing conditions are significantly more severe than idle hold time conditions (e.g. drying a product in a Rosenmund Filter for 3 days at 70 degrees C versus idle hold time of the empty non-cleaned filter at room temperature).
Increased Adhesion of material to surface (e.g. hygroscopic). If exposed to humid conditions, materials may become sticky and more difficult to remove. Example is corn starch.
Potential for Degradation compounds. Degradants may have different solubility, toxicity, and cleanability characteristics than the original compound. These may be easier or more difficult to clean and should be evaluated on a case by case basis.
History of failures. A product or equipment piece with a history of cleaning problems may be an indication that dirty equipment hold times are a factor that should be considered. This must be evaluated as part of the cleaning failure investigation.
The nature of the equipment surface such as aluminum, steel, hastelloy, plastic or rubber may be affected by the duration of the contact. Staining may result.
The solubility of the residue in cleaning agent. In some cases, the solubility of the residue in the cleaning agent is so great, non-clean equipment hold time does not affect the difficulty of cleaning.
Microbiological accumulation or proliferation. Organisms may grow exponentially if wet residues or stagnant water is left in equipment. Microbiological considerations should be evaluated when water rinsing is used. A microbiological assessment of residual product over time on the non-cleaned equipment should be considered. Conditions of temperature, exposure, time, and product history should be evaluated with respect to the ability of microorganisms to proliferate. The ability of the cleaning process to reduce microorganisms would also be a factor, along with the subsequent dosage form of the next product to be produced in the equipment.
If data are available to support dirty equipment hold times as non-critical These may include:
o Routine verification after each changeover cleaning (e.g. routine rinse sampling and testing for major equipment, routine visual inspection for minor equipment where the visual limit is at or below the RAL) may provide adequate data to support the conclusion that dirty equipment hold times for product residues are not critical. For example, in API manufacturing, rinse checks after cleaning are required for changeover cleaning of major equipment that cannot be 100% visually inspected.
o Lab recovery study data for the product residues may have been generated when residues are dried on representative sample surfaces (coupons). These data may also support non-cleaned equipment hold time rationales or data demonstrating that they are not critical. This may be more applicable for APIs, where only a single component is typically removed during cleaning (versus active and excipient mixtures in Drug Product).
Some ways to mitigate or reduce the possible negative impact of noncleaned equipment hold time include:
If cleaning can be initiated immediately after equipment use, this could reduce or eliminate the significance of dirty hold times with respect to product residue. This can include post campaign/batch flushing of the equipment.
The type, complexity and amount of disassembly of equipment (valves, lines, and hoses) may influence the amount of sampling needed to extend the hold time.
This type of risk assessment may be included in a Cleaning Evaluation, a protocol or a cleaning validation plan.
If dirty equipment hold times are determined to be critical to cleaning, the scheduling of cleaning activities following equipment use is important to minimizing equipment hold times. Allowable hold times of dirty equipment may vary considerably. Extending the hold times may be possible when supported with appropriate data and/or a documented technical rationale.
When the hold time is specified and critical for cleaning, it is required to document the duration of the hold time (e.g. in Batch records, log books, or using process automation data collection systems).
Recommended Data Product and Equipment Groups
If product grouping or matrixing is used in the validation program, the worst-case product with respect to the hold time must be evaluated compared to the other products in the group to determine if the dirty equipment hold time of the worst case material is representative of the worst case non-cleaned hold time scenario for the group. The worst case product for hold time could be different than the worst case product used for the cleaning validation.
Extending the hold times for grouped equipment may be accomplished by extending one representative item in the group. For example, data generated for 1 of 5 coating pans, may apply to the other pieces in the group, if the pieces, processing steps, and cleaning procedures used for all of the pieces are documented to be equivalent.
Number and Type of Verification
The amount of data, if any, for extending an existing hold time would depend on the factors described earlier. The following include some suggestions for APIs and dosage forms. Common approaches to managing hold times are:
For API manufacturing it is not common to validate this hold time. Most API sites have supported not doing so with data or rationales as outlined above (e.g. routine rinse verification data, use of organic solvents (versus water), recovery data, and visual inspection).
Many GMP sites currently requires one validation run for drug product equipment to validate hold times between equipment use and cleaning. The rationale for one run of data is that this is considered current industry standard based on recent external benchmarking data. Reproducibility will have been demonstrated in the replicates of the validation study. Some GMP sites have validated with 3 runs to assess variability. Other sites have validated with 1 run.
Dosage form specific considerations include:
* Creams, ointments, gels (topicals). The aqueous nature of drying and hardening may make residues more difficult to remove.
* Nonaqueous Liquids (oils), suspensions (e.g. oral, parenteral) -These dosage forms are usually free flowing and empty easily from equipment. The solids content, extent of drying and difficulty of removing residues are factors to consider.
* Solutions, Liquids (aqueous) -High sugar content syrups may result in stickiness and tendency for micro growth.
* Solid materials and dosages (powders, tablets, capsules) -usually visual inspection after cleaning of minor equipment is sufficient to extend the hold time when the micro risks are low and the product residue limit is visually detectable. If the material is made more difficult to remove due to environmental conditions (e.g. is hygroscopic), or possesses a non-visual limit, then visual inspection alone may not be adequate. The non-cleaned equipment hold time for drug product should be included in the validation study.
Run data execution may include the following verification, depending upon the circumstances:
a) Visual inspection for removal of residues.
b) Quantitative analysis results that the active residue meet established limits -Rinsate and/or swab test
c) Microbial results meet expected limits, where applicable.
Approved documentation of data and/or rationale(s) for the approach is required. It should have approvals by the site Technical, Production and Quality Authorities and should be included or referenced in site cleaning documentation.