Cleaning Validation Technologies

Destin A. LeBlanc-Technical Consulting Services


Below are definitions of terms as they are used for cleaning validation.

Acceptable Daily Exposure – Amount of a substance that is unlikely to cause an adverse health event or undesirable physiological effects by the designated route of exposure

Acceptable Daily Intake - Amount of a substance consumed on a daily basis that is considered safe

Acceptance limit – The amount or concentration of residue above which possible contamination of the next manufactured product would be considered unacceptable for safety or efficacy reasons. An acceptance limit may refer to the concentration in the next product, the surface concentration in the manufacturing equipment, the amount or concentration in the analyzed sample. All may have to be considered. The usual process is to first calculate the acceptance limit in the next product, and then to work backward to arrive at the acceptance limit in the analyzed sample.

Agitated immersion – A system of cleaning in which the manufacturing equipment is filled with cleaning solution, and the cleaning solution is agitated, usually with the existing agitation equipment in that equipment.

Agitation – The mixing or movement of the cleaning solution in the equipment. Agitation may occur from flow of the cleaning solution, or it may be due to mixers or impellers. Agitation continually supplies fresh cleaning solution to the surfaces.

Bioburden – The level of microorganisms present. For an antimicrobial process, the higher the bioburden, the more aggressive the process has to be (a longer time or higher chemical concentration).

Blank - Analytical sample with a background value that may be subtracted from an experimental value to determine the “true” value

Campaign - Multiple lots or batches of the same product manufactured serially in the same equipment

Clean hold time(CHT) - Time from the end of the cleaning process until the equipment is used again (which may be product manufacture, autoclaving, or a SIP cycle)

Clean In Place (CIP) – Cleaning involving cleaning equipment without first disassembling the equipment; usually performed with a spray device.

Cleaning agent – Chemical agent or solution used for cleaning. May be aqueous or solvent-based.

Concentrate – Concentrated form of formulated cleaning agent. A concentrate is usually diluted with water for use.

Contaminant – Drug active, excipient, degradant, processing aid, cleaning agent, bioburden, endotoxin, or foreign matter that, at a high enough level remaining after cleaning, may potentially contaminate the equipment surfaces or the next product.

Cleaning Validation – Documented evidence with a high degree of certainty that a cleaning process will consistently produce product meeting its predetermined quality attributes. Quality attributes are typically those related to potentially contaminating residues.

Clean Out of Place (COP) – Cleaning involving disassembling the equipment before cleaning it elsewhere.

Coupon – Small model surface used for either laboratory testing of cleaning performance, or for swab recovery studies.

Cycle development – Work done before the validation protocol to establish a cleaning SOP. May involve lab, pilot-scale, as well as full process testing.

Dead leg – An area in process piping which leads nowhere (think of it as a dead-end street). Is usually a difficult-to-clean location.

Dedicated equipment – Equipment only used for the manufacture of one product or one related product line.

Default limit – A limit that is chosen as a minimum if scientifically justified calculations result in limit values that would be practically excessive. A typical default limit in the next product for finished drug products is 10 ppm; a typical default limit in the next product for API’s is 100 ppm. A default limit is used only if it is lower than the dose-based limit.

Detergent – A type of cleaning agent, usually aqueous based and utilizing surfactants.

Dirty hold time(DHT) - Time from the end of product manufacture until the beginning of the cleaning process

DI water – Deionized water, or water from which all the ionized species have been removed.

Endotoxin – Toxins present in the cell walls of certain Gram-negative bacteria. Endotoxins may cause fever when injected into the blood stream, and are also called pyrogens).

Equipment train – Series of individual pieces of equipment linked together for a given process. May be cleaned individually or as a process train.

Finish (surface) – Degree of roughness or smoothness of a surface.

Grouping strategy – Validation strategy for multiproduct equipment in which three PQ runs are performed on a representative product (usually the most difficult to clean), and that performance is considered to apply to the cleaning of all products within that defined group.

Impingement – Process of a cleaning solution striking a surface. Impingement usually occurs in a spray process, and helps dislodge soils from surfaces.

Interference – Something in an analyzed sample which causes analytical results for the target analyte to less precise, less accurate, or just less applicable.

Installation Qualification (IQ) - Part of validation which documents that the cleaning equipment is installed correctly.

Limit of Detection (LOD) – Lowest level of analyte that can be detected, but not necessarily quantified.

Limit of Quantitation (LOQ) – Lowest level of analyte that can be reliably measured with acceptable accuracy and precision.

Master plan – Document which describes overall philosophy and manner of cleaning validation in a given facility.

Mock soil - A soil which is used in place of the manufactured product during a cleaning validation protocol (also called a “surrogate” soil)

Mock soiling - A process of soiling the equipment for a cleaning validation protocol in which soil is applied to the equipment surfaces to simulate the condition of the soil on those surfaces following typical product manufacturing (also called “artificial soiling”)

Monitoring – Process of routinely evaluating cleaning process during and after cleaning. It may include measuring of process as well as performance characteristics.

Neutralization – Process of changing the pH of a used aqueous cleaning solution to the ”neutral’ range of approximately 6-10 so it can be discharged into a waste treatment system.

Once-through – CIP cleaning process, or part of a CIP cleaning process, in which the cleaning solution or rinse water goes directly to the drain after passing through the equipment to be cleaned.

Operational Qualification (OQ) – Part of validation that documents that the cleaning equipment operates correctly.

Organoleptic – Measured by the senses, such as visual.

Pitch – Slope of pipes in the equipment train. A desirable pitch is a least 1/16 inch per foot (about 5 mm per meter) of length of pipe.

Placebo sampling – Method of sampling that uses the manufacture of a product placebo to sample the cleaned equipment.

Prerinse – A water flush (usually with cold water) of the equipment train prior to applying the cleaning solution. Also called a “Prewash”.

Prevalidation – Work done before approval of the validation protocol. Includes cycle development, determination of residue limits, and selection of analytical and sampling methods.

Process Qualification (PQ) – Part of validation that documents cleaning performance of the SOP, typically in three consecutive runs.

Process Validation – Documented evidence with a high degree of certainty that a process will consistently produce product meeting its pre-determined quality attributes.

Purified Water (PW) – Specially manufactured water with low conductivity and TOC, and with low bioburden.

Pyrogen – See Endotoxin.

Recirculation – CIP cleaning process, or part of a CIP cleaning process, in which the cleaning solution or rinse water passes through the CIP control unit, spray devices, and equipment multiple times. Typically used for the cleaning cycle of a CIP process.

Recovery – Percentage of analyte that is removed and analyzed during swab or rinse sampling procedure. Determined in lab by measuring recovery from spiked coupons.

Residue – Materials left behind after the cleaning process. May be chemical or microbiological in nature.

Revalidation – Process by which performance of a validated cleaning process is evaluated to ensure it is still under control. Might include re-validation upon significant change, or else validation confirmation upon review of appropriate documents, including original validation, change control, monitoring, and QC records.

Riboflavin testing – Procedure for testing coverage of the spray from a spray device. Done by coating the interior surfaces with dilute solution of riboflavin, running a short CIP cycle with water, and examining surfaces with a UV light.

Rinse sampling – Procedure for sampling involving flooding the surfaces with rinse solution to effectively remove target residues. The rinse solution is then analyzed for the target residue.

Shadow area – Any area that does not receive adequate cleaning solution from the spray device because of an impediment (agitator shaft, baffle, etc.) within the process vessel.

Shared product surface area – Surface area within the equipment train that that contacts manufactured product. Residues on shared product surface area can be transferred to the next product.

Soil – Material in equipment train to be removed by the cleaning process.

Standard Operating Procedure (SOP) – Written document with specific actions and steps to be taken in the cleaning process.

Specificity – Ability of an analytical method to unequivocally measure analyte in the presence of other components that might also be expected to be present.

Swab – Sampling tool that comprises a textile, fiber, or foam on the end of a moderately flexible handle. Examples include cotton on a wooden handle (for microbiological sampling) and knit polyester on a polypropylene handle for chemical sampling.

Swab sampling – Procedure for sampling surfaces involving wiping the surfaces with a swab, typically saturated with water or another sampling solvent, to remove residues from a surface. The swab is then desorbed, and a chemical analysis is performed on the desorbed material.

Template – Flat window frame device, usually made of PTFE (polytetrafluoroethylene), applied to a surface to restrict swab sampling to a defined area inside the window frame.

Total Organic Carbon (TOC) – A nonspecific analytical procedure that involves oxidizing the residue to carbon dioxide, and then measuring the generated carbon dioxide.

Use-dilution – Dilute solution of a cleaning agent concentrate, as it is used for cleaning.

Validation - See cleaning validation.

Verification – Documented evidence that an individual cleaning event has produced product contact surfaces that are acceptably clean. Verification is typically done for infrequent or varying processes, such as clinical trial production or product made only every two years.

Water for Injection (WFI) – Specially manufactured water with low conductivity and TOC, and with low bioburden and endotoxin.

Worst case – Those conditions within normal parameters most likely to give failure. For processing purposes, “worst case” means those values of normal operating parameters most likely to cause process failure. For sampling locations, “worst case” means those equipment locations most likely to have higher levels of residues after cleaning. For sampling recovery, “worst case” means those procedures, within normal sampling parameters, most likely to give poorer percentage recovery. For grouping strategies, “worst case” means selecting those products or acceptance limits most likely to give failing results.