It is an expectation of regulatory organizations that companies establish and monitor clean and dirty equipment hold times for manufacturing equipment as part of their cleaning validation program.
Although the regulatory agencies expect manufacturers to document and address hold times, they do not describe a process for establishing the hold times.
Dirty Hold Time
The maximum amount of time equipment can be left soiled before cleaning. Dirty hold time is usually defined as the time between the end of manufacturing and the beginning of the cleaning process.
Dirty hold times are regarded as “critical elements” in the cleaning process, especially for topicals, suspensions, and bulk drug operations where the drying of residues may directly affect the efficiency of a cleaning process.
In practice, dirty hold times are typically based on the requirements and time frames of the manufacturing process.
Typically, three consecutive applications of the cleaning procedure incorporating the maximum required dirty hold time should be performed and shown to be successful to prove that the method is validated.
The longer a product is held “clean” before use increases the chances of it becoming contaminated, and the risk of microbial growth on the equipment during storage.
Evidence that routine cleaning and storage does not proliferate microbial growth is required.
Clean Hold Time
The maximum amount of time equipment can be left clean before use. Clean hold time is generally considered to be the time between the completion of cleaning and the initiation of the subsequent manufacturing operation.
The main factors affecting the clean hold time are the storage conditions and the room classification / qualification.
In its Guide to Inspection of Validation of Cleaning Processes, the US Food and Drug Administration considers identifying and controlling the length of time between the end of processing and each cleaning step to be critical elements of the cleaning processes.
Associated Regulations
FDA
FDA also expects pharmaceutical companies to demonstrate that routine cleaning and storage of equipment does not allow for microbial proliferation.
FDA, Guide to Inspection of Validation of Cleaning Processes, Division of Field Investigations, Office of Regional Operations, Office of Regulatory Affairs (Rockville, MD), July 1993
European Union
The European Union expects companies to provide a validation master plan with clearly defined and documented validation program elements.
EU, Annex 15, European Union Guide to Good Manufacturing Practice, Working Party on Control of Medicines and Inspections, European Commission (Brussels, Belgium), July 2001
Health Canada
Health Canada looks for companies to describe the interval between the end of production and the beginning of the cleaning procedures as well timeframes and conditions for the storage of clean equipment that do not allow for microbial proliferation.
Health Canada, Cleaning Validation Guidelines (Guide-0028), Drug GMP Inspection Unit (Ottawa, Ontario) May 2000
PIC/S
The Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme (PIC/S) guideline looks for documentation of both dirty- and clean-hold times. The general practice among industry is to routinely document and track equipment-hold times to ensure ongoing compliance.
Recommendations on Validation Master Plan Installation and Operational Qualification; Non-Sterile Process Validation; and Cleaning Validation,” in proceedings of the PIC/S (PIC/S, July 2004).