Equipment Cleaning Protocol for Medicinal Products

1. Equipment Cleaning Protocol for Medicinal Products Product contact equipment, both major and minor, used in production, subdivision, or sampling of a drug product, in-process material, or raw material shall be cleaned and shall include, and not be limited to: ▪Changeover cleaning; ▪Interval cleaning during a campaign, as necessary; or ▪Dedicated equipment cleaning at the end of a campaign. Equipment cleaning for major equipment must be conducted following approved written instruction or standard operating procedures (SOP) with an attached checklist(s). Equipment use and cleaning history must be determined for product contact equipment that has been used by third parties or by another facility (e.g., trials, rentals, borrowed). The history shall demonstrate that the equipment was not used for and does not contain potential contamination from objectionable materials (e.g., penicillins or other beta-lactams, pesticides).

2. Equipment cleaning shall be designed to prevent cross-contamination including microbiological Laboratory procedures contamination, when applicable [based on the risk assessment, by reducing residues on all product contact surfaces to acceptable levels. the maximum allowable residue (MAR) and Residue Acceptability Limit (RAL) for equipment cleaning shall be established by qualified personnel based on the empirical data and the approved calculation method, prior to any use. Swab or Rinsate sampling methods must be validated through use of recovery studies. the analytical methods used to test for residue must also be validated. For changeover cleaning, routine verification of cleaning processes for major equipment where 100% visual inspection is not possible shall include: ▪Inspection to the extent practical to verify the equipment is Visibly Clean; ▪Periodic monitoring (e.g., using swab or rinsate sampling method as per validation) at a frequency defined based on a documented and approved risk assessment (e.g., up to 2 to 3 years) of the probability of contamination; and ▪Approved justification of the rationale for the frequency of the periodic monitoring. Routine verification of cleaning Process validation protocol for major equipment where 100% visual inspection is possible shall include inspection to verify the equipment is visibly clean (e.g., mills, filter housings, and tray driers). Lighting shall be sufficient to facilitate visual inspection for residues. For areas to be visually inspected, the equipment must be dry before inspection. Commercial production equipment, for a one time product (e.g., clinical batches/lots), for which cleaning has not been previously validated, must be verified as clean by visual and residue testing after the production of the product, before the next use of the equipment. the need for cleaning, type or level of cleaning, and cleaning frequency within a campaign shall be defined, and documented. interval cleaning shall be performed as required during a campaign. Personnel responsible for equipment cleaning operations and sampling must be trained and qualified in these operations. such training, along with evidence of training effectiveness, shall be documented.

3. Approved cleaning and sanitizing agents shall be used to clean product contact equipment and shall be compatible with the surfaces to be cleaned. these agents shall be purchased, received, stored, approved, dispensed, and transferred similarly to raw materials. Equipment cleaning, use and maintenance logs, consisting of chronological entries on sequentially numbered pages or equivalent validated electronic system, shall be maintained for each major equipment unit, and for each major equipment item that is not included in a defined equipment unit. For each equipment unit or item, the cleanliness status shall be indicated using labels and/or signs or a centralized paper-based or validated electronic system. cleaning status can only be changed to CLEANED once all monitoring results (when applicable) are obtained and found to be satisfactory. Examples of equipment cleaning status include, but are not limited to: ▪Hold for Cleaning, ▪Cleaning, and Measures to protect clean equipment must be taken during storage to prevent environmental or microbial contamination. for example: ▪Store equipment dry, ▪Close tank openings,

4. ▪Close tablet machine covers, ▪Cap or cover open flanges, and ▪Protect portable equipment (major and minor) from environmental exposure by sealing in a protective bag or by shrouding and storage in a clean location. ▪Cleaned Portable Equipment must be stored, segregated from, in-use and/or unclean equipment. Maximum allowable time intervals for periods between use and initiation of cleaning validation protocol shall be evaluated. if this time period potentially impacts the ability to clean the equipment then the time period must be specified and validated. if the maximum allowable time intervals are exceeded, the equipment must be re-cleaned and inspected prior to use. After completion of any maintenance or instrument calibration activities that required opening or disassembly of equipment, an evaluation must be conducted and documented to determine the level of cleaning required, if any, for product contact equipment.