Equipment Cleaning for Drug Products www.gmpsop.com 1
Scope and General Types of Cleaning • Product Contact Equipment , both Major and Minor ,… shall be cleaned and shall include …: – Changeover Cleaning ;… – Interval Cleaning*… ; or – Dedicated Equipment Cleaning • Equipment Cleaning: – Designed to prevent Cross Contamination www.gmpsop.com 2
Use of Cleaning Instructions • Equipment Cleaning must be conducted following written Instruction-Records that shall be Approved by the … Production and Quality before being issued. • Equipment Cleaning Instruction-Records: – Shall be written in a detailed stepwise format for Manual Cleaning Methods . – A defined sequential operation for Automated Cleaning systems. – Record the completion of each significant time dependent or time critical step. www.gmpsop.com 3
Cleaning Instructions (cont) • Equipment Cleaning Instruction-Records … shall include, and not be limited to… – cleaning and sanitizing agents, including amount to be used; – concentration of cleaning and sanitizing agents; – quality of water or other solvents used; – requirements for equipment disassembly and re-assembly; – temperature and pressure parameters; – flow rates for wash solutions and rinses for automated systems; – start and end times of each step; – volume/weight of rinse; – number of rinses; – tools/utensils employed; – agitation, recirculation, and/or reflux; – draining and drying; – identification/inspection of Dead-Legs ; – method for indicating equipment cleaning status; – verification of cleaning; – method for protecting clean equipment from contamination; and www.gmpsop.com 4 – maximum time intervals for between use and cleaning.
Cleaning Instructions • Are SOPs, cleaning logs, or checklists where critical steps are signed and dated satisfactory? – Yes, but DP (drug product) sites are moving to separate batch records. • Are draft procedures ok? – Signed, approved procedures are to be used in plant. • Must temperature and pressure be measured for manual cleaning? – If a parameter is critical to assure consistency, it must be measured. • Is volume or weight of rinse always required? – Primarily for vessels, line rinses and final rinse checks. May use time and flow rate. www.gmpsop.com 5
Primary Cleaning Parameters www.gmpsop.com 6
Equipment Logs • Equipment Cleaning, Use, and Maintenance Logs, … shall be maintained for each major Equipment Item … Information … shall include: – Documentation of cleaning, use, and maintenance; – Date; – Start and finish times of the activity; – Equipment use, including product name, as well as initial and final Lot or Batch Numbers , of a campaign; – Signature or initials of individual performing the work; and – Signature or initials of a second person verifying the work. www.gmpsop.com 7
Equipment Logs • May be more than one equipment logbook (e.g., separate cleaning & use vs maintenance log books) • Each activity to clearly have start and finish times and dates (e.g., cleaning vs use) • Second person verifies that work was performed and recorded in logbook, not as dual witness of equipment inspection unless there are no other primary records www.gmpsop.com 8
Routine Verification of Equipment Cleaning • Routine Verification of Manual Cleaning Processes for Major Equipment Where 100 Percent Visual Inspection is NOT Possible shall include inspection to verify the equipment is visibly clean and ….RAL. • Routine Verification of Automated Cleaning Processes for Major Equipment shall include inspection to verify the equipment is visibly clean, where accessible. • Routine Verification of Manual Cleaning Processes for Major Equipment Where 100 Percent Visual Inspection is Possible shall include inspection to verify the equipment is visibly clean… • Routine Verification of Cleaning Processes …for minor equipment shall include inspection to verify the equipment is visibly clean. www.gmpsop.com 9
Verification-Equipment Cleaning Summary • 100 % Inspection- Not Possible • 100 % Inspection- Possible – During Validation – During Validation • Visual • Visual • RAL (Critical points) • RAL (Critical points) – Routine – Routine • Visual • Visual • RAL (Unless automated) * Note- if only test is visual, then detection limit must be known Applies to major and minor equipment. www.gmpsop.com 10
Routine Verification • Do we need to have a RAL test (rinse or swab), after validation, if we cannot entirely see and inspect the equipment (e.g. large tanks)? – Yes, if procedure is manual and equipment is not 100% inspectable, then a quantitative RAL test is required after validation. – No, if automated cleaning, RALs not required routinely, only visual as practical. Balance inspection techniques for 100% (e.g. use of mirrors or cameras) and amount of equipment disassembly for thorough inspections. Otherwise, quantitative testing of the non-visual parts such as rinse checks are to be implemented. www.gmpsop.com 11
Manual Cleaning - Guidance • Requires detailed cleaning procedure and good training to be reproducible and effective – More prone to higher variability and human errors than automated or semi-automated methods • Unavoidable for certain equipment pieces – Small glassware items – Valves – Other intricate parts • Can be validated with 3 runs, but should be assessed more frequently than automated methods. www.gmpsop.com 12
Major vs Minor Equipment • Minor: – scoops, thiefs, paddles, attachments to major equipment (e.g. chutes) • Small and open to allow 100% inspection • No moving parts • Not a potential single point contamination (fill needle) • Major: – Metal detectors, Dedusters (moving parts) – Vessels and bins (large surface area) – Sieves and mills www.gmpsop.com 13
Visual Detection Limit • If the Only Verification of Cleaning Processes to be Conducted on a Piece of Equipment is Visual, then the visually detectable quantity must be known and documented. • Visually Detectable Quantities shall be based on literature or on laboratory studies. www.gmpsop.com 14
Visual Detection Limit • Quantify when visual is the only verification method for routine verification – No routine RAL – Meant for changeover cleanings • The level of visual acceptance may differ for the type of cleaning: changeover, interval or dedicated . • Literature limits may be used (4 mcg/cm2 = 25mcg/in2 ) www.gmpsop.com 15
Visual Guidance Laboratory studies typically include: • The spiking of coupons of a known surface area that represent the materials of construction present within the system. • The coupons are spiked at the swab RAL concentration and adjusted to be directly proportional to the size of the coupon. • The coupons are dried and examined under conditions designed to represent the actual manufacturing environment by trained analysts and designated as visible, or not visible, at the RAL. www.gmpsop.com 16
Visual Guidance (cont.) • If literature references are used as the basis for determining the likelihood of visual detection: Report any evidence that suggests the compound of interest is not visible at the RAL. For instance, during validation if rinse and/or swab checks for cleanliness fail test acceptance criteria, but the visual inspection noted no visible residues. • The same can be true for the laboratory determined visual limit. If evidence from manufacturing contradicts the limit reported by the laboratory the anomalies should be monitored carefully If deemed necessary, changes made to the lab conditions intended to represent the actual manufacturing environment (e.g., light intensity, distance from the subject, use of representative tools). www.gmpsop.com 17
Visual Inspection- Lighting • Lighting shall be sufficient to facilitate visual inspection for residues. – Question: What is sufficient? It depends. Extra lighting (e.g., flashlight) may be needed to see within a tank, where as room lighting is enough to inspect a hopper. Must be able to see residue. www.gmpsop.com 18
Double Checking • An Individual other than the one who performed the cleaning must verify that major equipment is visibly clean. Comment: The equipment and associated documents must be inspected by a second individual. May be Production or QA colleague. Does not need to be immediate. It not meant as a dual witness for individual steps. www.gmpsop.com 19
Cleaning Level and Frequency • The Need for Cleaning, Type/Level of Cleaning, and Cleaning Frequency Within a Campaign shall be defined and documented. Interval cleaning shall be performed as required during a campaign. • Rationale for Interval Cleaning and cleaning steps used shall be documented and shall be based on the product being manufactured. API has expanded text on restoration to intended use, deleted “rationale”. www.gmpsop.com 20
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