Selecting and Validating Detergents for CIP Applications- An ... - A3P

Selecting and Validating Detergents forCIP Applications- An OverviewGeorge VergheseSTERIS Corporationgeorge_verghese@steris.comNovember, 2006

Agenda• Issues to consider in selectingcleaning agents• Cleaning parameters and laboratorycleaning studies• Key issues to consider in scaling upfor CIP application• Validating detergents- limits,sampling, analytical methods

Selecting cleaning agentsIssues to consider• Effective cleaning, broad spectrum• Substrate compatibility• Known component(s)• Consistency, lot traceability• Stability• Low toxicity, safety

Selecting cleaning agentsIssues to consider (continued)• Analytical methods availability• Low foaming for spray applications• Free rinsing• Environmentally acceptable• Assured availability• Low overall cost !"#$!%%"&

Formulated detergentsBroad-spectrum cleaning effectivenessCleaner/componentFunction– Water Solubility– Solvents Solubility, stability– Surfactants Wetting, solubilization, emulsification,dispersion– Bases Alkalinity source, hydrolysis– Acids Acidity source, hydrolysis– Chelants Tie up calcium, iron– Builders Assist in detergency– Dispersants Suspend solids– Oxidants Oxidize, kill microbes– Antimicrobial Kill, reduce microbes

Selecting DetergentsBroad-spectrum cleaning effectiveness• Alkaline detergents– Alcohols– Aminoacids– Diols, triols– N-heterocyclics– Organic acids– Acid salts– Phosphates– Polysaccharides– Proteins, fermentation– Oils, fats, greases– Steroids– Sugars• Acidic detergents– Amines, alkaloids– Aldehydes, Amilines– Carbonates & Bicarbs– Ethers, Ketones– N-heterocyclics– Insoluble hydroxides– Metal Oxideshydroxides– Pyridines– Pyrrolidines

Cleaning process parameters andfactors– Time– Action– Concentration– Temperature– Surface type and finish– Soil level– Soil condition– Mixing– Rinsing & drying'()*++++*,--./0+*'*01$,--.&

Selecting detergents & parametersLaboratory cleaning evaluation- PACE• Coat product soil onto several coupons• Dry or bake coated coupons to simulateworst-case conditions• Clean using the selected process• Screen appropriate cleaning agents• Determine appropriate worst casecleaning parameters: concentration,temperature and time• Determine cleanliness by appropriatemethods• Study soil suspension, foaming,saturation

Scaling up parameters100Manual ScrubAutomated CIP0TmeActionConcTemp

CIP cleaning• Minimum disassembly• Surfaces should be capable of being CIP cleaned– Spray devices• static, dynamic• design/operating specs and parameters– Adequate flow thru tubes– Coverage testing• Various designs of CIP• Develop parameters for worst-case locations• Cycle development and pre-validation studiesVerghese G, “Developing a Validatable Cleaning Process”, Proceedings of the INTERPHEX Conference,Reed Exhibition Co, NY (1999)

CIP cleaningWorst-case locations in vessels

Substrate compatibility• Product contact surfaces should not be reactive,additive, or absorptive to affect safety, quality• Glass and glass lined vessels• Polymers• Metals• Iso-corrosion curves for alkaline cleaners• Gasket materials, EPDM, Teflon, others• Filters, membranes– Stainless steel, rouge, passivation– Soft metals and alloys'(234/++++5$!%%%&

Rinsability of formulated detergents% Removed100.095.090.085.080.075.070.065.060.055.050.045.040.035.030.025.020.015.010.05.00.0TOCSodium (IC)Potassium (IC)TitrationOrganic AcidChelant1530Rinse Time, seconds45

Case study- rinsability in a largeprocess10000010000ppm10001001010.1Wash R1 R2 R3 R4ActiveCleaner6*)7)1+/+8!9,%$!%%"&

Validating detergentsAcceptance criteria• Establish limits for cleaning agents andother contaminants– Toxicity based limits for cleaning agents• ADI (acceptable daily intake) based on NOEL (noobservable effect level) or LD 50 values– Other factors such as effect on stability,quality, equipment, or process– Visually clean2:);

Validating detergentsAcceptance criteria• Calculate and establish limits for productcontact surfaces and rinse samples– Concentration in subsequent product (ppm)– MAC, maximum allowable carryover (mg)– Amount per surface area (µg/cm 2 )– Amount in rinse water (µg/mL)– Amount in analytical swab sample (µg/mL):21)8**>*2+*+!!(,%$,--.&

Validating detergentsSampling–Cleanliness evaluated by• Validated sampling methods–Rinse–Swab• Visual examination– Varies with residue, substrate, distance, angle,light intensity, observerKirsch R.B. “Validation of Analytical Methods Used in Pharmaceutical Cleaning Assessment andValidation”,Supplement to Pharm Tech, 40-46 (1998)“Points to Consider for Cleaning Validation”, PDA J of Pharm Sci. & Technol, Tech Rep #29,Vol52, No 6, (1998)

Validating detergentsAnalytical methods• Validated analytical methods– Specific• E.g. HPLC– Non specific• E.g. TOC, Conductivity• Provides upper limit value• Example– TOC of swab sample = 0.8 ppm– %C of detergent = 20%– Therefore, maximum cleaner in sample = 0.8 ppm / 0.20 = 4 ppm– Compare to acceptance limitKirsch R.B. “Validation of Analytical Methods Used in Pharmaceutical Cleaning Assessment and Validation”,Supplement to Pharm Tech, 40-46 (1998)“Points to Consider for Cleaning Validation”, PDA J of Pharm Sci. & Technol, Tech Rep #29,Vol 52, No 6, (1998)

Summary• Factors to consider when selectingcleaning agents• Chemistry, cleaning parameters based onlab studies• Issues in scale-up and cycle development• Cleaning validation acceptance criteria,sampling and analytical

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