Cleaning and Validation

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Cleaning & cleaning validation in medical device manufacture : 

Cleaning & cleaning validation in medical device manufacture Muraleedharan CV Biomedical Technology Wing, SCTIMST, Trivandrum

Agenda : 

Agenda Cleaning Need Methods Cleaning validation Plan Procedure Contamination control

Cleaning : 

Cleaning

Need for device cleaning : 

Need for device cleaning Manufacturing Prior to use Open - but unused Reuse of single use devices (SUD) Reprocessing Resterilisation

Possible Contaminants : 

Possible Contaminants Bioburden / Endotoxins Detergents / surfactants / chemicals Metallic Components Cutting oils, polishing components, buffing wax Polymeric Components Plastisizers, olygomers, mould release agents Textile components Yarn sizing agents, surfactants, lubricating oils Entrapped chemicals, dyes

Ultrasonic Cleaning : 

Ultrasonic Cleaning Ultrasound creates waves of compression and expansion in the liquid. In the expansion phase, the molecules are pulled apart rapidly, causing the formation of microscopic vapour bubbles. Subsequently, these cavitation bubbles implodes releasing tremendous energy. Extreme temperature (~5000°C), combined with high velocity jets provides the cleaning action.

Ultrasonic Cleaning : Factors affecting the process : 

Ultrasonic Cleaning : Factors affecting the process Time Temperature Chemistry (cleaning medium, pH) Transducer/ part fixture design Ultrasonic frequency Power rating (watts/volume of liquid) Loading configuration

Cleaning Effectiveness:Ultrasonic Frequency : 

Cleaning Effectiveness:Ultrasonic Frequency

Cleaning Effectiveness : Proximity to the Surface : 

Cleaning Effectiveness : Proximity to the Surface

USC: Choice of Frequency : 

USC: Choice of Frequency 25-800 kHz range is being used 25 kHz : General purpose 40 kHz : Surgical tools / fabrics / composites 80kHz : IOL and optical products 120 kHz : fibers / membranes > 250 kHz : Electronics and IC manufacturing NOTE : Above 250 kHz the mechanism of cleaning is microstreaming, rather than cavitation. Miicrostreaming refers to localised, high velocity streams of liquid which shears the particles off the substrate

Multiple Frequency Cleaners : 

Multiple Frequency Cleaners

Ultrasonic Cleaning : Do’s & Don'ts : 

Ultrasonic Cleaning : Do’s & Don'ts Do not place objects directly on the bottom of the unit as they may may reflect the ultrasonic energy back into the transducers causing damage. Allow at least one inch gap between the tank bottom and the tray or bag for adequate cavitation. Keep solution within one inch of the top of the object in the bag or tray

Ultrasonic Cleaning : Do’s & Don'ts : 

Ultrasonic Cleaning : Do’s & Don'ts After fresh filling in the cleaner, degas the unit for 5 -10 minutes Use only thin PE / PP bags, plastic trays or perforated metallic trays for holding the objects. Use of glass vessels will limit transfer of ultrasonic energy into the cleaning solution

Typical USC Process : 

Typical USC Process Object in 0.5-2% soap solution in DW /DI water USC for 5 - 10 minutes Rinse and discard the soap solution Rinse with DW / DIW for 3-5 cycles USC for 3-5 minutes Repeat last TWO steps 2-3 times Dry & pack

Process Verification :Aluminum Foil Test : 

Process Verification :Aluminum Foil Test Aluminum foil of the size of the tank Degas the cleaner. Place foil into the tank in a vertical position. ( The should not touch the tank bottom.) Hold the foil steady and turn the ultrasonic cleaner on for 10-15 seconds. Check whether the foil surfaces is uniformly perforated & evenly covered with tiny pebbling effect

Rinsing : 

Rinsing Multiple dilution - manual rinsing Automated multiple dilution Different overflow schemes Typically each manual rinse cycle is found to reduce the contamination levels to one tenth. The rinse process depends on * residual contamination levels required * rinse water / solvent quality * agitation / flow mechanism

Drying : 

Drying Mechanical (Centrifugal) Thermodynamic (Oven, Vacuum ) Concentration gradients Dry gas purge Chemicals Drying Validation : Successive weighing till the readings stabilizes with in the required accuracy levels

Solvent Cleaning Techniques : 

Solvent Cleaning Techniques Vapour Degreasing : The solvent vapour is allowed to condense on the object. The process continues for a definite period. Solvent Extraction : The object is immersed in the solvent at higher temperatures. The cycle is repeated several times with fresh solvent

Solvent Extraction Methods : 

Solvent Extraction Methods Continuous solvent extraction Goldfish method Semicontinuous solvent extraction Soxhlet method Elevated pressure / temperature solvent extraction

Solvent Extraction-Selection of Solvent : 

Solvent Extraction-Selection of Solvent No single solvent is suitable for all extractions The solvent is chosen based on the contaminants Polar / Nonpolar Normally used solvents include Methyl & Ethyl Alcohol Diethyl Ether Methylene chloride Trichloroethylene n-propyl bromide Fluorinated carbon solvents

Degreasing + Extraction : 

Degreasing + Extraction Parts are placed in basket / carrier Pre-cleaning with hot solvent vapours (Zone A) Precision cleaning using ultrasonics and heat (Zone B) Zones A & B repeated to achieve the desired residue levels Parts moved to freeboard area (Zone C) to ensure that the trapped solvent vapours return to the vapour zone Combined vapour degreasing and solvent extraction schematic

Elevated P/T Solvent Extraction - Supercritical Fluid Extraction (SFE) : 

Elevated P/T Solvent Extraction - Supercritical Fluid Extraction (SFE) SFE is a separation technique that uses unique properties of a gas (usually CO2) above its critical temperature and pressure to extract or fractionate mixtures of compounds. When a gas is heated above its critical temperature, it cannot be liquidized regardless of pressure. However, as increasing pressure is applied, the density of the gas starts to increase and approaches that of a liquid, thus developing a tremendous capacity to dissolve compounds. Can be used for extraction in membranes, hollow fibers, filters …..

Cleaning cycle development : 

Cleaning cycle development Performed prior to process validation Characteristic of residuals Cleaning agent selection and concentration Rinse cycle time and volume Cleaning agent temperature Cleaning procedure development Cleaning-SOP change or improve Continuous data monitoring? Acceptance limit Operator training ? training report

Cleaning Validation : 

Cleaning Validation

Cleaning Validation : 

Cleaning Validation Residue identification Residue detection method selection Sampling method development Development of residue acceptance criteria Recovery studies

Cleaning Validation : 

Cleaning Validation Validation is a process of demonstrating, through documented evidence, that a process, procedure, method, piece of equipment, or facility will consistently produce a product or result that meets predetermined specifications and quality attributes Establishing the process of fitness for purpose ..

Cleaning validation plan : 

Cleaning validation plan must define What is to be validated How is it to be validated Who is to validate it Who is to approve the validation When it must be revalidated

Cleaning validation plan : 

Cleaning validation plan Should contain Appropriate cleaning procedure Identification of cleaning agent Description of sampling procedure Acceptance criteria Analytical method A copy of protocol and final report A list of equipment Manufacturing process( a flow diagram)

Residue Analysis : 

Residue Analysis UV-Visible Spectroscopy Phosphate detection (gravimetric assays) Protease enzyme analysis techniques Total organic carbon analysis pH measurement Surface residue detection HPLC, Flame photometry

Residue estimation : analytical techniques : 

Residue estimation : analytical techniques

Residue estimation : analytical techniques : 

Residue estimation : analytical techniques

Residue Analysis - Sampling : 

Residue Analysis - Sampling Rinse sampling (Final rinse is sampled to analyse the residue) Surface swabbing (Pure polymer swabs dipped in ultrapure water (or WFI) is used to swab the surface in a specific pattern; used for metallic / polymer rigid objects) Coupon sampling (components / coupons) Dummy products

Residue Acceptance Criteria : 

Residue Acceptance Criteria Levels are determined based on potential safety, toxicity, stability and contamination effects on the product Cleaning agent limits are generally covered under chemical criteria. The limits can be expressed as a maximum concentration in the product (ug/ml) amount per surface area (ug/cm2) amount in a swab sample (ug or ug/ml) concentration in equilibrated rinse water (ug/ml).

Detergent residue: Process Verification(pH measurement) : 

Detergent residue: Process Verification(pH measurement) Rinse a clean glass beaker with the source water - Repeat thrice Take the source water in the rinsed beaker and measure its pH Rinse the device under test with the source water (~ 0.1ml / cm2 of device surface area) Rinse the same glass beaker with this solution thrice Measure the pH of this solution Acceptable detergent residual level : The increase in pH should not be greater than 0.2 units in a pH meter with resolution of 0.1 units

Cleaning validation report : 

Cleaning validation report Introduction Method summary Results Acceptance criteria Conclusion Recommendation Appendices: analytical raw data, chromatogram, etc.

Cleaning Validation Heart Valve : UV Spectrophotometer Study : 

Cleaning Validation Heart Valve : UV Spectrophotometer Study Distilled Water 10 ppm Teepol solution 0.1 ppm Teepol solution Final rinse Absorbance Wavelength (nm)

Contamination control : 

Contamination control

Micro-contamination : How small is small ? : 

Micro-contamination : How small is small ? Cross-section of human hair 75 microns in thickness Smallest particle visible to the human eye 50 microns in diameter Contamination A particle of 0.5 microns

Environment : 

Environment Medical devices are manufactured inside clean rooms, in which the concentration of airborne particle is controlled to specific limits Cleanliness is rated according to the number of particles above certain sizes in a specific volume Eg. in a cubic foot volume of class 10,000 clean room, the number of particles >0.5micron size will be limited to 10,000 whereas particles > 5micron size will be limited to 70

Clean area classification : 

Clean area classification counts

Clean area requirements : 

Clean area requirements

Clean room standards : 

Clean room standards

Clean room concepts : 

Clean room concepts 20-30 air changes per hour Uses High Efficiency Particulate Air (HEPA) filter Maintain positive pressure inside Air locks for the entry and exit of people Provision for laminar air flow Proper selection of furniture, stationery, etc., which doesn’t shred particles Prevention or control of any activity which generates particles

Contamination by operator : 

Contamination by operator Minimum people as possible A person at rest will generate 100,000 particles (> 0.3 micron in diameter) per minute. A slow moving person will generate 1,000,000 particles per minute. A person walking at 3 kmph generates 5,000,000 particles per minute.

Contamination by operator : 

Contamination by operator Human Contamination Normal talking (saliva) – 2 to 3 Ft. Coughing (saliva / lung tissue) – 4 to 6 Ft. Sneezing – 10 to 15 Ft. Use gloves / masks when required : Fingerprints can not be completely removed by an alcohol wipe. On many materials they etch the surface causing permanent changes to the surface properties.

Planning to work in a clean room… : 

Planning to work in a clean room… Always Keep yourself clean (bathing, hand washing and nail cutting requirements) Remember to keep the environment clean Make sure you have everything you need with you to work in the clean room and that it is all clean room-compatible Avoid cosmetics and any other material which generates dust, like Bindi, sandal paste etc.

While entering the clean area … : 

While entering the clean area … Make sure that you have followed recommended clean room gowning procedures (dress, cap, mask, gloves …) Wash you hand (with gloves) and dry Ensure cleanliness of raw materials, tools , and components; etc taking into clean room, by wiping with alcohol

While inside the clean area … : 

While inside the clean area … Regulate the storage of tools, glassware and containers No tool should be allowed to rest on the bench for long time Dispose waste in the dust bin itself Don’t pick materials from the floor. Remove them after your work is over & clean it before use

In clean rooms : common mistakes : 

In clean rooms : common mistakes Touching face or hair with gloves Keeping face mask below the nose Using tools that have fallen down, with out recleaning Not changing gloves when there is a doubt Bringing tools and materials into clean area with out cleaning

Slide 51: 

Thank You

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