PROCESS VALIDATION OF STERILE PRODUCTS-NAVYA

Information about PROCESS VALIDATION OF STERILE PRODUCTS-NAVYA

Published on July 11, 2014

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SEMINAR ON:VALIDATION OF STERILIZATION METHOD A seminar on process validation of sterile products : SEMINAR ON:VALIDATION OF STERILIZATION METHOD A seminar on process validation of sterile products 7/11/2014 1 Presented by: G . N a v y a Roll no: 1 4 0 0 4 P 1 0 2 3 M pharmacy I year I semester Department of pharmaceutics University college of pharmaceutical sciences , KU A SEMINAR ON PROCESS VALIDATION OF STERILE PRODUCTS LIST OF CONTENTS : LIST OF CONTENTS Introduction Process validation order of priority Definition of sterile Process of microbial destruction Basic principles Various Methods of sterilization Steps involved in process validation of sterile products Conclusion References 7/11/2014 2 PROCESS VALIDATION: PROCESS VALIDATION “ A documentary evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes.” HISTORY 1963: A requirement for process validation has been raised. 1970:The concept of process validation was first applied to the pharmaceutical industry. Major causes for the implementation of process validation: ---To reduce burden on FDA in providing data , collecting , analyzing samples ---Properly validated process will yield less rework , resulting in increased input ---Process validation facilitates good business sense 7/11/2014 3 Process validation : order of priority: Process validation : order of priority 1. Sterile products and their processes : > LVP’S, >SVP’S, >MEDICAL DEVICES 2.Non sterile products and their processes Properties of sterile products : >Freedom from micro organisms > Freedom from pyrogens > Freedom from particulates > High standards of purity and quality Historically judgement of sterility has relied on an official sterility test , but it suffers from some limitations and the most obvious limitation is –It cannot detect accidental contamination… 7/11/2014 4 sterile:: sterile: . Free from micro organisms Practically not possible.. Defined as the probability of 1 in a million of a container being contaminated (10 -6 ) Number of contaminated packs = 1 = 10 -6 Number of total packs 1000000 This referred to as the Sterility Assurance Level (SAL ) Sterilization: Validated process used to render a product free of living microorganisms . Sterilization validation : validating the process of sterilization Bioburden : Total number of viable microorganisms on or in pharmaceutical product prior to sterilization 7/11/2014 5 Principles involved in the validation process for sterile product:: Principles involved in the validation process for sterile product: ___ To build sterility into a product ___To assure to a maximum level of probability that the processing & sterilization methods have established sterility to all units of a product batch ___To provide greater assurance & support of the results 7/11/2014 6 Process of microbial destruction: Process of microbial destruction Regardless the type of lethality induced by a sterilization process i.e., Heat, Radiation, Chemicals etc Microorganisms upon exposure to adequate levels of such treatments will die according to a logarithmic relationship between the concentration of living cells & the time exposure/radiation dose to the treatment. Considerations:  D-Value  Z-Value  F H -Value  FO-Value 7/11/2014 7 PowerPoint Presentation: D - Value : Resistance of an organism is referred as its “D-value” D-value - Time (or dose) required to reduce the population of organisms by 1 log (or 90%) at base temperature. D-value 7/11/2014 8 PowerPoint Presentation: 7/11/2014 9 PowerPoint Presentation: Determination of Z – Value : def : Defined as temperature required for 1 log reduction in the D value . • Determine the D - value of an organism at min. three different temperatures . • Construct a Thermal Death Curve by plotting the logarithm of the D- Value versus temperature. • In general, for Dry Heat sterilization, Z- Value may be assumed as 20 °C . And for Steam Sterilization as 10 °C . 7/11/2014 10 PowerPoint Presentation: 7/11/2014 11 PowerPoint Presentation: F value- No.of mins to kill a specified no.of microorganisms with a specified Z-value at a specific temperature. Also defined as : • FH For Dry Heat Sterilization • Fo For Steam Sterilization • The equivalent sterilization time spent at the base temperature. • Tb: 170 °C (For Dry Heat Sterilization) • Tb: 121 °C (For Steam Sterilization ) F = ΔtΣ10 (T-Tb/Z ) 7/11/2014 12 F-Value: PowerPoint Presentation: Δ t : Cycle time T : Actual Cycle temperature Tb : Base Temperature Z : Microbial Death Rate Constant 7/11/2014 13 Example: Determination of F H of a 3 min. dry heat sterilization cycle at 175 °C , t = 3 min ;T = 175 °C ;Tb = 170 °C ; z = 20 °C F H = 3 x 10 (175-170)/20 F H = 7.5 >Sterilization at 175 °C for 3 min. is equivalent to 7.5 min. at 170 °C LETHALITY CALCULATION ------------------------------------------- PowerPoint Presentation: METHODS OF STERILIZATION 7/11/2014 14 1.Heat > Moist heat (autoclave) >Dry heat oven or tunnel Chemical methods 2.Gas > Ethylene oxide > Chlorine dioxide Non thermal methods 3.Radiation Gamma Beta 4.Filtration Thermal methods PowerPoint Presentation: 7/11/2014 15 Sterilization method ------------------ 1)Moist heat 2)Dry heat Type of lethality ------------------ Steam under pressure Dry heat Common cycles -------------------- 121 °C for 15 mi >134°C for 3 min Other cycles of lower temperature and longer time may be used (e.g. 115°C for 30 min) 160 °C for 120 min °C For 60min 180 °C for 30min Uses ------------------ >terminal sterilization of aqueous injections, >ophthalmic preparations, >irrigation & haemodialysis solutions, >equipment used in aseptic processing glassware &product containers used in aseptic manufacture, non aqueous thermostable powders &liquids (oils) Disadvantag ------------------ --Not suitable for non-aqueous/dry preparations Higher temperatures and longer exposure times required PowerPoint Presentation: 7/11/2014 16 . Either pure or in mixtures with other inert gases .Acts by affecting the reproductive process. . Requires presence of moisture . Complex process Used for : ---- heat labile product containers , -- - surface sterilization of powders --- ETHYLENE OXIDE PowerPoint Presentation: Filtration Removes organisms from liquids and gasses 0.20 - 0.22 micron pore size filter media is capable for sterilization Composed of cellulose acetate or other polymeric materials Filter material must be compatible with liquid being filtered Used for bulk liquids, gasses 7/11/2014 17 PowerPoint Presentation: Validation - Overview Selection of sterilzation process must be appropriate for product -terminal sterilization is the method of choice -moist heat (autoclaving) is the most common process used for terminal sterilization -product must not be affected by heat -container/closure integrity must be established 7/11/2014 18 Steps involved in validation of sterile products Taking moist heat sterilization as an example : Steps involved in validation of sterile products Taking moist heat sterilization as an example General considerations Qualification and calibration > Mechanically checking , upgrading , qualifying the sterilizer unit >Selection and calibration of thermocouples >Selection and calibration of biological indicators Heat distribution studies Heat penetration studies 7/11/2014 19 PowerPoint Presentation: 7/11/2014 20 Concept of F o , Def --no . of mins to kill a specified no.of microorganisms with z-value of 10 °C at a temperature of 121 °C Lethality factor equivalent to time at 121°C -1 minute at 121°C is equivalent to F o of 1. F o is calculated using the following equation: F o = ΔtΣ10 (T-121 °C /10) GENERAL CONSIDERATIONS PowerPoint Presentation: 7/11/2014 21 where: >“Δt” is the time interval between measurements of temperature (T) >“T” is the temperature of sterilized product at time (t) >“Z” is a temperature coefficient which measures the number of degrees required to change the D-value of an organism by 1 log The minimum F o required by a sterilization process is related to the resistance of the bioburden (D-value) F o = D 121 ( Log A - Log B) PowerPoint Presentation: 7/11/2014 22 Fo values may be calculated in 2 ways 1.By manually recording the temperature of the monitored product at specific time intervals 2.Using the biological approach >this approach is used when D121 and A,B(Probability of non-sterility) taken into consideration. Fo = D 121( log A-log B ) if D121=1.0min ,A= 10 6 ,B= 10 -6 Fo=1(6(1)+6(1))=12mins A = Initial no . of microorganisms per container B = ” is the maximum acceptable probability of survival (Sterility Assurance Level , 10 -6) PowerPoint Presentation: FO = = ΔtΣ10 (T-121/10 23 Sterilization Time(min) ----------------------- 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 Product temperature ( °C) ---------------------- 100 103 106 109 112 115 118 121 121 121 118 115 112 109 106 103 100 10 (T-121/10) ---------------------------------- 0.008 0.016 0.032 0.063 0.126 0.251 0.501 1.000 1.000 1.000 0.501 0.251 0.126 0.063 0.032 0.016 0.008 A manual calculation of Fo value 1(5.000) =5 min PowerPoint Presentation: 7/11/2014 24 A written plan…….. Validation protocol should Include the following details for each sterilization process >Process objectives in terms of product type, container/closure system, SAL required >Specifications for time, temperature, pressure and loading pattern >Description of all equipment and support systems in terms of type, model, capacity and operating range >Performance characteristics of all equipment e.g. pressure gauges, valves, alarm systems, timers, steam flow rates/pressures, controller functions. >Methodology for monitoring performance of equipment and the process and laboratory testing methodology >Personnel responsible for all stages and final evaluation (should have experience and necessary training ) Validation protocol Qualification and calibration: Qualification and calibration a)Mechanically checking , upgrading , and qualifying the sterilizer unit Main concern : complete removal of air from chamber and replacement with saturated steam. > Installation qualification and Operational qualification Must be done properly. >Temperature and pressure instrumentation must be calibrated. 7/11/2014 25 b)Selection and calibration of thermocouples: b)Selection and calibration of thermocouples Thermocouples are used as temperature indicators in autoclave…therefore must be durable for repeated use. >connected to recorders to get continuous record of actual temp at the location of thermocouples >copper constantan wires coated with teflon are a popular choice >accuracy of thermocouples should be + 0.5 °C >An error of just 0.1 °C in temperature measurement might produce a 2.3% error in Fo value. >Thermocouple accuracy is determined by using National Bureau of Standards . >Thermocouples should be calibrated before and after validation experiment. 7/11/2014 26 c)Selection and calibration of biological indicators: c)Selection and calibration of biological indicators >Most heat resistant bacterial spores are used as biological indicators. D 121 and f values of BI must be accurately known . 7/11/2014 27 storage : proper storage conditions are provided for BI’s Freeze storing provides a more stable resistance profile for BI’s shelf life PowerPoint Presentation: 7/11/2014 28 Different types of biological indicators products available in the market spore suspensions Spore strips HEAT DISTRIBUTION STUDIES: HEAT DISTRIBUTION STUDIES The main concern is to identify the coolest spot and the effect of load size > 10 -20 thermocouples are placed in definite arrangement > Teflon tape can be used to secure thermocouples > Wire should not make contact with the autoclave interior walls or any metal surface. >Two thermocouples are taken as references , one is placed in ice-bath and other in increase temperature oil bath during each cycle >The difference in temperature between coolest spot and mean chamber temperature should not be more than + 2.5 ° Greater temperature differences -indicates malfunction of equipment 7/11/2014 29 PowerPoint Presentation: 7/11/2014 30 Includes 2 phases >Heat distribution in an empty autoclave chamber >Heat distribution in a loaded autoclave chamber >>Heat distribution studies in empty chamber > To ensure that the heat distribution is uniform through out the chamber __ The key is to identify the location of cool spot . __Fewer thermocouples are employed to identify the cool spot in the empty chamber. ___location of devices should be documented and ensure that heat distribution is uniform. PowerPoint Presentation: 7/11/2014 31 >>Heat distribution of maximum and minimum chamber load configurations > The key is to identify the effect of load on the cool spot > Multiple thermocouples throughout chamber (not inside product containers) to determine effect of load configuration on temperature distribution. >Temperature distribution for all loads using all container sizes used in production should be tested. >Position of thermocouples >Cold spots in each run >Temperature distribution profile for each chamber load >Repeat runs should be performed to check variability . documented HEAT PENETRATION STUDIES: HEAT PENETRATION STUDIES -- The most critical component of the entire validation process. -- Most important step is to find out Fo Value of cold spot . --Minimum and maximum loading configurations should be studied. --Thermocouples will be placed both inside and outside the container at the cool spot location. Heat penetration studies to detect the maximum and minimum temperature within all loads B iological indicators are placed in the relatively cool spot identified in heat dist.studies All parts of each load must be in contact with steam, Need to determine lowest and highest temperature locations . Fo value will be calculated based on the temperature recorded by the thermocouple inside the container at the cold spot of the load. Upon the completion of cycle , the Fo value indicates whether the cycle is adequate or any alterations are needed. 7/11/2014 32 Final step in sterilization validation :establishment of a monitoring program: Final step in sterilization validation :establishment of a monitoring program > Aim is to ensure that the validated cycle remains unchanged in the future. > Any changes in the load size , container characteristics(volume , geometry etc) must be accompanied by repeat validation studies EVALUATION: Upon completion of experimental phase of validation , the data are compiled and evaluated by qualified personnel. The results may be summarized on a summary sh eet . 7/11/2014 33 PowerPoint Presentation: 7/11/2014 34 STEAM STERILIZATION PROCESS SUMMARY SHEET >Autoclave identification number : p6037 >Location : building 22,floor 1 >Tag no : 896101 >Validation date : 10-14-99 >Revalidation date : 04-14-00 >Description of process validated : load containing filling equipment and accessories not to exceed 102 kg >Temp set point for validation : 121 °C . >Temp range for validation : + 0.5 °C >Cycle validated : 35min >Validation records stored in archives : A105-11 >Revalidation records stored in archives : C314-70 PowerPoint Presentation: 7/11/2014 35 CONCLUSION: >Even today ,emphasis on the validation of sterile products is placed mainly on sterilization process. >No manufacturing process can be considered under complete control without qualification of every system . > Process validation directly or indirectly is most advantageous for the manufacturer and as well as individual in both business and time aspects. REFERENCES:: REFERENCES: NASH R.A.,” Pharmaceutical process validation” 3 rd edition LACHMAN L.,LIEBERMAN.,JOSEPH L.KANIG- The theory and practice of industrial pharmacy 3 rd edition. R.G.LEWIS , “ practical guide to Autoclave validation “, pharmaceutical engineering. “Validation of moist heat sterilization process” ;PDA technical report no.1 revised 2007 7/11/2014 36 PowerPoint Presentation: 7/11/2014 37

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